March 2025
Medicolegal evaluation of firearm injury cases admitted to a university hospital
Ugur Demir, Hüseyin Kafadar
Department of Forensic Medicine, Faculty of Medical, Harran University, Şanlıurfa, Turkiye
DOI: 10.4328/ACAM.22408 Received: 2024-09-16 Accepted: 2024-11-04 Published Online: 2024-11-13 Printed: 2025-03-01 Ann Clin Anal Med 2025;16(3):152-156
Corresponding Author: Ugur Demir, Department of Forensic Medicine, Faculty of Medical, Harran University, Şanlıurfa, Turkiye. E-mail: ugurdmr81@gmail.com P: +90 414 344 44 44 Corresponding Author ORCID ID: https://orcid.org/0000-0003-3266-2861
Other Authors ORCID ID: Hüseyin Kafadar, https://orcid.org/0000-0002-6844-7517
This study was approved by the Ethics Committee of the Clinical Research Ethics Committee of Harran University Rectorate (Date: 2024-04-30, No: E-76244175-050.04-330802)
Aim: It aims to improve our knowledge about clinical care after gunshot wounds, whether surgery is required, the characteristics and origins of the injury, and the localization in which it is frequently seen on the body.
Material and Methods: The hospital records for the five years between 2019 and 2023 were examined retrospectively, and cases with firearm injuries were identified and included in the study. The patient data, including age, sex, etiology, anatomic location of the firearm injury, treatment modality, and hospitalization duration, were obtained from the Hospital Information Management System (FONET) of xxx University Hospital.
Results: When the origin of gunshot wounds before hospital admission was examined, it was found that the most common admission was after assault injuries, with a rate of 51.7% (n=75). Most of the patients applying were in the young age group between 18-35 years of age, with 47.9% (n=70), and the most frequently injured internal organs were the small and large intestines (25 cases).
Discussion: In the studies conducted, the mean age was determined as 27.5, 29, 31.4, 34.5, and 36, and it was reported that 83-97.1% of the cases were male. Similarly, in our study, the mean age of all cases applying with gunshot wounds was found to be 28.9, and 83.6% of the cases were male. Similar to the studies in the literature and our analysis, most of the gunshot wounds occurred as a result of intentional injuries, that is, assaults. Very few of them resulted from suicide attempts because most of the gunshot wounds that occurred after suicide attempts resulted in death at the scene, which keeps the hospital admission rate low.
Keywords: Firearm, Injury, Forensic Medicine, Assault, Suicide Attempt
Introduction
Gunshot wounds are complex, severe, and traumatic injuries frequently encountered in forensic medicine practice and constitute a significant portion of trauma patients admitted to hospitals. As firearms become easier to obtain, firearm-related injuries and deaths are becoming more common. Firearm-related injuries are an important public health problem that causes premature death, disease, and disability [1- 3]. However, the number of nonfatal gunshot wounds and the characteristics of patients and injuries are not well known [4].
Gunshot wounds are usually characterized by serious damage caused by bullets or shrapnel fragments that penetrate tissue at great speed. The severity of the injury varies depending on many factors, such as the caliber of the bullet, the angle of entry, the organs damaged, and the duration of first aid [5].
The points where the bullet enters and exits the body and the path it follows in the body provide important clues in the initial assessment to help determine the prognosis, evaluation, and treatment of gunshot wounds [5, 6].
Following gunshot wounds, pneumothorax, hemothorax, and cardiac tamponade in the chest area; liver, spleen, small and large intestine perforations and major vascular injuries in the abdomen; bone fractures, vascular and nerve injuries in the extremity area are common medical conditions requiring emergency intervention [7].
Rapid diagnosis and correct intervention are of vital importance for patients presenting after gunshot wounds [7]. In the first stage, after such injuries, the patient should be stabilized, and life-threatening conditions should be quickly identified. When necessary, the condition of the internal organs should be assessed with imaging methods such as X-ray, ultrasound, and CT. Although the treatment process varies according to the severity of the injury and the damaged organs, it has been reported that cases requiring surgical intervention should be taken to emergency surgery to repair the damage [7, 8].
This study describes gunshot wounds treated at Harran University Hospital and aims to improve our knowledge about these injuries, clinical care, characteristics, and origins of injuries. It also provides information about the locations where gunshot wounds are frequently seen in the body and the medical conditions frequently seen after gunshot wounds.
Material and Methods
The patient data, including age, sex, etiology, anatomic location of the firearm injury, treatment modality, and hospitalization duration, were obtained from the Hospital Information Management System (FONET) of Şanlıurfa Harran University Hospital. The hospital records for the five years between 2019 and 2023 were examined retrospectively, and cases with firearm injuries were identified and included in the study.
Cases presenting with firearm injuries, according to the application history, were divided into four groups: intentional injuries, suicide attempts, unintentional injuries, and unknown.
Firearm injuries are classified as face, head and neck area, upper extremity, chest region, abdominal region, back, and lower extremity according to the body location of the bullet or shrapnel.
The study was conducted on cases admitted to Harran hospital. The hospital is 18 km away from the city center, and since there are many hospitals in the city center. However, the study was conducted in a large city in southeastern Turkey, and the number of cases was limited because patients tend to seek emergency treatment at the nearest hospital after gunshot wounds.
Statistical analysis
Data were analyzed using SPSS for Windows version 21.0 software (IBM Corp., Armonk, NY, USA). Descriptive statistics were presented as mean and standard deviation (SD) values for continuous variables and as frequency (n) and percentage (%) for categorical variables. A Chi-squared test was used in the analysis of contingency tables when the sample size was > 5. Fisher’s Exact test was used to determine relationships between categorical variables in crosstabs with an expected count < 5. A value of p < 0.05 was accepted as the level of statistical significance.
Ethical Approval
This study was approved by the Ethics Committee of the Clinical Research Ethics Committee of Harran University Rectorate (Date: 2024-04-30, No: E-76244175-050.04-330802).
Results
Over the five years between 2019 and 2023, 146 patients were admitted to our hospital due to Firearm Injury. The 146 patients comprised 122 (83.6%) males with a mean age of 28.8±13.03 years (range, 5 – 75 years) and 24 (16.4%) females with a mean age of 29.1±18.26 years (range, 7 -64 years).
Among the patients admitted after gunshot wounds, 24% (n=35) were younger than 18 years old, 47.9% (n=70) were aged 18–35 years, 19.9% (n=29) were aged 36–50 years, and 8.2% (n=12) were older than 50 years.
Regarding the cause of gunshot wounds, 51.7% (n=75) were assault injuries, 4.8% (n=7) were unintentional injuries, 3.4% (n=5) were suicide attempts, and 40.4% (n=59) were unknown.
The localization of the gunshot wounds was determined as follows: the face, head, and neck region in 33 cases (22.6%), the upper extremity in 7 cases (4.8%), the chest region in 20 cases (13.7%), the abdomen in 36 cases (24.7%), the back in 10 cases (6.8%), and the lower extremity in 40 cases (27.4%) (p=0.000).
For the treatment of gunshot wounds, 87 patients (59.6%) underwent surgery, while 59 patients (40.4%) did not. Among those who required surgery, patients with abdominal region injuries were operated on most frequently. The most frequently injured internal organs among the operated cases were the small and large intestines (25 cases), followed by the lungs (19 cases), brain (8 cases), liver (6 cases), kidneys (5 cases), stomach (4 cases), spleen (4 cases), testis (3 cases), pancreas (1 case), heart (1 case), and esophagus (1 case).
Vascular injuries were present in 10 patients (6.8%) admitted after gunshot wounds, while vascular injuries were not detected in 136 patients (93.2%). In 10 cases, injuries were detected in 12 different vessels, the most common being the inferior vena cava (3 cases), followed by the popliteal arteries (2 cases), renal arteries (2 cases), femoral artery (1 case), abdominal aorta (1 case), subclavian artery (1 case), jugular vein (1 case), and tibial artery (1 case).
The most frequently broken bones were skull bones (12 cases), followed by the femur (9 cases), vertebrae (7 cases), pelvis (6 cases), scapula (4 cases), foot bones (4 cases), tibia (3 cases), fibula (1 case), and radius (1 case).
Of the cases admitted to the hospital with gunshot wounds, six patients (4.1%) died without surgery, and eight patients (5.5%) died during or after surgery. In total, 14 patients (9.6%) died. Among the deceased cases, 12 patients had internal organ injuries, three patients had vascular injuries, and five patients had bone fractures.
The mean hospitalization duration was 9.2 ± 26.0 days (range, 1-282 days).
Discussion
In our study, the average age of men presenting with gunshot wounds was 28.8, the average age of women was 29.1, the average age of all cases was 28.9, and 83.6% of the cases were male. In the study conducted by Rivara et al., the average age was found to be 29, and 83% of the cases were reported as male [4]. In the study conducted by Karaca et al., the average age was found to be 36, and 90.1% of the cases were reported to be male [7]. In the study conducted by Spitzer et al., the average age of individuals with gunshot wounds was 27.5, and 89.6% were male [9]. The study conducted by Shah et al. found the average age of individuals with gunshot wounds to be 34.5, with 97,1% being male [10]. In their Gunshot Wounds to the Head, the study conducted by Schoen et al. stated that the average age of patients applying to the hospital was 31.4, with 91,4% being male [11]. Our study had an average age compatible with the literature and consisted largely of male cases.
In our study, the most common known cause was assault at 51.4%, while the least common was attempted suicide at 3.4%. Rivara et al. stated that 72.9% of gunshot injuries occurred due to assault, while 3.9% were due to suicide attempts [4]. In the study conducted by Gastineau et al., approximately 65% of gunshot injuries were due to homicide, 30% to suicide, 3.5% to unintentional injuries, 2% to intent, and 0.5% to legal interventions [12]. In the Spitzer study, assault injuries were the most common at 69.7%, while self-inflicted injuries were the least common at 1.7% [9]. In the Simpson study, assault injuries were the most common at 58.09%, while self-inflicted injuries were the least common at 3.26% [13]. In our study and line with the literature, the majority of gunshot wounds occur as a result of intentional injuries, i.e., assaults, while very few results from suicide attempts because the majority of gunshot wounds occurring after suicide attempts result in death at the scene [14], which keeps the hospitalization rate low.
In our study, in terms of distribution according to body localization, it was most frequently seen in the lower extremities, with a rate of 27.4%. This was followed by the abdominal region with a rate of 24.7%, the face, head, and neck region with a rate of 22.6%, and the least frequently seen in the upper extremities with a rate of 4.8%. In the study conducted by Karaca et al., it was reported that gunshot wounds were most frequently seen in the lower extremities (48%) [7]. In the Simpson study, it was reported that gunshot wounds were most frequently seen in the Extremities/pelvic bones (46.5%) [13]. In the study by Nyberger et al., gunshot wounds were most frequently seen in the lower extremities (29.7%) [15]. This situation is compatible with the literature; this is thought to be because the majority of gunshot wounds in hospital admissions are offensive, with the aim being to injure rather than kill, meaning that attackers target the lower extremities rather than lethal body parts.
In our study, 59.6% of the patients received surgical intervention, and 40.4% did not receive surgical intervention. Nguyen et al. reported that 78.5% of gunshot wounds in the study that resulted in injuries to the extremities only were in the lower extremities, and 71.8% required surgery [16]. Karaca et al. reported that 49% of gunshot wounds required surgical treatment [7].
In our study, among the patients admitted after gunshot wounds, 24% were younger than 18 years old, 47.9% were aged 18–35 years, 19.9% were aged 36–50 years, and 8.2% were older than 50 years. Gunshot-related deaths were reported to be increasing annually in all countries, with gunshot wounds affecting people of all ages but largely concentrated in young males in large cities [15]. Rivara et al. It was stated that 81% of the gunshot injuries were between the ages of 20 and 65 in the distribution by age [4]. Karaca et al. reported that gunshot wounds were seen in people between the ages of 30-40 [7]. Sheffy et al. reported that 60% of gunshot victims were young people between the ages of 19 and 30 [10]. In our study, similar to the literature, it was observed that the most frequent application was in the young age group.
In our study, vascular injuries were detected in 12 different vessels in 10 cases (6.8%) that presented after gunshot wounds. The most common of these was the inferior vena cava, with 3 cases, followed by the popliteal and renal arteries, with 2 cases each. Among the deceased cases, 12 patients had internal organ injuries, and three patients had vascular injuries. Nguyen et al. reported that the most common anatomic vascular injury was in the lower extremity (41.7%), and the most common vascular injury was the common femoral artery (17.6%), followed by the superficial femoral (7.1%) and iliac arteries (7.1%) [17]. Ghorbani et al. reported that hemorrhage was the cause of death in 70% of all penetrating trauma cases [18]. Gunshot-related vascular injuries, particularly those in the chest and abdomen, have been reported to cause significant morbidity and mortality [17].
The mean hospitalization duration was 9.2 ± 26.0 days (range, 1-282 days). Ghorbani et al. reported that the median length of hospital stay was three days [18]. Budema et al. reported that the median length of hospital stay was 34 days in their study [19]. In our study, the average length of hospital stay was determined as nine days. A significant difference was found between the minimum and maximum periods in the literature and in our study, and it was thought that this difference may be because the length of hospital stay may vary depending on the location and severity of injury in hospitalized patients.
Study limitation
The biggest limitation of the current study was our limited number of patients. Our insufficient sample size prevented the data distributions from reaching statistical significance. The second limitation of our study was that it was retrospective, and we were not able to extract more descriptive data. Finally, this study was conducted in a single tertiary hospital in the southeastern region of Turkey, and large multicenter series are needed for useful results that broadly reflect national data.
Conclusion
It has been found that assault is the most common cause of firearm injuries, and it continues to be a serious and costly public health problem in our country. Gunshot wounds have serious consequences, both medically and socially. By being informed about the medical disorders frequently seen in the management of such cases, the patient’s chance of survival can increase with rapid and effective intervention.
Additionally, considering the lethal nature of gunshot wounds, enacting firearm control laws to prevent such injuries and making it difficult for unauthorized individuals to access firearms will reduce the frequency of such hospital admissions in the long term.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and Human Rights Statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or compareable ethical standards.
Funding: None
Conflict of Interest
The authors declare that there is no conflict of interest.
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Download attachments: 10.4328.ACAM.22408
Ugur Demir, Hüseyin Kafadar. Medicolegal evaluation of firearm injury cases admitted to a university hospital. Ann Clin Anal Med 2025;16(3):152-156
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135 Case retrospective analysis of adrenalectomy: A 10-year single-center experience
Ömer Kişi 1, Arslan Hasan Kocamaz 2, Abdulkadir Çelik 3, Yasin Esen 1, Mustafa Şentürk 1
1 Department of General Surgery, Faculty of Medicine, Necmettin Erbakan University, Konya, 2 Department of General Surgery, Kayseri State Hospital, Kayseri, 3 Department of General Surgery, Gaziantep Dr. Ersin Arslan Training and Research Hospital, Gaziantep, Turkiye
DOI: 10.4328/ACAM.22427 Received: 2024-09-28 Accepted: 2024-11-04 Published Online: 2024-11-12 Printed: 2025-03-01 Ann Clin Anal Med 2025;16(3):157-160
Corresponding Author: Ömer Kişi, Department of General Surgery, Faculty of Medicine, Necmettin Erbakan University, Konya, Turkiye. E-mail: omkisi91@gmail.com P: +90 505 959 95 35 Corresponding Author ORCID ID: https://orcid.org/0000-0001-8606-2453
Other Authors ORCID ID: Arslan Hasan Kocamaz, https://orcid.org/0000-0002-5257-9611 . Abdulkadir Çelik, https://orcid.org/0000-0002-5537-7791 . Yasin Esen, https://orcid.org/0009-0007-3166-6883 . Mustafa Şentürk, https://orcid.org/0000-0002-3230-1743
This study was approved by the Ethics Committee of Necmettin Erbakan University for Non-Drug and Non-Medical Device Research (Date: 2024-09-20, No: 2024/5195)
Aim: Adrenal masses encompass a range of tumors from benign adrenal cortical adenomas to malignant adrenal cortical carcinomas. This study aims to evaluate the demographic, histopathological, and surgical characteristics of patients who underwent adrenalectomy due to various adrenal gland pathologies in our clinic over the past decade.
Material and Methods: Records of patients who underwent adrenalectomy at the General Surgery Clinic of Necmettin Erbakan University Medical Faculty between 2014 and 2024 were retrospectively analyzed. Demographic characteristics, clinical, radiological, and histopathological data, as well as surgical methods, were examined. The characteristics of the tumors were determined using imaging and histopathological evaluations, and preferences for surgical methods were assessed.
Results: The mean age of the 135 patients included in the study was 49.3 (21-83) years. Of the patients, 86 (63.7%) were female, and 49 (36.3%) were male. Seventy-eight tumors (57.8%) were located in the left adrenal gland, while 56 (41.5%) were in the right adrenal gland. Among surgical methods, laparoscopic surgery was performed in 87 (64.4%) patients, and open surgery in 48 (35.6%) patients. The average tumor diameter was 5.2 (0.6-17) cm. When examining the definitive pathological diagnoses, adrenal cortical adenomas accounted for 53.3%, pheochromocytomas for 22.2%, cystic lesions for 5.2%, and metastatic lesions for 5.2%.
Discussion: Adrenal masses are often found incidentally, highlighting the need for preoperative laboratory tests to assess functional characteristics. Size and functionality are critical in surgical decision-making, with both laparoscopic and open techniques available for treatment.
Keywords: Adrenal Mass, Laparoscopic Adrenalectomy, Adrenal Gland
Introduction
Adrenal masses refer to a broad term encompassing various lesions that occur in the adrenal glands. These masses range from benign adrenal cortical adenomas to malignant adrenal cortical carcinomas and include endocrine-active tumors such as pheochromocytomas. The evaluation of adrenal masses poses significant challenges in the diagnostic and treatment process; some masses may not exhibit apparent symptoms, while others can lead to severe clinical issues [1, 2].
Imaging techniques play a critical role in diagnosing adrenal masses. Computed tomography (CT) and magnetic resonance imaging (MRI) provide important information about tumor sizes and characteristics, assisting in determining the need for surgical intervention [3]. Surgical treatment options include open surgery and laparoscopic surgery. Due to its minimally invasive nature, laparoscopic surgery is often preferred and tends to shorten postoperative recovery times [4]. However, factors such as the patient’s overall condition, tumor size, and localization play a crucial role in determining the surgical approach [5].
The definitive pathological diagnosis is made through a detailed histopathological examination of tissue samples obtained postoperatively. Recent studies have demonstrated significant advancements in pathological evaluation methods, leading to improved rates of accurate diagnosis [6]. Tumor sizes are generally considered an important parameter in determining diagnostic and treatment strategies [7].
The Weiss score is a histopathological scoring system used to assess the malignant potential of adrenal cortical masses. Typically, scores of 3 or lower indicate benign adrenal cortical adenoma, while scores of 4 and above classify as malignant adrenal cortical carcinoma [8]. The Ki-67 index is a biomarker used to evaluate cellular proliferation; this index indicates the percentage of the Ki-67 protein present in tumor cells, with a high Ki-67 value signifying an increased rate of cellular division and thus an elevated potential for malignancy [9]. Generally, carcinomas with a Ki-67 index below 10% are associated with lower proliferation and better prognosis, while those with a Ki-67 index of 30% or higher may indicate high proliferation and poor prognosis. Both measurements provide valuable insights into the management of adrenal tumors.
This study aims to evaluate the clinicopathological characteristics of patients who underwent adrenalectomy for adrenal masses at a tertiary university hospital.
Material and Methods
Cases of adrenalectomy performed for adrenal masses at the General Surgery Clinic of Necmettin Erbakan University Medical Faculty from 2014 to 2024 were included in the study. Following approval from the ethics committee, data were retrospectively collected from a prospectively recorded database. Patients over the age of 18 were included. Variables such as age, gender, tumor sizes, histopathological classification, subtype of adenoma, and surgical techniques used (open/minimally invasive) were evaluated.
Imaging techniques utilized in the diagnosis of adrenal adenomas included computed tomography (CT) and magnetic resonance imaging (MRI). Tumor diameters were assessed using these imaging techniques. The details of open and laparoscopic surgical methods were determined based on the surgeon’s preference and the characteristics of the tumor.
Statistical Analysis
Bio-statistical analysis was performed using the Statistical Package for the Social Sciences (SPSS Inc., Chicago, IL, USA). When presenting data as mean values, standard deviation values were provided; when presented as median values, minimum (min) and maximum (max) values were also specified.
Ethical Approval
This study was approved by the Ethics Committee of Necmettin Erbakan University for Non-Drug and Non-Medical Device Research. (Date: 2024-09-20, No:2024/5195).
Results
A total of 135 patients were included in the study. The mean age of the patients was 49.3 (21-83) years. The number of female patients was 86 (63.7%), and the number of male patients was 49 (36.3%). According to tumor localization, the distribution of adrenal adenomas was as follows: left adrenal mass 78 (57.8%), right adrenal mass 56 (41.5%), and bilateral mass 1 (0.7%). Among the surgical methods, laparoscopic surgery was preferred in 87 patients (64.4%), while open surgery was performed in 48 patients (35.6%). In 7 patients, surgery was initiated laparoscopically but was converted to an open procedure due to bleeding and insufficient exploration. The average tumor diameter was approximately 5.2 (0.6-17) cm (Table 1).
Regarding pathological results, the most common causes of adrenal masses were adrenal cortical adenoma in 72 patients (53.3%) and pheochromocytoma in 30 patients (22.2%) (Table 2).
The histopathological data were as follows: the average Weiss score was 0.68 (0-6), and the average Ki-67 index was 4.04 (1-90). However, in patients diagnosed with adrenal cortical carcinoma, the average Weiss score was 4 (2-6) and the average Ki-67 index was 36 (15-90).
Discussion
Recent studies have reported that adrenal masses are most commonly seen in middle-aged individuals. In a study conducted by Caglar et al., the average age of patients diagnosed with adrenal masses was reported as 50 years [10]. Another study determined the average age of patients diagnosed with adrenal masses to be 48 years, stating that these masses are most frequently found in individuals aged 40-60 years [11]. In our study, the average age was found to be 49, which is consistent with the literature.
In a series of 200 patients conducted by Küçük et al., the prevalence of women was found to be 62% [12]. In another study examining 150 patients diagnosed with adrenal masses, the percentage of female patients was determined to be 58%, suggesting a possible association with hormonal factors [13]. In our study, the prevalence of women was 63.7%, which is similar to other studies in the literature.
In a study analyzing the localization of adrenal masses in 300 patients, the prevalence of left adrenal masses was found to be 55% [14]. Kim et al. analyzed 250 patients with adrenal masses and reported that the percentage of right adrenal masses was 44% and left adrenal masses was 52% [15]. In our study, we identified left adrenal masses in 78 patients (57.8%), right adrenal masses in 56 patients (41.5%), and bilateral masses in 1 patient (0.7%).
In a study conducted by Cohen et al., data from 200 patients who underwent surgical intervention for adrenal masses were examined. It was noted that laparoscopic surgery was preferred in 70% of cases, and open surgery was generally performed for larger tumors. The study emphasized that laparoscopic surgery provides shorter recovery times and lower complication rates [16]. Another retrospective study investigated 150 patients who underwent surgical intervention for adrenal masses, finding that laparoscopic surgery was preferred in 65% of cases, while open surgery was more frequently applied to tumors with malignant features [17]. In our study, laparoscopic surgery was preferred in 87 patients (64.4%), while open surgery was performed in 48 patients (35.6%). In 7 patients, surgery was initiated laparoscopically but converted to an open procedure due to bleeding and insufficient exploration.
In a study analyzing 180 patients diagnosed with adrenal masses, the average tumor diameter was determined to be 4.2 cm, and larger tumors were generally associated with an increased risk of malignancy. Additionally, a relationship between tumor size and histopathological malignancy was identified [18]. In another study analyzing 220 patients, the tumor diameter was reported as 3.5 cm, with larger tumors (over 5 cm) having higher rates of malignancy [19]. In our study, the average tumor diameter was approximately 5.2 (0.6-17) cm. This finding, which aligns with higher tumor diameter results in the literature, suggests that as a tertiary and the largest healthcare institution in our region, surgical interventions might be challenging, and cases with larger tumor diameters may have been referred to our hospital.
In a series of 200 patients diagnosed with adrenal masses, the percentages of adenoma, pheochromocytoma, and adrenal cortical carcinoma were reported as 30%, 20%, and 15%, respectively [20]. In a study by Gomez et al., analyzing 250 cases, the rates for adrenal cortical adenoma, pheochromocytoma, and adrenal cortical carcinoma were 35%, 18%, and 12%, respectively [21]. In our study, we identified adrenal cortical adenoma in 72 patients (53.3%), pheochromocytoma in 30 patients (22.2%), and adrenal cortical carcinoma in 5 patients (3.7%). The high percentage of adrenal cortical adenomas (53%) in our study may suggest that there is a concentrated profile among patients presenting to the healthcare institution for adrenal masses, or it may be influenced by genetic predispositions and environmental factors in different geographical regions.
Eisenhofer et al. examined the relationship between the Weiss score and Ki-67 index, finding that high Weiss scores and high Ki-67 index values were strongly associated with malignancy [22]. Zhang et al. reported that adrenal cortical carcinomas exhibited high Ki-67 index values along with high Weiss scores [23]. In our study, both the Weiss score and Ki-67 index were found to be higher than average in adrenal cortical carcinoma cases, which is consistent with the literature.
Limitation
This study has several limitations that should be acknowledged. First, being a retrospective analysis conducted at a single center may limit the generalizability of the findings to broader populations. The sample size, although sufficient for preliminary conclusions, may not capture the full spectrum of adrenal masses and their outcomes.
Additionally, the reliance on previously recorded data may introduce biases related to incomplete or inconsistent documentation of clinical and histopathological parameters. The heterogeneity in the surgical techniques employed and the varying experience levels of the surgical teams could also affect the outcomes and complication rates observed.
Future studies with larger, multicenter cohorts and standardized protocols for data collection and follow-up are essential to confirm these findings and improve the understanding of adrenal masses and their management.
Conclusion
We analyzed patients who underwent adrenalectomy due to adrenal masses over a ten-year period. These masses were more frequently found in the left adrenal gland and in female patients. We observed that most cases involved non-functional tumors with nonspecific symptoms and an increasing trend in their frequency. Surgical intervention was the most effective treatment method. The Weiss score and Ki-67 index are important parameters for diagnosing malignancy. Early detection of adrenal cortical carcinomas and the development of more effective treatment methods require exploration of molecular mechanisms and support from large clinical studies.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and Human Rights Statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or compareable ethical standards.
Funding: None
Conflict of Interest
The authors declare that there is no conflict of interest.
References
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2. Kloos RT, Korobkin M, Lee J, Young WF, Francis IR, Kauffman HL. The management of adrenal incidentalomas. J Clin Endocrinol Metab. 2022;107(4):1234-42.
3. Wang M, Kuo J, Chen H, Sosa JA, Young WF, Duh QY. Factors influencing surgical approach in adrenal tumor resection. Ann Surg Oncol. 2020;27(11):4412-9.
4. Carling T, Deeb K. Adrenal surgery for benign disease. Surg Endosc. 2013;27(2):366-74.
5. Sarmiento JM, Delaney CP. Minimally invasive adrenal surgery: Techniques and outcomes. J Surg Oncol. 2012;106(7):801-6.
6. Agha RA, Fowler AJ. The importance of pathology in the management of adrenal tumors. Int J Surg. 2016;36(1):215-20.
7. Terzolo M, Fassnacht M. Management of adrenal tumors: Current perspectives. J Clin Oncol. 2014;32(17):1934-41.
8. Weiss LM, Medeiros LJ. Adrenocortical tumors: A histopathologic study of 48 cases. Am J Surg Pathol. 1984;8(4):263-76.
9. Perez MA, Pardo J, Soler M, Galera M, Moya C, Lopez G. Ki-67 as a prognostic marker in adrenal tumors: A review. Pathol Res Pract. 2020;216(9):152893.
10. Caglar S, Aydin H, Kocak M, Ozturk S, Onal B, Unal N. Clinical characteristics and management of adrenal tumors: A single center experience. J Endocrinol Invest. 2022;45(1):101-8.
11. Zhang Y, Kato Y, Fukuda Y, Yoshida T, Tanaka M, Saito H. Clinical outcomes and characteristics of patients with adrenal tumors: A retrospective study. Endocr J. 2023;70(3):215-23.
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Ömer Kişi, Arslan Hasan Kocamaz, Abdulkadir Çelik, Yasin Esen, Mustafa Şentürk. 135 Case retrospective analysis of adrenalectomy: A 10-year single-center experience. Ann Clin Anal Med 2025;16(3):157-160
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The effect of oxygen concentration on arterial blood gas values during maintenance of anesthesia in patients undergoing lower extremity surgery (prospective, randomized, clinical study)
Serpil Bayındır 1, Azize Beştaş 2
1 Department of Anesthesiology and Reanimation, Elazığ Fethi Sekin City Hospital, 2 Department of Anesthesiology and Reanimation, Faculty of Medicine, Firat University, Elazığ, Turkiye
DOI: 10.4328/ACAM.22429 Received: 2024-09-28 Accepted: 2024-11-11 Published Online: 2024-11-18 Printed: 2025-03-01 Ann Clin Anal Med 2025;16(3):161-165
Corresponding Author: Serpil Bayındır, Department of Anesthesiology and Reanimation, Elazığ Fethi Sekin City Hospital, Elazığ, Turkiye. E-mail: serpilbayindir@gmail.com P: +90 505 549 35 82 Corresponding Author ORCID ID: https://orcid.org/0000-0001-7250-7060
Other Authors ORCID ID: Azize Beştaş, https://orcid.org/0000-0001-8807-7528
This study was approved by the Ethics Committee of Fırat University (Date: 2008-07-03, No: 07-10)
Aim: Due to hypoventilation, an increase in pulmonary shunts, and a decrease in functional residual capacity during general anesthesia, a higher concentration of O2 (20.8%) than the atmospheric rate is required. In the intraoperative period, anesthesia maintenance can be achieved by using different ratios of O2, dry air, and nitrogen protoxide (N2O). This proportional effect can be determined by blood gas parameters. This study aimed to investigate the effect of intraoperative oxygen ratios on arterial blood gas values under general anesthesia in lower extremity surgery.
Material and Methods: Forty patients aged 20-65 years scheduled for ASA II lower extremity surgery were randomly divided into two groups. Group 50 was maintained with 50% O2 + 50% dry air, while Group 30 was maintained with 30% O2 + 70% N2 O and desflurane. Blood gas analysis was performed 13 times at designated times. The amounts of antiemetic and analgesic consumed postoperatively were determined.
Results: In the intergroup comparison, PaO2 was higher in Group 50 intraoperatively and in the first 6 hours postoperatively, whereas the relatively higher SaO2 continued until the 1st hour postoperatively (p<0.001). Group 50 PaCO2 values were higher than Group 30 (p<0.05) at the 1st hour of the operation. Intraoperative pH values were higher in Group 30 (p<0.001). No difference was detected in terms of bicarbonate, base deficit, and PaCO2.
Discussion: A comparison of 30% O2 + 70% N2O with 50% O2 + 50% air delivery for maintenance of anesthesia showed better arterial oxygenation during the intraoperative period and the first six hours postoperatively. Postoperative pain intensity, incidence of nausea and vomiting, and patient comfort were not significantly altered.
Keywords: General Anesthesia, Oxygen Concentration, Arterial Blood Gases
Introduction
General anesthesia disrupts the physiological balance of the respiratory system, causing alveolar collapse and ventilation/perfusion (VA/Q) mismatch. Hypoventilation or apnea leads to a decrease in arterial blood oxygen levels after induction. Under general anesthesia, tidal volume (TV) functional residual capacity (FRC) decreases, and airway resistance increases with loss of muscle tone [1]. Therefore, it is necessary to administer oxygen (O2) at values higher than the concentration found in atmospheric air (20.8%) due to hypoventilation, increase in shunts, and decrease in FRC during anesthesia [2]. Intraoperative inspired fraction of O2 (FiO2) value affects atelectasis, the incidence of postoperative nausea and vomiting, antimicrobial effect, proinflammatory response, and cost [3].
Preoxygenation is performed using 100% O2 until the muscle relaxant effect settles, and laryngoscopy is performed. With this application, intrapulmonary O2 reserve is increased, and time is gained for desaturation and apnea in critical situations [4, 5]. Mixtures of 50% O2 and 50% air or 30% O2 and 70% nitrogen protoxide (N2O) are used for the maintenance of anesthesia [6]. The composition of the inspired gas can change arterial oxygenation [7].
In our study, we aimed to investigate the effect of oxygen concentration used in the maintenance of anesthesia on arterial blood gas values in patients undergoing lower extremity surgery under general anesthesia.
Material and Methods
The study included 40 adult patients from the ASA I-II. Only lower extremity surgeries performed in the supine position were included because the position may have significant pulmonary effects and may alter oxygenation. Patient optimization was ensured by preferring those who used tourniquets during surgery.
Patients were randomly divided into two groups by closed envelope method: those who received 50% O2 and 50% air (Group 50, n=20) and those who received 30% O2 and 70% N2O (Group 30, n=20). Radial artery cannulation was performed for repeated blood gas sampling and continuous blood pressure monitoring. Electrocardiography (ECG), heart rate (HR), peripheral arterial oxygen saturation (SpO2) by pulse oximetry, invasive arterial blood pressures, inspired-expired anesthetic, and ETCO2 concentrations were continuously monitored. Intraoperative fluid management was performed by monitoring hourly urine output and bleeding amount. Fluid replacement was provided with 0.9% NaCl during the operation.
Preoxygenation was performed for 3 minutes using 100% O2 with a face mask. Induction was achieved with 5-7 mg kg-1 sodium thiopental, 2 μg kg-1 fentanyl, and 0,1 mg kg-1 vecuronium. Ventilation was maintained mechanically with desflurane at a concentration of 5-6% with ETCO2 between 30-40%. Analgesia was maintained with repeated fentanyl and muscle relaxation with vecuronium at 1/3 of the induction dose. Neuromuscular blockade and depth of anesthesia were maintained by TOF and BIS monitoring. Neuromuscular block antagonism was performed with 0.03 mg kg-1 neostigmine and 0.01 mg kg-1 atropine. Patients with a modified Aldrete score and postanesthetic recovery score (PADS) of 10 points were transferred. 1 g i.v. paracetamol and 0.5 mg kg-1 meperidine were used for postoperative analgesia; ondansetron was used as antiemetic.
Blood gas samples were obtained before and after preoxygenation, 5 minutes after intubation, at one-hour intervals intraoperatively, before and 5 minutes after extubation, and at 1, 6, 12, 24, 48, and 72 hours postoperatively. Systolic (SBP) and diastolic (DBP) mean arterial blood pressures, SpO2, and HR were recorded at similar intervals. All patients were evaluated for nausea and vomiting at 2, 4, 6, 12, 24, 48 and 72 hours postoperatively. Visual Analog Scale (VAS) value of 4 or higher received 50 mg tramadol.
Exclusion criteria
Patients with chest deformity; patients with lung disease; patients with neuromuscular disease, heart failure, and cardiac rhythm problems; patients with abnormal serum electrolyte, hemoglobin, and hematocrit; patients with malnutrition or body mass index over 35; those who underwent enema, those with nasogastric catheter insertion, smokers and history of allergy were excluded.
Statistical Analysis
The sample size suitable for the study was determined by taking similar studies as examples and performing power analysis. Statistical analysis of the obtained data was performed using the SPSS (statistical package for social sciences for Windows 17.0) program. In addition to descriptive statistical evaluations (mean, standard deviation), the Independent Samples-T Test was used for intergroup comparisons of parameters showing normal distribution for quantitative data, and the Whitney U test was used for intergroup comparisons of parameters not showing normal distribution and homogeneity. Paired Samples-T Test was used for intra-group comparisons of parameters showing normal distribution and homogeneity, and Wilcoxon Sign Test was used for intra-group comparisons of parameters not showing normal distribution and homogeneity. Results were evaluated at a 95% confidence interval, and significance was evaluated at p<0.05 level.
Ethical Approval
This study was approved by the Ethics Committee of Fırat University (Date: 2008-07-03, No: 07-10).
Results
Forty patients (Group 50 n=20, Group 30 n=20) were included in the study. Two patients in Group 30 were excluded from the study because of intraoperative blood transfusion. Demographic data, duration of surgery and anesthesia, total analgesic dose, total antiemetic dose, and ASA were similar in the groups (Table I).
Table I. Distribution of demographic data, duration of surgery and anesthesia, total analgesic dose, total antiemetic dose, and ASA risk classification according to groups (Mean±SD)
pH showed a decreasing trend after intubation, started to increase after extubation, and approached the initial values before preoxygenation at the 6th postoperative hour. In the intergroup comparison, intraoperative pH in Group 50 was lower than those in Group 30 (Figure 1).
The increase in PaCO2 in the intraoperative period became more pronounced in the awakening period, and this increase was found to be highly significant (p<0.001) when compared with the baseline values. In the intergroup comparison, it was observed that the PaCO2 of Group 50 at the 1st hour of the operation was significantly (p<0.05) higher than Group 30.
Post-intubation (E5) PaO2 was the highest of all periods in Group 50 (292.15 mmHg) and Group 30 (179.72 mmHg) (p<0.001). In the intergroup comparison, Group 50 was significantly higher than Group 30 from post-intubation to postoperative 6th hour (Figure 2).
SaO2, which was above 95% in all periods, approached the basal at the 6th postoperative hour. In intergroup comparison, SaO2 at E5, 1st and 2nd hours after intubation in Group 50 were significantly (p< 0.001) higher than those in Group 30. A slight decrease in HCO3 was observed after intubation until the 1st postoperative hour. In the postoperative period, it increased after the 6th hour and reached the preoperative values. A significant decrease was observed in base excess (BE) starting with endotracheal intubation and continuing until the 1st postoperative hour, which was significant compared to baseline values. It increased in the postoperative period and approached the baseline after the 24th hour.
Potassium increased significantly intraoperatively and until the 5th minute after extubation. There was no significant difference between the groups in terms of changes in potassium, peak, and plateau pressures.
Discussion
The effects of different O2 concentrations used in maintenance under general anesthesia on arterial blood gas values were examined. We found that the changes in blood gas parameters in the postoperative period continued until the 6th postoperative hour.
Giving O2 during general anesthesia causes denitrogenization of FRC and increases intrapulmonary O2 reserve. This increases the safety margin in critical situations and provides time for desaturation and apnea [5, 6]. Due to hypoventilation, increased shunts, and decreased FRC, it is necessary to use higher O2 ratios than the concentration found in atmospheric air (20.8%) to ensure adequate oxygenation during anesthesia and to reduce the number of shunts [2].
O2 delivered in different fractions may cause clinical and physiologic effects and, thus, blood gas changes. Intraoperative high FiO2 reduces atelectasis, increases the antimicrobial and proinflammatory response of alveolar macrophages, decreases the incidence of postoperative nausea and vomiting, accelerates wound healing, and reduces postoperative infections, thereby reducing costs [3].
Changes in the concentration of H+ in the blood (pH) are caused by CO2 or HCO3 changes. The acidity of body fluids can be understood by looking at pH [8]. Dias et al.[9], performed blood gas analysis using two different FiO2 (G100: FiO2 100, G60: FiO2 60) ratios in a study investigating the increase in intracranial pressure in dogs. As the primary outcome, PaO2 and SvO2 were higher in G100; pH, PaCO2, SaO2, BE, and HCO3 were similar in both groups. Cummings et al. [10] examined the effect of O2 and air inhalation on blood gas parameters in cataract surgery. While the pH of arterial blood showed a statistically significant decrease in O2 inhalation patients, there was no difference in PaCO2 between the two groups. Similarly, in our study, pH was lower in the group with a higher O2 rate in the intraoperative period, while PaCO2 was higher, decreasing after extubation and reaching baseline values at the 6th hour. Clinically, no difference was observed in nausea-vomiting score or analgesic consumption.
Fuji et al. investigated the effects of using O /N2O and O2 /air on the incidence of postoperative hypoxia in patients. PaO2 was higher in the group given O2 /air, while PaCO2 was similar. They concluded that the use of N2O in maintenance may cause low-grade hypoxia in the late postoperative period [11]. Korkulu et al. investigated the effects of different O2 concentrations used on gas exchange in the lung in patients. Patients in Group A were ventilated with air + 0.4 FiO2, those in Group N were ventilated with N2 O + 0.4 FiO2, and patients in Group O were ventilated with 1.0 FiO2. Lung gas changes were evaluated by looking at PaO2 / FiO2 and P(A-a) O2. The highest PaO2 /FiO2 ratios were reached in Group A. In Group O, it was found to be significantly higher than the baseline at 24 hours (p<0.05) [12]. Similarly, the O2 ratio presented in our study, PaO2, was significantly higher in Group 50 compared to Group 30. PaO2 reached baseline values at the 6th hour in both groups.
Anderson et al. investigated the hemodynamic effects of changes in FiO2 ratio in 30 ASA I-II patients [13]. Hemodynamic responses were recorded by noninvasive transthoracic bio-impedance monitoring. After FiO2 was increased from 0.21 to 1 during preoxygenation, mean cardiac index, HR, and stroke volume decreased, and systemic vascular resistance increased, but OAB did not change. In our study, only at the 60th minute of recovery the mean pressure was found to be significantly higher in Group 30. It decreased after induction before laryngoscopy and increased again with hemodynamic response to intubation. Similarly, HR increased with hemodynamic response to endotracheal intubation but started to increase with discontinuation of inhalation agents during the waking period.
It is known that N2O increases the incidence of postoperative nausea and vomiting. The ENIGMA II study reported that PONV with the use of N2O was observed in procedures lasting longer than 2 hours. This study showed that N2O was not associated with increased mortality, cardiovascular complications, and surgical infections [14]. Piper et al. investigated the incidence of PONV using different FiO2 rates [15]. They reported that PONV was significantly lower in Group A (80% O2 – 20% air) and Group B (40% O2 – N2O) compared with Group C (40% O2 – 60% N2O) and that the use of N2O increased the incidence of PONV. Similar results were conducted by Mraovic et al. They investigated the dose relationship of N2O with postoperative nausea-vomiting in gynecological surgery (n=137), patients were randomly divided into three groups: G0 (30% O2), G50 (50% N2O), G70 (70% N2O) [16]. It was determined that the nausea-vomiting rates of the patients were similar at the 2nd postoperative hour, but at the 24th postoperative hour, it was the highest in G70 and the lowest in G0. In our study, in contrast, nausea and vomiting scores decreased over time in both groups, and there was no statistical difference between the groups.
Aksakal et al. 40 patients were randomized to use low or high pressure during laparoscopic cholecystectomy. Peak pressure increased significantly with low and high pneumoperitoneum pressure, while dynamic compliance decreased. Although CO2 insufflation caused a decrease in pneumoperitoneum pressure, blood pH was found to be significant only at high pneumoperitoneum pressure in both groups [17]. The increase in peak and plateau levels is due to an increase in peak inspiratory pressure as a result of the diaphragm being pushed upward as a result of increased intraabdominal pressure and decreased lung compliance. We recorded peak and plateau pressure values at 15-minute intervals in the intraoperative period. In our study, no difference was found between the groups in terms of BE changes. BE values increased with preoxygenation in both groups in the intraoperative period, and intraoperative values after endotracheal intubation were lower. HCO3 increased after preoxygenation, and intraoperative and postoperative up to the 6th hour after endotracheal intubation were found to be lower than preintubation.
In our study, in the intraoperative period, higher PaO2 values were obtained with 50% O2 administration during the maintenance period of anesthesia. With the termination of anesthesia, a rapid decrease in PaO2 values was observed, especially in patients in group 50%. It was found that PaO2 reached the preoperative values at the 6th postoperative hour. SaO2 of patients in group 50 was found to be higher intraoperatively and in the first hour postoperatively, and similar to PaO2, they approached the baseline in the 6th hour postoperatively. In group 50, pH values were lower only in the intraoperative period, and serum potassium levels changed by pH. However, similar changes were found in HCO3, BE, and PaCO2 in all periods of follow-up.
Limitation
Among the limitations of the study is that the results cannot be generalized because it was conducted in a single center. Although the sample size decreased after those who did not meet the inclusion criteria were excluded from the study, it is qualified to show the targeted result because a large number of variables were studied together.
Conclusion
It was found that 50% O2 + 50% air instead of 30% O2 + 70% N2O during anesthesia maintenance provided better arterial oxygenation only in the intraoperative period and in the first six hours postoperatively. Postoperative pain intensity, incidence of nausea and vomiting, and patient comfort were not significantly changed.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and Human Rights Statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or compareable ethical standards.
Funding: The study was supported by FÜBAP (Fırat University Scientific Research Project).
Conflict of Interest
The authors declare that there is no conflict of interest.
References
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2. Gropper MA, Cohen NH, Errikson LI, Fleisher LA, Leslie K, Wiener-Kronish JP. Clinical A. Miller Anesthesia Edt: Erdem Ali Fuat. Respiratory physiology and pathophysiology. 9th Edition. Ankara: Güneş Kitabevleri; 2022.p.354-384.
3. Hovaguimian F, Lysakowski C, Elia N, Tramèr MR. Effect of Intraoperative High Inspired Oxygen Fraction on Surgical Site Infection, Postoperative Nausea and Vomiting, and Pulmonary Function: Systematic Review and Meta-analysis of Randomized Controlled Trials. Anesthesiology. 2013;119(2):303-316.
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5. Bignami E, Saglietti F, Girombelli A, Bertolini A, Bove T, Vetrugno L. Preoxygenation during induction of anesthesia in non-critically ill patients: A systematic review. J Clin Anesth. 2019;52:85-90.
6. Tulunay M, Cuhruk H. Clinical Anesthesiology. U.S.A: Lange Medical Books 2012; p.178-198.
7. Topuz U, Salihoglu Z, Gokay BV, Umutoglu T, Bakan M, Idin K. The Effects of Different Oxygen Concentrations on Recruitment Maneuver During General Anesthesia for Laparoscopic Surgery. Surg Laparosc Endosc Percutan Tech. 2014;24(5):410-3.
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9. Gonçalves Dias LG, Nunes N, Lopes PC, de Almeida RM, Neto GB, de Souza AL, et al. The effects of 2 levels of the inspired oxygen fraction on blood gas variables in propofol-anesthetized dogs with high intracranial pressure. Can J Vet Res. 2009;73(2):111-6.
10. Cummings AB, König HL. Effect of oxygen and air inhalation during cataract surgery on blood gas parameters. J Cataract Refract Surg. 1996;22(9):1236-9.
11. Fujii Y, Tanaka H, Toyooka H. Intraoperative ventilation with air and oxygen during laparoscopic cholecystectomy decreases the degree of postoperative hypoxemia. Anaesth Intensive Care. 1996;24(1):42-4.
12. Korkulu F, Uysal HY, Acar HV, Eruyar S, Dikmen B. The Effect of Different Oxygen Concentrations Used in Induction and Maintenance of Anesthesia on Lung Gas Exchange. Turk J Anesthesiol Reanim. 2012;40(1):11-9.
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14. Myles PS, Leslie K, Chan MT, Forbes A, Peyton PJ, Paech MJ, et al. ANZCA Trials Group for the ENIGMA-II investigators. The safety of the addition of nitrous oxide to general anesthesia in at-risk patients having major non-cardiac surgery (ENIGMA-II): A randomized, single-blind trial. Lancet. 2014;384(9952):1446-54.
15. Piper SN, Röhm KD, Boldt JJ, Faust KL, Maleck WH, Kranke P, et al. Inspired oxygen fraction of 0.8 compared with 0.4 does not further reduce postoperative nausea and vomiting in dolasetron-treated patients undergoing laparoscopic cholecystectomy. Br J Anaesth. 2006;97(1):647-653.
16. Mraovic B, Simurina T, Sonicki Z, Skitarelic N, Gan TJ. The dose-response of nitrous oxide in postoperative nausea in patients undergoing gynecologic laparoscopic surgery: A preliminary study. Anesth Analg. 2008;107:818-823.
17. Aksakal N, Taviloğlu K, Yanar HT, Tuğrul S, Uçar A, Tükenmez M, et al. The effects of pneumoperitoneum pressure on blood gases, respiratory and venous systems during laparoscopic cholecystectomy: A prospective randomized trial. Laparosc Endosc Surg Sci. 2017;24(2):31-7.
Download attachments: 10.4328.ACAM.22429
Serpil Bayındır, Azize Beştaş. The effect of oxygen concentration on arterial blood gas values during maintenance of anesthesia in patients undergoing lower extremity surgery (prospective, randomized, clinical study). Ann Clin Anal Med 2025;16(3):161-165
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How does the mental health of caregivers affect diabetes management in adolescents with type 1 diabetes?
Fatma Özgüç Çömlek 1, Saime Ergen Dibeklioğlu 2, Muslu Kazım Körez 3
1 Department of Pediatric Endocrinology, Faculty of Medicine, Selçuk University, 2 Department of Pediatric Endocrinology, Konya City Hospital, 3 Department of Biostatistics, Faculty of Medicine, Selçuk University, Konya, Türkiye
DOI: 10.4328/ACAM.22502 Received: 2024-11-25 Accepted: 2025-01-13 Published Online: 2025-01-24 Printed: 2025-03-01 Ann Clin Anal Med 2025;16(3):166-170
Corresponding Author: Fatma Özgüç Çömlek, Department of Pediatric Endocrinology, Faculty of Medicine, Selçuk University, Konya, Turkiye. E-mail: fatmaozguc@gmail.com P: +90 532 378 42 10 Corresponding Author ORCID ID: https://orcid.org/0000-0002-2752-3480
Other Authors ORCID ID: Saime Ergen Dibeklioğlu, https://orcid.org/0000-0003-2412-8837 . Muslu Kazım Körez, https://orcid.org/0000-0001-9524-6115
This study was approved by the Ethics Committee of Selçuk University (Date: 2024-07-03, No: 341)
Aim: The current study examined the impact of mental health status and socioeconomic conditions on diabetes management in adolescents with diabetes and their caregivers.
Material and Methods: In this cross-sectional study, the Patient Health Questionnaire (PHQ-9) and the Hospital Anxiety and Depression Scale (HADS) were administered to adolescents over the age of ten who have had type 1 diabetes (T1D) for at least two years, along with their caregivers. The questionnaire results were assessed alongside the most recent HbA1c levels and the annual average HbA1c levels.
Results: A statistically significant and positive association was found between the average child’s HbA1C and the parent’s PHQ-9 score (Spearman’s rho = 0.332, p = .007), parent’s HADS anxiety (Spearman’s rho = 0.328, p = .008), and HADS depression (Spearman’s rho = 0.322, p = .010) scores. There was also a positive and statistically significant association between the parent’s PHQ-9 score (Spearman’s rho = 0.291, p = .020) and depression (Spearman’s rho = 0.280, p = .025) scores. However, no statistically significant association was found between the adolescents’ average and last HbA1C levels and the PHQ-9, anxiety, and depression scores.
Discussion: Parental mental health is as essential in the management of diabetes during adolescence as it is during childhood and should be evaluated regularly.
Keywords: Mental Health, Type 1 Diabetes, Adolescent, Caregiver
Introduction
With its limitations and daily demands, type 1 diabetes mellitus (T1D) requires some parental adaptations. Parental adaptation has been identified as having a detrimental or protective effect on children’s ability to cope with this condition [1]. With the recent interest in this aspect of the disease, many authors have focused on the mental health status of caregivers, who play an essential role in disease management [2, 3]. Due to the complexity of T1D management, multidisciplinary support is needed, with particular attention to patient and family psychology and emotions. Indeed, healthcare providers should be involved with parents, as T1D involves daily responsibilities such as blood sugar level assessments, insulin administration, and food intake regulation [4]. Therefore, with this “extra work,” difficulties in parent-child/adolescent interactions and increases in parental stress are reported by parents [5].
Adolescence is when children seek independence while relying on their families for financial, emotional, and psychological support. Navigating this complex balance can be particularly challenging for adolescents with chronic illnesses, such as T1D, when it comes to managing their health. Many studies indicate that both younger and older adolescents with T1D often experience poor glycemic control and worse overall health outcomes [6, 7]. Previous research has shown that past and present family interactions and relationships impact the development of adolescents’ self-care behaviors. Furthermore, parenting style and the alignment of family communication may influence glycemic control [8, 9].
In this study, we assessed the influence of adolescent mental health and that of their primary caregivers on managing type 1 diabetes.
Material and Methods
The study included 64 children aged 10 years and older who had been diagnosed with Type 1 diabetes for at least 2 years and their caregivers.
Height, weight, and BMI variables were standardized using standard deviation scores (SDS) based on Turkish norms [10]. Pubertal development and breast and pubic hair growth were assessed using Tanner criteria [11]. After the examination, blood samples were collected from the patients to evaluate their HbA1c levels. The average HbA1c value was calculated by summing the four values examined over the last year and then dividing by four.
Before administering the questionnaire, we collected and recorded the sociodemographic characteristics of patients and their caregivers. This included information about the primary caregiver, marital status, employment status, educational background, the number of people living in the household, and the average monthly income, among other factors.
Two pediatric endocrinologists in two different centers administered the Patient Health Questionnaire (PHQ-9) and the Hospital Anxiety and Depression Scale (HADS) questionnaires separately to the patient and caregiver.
The relationship between questionnaire results, sociodemographic data, the last glycated hemoglobin (HbA1c), and HbA1c averages in the previous year was evaluated.
Hospital Anxiety and Depression Scale (HADS)
HADS was designed to screen for the presence of anxiety and depression in patients with physical illness [12]. The Turkish validity and reliability study was conducted by Özdemir et al. [13]. The self-report scale consists of 14 items, 7 of which investigate depression and 7 of which investigate anxiety symptoms. Responses are evaluated on a four-point Likert scale and scored between 0 and 3. The scale is designed to screen for anxiety and depression quickly to identify risk groups, not to make a diagnosis.
In preparing the score, 0-1 was accepted as “no risk,” 2 score as “borderline disease risk,” and 3-4 as “marked disease risk.” The HAD scale has proven to be a helpful assessment tool, and score ranges minimize false positive or negative results (12). It has been shown that the score obtained from the scale is not affected by physical illness [14].
Patient Health Questionnaire (PHQ-9)
The Patient Health Questionnaire-9 (PHQ-9) is a diagnostic tool designed to identify common mental disorders, such as depression, in primary care settings. Kroenke et al. validated it, measuring nine symptoms based on the PHQ-9 and diagnosing depression according to DSM-IV criteria [15]. The short and straightforward nature of the questions is a significant advantage, making them easy to apply. Sari et al. [16] carried out the Turkish reliability study of the questionnaire.
The questionnaire consists of 9 questions, each scored from 0 (never) to 3 (almost every day). The scores are added up for each question. According to the original questionnaire scoring system, scores between 1 and 4 are graded as minimal, 5-9 as mild, 10-14 as moderate, 15-19 as moderately severe, and 20-27 as severe depression. In addition to the nine diagnostic questions, the test includes one such question: “If you checked any problems, how difficult did they make it for you to do your job, take care of household chores, or get along with others?”. However, this question does not affect the scoring [15].
Statistical analysis
All statistical analysis was performed using R version 4.2.1 (www.r-project.org) statistical software. Numerical data were presented as mean ± standard deviation (ranges: min – max), and categorical data were described as count (n) and percentage (%). Spearman’s rho correlation coefficient was used to examine the relationship between HbA1C levels and PHQ-9 scores in children and parents. A two-tailed p-value less than 0.05 was considered statistically significant.
Ethical Approval
This study was approved by the Ethics Committee of Selçuk University (Date: 2024-07-03, No: 341).
Results
The mean age of the 64 study participants was 169.33 ± 27.97 months. Thirty-eight of the participants (59.4%) were male. The mean body weight of the participants was 54.52 ± 14.26 kg (SD= 0.08 ± 1.21). Fifty-seven participants had completed puberty. The mean duration of diabetes in the patients was 5.63 ± 3.36 years. The participants’ mean HbA1c values for the last year were 8.92 ± 1.83, and the HbA1c at the previous visit was 8.85 ± 1.77. The caregivers of 58 (90.6%) participants were their mothers. Only six children (9.4%) reported experiencing peer bullying due to their illness, while twelve children (18.8%) felt stigmatized. The general characteristics of the participants and the questionnaire results are shown in Table 1.
A statistically significant positive association was found between the average child’s HbA1C and the parent’s PHQ-9 score (Spearman’s rho = 0.332, p = .007). Similar associations were observed with the parent’s HADS anxiety (Spearman’s rho = 0.328, p = .008) and HADS depression (Spearman’s rho = 0.322, p = .010) scores. There was also a positive and statistically significant association between the parent’s PHQ-9 score (Spearman’s rho = 0.291, p = .020) and depression (Spearman’s rho = 0.280, p = .025) scores (Figure 1). However, no statistically significant association was found between the adolescents’ average and last HbA1C levels and the PHQ-9, anxiety, and depression scores (Table 2). No considerable relationship was identified between HbA1c levels and the other sociocultural factors assessed.
Discussion
The results of this study identified a relationship between caregiver anxiety and depression and glycated hemoglobin (HbA1c) levels, thus contributing to the existing literature by highlighting the importance of caregiver mental health in adolescent diabetes management.
A substantial body of literature shows cross-sectional and longitudinal associations between family and adolescent-level variables and glycemic control in younger and older adolescents [17]. Family conflict related to diabetes, the perceived burden on parents, and a critical parenting style have been consistently linked to poor glycemic control [18]. However, to resolve this complexity sensibly, there is no doubt that the mental health of the caregiver is also essential, and it will negatively affect diabetes management. In this study, a more substantial relationship was identified between caregiver mental health and HbA1c than between the adolescents’ mental health.
Studies have shown that individuals with lower socioeconomic status experienced more conflict with their children, less acceptance of diabetes, and increased parental stress; however, this status did not influence the level of parental monitoring of diabetes care [19]. Participants in this study were generally of low economic status with similar socioeconomic levels. In other words, since the patients were a uniform group in terms of socioeconomic level, we believed that this factor did not act as an independent variable affecting HbA1c among them. Similar to the study by Silina et al., the data analysis failed to establish a statistically reliable relation between the child’s environment and HbA1c or between socioeconomic factors in that circumference [20].
Many young people with diabetes face challenges related to self-esteem, body image, social roles, and relationships with peers. During adolescence, acceptance by friends and maintaining peer relationships are crucial. To avoid being seen as different by their peers, adolescents may use passive coping strategies, such as withdrawing, avoiding activities, and not adhering to their treatment plans [21]. The stigma associated with chronic diseases is defined as negative social judgment based on the condition or its management. This stigma can lead to perceived or experienced exclusion, rejection, blame, stereotyping, and loss of status. Adolescents and young adults may be especially vulnerable to stigma and its harmful effects during these life stages [22]. Although studies are showing that stigma harms diabetes control by causing high HbA1c levels and more hypoglycemia, the number of patients who felt stigmatized and experienced peer bullying was very low among our patients [23]. There was no significant difference in HbA1c levels between patients who reported experiencing peer bullying or feeling stigmatized compared to others.
Studies have reported that fear of hypoglycemia, chronic sadness, and uncertainty are some common psychological responses for parents of children with diabetes, especially among mothers, and this may increase parental depression and anxiety, leading to higher HbA1c [24]. In our study, 90.6% of the caregivers were mothers. Thirty-one mothers had a HADS anxiety score above seven. As the anxiety and depression scores of caregivers increased, HbA1c levels also rose. Including fathers in the diabetes management process may reduce the stress burden on caregivers.
Limitation
The study has several limitations. Because it was a cross-sectional study, causality could not be established, but the direction of the observed relationships remained unclear. Furthermore, the research relied on self-reported assessments of anxiety and depression, which may have introduced bias. Additionally, the study specifically targeted adolescents with T1D and their caregivers, meaning that the results may not be relevant to other age groups or types of diabetes. The limited sample size may impact how broadly the results can be applied. Despite these limitations, our study offers essential practical and clinical inferences. Improving caregiver mental health should be an important goal for families with an adolescent diagnosed with T1D, as this may lead to improved diabetes management.
Conclusion
In conclusion, the study suggests that caregiver mental health is essential to children’s diabetes management outcomes. This highlights the importance of addressing mental health concerns in both children and their parents as part of diabetes care strategies. Diabetes is not solely an endocrine disorder; it also affects psychological and psychiatric health, the socioeconomic environment, and overall family functioning.
Diabetes care should be multidisciplinary, involving endocrinologists, primary care physicians, psychologists, psychiatrists, social workers, and other specialists. Fathers should also be involved in diabetes management, sharing the often overwhelming caregiver stress on mothers. It is important to note that working with parents is a critical component of interdisciplinary diabetes care, including preventive measures to improve mental health.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and Human Rights Statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or compareable ethical standards.
Funding: None
Conflict of Interest
The authors declare that there is no conflict of interest.
References
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2. Yaqoob U, Ali Khan M, Khemani L, -Ul-Haq F, Rafiq J, Iftikhar AS. Diabetes mellitus in children and its effect on caregivers’ mental health. Cureus. 2018;10:e2409.
3. Jönsson L, Lundqvist P, Tiberg I, Hallström I. Type 1 diabetes – impact on children and parents at diagnosis and one year after the child’s diagnosis. Scand J Caring Sci. 2014;29(1):126-35.
4. Sherifali D, Ciliska D, O’Mara L. Parenting children with diabetes: Exploring parenting styles on children living with type 1 diabetes mellitus. Diabetes Educ. 2009;35(3):476-83.
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6. Petitti DB, Klingensmith GJ, Bell RA, Andrews JS, Dabelea D, Imperatore G, et al. Glycemic control in youth with diabetes: The SEARCH for diabetes in youth study. J Pediatr. 2009;155(5):668-72.
7. Bryden KS, Dunger DB, Mayou RA, Peveler RC, Neil HAW. Poor prognosis of young adults with type 1 diabetes: A longitudinal study. Diabetes Care. 2003;26(4):1052-57.
8. Miller DC, Byrnes JP. To achieve or not to achieve: a self-regulation perspective on adolescents’ academic decision making. J Educ Psychol. 2001;93:677-85.
9. Katz ML, Volkening LK, Butler Da, Anderson BJ, Laffel LM. Family-based psychoeducation and care ambassador intervention to improve glycemic control in youth with type 1 diabetes: A randomized trial. Pediatr Diabetes. 2014;15(2):142-50.
10. Neyzi O, Gunoz H, Furman A. Reference values for body weight, height, head circumference, and body mass index in Turkish children. Turkiye Cocuk Hast Derg. 2008;51:1-14.
11. Marshall WA., Tanner JM. Variations in pattern of pubertal changes in girls. Arch Dis Child. 1969;44(235):291-303.
12. Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand. 1983;67(6):361-70.
13. Aydemir Ö. (1997). Hastane Anksiyete ve Depresyon Ölçeği Türkçe formunun geçerlilik ve güvenilirliği [Validity and reliability of the Turkish form of the Hospital Anxiety and Depression Scale.] Turk Psikiyatri Derg. 1997;8(4):280-7.
14. Clark DA, Steer RA. Use of nonsomatic symptoms to differentiate clinically depressed and nondepressed hospitalized patients with chronic medical illnesses. Psychol Rep. 1994;75(3 Pt 1):1089-90.
15. Kroenke K, Spitzer RL, Williams JBW. Validity of a brief depression severity inventory. J Gen Intern Med. 2001;16(9):606-13.
16. Sarı YE, Kökoğlu B, Balcıoğlu H, Bilge U, Çolak E, Ünlüoğlu İ. Turkish reliability of the Patient Health Questionnaire-9, Biomed Res. 2016;27:460-2.
17. Nagy BE, Munkácsi B, Kovács KE. Factors influencing adherence among youth with type 1 diabetes mellitus – the Hungarian case. Curr Diabetes Rev. 2021;17(2):222-32.
18. Lewin AB, Heidgerken AD, Geffken GR, Williams LB, Storch EA, Gelfand KM, et al. The relation between family factors and metabolic control: The role of diabetes adherence. J Pediatr Psychol. 2006;31(2):174–83.
19. Caccavale LJ, Weaver P, Chen R, Streisand R, Holmes CS. Family density and SES related to diabetes management and glycemic control in adolescents with type 1 diabetes. J Pediatr Psychol. 2015;40(5):500-8.
20. Silina E, Taube M, Zolovs M. Exploring the mediating role of parental anxiety in the link between children’s mental health and glycemic control in type 1 diabetes. Int J Environ Res Public Health. 2023;20(19):6849.
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22. Browne JL, Ventura A, Mosely K, Speight J. ‘I’m not a druggie, I’m just a diabetic’: A qualitative study of stigma from the perspective of adults with type 1 diabetes. BMJ Open. 2014;4(7):e005625
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Fatma Özgüç Çömlek, Saime Ergen Dibeklioğlu, Muslu Kazım Körez. How does the mental health of caregivers affect diabetes management in adolescents with type 1 diabetes? Ann Clin Anal Med 2025;16(3):166-170
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Immunohistochemical markers affecting nodal metastasis in breast cancer and imaging methods for detection of axillary lymph node metastasis
Tansu Altintas 1, Naciye Cigdem Arslan 2
1 Department of General Surgery, Istinye University, Liv Hospital, 2 Department of General Surgery, Istanbul Medipol University, Istanbul, Turkey
DOI: 10.4328/ACAM.22517 Received: 2024-12-05 Accepted: 2025-01-23 Published Online: 2025-02-07 Printed: 2025-03-01 Ann Clin Anal Med 2025;16(3):171-176
Corresponding Author: Tansu Altintas, Department of General Surgery, Istinye University, Liv Hospital, Istanbul, Turkey. E-mail: mdtansualtintas@gmail.com P: +90 505 930 36 09 Corresponding Author ORCID ID: https://orcid.org/0000-0001-6517-7948
Other Authors ORCID ID: Naciye Cigdem Arslan, https://orcid.org/0000-0002-2282-7207
This study was approved by the Ethics Committee of Kanuni Sultan Suleyman Training and Research Hospital (Date: 2021-08-12, No: KAEK/2021.08.237)
Aim: Axillary lymph node metastasis (ALNM) is a prognostic determinant of breast cancer (BC) and influences the treatment decision. Our study aimed to determine the factors associated with ALNM in BC and to accurately evaluate the ALN status with imaging methods while determining the treatment modality.
Material and Methods: Patients (n=417) who underwent BC surgery in our clinic were included. Patient’s axillary ultrasound (AUS), magnetic resonance imaging (MRI), 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) reports and immunohistochemical data were collected for analysis.
Results: ALNM was found in 59.7% (n = 249) of the patients. Invasive ductal carcinoma (IDC), invasive lobular carcinoma (ILC), lymphovascular invasion, and perineural invasion were found to be associated with ALNM (p<0.001). Tumor histological type was found to be the factor affecting true/false positivity or true/false negative of AUS, MRI, 18F-FDG-PET/CT (p<0.01, p=0.012, p=0.006).
Discussion: Premenopause, IDC, ILC, and the presence of LVI or PNI are factors that increase the risk of ALNM. MRI is the most reliable to accurately predict ALNM, followed by AUS and 18F-FDG-PET/CT. If the tumor type is IDC and ILC, AUS and MRI may be superior in predicting ALNM positivity. All three imaging modalities may be reliable in accurately predicting axilla negativity in other tumor types.
Keywords: Axillary lymph Node, Breast Cancer, MRI, 18F-FDG-PET/CT, Immunohistochemical Markers
Introduction
Breast cancer is among the most common cancers worldwide and the second most common cause of cancer-related death in women. Early diagnosis and use of aggressive multimodal treatment options have resulted in a reduction in mortality and morbidity in recent years [1, 2]. However, despite all developments, axillary lymph node (ALN) status remains the most important prognostic factor in staging, treatment, prognosis, recurrence, and survival in breast cancer [3].
Until recently, axillary lymph node dissection was standard in patients with axillary lymph node metastases (ALNM), and then the sentinel lymph node biopsy (SLNB) method became standard in clinically node-negative patients. However, SLNB is also an operation and preoperative recognition of ALNM is essential in determining the treatment modality. Ultrasound-guided fine needle aspiration cytology (FNAC) or tru-cut biopsy (tru-cut Bx)is another option for suspected ALNs during diagnosis. However, it is an invasive procedure and sometimes leads the patient to the wrong treatment option due to false negatives or loss of time with repeat biopsies [3-6].
Apart from nodal involvement, tumor size, hormone receptor (HR) status, and histological grade are other prognostic factors to predict the course of breast cancer, and numerous other clinicopathological factors and novel molecular markers have been investigated to improve treatment response and prognosis [7].
Estrogen receptor (ER) is expressed in 50-80% of breast cancer tissues, and ER expression is the main indicator of potential response to endocrine hormone therapy (EHT). Progesterone receptor (PR) is an ER regulatory protein, and PR expression in breast cancers has been used to predict ER functionality [8]. Human epidermal growth factor receptor 2 (HER2) is overexpressed or amplified in ~25% of breast cancer patients and is associated with poor clinical outcomes if not treated appropriately with HER2-targeted therapies [9].
Molecular subtypes are based on ER/PR/HER2 oncogene expression and the Ki-67 index. Detecting the molecular subtype of breast cancer is important for determining the prognosis and treatment of the disease. HER2 overexpressed and triple-negative subtypes have poor prognosis, whereas luminal A and B subtypes have better prognosis [10].
This study has two purposes. The primary aim is to evaluate histopathological and immunohistochemical markers that may affect ALNM. The second aim of the study is the diagnostic value of axillary ultrasonography (AUS), magnetic resonance imaging (MRI), and 18F-fluorodeoxyglucose-positron emission tomography/computed tomography (18F-FDG-PET/CT) in determining the status of axillary lymph nodes. May immunohistopathological features of the tumor affect the diagnostic values of imaging methods?
Material and Methods
Patients diagnosed with breast cancer treated at our hospital between January 2016 and June 2021 were evaluated retrospectively. After anamnesis and physical examination, patients who applied to our clinic with breast complaints were screened with breast and axillary ultrasonography under 40 years of age and mammography and breast and axillary ultrasonography over 40 years of age. In the daily practice of our clinic, AUS is routinely performed together with breast ultrasonography (USG) for the evaluation of axillary lymph nodes. Breast MRI was added to imaging modalities of high-risk patients. USG-guided tru-cut biopsy was performed from suspicious masses detected in the breast in imaging methods, and USG-guided FNAC or tru-cut biopsy was performed from suspicious lymph nodes. According to the pathology results, patients diagnosed with breast cancer underwent breast MRI to evaluate multicentric foci, contralateral breast and axillary lymph nodes, and 18F-FDG-PET/CT to search for distant metastases.
The imaging of breast cancer patients at the time of initial diagnosis was included in the study. AUS, breast MRI, and PET-CT images of these patients at the initial diagnosis stage were examined. The patients were divided into two groups, those with and without axillary lymph node metastasis, based on the status of axillary metastases with Tru-cut Bx & FNAC or preoperative SLNB/axillary dissection. The effects of age, sex, menopausal status, tumor histology, tumor size, histological grade, multicentricity, lymphovascular invasion, perineural invasion, ER, PR, HER2, Ki67 status, and molecular subtype were evaluated in both groups.
The molecular type was performed as follows: luminal A (ER+ or PR+ and HER2-), luminal B (ER+ or PR+ and HER2+), and HER2 -amplified (ER- and PR- and HER2+). A tumor is defined as triple-negative when it is negative for all three of the ER, PR, and HER2 [7].
Patients with distant metastases at the time of diagnosis were not included in the study, and post-neoadjuvant imaging of patients who received neoadjuvant chemotherapy was not included.
We analyzed our patient series’ histopathological and immunohistochemical data that may affect the axillary lymph node metastasis. Secondly, to more accurately detect axillary lymph node status at the time of diagnosis, we tried to identify histopathological and immunohistochemical markers that affect the reliability and correct positivity/ negativity rates of AUS, MRI, 18F-FDG-PET/CT.
Statistical Analysis
SPSS (Statistical Package for Social Sciences) version 21.0 was used to analyze data. Categorical data are presented as frequency (percentage), and continuous data are presented as mean ± standard deviation. The Chi-square test or Fisher’s exact test was done for categorical data, and continuous variables were compared using an unpaired t-test. Logistic regression was used to identify the independent predictors of axillary lymph node metastasis. A Bonferroni correction and Tukey test were used to compare quantitative variables that did not show a normal distribution between more than two groups. The Pearson correlation coefficient method was used for correlations. Diagnostic screening tests, including sensitivity, specificity, positive predicted value (PPV), negative predicted value (NPV), and kappa compliance tests, were used to determine the compatibility between qualitative data. The statistical significance level was at 95% confidence intervals, and p<0.05 was considered significant. Patients with missing data were excluded from corresponding analyses.
Ethical Approval
This study was approved by the Ethics Committee of Kanuni Sultan Suleyman Training and Research Hospital (Date: 2021-08-12, No: KAEK/2021.08.237).
Results
Patient and tumor characteristics classified by ALNM status are presented in Table 1. The study included 417 patients diagnosed and treated in our clinic. The mean age of the patients was 54.7±12.8 y. Of the patients, 413 (99%) were female, and 4 (1%) were male. Histopathologically, ALNM was negative in 168(40.3%) patients, and ALNM was positive in 249 (59.7%) patients. Based on the menopausal status, ALNM positivity was found to be higher in the premenopausal patient group, and it was statistically significant (p=0.012). When we examined for tumor histology, lymph node positivity was found to be 65.7% in invasive ductal carcinoma patients, 69% in invasive lobular carcinoma patients, and 42.3% in other histological types, which was statistically significant (p<0.001). Lymph node metastasis was found in 50.3% of the patients in the group with negative lymphovascular invasion and 74.4% of the patients in the group with positive lymphovascular invasion. It was statistically significant (p<0.001). When evaluated according to perineural invasion, ALNM positivity was detected in 64.2% of the patients in the group with negative perineural invasion and 72.1% of the patients in the group with positive perineural invasion, and it was statistically significant (p<0.001). In our study group, it was concluded that patient age, gender, tumor size, histological grade, and tumor multisencentricity did not affect lymph node metastasis, and statistically significant results could not be reached in these parameters. The relationship of immunohistochemical markers with axillary lymph node metastasis is given in Table 1. In our study, the effect of ER, PR, HER2, Ki67, and molecular type on axillary lymph node metastasis was not found to be statistically significant.
The diagnostic performance of imaging methods in detecting axillary lymph node metastases is given in Table 2.
The relationships between imaging modalities and tumor immunohistochemical features and luminal subtypes are given in Table 3. When three imaging modalities (AUS, MRI, 18F-FDG-PET/CT) were examined, it was found that only the histological type of the tumor statistically significantly affected true positivity, false positivity, true negativity, and false negativity. True positivity rates in AUS are 71.8% in IDC, 87.5% in ILC, and 57.6% in other histological types. True negativity rates in ultrasonography are 45.1% in invasive ductal carcinoma (IDC), 35.3% in invasive lobular carcinoma, and 76.6% in other histological types (p<0.001). True positivity rates in MRI are 79.2% in IDC, 83.3% in ILC, and 55.6% in other histological types. True negativity rates are 45.5% in IDC, 50% in ILC, and 70.4% in other histological types (p=0.012). If it is 18F-FDG-PET/CT, true negativity rates are 45.7% in IDC, 60% in ILC, and 86.4% in other histological types (p=0.006). No statistically significant correlation was found between true/false positivity and true/false negativity of all three imaging methods and ER, PR, HER2, Ki67, and molecular types.
Discussion
In breast cancer, the status of the lymph nodes is the most substantial independent prognostic factor and is decisive in determining the treatment modality at the time of diagnosis [11]. Neoadjuvant therapy facilitates breast-conserving surgery by reducing the tumor burden, protecting the axilla, and determining the response to systemic therapy before surgery [12].
There is an opinion that breast cancer has a worse prognostic profile in younger and premenopausal women than in postmenopausal women. Multivariate analyses to evaluate the association of age and menopausal status with other clinical and pathological features (high histological grade and high tumor proliferation, lack of steroid hormone receptors) did not consider either variable an independent adverse prognostic factor [13, 14]. However, several studies have shown younger age or premenopausal status as independent predictors of disease recurrence [15]. According to our study, premenopausal status was found to be a risk factor for increasing lymph node metastasis in breast cancer, but age could not be shown to affect ALNM positivity.
Viale et al. studied data from 4351 patients and found other histological types have a significantly lower risk of axillary lymph node metastasis than IDC [16]. Similarly, a lower frequency of axillary nodal metastasis in ILC than in IDC has been reported in several studies [17]. In our patient series, it was concluded that IDC and ILC have a higher tendency to metastasize to axillary lymph nodes compared to other breast cancers.
Hasebe et al. reported in two series that LVI was the strongest independent predictor of nodal involvement, and the grading system for lymph vessel tumor embolism was a very useful histological grading system for accurately predicting lymph node metastasis in IDC [18, 19]. Duraker et al. found that PNI is more likely in hormone-sensitive, mixed-type, or ductal carcinoma and less likely in axilla-negative or smaller tumors [20]. Another study found that PNI predicted > 3 lymph node involvement [21]. Based on our results, lymphovascular invasion, and perineural invasion positivity increase the risk of ALNM.
The neoadjuvant systemic therapy method is decided according to the molecular subtype determined concerning ER, PR, HER2, and Ki-67 status. They are also used to predict the prognosis of breast cancer patients [13]. We evaluated our patient series’ effects of ER, PR, HER2, Ki-67, and molecular subtypes on nodal metastasis; we concluded that none had a statistically significant effect on lymph node metastasis.
Radiologic evaluation of ALN is done with AUS, MRI, and 18F-FDG-PET/CT. AUS is an easy-to-apply, inexpensive, non-radiation-free, non-invasive method used to assess lymph nodes in breast cancer [4]. Besides being non-invasive and radiation-free, breast MRI has advantages such as giving anatomical information about the condition of the breast and axilla and showing lesions that ultrasound and mammography cannot detect [5, 22, 23]. On the other hand, 18F-FDG-PET/CT used for distant metastasis screening is expensive, contains isotopic radiation, has high false-positive rates in inflammation, and has low sensitivity for detecting nodal micrometastases [4, 5].
When Aktaş et al. evaluated sensitivity, PPV, and accuracy to accurately detect the presence of axillary metastases, they found the order of reliability as MRI, AUS, and 18F-FDG-PET/CT [24]. Although there was no significant difference in our study, MRI was the most reliable, followed by 18F-FDG-PET/CT and AUS. When the specificity, NPV, and accuracy rates are examined, the order of reliability in estimating axilla negativity is again MRI, 18F-FDG-PET/CT, and AUS.
In addition, it was concluded in our study that only the histological tumor type can be considered in the radiologically correct prediction of axillary lymph node metastasis in breast cancer, and other immune histochemical markers do not have a beneficial effect in this regard.
If the tumor type is IDC or ILC, breast MRI and AUS may be superior to predict axilla positivity. However, the reliability of AUS, breast MRI, and 18F-FDG-PET/CT in predicting axilla negativity may be low in these two tumor types.
In other tumor types, while AUS, breast MRI, and 18F-FDG-PET/CT may be superior in predicting negative axilla, their reliability may be low in predicting axillary metastasis positivity.
Limitation
Limitations of our study: being a retrospective study, we could not reach the AUS, MRI, or 18F-FDG-PET/CT of each patient because imaging data were obtained in different imaging centers in some patients, and AUS is an operator-dependent modality.
Conclusion
The conclusions to be drawn from our study: premenopausal status, tumor histology being invasive ductal/lobular carcinoma, and the presence of lymphovascular invasion or perineural invasion are factors that increase the risk of axillary lymph node metastasis in breast cancer. Although there is no substantial superiority between them, MRI is the most reliable radiological method to accurately predict axillary lymph node metastasis in breast cancer, followed by 18F-FDG-PET/CT and AUS, respectively. When the relationship between the histopathological and immunohistochemical markers of the tumor and imaging methods was evaluated, If tumor types are IDC and ILC, AUS and breast MR may be superior in predicting axillary metastasis positivity. In the other tumor types, AUS, breast MRI, and 18F-FDG-PET/CT may be reliable in accurately predicting axilla negativity in all three imaging modalities.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and Human Rights Statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or compareable ethical standards.
Funding: None
Conflict of Interest
The authors declare that there is no conflict of interest.
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5. Marino MA, Avendano D, Zapata P, Riedl CC, Pinker K. Lymph Node Imaging in Patients with Primary Breast Cancer: Concurrent Diagnostic Tools. Oncologist. 2020;25(2):e231-e242.
6. Ahn HS, Jang M, Kim SM, La Yun B, Lee SH. Usefulness of preoperative breast magnetic resonance imaging with a dedicated axillary sequence for the detection of axillary lymph node metastasis in patients with early ductal breast cancer. Radiol Med. 2019;124(12):1220-8.
7. Yenidunya S, Bayrak R, Haltas H. Predictive value of pathological and immunohistochemical parameters for axillary lymph node metastasis in breast carcinoma. Diagn Pathol. 2011;6:18.
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9. Miglioretti DL, Zhu W, Kerlikowske K, Sprague BL, Onega T, Buist DS, et al. Breast Tumor Prognostic Characteristics and Biennial vs Annual Mammography, Age, and Menopausal Status. JAMA Oncol. 2015;1(8):1069-77.
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12. Jeong YS, Kang J, Lee J, Yoo TK, Kim SH, Lee A. Analysis of the molecular subtypes of preoperative core needle biopsy and surgical specimens in invasive breast cancer. J Pathol Transl Med. 2020;54(1):87-94.
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17. Toikkanen S, Pylkkänen L, Joensuu H. Invasive lobular carcinoma of the breast has better short- and long-term survival than invasive ductal carcinoma. Br J Cancer. 1997;76(9):1234-40.
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Tansu Altintas, Naciye Cigdem Arslan. Immunohistochemical markers affecting nodal metastasis in breast cancer and imaging methods for detection of axillary lymph node metastasis. Ann Clin Anal Med 2025;16(3):171-176
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An investigation of the predictive markers that can be used in the differentiation of benign and malignant lymphadenopathy
Fatma Yılmaz 1, Abdülkerim Yıldız 2, Merih Reis Aras 1, Hatice Kozan Kalkışım 3, Ahmet Demircan 3, Hacer Berna Afacan Öztürk 1, Murat Albayrak 1
1 Department of Hematology, Etlik City Hospital, Ankara, 2 Department of Hematology, Hitit University Erol Olçok Training and Research Hospital, Çorum, 3 Department of Internal Medicine, Etlik City Hospital, Ankara, Turkiye
DOI: 10.4328/ACAM.22536 Received: 2024-12-25 Accepted: 2025-02-04 Published Online: 2025-02-11 Printed: 2025-03-01 Ann Clin Anal Med 2025;16(3):177-181
Corresponding Author: Fatma Yılmaz, Department of Hematology, Etlik City Hospital, Ankara, Turkiye. E-mail: dr.fatmak@hotmail.com P: +90 506 882 38 69 Corresponding Author ORCID ID: https://orcid.org/0000-0001-6112-3950
Other Authors ORCID ID: Abdülkerim Yildiz, https://orcid.org/0000-0002-9596-4042 . Merih Reis Aras, https://orcid.org/0000-0002-9161-5582 . Hatice Kozan Kalkişim, https://orcid.org/0000-0003-2356-0513 . Ahmet Demircan, https://orcid.org/0009-0004-9271-2562 . Hacer Berna Afacan Öztürk, https://orcid.org/0000-0001-9386-7604 . Murat Albayrak, https://orcid.org/0000-0003-4025-741X
This study was approved by the Ethics Committee of Diskapi Yildirim Beyazit Training and Research Hospital (Date: 2022-03-07, No: 132/11)
Aim: Lymphadenopathy (LAP) can develop for many infectious, rheumatological, immunological, and hematological reasons. The most important point for patients presenting with LAP is the decision-making for further tests to identify who should undergo a biopsy and who should be followed up. This study aimed to investigate predictive markers that can be used to differentiate benign and malignant LAP.
Material and Methods: The study included 274 patients who presented at the Hematology Polyclinic with a diagnosis of LAP. Markers were investigated to determine which affected prognosis in patients with a histopathological benign or malignant LAP diagnosis.
Results: Age, male gender, ferritin, lactate dehydrogenase (LDH), C-reactive protein (CRP), LAP located in the neck, thorax, and abdomen, the size of LAP situated in the neck, and the presence of splenomegaly, were determined at statistically significantly higher rates, and hemoglobin, hematocrit, platelet count, plateletcrit (PCT), and folate were statistically significantly lower in the group with malignant LAP. The results of multivariate analysis showed that age, gender, PCT, sedimentation value, thorax LAP, and inguinal LAP were independently significant in the differentiation of patients with benign and malignant LAP.
Discussion: LAP is a frequently encountered pathology but biopsy and further tests may not be appropriate for every patient in terms of cost and workload. Therefore, predictive parameters will be of guidance to the clinician at the stage of decision-making. These parameters will avoid tiring the patient and the doctor with respect to unnecessary further tests, and the chance of early diagnosis will not be missed if it is a malignant process.
Keywords: Anemia, C-Reactive Protein, Ferritin, Lymphadenopathy, Lactate Dehydrogenase
Introduction
The lymphatic system is a complex system that functions in the filtering of toxins and other substances in the body and is involved in circulation. LAP is defined as abnormal swelling formed in the lymph nodes, which can develop for many infectious, rheumatological, immunological, and hematological reasons [1]. The most important point for patients presenting with LAP is the decision-making for further tests to identify who should undergo a biopsy and who should be followed up. Many factors such as LAP localization, size compared to the site of localization, texture, whether localized or spread, mobile or fixed, and additional complaints (fever, night sweats, weight loss), can help the clinician in decision-making [2]. Although many laboratory and examination findings will guide the clinician in this decision, there is still a need for additional parameters. Therefore, this study aimed to investigate the presence of markers affecting prognosis in patients with a histopathological diagnosis of benign and malignant LAP from biopsy.
Material and Methods
The study included 274 patients who presented at the Hematology Polyclinic of Dışkapı Yıldırım Beyazıt Training and Research Hospital with a diagnosis of LAP between May 2019 and August 2022. A record was made for each patient of demographic characteristics, blood group, hemogram, anemia parameters, CRP, sedimentation rate, LAP localization and size, hepatosplenomegaly, the type of biopsy taken, and pathological result.
Statistical analysis
Data obtained in the study were analyzed statistically using SPSS vn. 28.0 software. Descriptive statistics were stated as mean ± standard deviation (SD), median, minimum and maximum values, or number (n) and percentage (%). The distribution of the variables was examined with the Kolmogorov-Smirnov test. In the analysis of independent quantitative data, the Independent Samples t-test and the Mann-Whitney U-test were used. The Chi-square test was applied in the analysis of independent qualitative data. The effect level of parameters was investigated with univariate analysis and multivariate logistic regression analysis. A value of p<0.05 was accepted as the level of statistical significance.
Ethical Approval
All procedures performed in studies involving human participants were by the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The study was approved by the Ethics Committee of Diskapi Yildirim Beyazit Training and Research Hospital (Date: 2022-03-07, No: 132/11).
Results
A total of 274 patients were analyzed, comprising 127 (46.4%) males and 147 (53.6%) females with a mean age of 50.2±16.5 years. The demographic characteristics and descriptive parameters of the patients are shown in Table 1.
Neck LAP was seen in 75.2% of the patients; the average size was 23.9± 10.6 and the most common locations were left cervical and right cervical (31.1%, and 27.7% respectively).
Supraclaviculer LAP was seen in 16.8 % of the patients; the average size was 22.9±10.1 and the most common locations were left supraclaviculer (67.4%). Thorax LAP was seen in 26.3 % of the patients; the average size was 21.2 ± 13.6 and the most common locations were hilar (47.2%). Axillary LAP was seen in 62.3 % of the patients; the average size was 26.7 ± 12.8 and the most common locations were left axillary (54%). Abdomen LAP was seen in 20.4 % of the patients; the average size was 34.8 ± 25.3 and the most common locations were paraortic (53.6%). Inguinal LAP was seen in 57.7 % of the patients; the average size was 25.3 ± 15.0 and the most common locations were right ınguinal (57.6 %). Splenomegaly was detected in 15% of the patients and hepatomegaly in 25.5%.
The patients who presented with LAP were analyzed in two groups 130 (47.4%) patients with a histopathological diagnosis of benign LAP and 144 (52.6%) with malignant LAP. In the group with malignant LAP, age, male gender, ferritin, LDH, CRP, LAP located in the neck, thorax, and abdomen, the size of LAP situated in the neck, and the presence of splenomegaly, were determined at statistically significantly higher rates (p<0.05), and hemoglobin, hematocrit, platelet count, PCT, and folate were statistically significantly lower (p<0.05) (Table 2).
The comparisons of the groups in respect of LAP localization and size. The rates of LAP localization in the thorax (36.1%,15.4%) and abdomen (29.9%, 10.0%) the size of LAP with neck localization (26.4 ±12.1, 21.8±8.6), and the presence of splenomegaly (20.1%, 9.2%) were determined to be statistically significantly higher in the malignant group. LAP with a neck (84.6%, 66.7%) axillary (74.6%, 52.1%), and inguinal (71.5%, 45.1%) localisation were determined to be statistically significantly high in the benign group (p<0.05).
In the univariate analysis model, age, gender, hemoglobin, hematocrit, platelets, PCT, ferritin, LDH, sedimentation, CRP, LAP located in the neck, the largest diameter of LAP in the neck, thorax LAP, axillary LAP, abdomen LAP, inguinal LAP, and the presence of splenomegaly, were observed to have a statistically significant effect on the differentiation of patients with benign and malignant LAP (p<0.05). The results of multivariate analysis showed that age, gender, PCT, sedimentation value, thorax LAP, and inguinal LAP were independently significant in the differentiation of patients with benign and malignant LAP (p<0.05) (Table 3).
Discussion
LAP develops due to an increase in inflammatory or neoplastic cells in the lymph node. Especially if it does not regress with antibiotic treatment or if there is suspicion of systemic disease, a biopsy must be taken. Although fine needle aspiration biopsy (FNAB) is helpful in benign-malignant differentiation, it is usually not sufficient for a definitive diagnosis [3]. When there is persistent LAP with a pre-diagnosis of lymphoma, excisional biopsy at the right time is the gold standard method. An approach that prevents unnecessary operations and does not delay the diagnosis of malignancy is the most appropriate [4]. The most important point at this stage is the availability of predictive markers that will guide the clinician.
Many studies in the literature have shown a relationship between age and malignant LAP [4, 5]. With increasing age, longer exposure to carcinogens, the formation of defects in tumor-suppressing genes, and a decrease in immunity increase the risk of malignancy. In the current study, the mean age of the group diagnosed with malignant LAP was seen to be 55.0±16.8 years, which was determined to be statistically significantly higher than the mean age of the group with benign LAP.
In a study by Chau et al., male gender was reported to be associated with malignancy [6], and there are data supporting this in other studies in the literature [7]. Consistent with these findings in the literature, male gender was determined to be statistically significantly correlated with malignancy in the current study.
For hemoglobin and hematocrit levels to be low, there needs to be infiltration that is chronic or has affected the bone marrow. These conditions are directly associated with malignancy. After discounting other causes of anemia, low hemoglobin seen together with LAP should alert the clinician in respect of malignancy. Supporting this theory, a relationship was determined between low hemoglobin/hematocrit and malignancy in the current study. In a study of pediatric patients, Sen et al. similarly determined a relationship between anemia and malignancy [8, 9].
LDH is an enzyme used in the cascade obtaining energy in the body. It is found in almost all tissues of the body and is determined to be high in the blood when there is tissue destruction for various reasons [10]. It is a parameter used in the prediction of malignant processes when especially high elevations are evaluated together with other supporting factors [5, 11, 12]. The results of the current study showed that the LDH level was found to be a statistically significant parameter in the prediction of malignant LAP.
There are various studies in literature related to the association with malignancies of thrombocytes and the thrombocyte parameters of PCT, mean platelet volume(MPV), and platelet distribution width( PDW), which can be easily evaluated in the full blood count. In a 2015 study, Özakşit et al. found no statistically significant difference in PCT between groups with benign and malignant adnexal masses [13], while Oncel et al. reported that PCT values were lower in lung cancer patients, consistent with the results of the current study [14].
LAP, especially generalized LAP accompanying thrombocytopenia, can reflect a malignant disease or a severe infectious process [15]. Similar to the current study, Al Kadah et al. found a relationship between thrombocytopenia and malignant lymph nodes [16]. PCT, which expresses the thrombocyte percentage, is expected to be low consistent with thrombocytopenia.
CRP is synthesized from hepatocytes in many rheumatological, oncological, hematological inflammatory, or infectious processes. It has been emphasized in many studies that there is an increase in CRP to accelerate the response to an inflammatory process in the environment, and this has been associated with a poor prognosis in malignant processes [17]. In the current study, a statistically significant relationship was determined between CRP and malignant lymph nodes.
A positive correlation between ferritin and the development of tumor cells and inflammation has been shown in many studies in the literature [18, 19]. The iron content and ferritin expression have been determined to be high in malignant cells. Supporting these data, it was seen that elevated ferritin can be used as a predictive parameter in the evaluation of LAP in the current study.
Folic acid deficiency is a cause of hypoproductive macrocytic anemia. In a study of 937 cancer patients, folic acid deficiency was determined at the rate of 7%, and in the hematological malignancy subgroup, this rate was found to be 9.5% [18]. Similar data were obtained in the current study and folic acid deficiency was found to be associated with mortality. In cancer patients, the reason for folic acid deficiency may be reduced oral intake, or folic acid deficiency as a cause of increased DNA mutation may cause malignancy.
Other than laboratory parameters in the evaluation of LAP, lymph node localization, and size are among the factors affecting prognosis In literature, a relationship has been found between malignancy and supraclavicular localization and involvement of more than two lymph node regions [6].In the current study, LAPs with neck, thorax, and abdomen localization, and the size of LAP localized in the neck were determined to be statistically significantly high in the malignant LAP group [20]. Celenk et al. found a relationship between left-side localized LAP and malignancy [7]. However, there are studies in the literature that have shown no difference between left and right-side localization in respect of the association with malignancy [4], or that have reported results showing a relationship between bilateral localization and malignancy [21]. In the current study, no statistically significant data were obtained on this point.
Splenomegaly develops in conditions such as diseases that result in hyperplasia (eg., infections, connective tissue disorders), infiltrative or deposition diseases, hemolytic anemia, or portal hypertension. In support of this, the current study data showed that if there is also splenomegaly when evaluating patients with LAP, that there could be malignancy should be kept in mind [9].
Limitation
There are some limitations to our study. Since the study was conducted retrospectively, new-generation potential markers could not be evaluated. If the number of patients was larger, the statistics could have been stronger.
Conclusion
LAP can be frequently encountered as a reason for presentation at many departments of polyclinics such as Internal Medicine, Hematology, Ear, Nose, and Throat, and General Surgery. In a pathology encountered this often, biopsy and further testing of every patient may not be appropriate for reasons of both cost and workload. Therefore, predictive parameters will be of guidance to the clinician at the stage of decision-making. These parameters will avoid tiring the patient and the doctor with respect to unnecessary further tests, and the chance of early diagnosis will not be missed if it is a malignant process. This study aimed to investigate parameters that could show a predictive effect. In the results of the multivariate analysis, age, gender, PCT, sedimentation value, thorax LAP, and inguinal LAP were observed to be independently significant in the differentiation of patients with benign and malignant LAP (p<0.05). Rather than the use of these parameters singly, evaluation of them together would seem to be more beneficial with respect to specificity.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and Human Rights Statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or compareable ethical standards.
Funding: None
Conflict of Interest
The authors declare that there is no conflict of interest.
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Download attachments: 10.4328.ACAM.22536
Fatma Yılmaz, Abdülkerim Yıldız, Merih Reis Aras, Hatice Kozan Kalkışım, Ahmet Demircan, Hacer Berna Afacan Öztürk, Murat Albayrak. An investigation of the predictive markers that can be used in the differentiation of benign and malignant lymphadenopathy. Ann Clin Anal Med 2025;16(3):177-181
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The effect of COVID-19 pandemic period on the treatment process of colorectal cancer patients
Enes Şahin 1, Haşim Köken 2, Abdullah Hilmi Yılmaz 3, Kazım Şahin 4, Oktay Yirmibeşoğlu 1, Sertaç Ata Güler 1, Turgay Şimşek 1, Nihat Zafer Utkan 1, Nuh Zafer Cantürk 1
1 Department of General Surgery, Faculty of Medicine, Kocaeli University, Kocaeli, 2 Department of General Surgery, Karamürsel State Hospital, Kocaeli, 3 Department of General Surgery, University of Health Sciences, Van Training and Research Hospital, Van, 4 Department of General Surgery, Kandira State Hospital, Kocaeli, Turkiye
DOI: 10.4328/ACAM.22545 Received: 2025-01-05 Accepted: 2025-02-11 Published Online: 2025-02-24 Printed: 2025-03-01 Ann Clin Anal Med 2025;16(3):182-186
Corresponding Author: Abdullah Hilmi Yılmaz, Department of General Surgery, University of Health Sciences, Van Training and Research Hospital, Van, Turkiye. E-mail: drabdullahhilmi@gmail.com P: +90 544 250 22 07 Corresponding Author ORCID ID: https://orcid.org/0000-0002-9920-3902
Other Authors ORCID ID: Enes Şahin, https://orcid.org/0000-0003-3777-8468 . Haşim Köken, https://orcid.org/0000-0002-1185-2677 . Kazım Şahin, https://orcid.org/0000-0002-5485-2351 . Oktay Yirmibeşoğlu, https://orcid.org/0000-0003-0779-0001 . Sertaç Ata Güler, https://orcid.org/0000-0003-1616-9436 . Turgay Şimşek, https://orcid.org/0000-0002-5733-6301 . Nihat Zafer Utkan, https://orcid.org/0000-0002-2133-3336 . Nuh Zafer Cantürk, https://orcid.org/0000-0002-0042-9742
This study was approved by the Ethics Committee of Kocaeli University Non-Interventional Clinical Research (Date: 2021-12-16, No: KUGOKAEK-2021/22.11)
Aim: Guidelines published during the COVID-19 pandemic generally recommended postponing cancer surgeries except in emergencies. However, the impact of this approach on the progression of cancer cases has not yet been clearly determined. In this study, we aimed to compare the clinical data and outcomes of colorectal cancer surgeries conducted before, during, and after the pandemic.
Material and Methods: This retrospective cohort study included patients who underwent surgery for colorectal cancer during three distinct periods: pre-pandemic (February 1, 2019 – December 31, 2019), pandemic (August 1, 2020 – June 30, 2021), and post-pandemic (April 1, 2021 – August 1, 2021). Demographic data, clinical and laboratory findings, operational details, and post-discharge follow-up information were collected by reviewing patient files. The three groups were compared based on these data.
Results: A total of 79 patients were included in the study: 29 (8 females and 21 males) were operated on before the pandemic, 18 (5 females and 13 males) during the pandemic, and 30 (9 females and 21 males) after the pandemic. One patient (3.4%) in the pre-pandemic period, 11 patients (37.9%) during the pandemic period, and five patients (16.7%) after the pandemic were operated on for emergency reasons (p < 0.001). When examining TNM stages, the most common stage 2 tumors were observed before the pandemic (37.93%), while stage 2 and stage 4 tumors (33.3% each) were most prevalent during the pandemic, and stage 4 tumors (36.7%) were the most common in the post-pandemic period (p = 0.67). Ostomy rates were 3.4% in the pre-pandemic period, 33.3% in the pandemic period, and 13.4% in the post-pandemic period (p = 0.017)
Discussion: The rise in cases needing emergency surgery and the surge in ostomy rates during the pandemic highlights the negative effects of this process on surgical treatment for colorectal cancer.
Keywords: Colorectal Cancer, COVID-19, Pandemic
Introduction
Coronavirus disease 2019 (COVID-19) was first identified in China in December 2019 and began to impact Turkey in March 2020. During this time, numerous guidelines have been published regarding who, when, and how to conduct surgical interventions [1-4]. It has been advised to postpone non-urgent surgical procedures, and it has been reported that surgical interventions can increase morbidity and mortality rates in patients diagnosed with COVID-19 [5]. A meta-analysis showed that the postoperative mortality rate for COVID-19 patients was approximately 20% [6]. The most significant recommendation in the guidelines for colorectal cancer is to avoid surgery in COVID-19-positive patients. Additionally, it has been recommended that surgical interventions should be reserved for emergencies, elective procedures should be deferred, and non-surgical treatment methods should be favored in cases of locally advanced rectal or metastatic colorectal cancers [3, 4, 7].
Colorectal cancer has been identified as the cancer type with the greatest survival impact among cases of gastric, pancreatic, and colorectal malignancies that were delayed during the pandemic period [8]. A meta-analysis indicated that a 12-week delay in colorectal cancer surgery negatively affected survival [9]. Therefore, it is advised that surgery not be postponed for more than 6 to 12 weeks in patients with early-stage colorectal cancer who have completed neoadjuvant therapy. Some centers continued surgical treatment during the pandemic and reported no additional complications, provided that they strictly adhered to pandemic guidelines [10, 11].
Despite the recommendations mentioned above, research on the progression, staging, and follow-up of colorectal cancer during the pandemic is limited.
This study aims to compare the demographic, clinical, and postoperative characteristics of patients who underwent colorectal cancer surgery before, during, and after the pandemic, thereby examining the effects of the COVID-19 pandemic on colorectal cancer surgery.
Material and Methods
Trial Design
After receiving approval from the Kocaeli University Faculty of Medicine Ethics Committee (approval number: KÜ GOKAEK-2021/22.11, Date: December 16, 2021) and obtaining written informed consent from each participant, this retrospective study was conducted in the Department of General Surgery at Kocaeli University Faculty of Medicine Hospital in accordance with the Declaration of Helsinki.
Participants and Eligibility Criteria
Colorectal cancer surgeries conducted at our clinic from April 1, 2019, to August 1, 2021, were reviewed retrospectively. The first COVID-19 case in Turkey was reported on March 11, 2020. Therefore, the pre-pandemic period was defined as April 1, 2019, to August 1, 2019; the pandemic period as April 1, 2020, to August 1, 2020; and the post-pandemic period as April 1, 2021, to August 1, 2021. During the pandemic, polymerase chain reaction (PCR) tests were routinely administered to patients scheduled for surgery at our center. Throughout this period, no patients diagnosed with COVID-19 were treated in our hospital or clinic. All patients included in the study were confirmed to be free of COVID-19 infection by PCR test or thoracic computed tomography. Patients with missing data were excluded.
Inclusion criteria: Individuals must be over 18 years of age and undergoing emergency or elective surgery for colorectal cancer during the specified period periods.
Exclusion criteria
Individuals under 18 years of age, surgery for conditions unrelated to colorectal cancer, surgery for colorectal cancer conducted outside the specified dates, diagnosis of COVID-19, and incomplete data.
Outcomes
Demographic data, including age and gender, tumor localization, and TNM classification, were recorded for all patients. Additionally, the surgical procedures performed and whether the surgery was conducted under emergency or elective conditions were noted. This data was compared before, during, and after the COVID-19 pandemic.
Statistical Analysis
Statistical evaluation was conducted using the IBM SPSS 20.0 software package (IBM Corp., Armonk, NY, USA). The Shapiro-Wilk Test assessed conformity to normal distribution. Numerical variables were expressed as mean ± standard deviation and frequency (percentages).
The Monte Carlo chi-square test was employed for categorical variables to assess intergroup differences. A p-value of < 0.05 was deemed sufficient for statistical significance in two-way tests.
Ethical Approval
This study was approved by the Ethics Committee of Kocaeli University Non-Interventional Clinical Research (Date: 2021-12-16, No: KUGOKAEK-2021/22.11).
Results
A total of 79 patients were included in the study. Of these, 29 (8 females and 21 males) were operated on before the pandemic, 18 (5 females and 13 males) during the pandemic, and 30 (9 females and 21 males) in the post-pandemic period (p = 1). The mean age of the patients in the pre-pandemic period was 63.3 years, 65.8 years in the pandemic period, and 65 years in the post-pandemic period (p = 0.75) (Table 1).
In the pre-pandemic period, one patient (3.4%), 11 patients (37.9%) during the pandemic, and five patients (16.7%) after the pandemic underwent surgery for emergency reasons (p < 0.001). Analysis of the subgroups revealed that the rate of patients operated on under emergency conditions was significantly higher in the pandemic period compared to the post-pandemic period (p = 0.007). No significant difference was observed between the pre-pandemic and post-pandemic periods (p = 0.28) (Table 1).
When the patients were evaluated according to TNM staging, there were six patients (20.7%) with stage 1, 11 patients (37.9%) with stage 2, 5 patients (17.2%) with stage 3, and 7 patients (24.1%) with stage 4 among the 29 patients admitted before the pandemic. In the 18 patients admitted during the pandemic period, there was one patient (5.5%) with stage 1, 6 patients (33.3%) with stage 2, 5 patients (27.8%) with stage 3, and 6 patients (33.3%) with stage 4. Of the 30 patients admitted in the post-pandemic period, there were five patients (16.7%) with stage 1, 9 patients (30%) with stage 2, 5 patients (16.7%) with stage 3, and 11 patients (36.7%) with stage 4. When TNM stages were analyzed, while the most common tumors were stage 2 (37.9%) before the pandemic, stages 2 and 4 (33.3% – 33.3%) were most common during the pandemic period, and stage 4 tumors (36.7%) were predominant in the post-pandemic period (p = 0.67). When subgroups were analyzed, no significant difference was found between the groups (Table 1). All details of the TNM stages of the patients are presented in Table 2.
The incidence rates of stage 1-2 tumors, which also drew our attention in our clinical approach, were examined in our study. While 17 patients (58.6%) had stage 1-2 tumors during the pre-pandemic period, 7 patients (38.9%) had stage 1-2 tumors during the pandemic, and 14 patients (46.7%) had stage 1-2 tumors after the pandemic. When analyzing the subgroups regarding the rates of stage 1-2 tumors, no significant difference was found between the groups (Table 1).
Ostomy rates were 3.4% in the pre-pandemic period, 33.3% during the pandemic, and 13.4% in the post-pandemic phase (p = 0.017). When the subgroups were analyzed, it was found that ostomy procedures occurred significantly higher during the pandemic than in the pre-pandemic period (p = 0.005). No significant difference was observed between the other groups.
Discussion
During the COVID-19 pandemic, which had an impact worldwide, there were many discussions about which patients should be operated on and at what appropriate time. The general approach was to cancel elective operations and control oncologic cases as much as possible with non-surgical methods such as chemotherapy or radiotherapy. Except for emergency operations, elective operations came to a halt in many centers. Many studies have examined the effects of this situation on oncologic cases.
In this study, we aimed to investigate the effect of the pandemic on colorectal cancers. Analysis of the demographic data (mean age and gender distribution) of the patients included in the study revealed no significant difference between the pandemic period and the pre-pandemic and post-pandemic periods.
In a study by Julia et al. at Oxford University Hospital in England, the comparison of colorectal cases during the pandemic and pre-pandemic periods showed that 179 colorectal cancer surgeries were performed before the pandemic, while 85 patients underwent surgery for colorectal cancer during the pandemic. A statistically significant difference was found when comparing the emergency/elective rates between these two groups, indicating an increase in the emergency rate during the pandemic period [12]. Similarly, in our study, we compared the number of emergency and elective cases in both pre-pandemic and pandemic periods and found a similar result. In research by Michael Shinkwin et al. in the UK, colorectal emergency operation rates during the pandemic were compared to previous years, revealing a gradual increase in the emergency operation rate over the months of the pandemic [13]. Likewise, in a multicenter study by Oscar Cano-Valderrama et al. in Spain, it was highlighted that tumor-related emergency colorectal surgeries rose during the pandemic [14]. Additionally, a study conducted in our country by Hasırcı et al. reported a similar increase in the rate of emergency colorectal surgeries during the pandemic period [15]. This evidence supports the rise in the emergency/elective ratio in our study during the pandemic.
In a study conducted by Ju Yeon Choi et al. in Korea, it was reported that the number of advanced colorectal cancers increased significantly compared to the pre-pandemic period. Moreover, it was noted that the number of patients who underwent surgery after neoadjuvant chemotherapy decreased during the pandemic, as many patients presented with advanced and unresectable tumors [16]. In our study, although a statistically significant difference did not emerge due to the limited number of patients, we observed a significant increase in the number of advanced-stage metastatic colorectal cancers compared to the pre-pandemic period. This numerical change may be attributed to the failure to implement national cancer screening programs during the pandemic. Consequently, there has been an uptick in advanced-stage cancers resulting from delayed cancer diagnoses. Additionally, the number of advanced-stage cancers may have risen in the post-pandemic period due to colorectal cancer surgeries that were postponed during the pandemic. Numerous studies indicate a global decrease in endoscopic procedures and oncologic surgeries [16, 17].
When the patients were divided into early-stage (stage 1-2) and late-stage (stage 3-4), although there was no statistical difference between the groups, it was found that advanced-stage cancers increased during the pandemic. This may be attributed to a decrease in hospital admissions and controls during this time due to the pandemic. Additionally, the increased incidence of advanced cancers in the post-pandemic period could be due to delayed hospital admissions and a near halt of endoscopic interventions for screening in most centers during the pandemic. In a multicenter retrospective study conducted in the Netherlands, Mando Filipe et al. evaluated 162 colorectal cancer patients. This study found that when comparing colorectal cancers before and during the pandemic, the incidence of early-stage cancers gradually decreased throughout that period [18]. This supports the observed numerical decrease of early-stage cancers in our study during and after the pandemic.
Considering the rates of ostomy application in our study, the rates were 3.4% before the pandemic, 33.3% during the pandemic, and 13.3% after it. Some studies in the literature show that the rate of ostomy application increased significantly during the pandemic [16, 17]. However, some authors argued that there was no significant change in this regard. In our study, we found that the rate of ostomy application increased significantly during the pandemic, especially compared to the pre-pandemic period [18]. This proportional difference in the number of ostomies may be attributed to the preference for ostomy over anastomosis in emergency and infectious conditions during the pandemic period.
Conclusion
The findings of this study reveal the impact of the COVID-19 pandemic on colorectal cancer. The disruption of national cancer screening programs and the postponement of elective surgeries during the pandemic may have led to the emergence of more advanced cancer cases. Specifically, the increase in cases requiring emergency surgery and the rise in ostomy rates during the pandemic highlights the negative effects of this situation on surgical treatments. However, although no significant statistical difference was observed when comparing tumor stages, it is believed that significant results may emerge from larger groups. In conclusion, the COVID-19 pandemic disrupted diagnostic and therapeutic processes in colorectal cancer treatment, negatively affecting surgical outcomes. These findings may significantly contribute to the development of strategies for similar global health crises in the future.
Limitation
The most important limitations of the study are its retrospective nature and the small number of cases.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and Human Rights Statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or compareable ethical standards.
Funding: None
Conflict of Interest
The authors declare that there is no conflict of interest.
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Download attachments: 10.4328.ACAM.22545
Enes Şahin, Haşim Köken, Abdullah Hilmi Yılmaz, Kazım Şahin, Oktay Yirmibeşoğlu, Sertaç Ata Güler, Turgay Şimşek, Nihat Zafer Utkan, Nuh Zafer Cantürk. The effect of COVID-19 pandemic period on the treatment process of colorectal cancer patients. Ann Clin Anal Med 2025;16(3):182-186
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Histopathological examination of a1 pulley tissue resected in trigger finger surgery and correlation with clinical results
Berna Eriten 1, Serdar Menekşe 2
1 Department of Medical Pathology, Martyr Prof. Dr. ilhan Varank Training and Research Hospital, İstanbul, 2 Department of Orthopedics and Traumatology, Adana Seyhan State Hospital, Adana, Turkiye
DOI: 10.4328/ACAM.22547 Received: 2025-01-05 Accepted: 2025-02-11 Published Online: 2025-02-21 Printed: 2025-03-01 Ann Clin Anal Med 2025;16(3):187-192
Corresponding Author: Berna Eriten, Department of Medical Pathology, Martyr Prof. Dr. ilhan Varank Training and Research Hospital, İstanbul, Turkiye. E-mail: bernaeriten@gmail.com P: +90 530 552 84 23 Corresponding Author ORCID ID: https://orcid.org/0000-0003-3710-1502
Other Authors ORCID ID: Serdar Menekşe, https://orcid.org/0000-0002-4121-8917
This study was approved by the Ethics Committee of Adana City Hospital (Date: 2025-01-02, No: 314)
Aim: The aim was to analyze the histopathological features of the A1 pulley tenosynovial tissue surgically removed with the diagnosis of the trigger finger and to reveal its correlation with the clinic.
Material and Methods: Pathological tissue samples of 120 patients who underwent A1 pulley surgical resection with the diagnosis of trigger finger between January 2020 and December 2023 were retrospectively examined. The samples were evaluated with H&E, Alcian blue staining, and CD44 immunohistochemistry. The detected inflammation level, increased vascularization, degree of fibrosis, collagen structure, tenocyte proliferation, and hyalinization were scored semi-quantitatively. The relationship between histopathological findings and the clinic was evaluated statistically.
Results: In 81.7% of the examined cases, inflammation at different levels (mild 37.5%, moderate 30.0%, severe 14.2%) and increased vascularization were detected in 68.3%. In terms of fibrosis, varying degrees of involvement (mild 31.7%, moderate 40.0%, severe 18.3%) were observed in 90% of the cases. Collagen alignment was found to be disrupted in 71.7% of the cases. Tenocyte proliferation was positive in 76.7% and hyalinization was positive in 63.3%. A significant positive correlation was found between the degree of inflammation and VAS score (r = 0.684, p < 0.001) and between the degree of fibrosis and symptom duration (r = 0.712, p < 0.001).
Discussion: In the pathogenesis of the trigger finger, the presence of chondrocyte-like cells in the tenosynovial tissue, hypocellular collagen matrix containing hyaluronic acid, and inflammatory changes stand out as characteristic findings. A significant correlation was determined between the severity of these histopathological changes and clinical findings.
Keywords: Trigger Finger, A1 Pulley, Tenosynovitis, Histopathology, Cd44, Hyaluronic Acid
Introduction
Trigger finger (stenosing tenosynovitis) is a pathology that occurs with thickening and histomorphological changes in the fibrous structure of the flexor tendon sheath and A1 pulley. Accordingly, the movement functions of the flexor tendons are impaired, and clinical symptoms develop [1]. Histopathological studies have revealed complex tissue changes such as inflammatory changes, increased vascularization, and fibrosis in the A1 pulley tissue [2, 3].
When the A1 pulley is examined microscopically, its natural structure consists of regular collagen fibrils, minimal vascularity, and sparse fibroblasts. However, in the case of the trigger finger, disruption in the arrangement of collagen fibers, an increase in type III collagen, and significant proliferation in vascular structures are observed [4, 5]. Immunohistochemical studies have revealed infiltration of macrophages and increased expression of transforming growth factor-β (TGF-β) [6, 7].
In histopathological evaluations, acute inflammatory cell infiltration and vascular proliferation are evident in the early phase of the disease, while fibrosis and hyalinization are more prominent in the chronic phase. In particular, increased tenocytes and extracellular matrix changes play a key role in the worsening of the disease [8, 9, 10]. In analyses performed with semi-quantitative histopathological scoring systems, it was observed that these changes correlated with the clinical severity of the disease [11, 12].
Material and Methods
Patient Selection and Clinical Evaluation
In our study, 120 patients who underwent A1 pulley surgery due to a trigger finger in our clinic between January 2020 and December 2023 were retrospectively examined. Patients were staged preoperatively using Green’s classification [11]. Patients who had previously received corticosteroid injections due to trigger finger had inflammatory rheumatic diseases, and had undergone revision surgery on the same finger were excluded from our study [13].
Surgical Sample Collection and Tissue Follow-up
A1 pulley tissue samples we obtained through the surgical procedure were placed in 10% buffered formalin for pathological analysis. They were fixed for 24 hours. We performed tissue tracking as follows [8, 14]:
•Dehydration with alcohol series
•Clearing with xylol
•Paraffin application and blocking
•Taking 4 μm thick sections with a microtome
•H&E staining and Masson trichrome staining in selected preparations
Histopathological Examination
We evaluated the prepared sections according to the following criteria based on the clinical information of the patients [15, 16]:
•Inflammation Assessment:
oNone: Inflammatory cell infiltration
oMild: Focal minimal infiltration
oModerate: Widespread moderate infiltration
oSevere: Dense diffuse infiltration
•Other Parameters:
oAssessment of increase in vascular structures
oFibrosis degree (absent/mild/moderate/severe)
oCollagen fiber pattern analysis
oTenocyte proliferation
oPresence of hyaline changes
In case of discrepancy, we made a mutual decision by evaluating with kappa analysis together with another pathologist at the microscope [17].
Statistical Analysis
The data obtained in this study were analyzed using SPSS Statistics 25.0 software. Descriptive statistics for continuous variables are presented as mean ± standard deviation, and for categorical variables as percentage (%).
To analyze the relationship between histopathological findings and clinical data:
•Spearman Correlation Analysis: To evaluate the nonlinear relationship between continuous variables (e.g., the relationship between the degree of inflammation and VAS score).
•Chi-Square Test: To analyze the relationship between categorical variables (e.g., the relationship between increased vascularization and the development of complications).
•Independent Sample T-Test: To compare the means of continuous variables between two groups (e.g., QuickDASH scores for groups with and without increased vascularization).
•Mann-Whitney U Test: To compare continuous variables that do not show normal distribution (e.g., the relationship between the degree of fibrosis and the duration of symptoms).
•Kappa Analysis: Used to measure the agreement between the evaluations between two pathologists.
The Kolmogorov-Smirnov Test was used to test normality distribution. Nonparametric tests were preferred for data that did not show normal distribution. The significance level in the analyses was accepted as p < 0.05.
Patient Selection
Our study was conducted retrospectively and 120 patients who underwent A1 pulley surgery due to trigger finger in our clinic between January 2020 and December 2023 were included in the study [11].
Inclusion Criteria:
•Being over 18 years of age
•Being diagnosed with trigger finger
•Accepting surgical treatment
•Committing to regular postoperative follow-ups
Exclusion Criteria:
•Having previously undergone trigger finger surgery on the same finger
•Having received local corticosteroid injection within the last 6 months
•Presence of rheumatoid arthritis or other inflammatory rheumatic diseases
•History of trauma/surgery on the wrist or finger
•Presence of carpal tunnel syndrome
•Presence of Dupuytren’s contracture
•Pregnancy
•Insufficient tissue sample for pathological examination [14, 15].
Ethical Approval
This study was approved by the Ethics Committee of Adana City Hospital (Date: 2025-01-02, No: 314).
Results
Demographic and Clinical Features
When the demographic data of 120 patients included in this study were examined, the mean age was found to be 54.3 ± 11.2 years. More than two-thirds of the patients were women (68.3%, n = 82), while the proportion of men was 31.7% (n = 38).
The mean time from the onset of symptoms to surgical intervention was calculated as 8.4 ± 4.2 months, indicating a significant delay in surgical intervention. Dominant hand involvement was observed in 65% of the patients (n = 78), while non-dominant hand involvement was detected in 35% (n = 42).
The mean body mass index (BMI) of the patients was 27.8 ± 4.6 kg/m², indicating that the patients were in the slightly obese class. The most common comorbid disease was Diabetes Mellitus, which was detected in 26.7% (n = 32) of the patients. This was followed by Hypertension (23.3%, n = 28) and Hypothyroidism (12.5%, n = 15). In the evaluation made according to occupational groups, it was determined that the majority of the patients were housewives (37.5%, n = 45), followed by office workers (26.7%, n = 32), workers (20.8%, n = 25) and retirees (15.0%, n = 18) (Table 1).
The most commonly affected finger was the thumb (38.3%, n = 46), followed by the middle finger (26.7%, n = 32), index finger (23.3%, n = 28), ring finger (8.3%, n = 10) and little finger (3.3%, n = 4).
The largest group consisted of Grade III patients (%43.3, n = 52). This was followed by Grade II (%31.7, n = 38), Grade IV (%15.0, n = 18) and Grade I (%10.0, n = 12) patients, respectively. In the preoperative functional evaluation, the mean QuickDASH score indicating the limitation in the patient’s daily living activities was determined as 48.6 ± 12.4. In the pain evaluation, the mean VAS (Visual Analog Scale) score was 7.2 ± 1.8, indicating severe pain level. The mean hand grip strength was calculated as 18.4 ± 6.2 kg and the range of motion of the affected finger was severely limited with an average of 35.2 ± 12.6 degrees.
Histopathological Examination Results
In the microscopic evaluation of the resected A1 pulley tissue; In terms of inflammatory changes, varying degrees of inflammation were seen in the majority of cases (%81.7, n = 98). While the degree of inflammation was distributed as mild (%37.5, n = 45), moderate (%30.0, n = 36) and severe (%14.2, n = 17), inflammation was seen in only 18.3% (n = 22) of the cases. Proliferation in vascular structures was seen as positive in a significant majority of the patients (%68.3, n = 82). When the fibrotic structure was examined, varying degrees of fibrosis were detected in the majority of the cases (%90.0, n = 108). The distribution of fibrosis was as follows: moderate (%40.0, n=48), mild (%31.7, n = 38), and severe (%18.3, n = 22). Normal collagen formation was preserved in only 28.3% (n = 34) of the patients and was markedly irregular in the majority (71.7%, n = 86). Tenocyte proliferation was positive in more than three-quarters of the cases (76.7%, n = 92), and hyaline changes were positive in approximately two-thirds of the cases (63.3%, n = 76) (Figure 1).
In histopathological examination, a single-layer synovial cell layer was observed in the normal A1 pulley tissue (Figure 2A), while in trigger finger cases, significant inflammation and increased vascularization were observed (Figure 2B). Chondrocyte-like cells were also observed under the microscope (Figure 2C). Hyaluronic acid accumulation, which showed positive staining with Alcian blue, was observed around these cells (Figure 2D) and the staining disappeared after hyaluronidase application (Figure 2E). Chondrocyte-like cells showed positive expression with CD44 immunohistochemistry (Figure 2F).
Clinicopathological Correlation Analysis
In our correlation analyses, a strong positive relationship was found between the degree of tissue inflammation and both pain scores (r = 0.684, p < 0.001) and functional disability level (QuickDASH score) (r = 0.625, p < 0.001). Fibrosis level showed a significant positive correlation with symptom duration (r = 0.712, p < 0.001), which revealed that fibrotic changes increased with the prolongation of disease duration. Pain scores were found to be significantly higher in patients with increased vascularization (r = 0.548, p < 0.001) (Figure 3).
Discussion
Histopathological analysis of A1 pulley tenosynovial tissue is critical in understanding the pathogenesis of the trigger finger [1]. The microscopic findings and their clinical implications in our study provide very important data in terms of understanding the basis of the disease [17]. Recent literature studies also highlight the dynamic role of tenosynovial tissue [2].
Immunohistochemical Findings And Cellular Changes
CD44-positive chondrocyte-like cells observed in tenosynovial tissue explain the cellular basis of pathogenesis [16]. S-100 protein negativity and CD44 positivity in these cells support the fibroblastic differentiation hypothesis in the literature [3]. These findings, which are parallel to the cell population defined by Yang et al. [6], exhibit explanatory features for the pathogenetic mechanism when considered together with the matrix organization study by Fritz et al. [7]. The tenosynovial tissue ultrastructure analysis by Ettema et al. [22] provides biomechanical support for this mechanism.
Matrix Changes And Ultrastructural Analysis
The hypocellular collagen matrix and hyaluronic acid accumulation we observed are quite similar to the study of Coronel et al. [10]. The standardized scoring of these changes was based on the criteria of Angrisani et al. [8], and it was found that there was a correlation with the ultrasonographic findings of Bianchi et al. [24].
Inflammatory Process And Vascularization
Inflammatory patterns and vascular proliferation added new parameters to the scoring defined by Muthu et al. [17]. The chronic inflammation findings presented by Johnson et al. [18] are also parallel to the clinical progression analysis of Huang et al. [23]. These findings show significant differences from the normal tenosynovial structure described by Cohen et al. [4]. Our analysis of the relationship between time from symptom onset to surgery (mean 8.4 ± 4.2 months) and inflammatory changes revealed that patients with longer waiting times tended to show more severe inflammatory patterns. Among patients with inflammation (81.7%), we observed a progression from mild (37.5%) to moderate (30.0%) and severe (14.2%) inflammation that corresponded with increasing duration of symptoms. This observation has important clinical implications, suggesting that prolonged waiting time for surgery may contribute to increased inflammatory severity. This finding aligns with Straszewski et al.’s [14] conclusions about the importance of surgical timing in managing inflammatory progression.
Clinical And Radiological Correlations
The prognostic factors specified in the study of Belloti et al. [19] showed a strong correlation with our histopathological analysis results. These correlations confirm the hypotheses put forward in the early studies of Sbernardori et al. [5].
Treatment Implications
The factors affecting treatment success highlighted in the meta-analysis of Lo et al. [20] can be explained by our findings obtained with histopathological analysis. The literature review of Markowitz et al. [21] emphasizes the role of histopathological changes in predicting treatment response. This approach is also in line with the evidence-based treatment recommendations of Amirfeyz et al. [11].
Methodological Approach And Standardization
The standardized methodology we used adds strength to our study [8]. Our approach for analyzing advanced-stage cases aligns with recommended standards [25] and is consistent with the clinical evaluation criteria of Bridges et al. [12].
Future Perspectives
The results obtained in our study support the conclusion that the clinical reflections of histopathological findings are decisive in the treatment of trigger fingers, emphasized in a recent review by Donati et al. [9]. The conservative treatment evaluation of Lunsford et al. [13] and the temporal relationship analysis between corticosteroid injection and surgical outcomes by Straszewski et al. [14] are guiding future research. It seems that the evaluation of postoperative complication rates in diabetic patients by Federer et al. [15] will contribute to the development of objective evaluation criteria. The histopathological patterns defined by Uchihashi et al. [2] may also shed light on new treatment goals.
Limitation
This study has the following limitations:
1.Methodological Limitations:
•Retrospective study design
•A limited number of control tissue samples
•Inability to perform electron microscopic evaluation
•Collection of samples from a single center
2.Technical Limitations:
•Analysis restricted to surgical specimens only
•Inability to study advanced molecular markers
•Limited immunohistochemical panel (only H&E, Alcian blue, and CD44)
•Absence of high-throughput molecular analyses
•Lack of fresh frozen tissue samples for specialized studies
3.Clinical Limitations:
•Inability to evaluate preoperative radiological findings
•Absence of long-term follow-up data
•Unable to assess the effect of treatment response on histopathological changes
•Variation in the time interval between symptom onset and surgery
4.Statistical Limitations:
•Small sample size in subgroup analyses
•Non-homogeneous distribution between diabetic and non-diabetic patient groups
•Limited power for correlation analyses in certain histopathological parameters
These limitations should be considered when interpreting the results, and future studies should address these constraints through more comprehensive and prospective evaluations with larger sample sizes and advanced molecular techniques.
Conclusion
Our study provides important data in terms of a detailed description of histopathological changes in A1 pulley tissue in the pathogenesis of the trigger finger. Histopathological findings such as inflammation, fibrosis, increased vascularization and hyalinization in particular show a significant correlation with clinical symptoms. These results may contribute to the establishment of objective criteria in the staging of trigger finger disease.
In terms of clinical application, the findings obtained in our study can be evaluated as follows:
•The degree of inflammation and fibrosis may be enlightening in predicting the severity of a patient’s clinical symptoms and their potential for recovery after surgery.
•Chondrocyte-like cells, especially detected by CD44 immunohistochemical staining, may provide opportunities for new treatment strategies targeting cellular targets.
•The effect of vascular proliferation on treatment results may suggest the need for revision of surgical techniques or additional complementary treatments.
Our recommendations for future research are as follows:
1.Investigation of Molecular Mechanisms: Studies investigating the genetic and biochemical basis of CD44-positive cells and extracellular matrix changes in understanding the pathogenesis of trigger finger disease may yield very good results.
2.Development of Treatment Approaches: The effect of these histopathological findings on the response to treatment can be analyzed and patient-specific treatment approaches can be investigated.
3.Early Diagnostic Criteria: There is a strong relationship between clinical symptoms and histopathological findings. Early diagnostic criteria can be developed with advanced imaging and
biomarker analyses.
In conclusion; this study draws attention to the importance of histopathological changes in trigger finger pathogenesis and makes valuable contributions to the clinical management process. New treatment strategies to be developed based on these findings in the future may improve the quality of life of patients and stop the progression of the disease.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and Human Rights Statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or compareable ethical standards.
Funding: None
Conflict of Interest
The authors declare that there is no conflict of interest.
References
1. Shohda E, Sheta RA. Misconceptions about trigger finger: A scoping review. Adv Rheumatol. 2024;64(1):53-8.
2. Uchihashi K, Tsuruta T, Mine H, Aoki S, Nishijima-Matsunobu A, Yamamoto M, et al. Histopathology of tenosynovium in trigger fingers. Pathol Int. 2014;64(6):276-82.
3. Stirling PHC, Jenkins PJ, Duckworth AD, Clement ND, McEachan JE. Functional outcomes of trigger finger release in non-diabetic and diabetic patients. J Hand Surg Eur Vol. 2020;45(10):1078-82.
4. Ng WKY, Olmscheid N, Worhacz K, Sietsema D, Edwards S. Steroid injection and open trigger finger release outcomes: A retrospective review of 999 digits. Hand (N Y). 2020;15(3):399-406.
5. Matzon JL, Lebowitz C, Graham JG, Lutsky KF, Beredjiklian PK. Risk of infection in trigger finger release surgery following corticosteroid injection. J Hand Surg Am. 2020;45(4):310-6.
6. Yang TH, Chen HC, Liu YC, Shih HH, Kuo LC, Cha S, et al. Clinical and pathological correlates of severity classifications in trigger fingers based on computer-aided image analysis. Biomed Eng Online. 2014;13(100):1-11.
7. Fritz T, Ducommun P, Pohlemann T, Calcagni M, Tschernig T, Menger MD, et al. Flexor tendon grafts for pulley reconstruction – morphological aspects. Ann Anat. 2020;231(1):1-7.
8. Angrisani N, Willbold E, Kampmann A, Derksen A, Reifenrath J. Histology of tendon and enthesis. Eur Cell Mater. 2022;43(1):228-51.
9. Donati D, Ricci V, Boccolari P, Origlio F, Vita F, Naňka O, et al. From diagnosis to rehabilitation of trigger finger. BMC Musculoskelet Disord. 2024;25(1):1-14.
10. Coronel L, Mandl P, Miguel-Pérez M, Blasi J, D’Agostino MA, Martinoli C, et al. Characterization of digital annular pulleys and their entheses: an ultrasonographic study with anatomical and histological correlations. Rheumatology (Oxford). 2024;63(11):3050-5.
11. Amirfeyz R, Clark D, Jones J, Singh R, Watkins T. Evidence-based management of adult trigger digits. J Hand Surg Eur Vol. 2017;42(5):473-80.
12. Bridges TN, Ohliger E, Kistler JM. Trigger finger: Evaluation, management. SurgiColl. 2023;1(1):1-6.
13. TLunsford D, Peterson L, Roy S, Chambers M, Blake F. Conservative management of trigger finger. J Hand Ther. 2019;32(4):417-29.
14. Straszewski AJ, Lee CS, Dickherber JL, Wolf JM. Temporal relationship of corticosteroid injection and open release for trigger finger and correlation with postoperative deep infections. J Hand Surg Am. 2022;47(11):1116-26.
15. Federer AE, Baumgartner RE, Cunningham DJ, Mithani SK. Increased rate of complications following trigger finger release in diabetic patients. Plast Reconstr Surg. 2020;146(4):420-7.
16. Lundin AC, Bergstrom J, Olsson H, Andersson P. Trigger finger and tendinosis. Scand J Med Sci Sports. 2014;24(2):363-8.
17. Muthu S, Patel R, Shah R, Kumar V, Gupta K. Tenosynovitis of hand: Causes and complications. World J Clin Cases. 2024;12(4):671-6.
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21. Markowitz MI, Lewis S, Green R, Singh A, Patel M. Most cited publications. J Hand Surg. 2023;48(2):188-95.
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23. Huang HK, Chen YC, Wu PH, Tsai CH. Outcomes and complications after percutaneous release for trigger digits. J Hand Surg Eur Vol. 2015;40(7):735-59.
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25. Dardas AZ, Vandenberg J, Olson J, Gelberman RH, Calfee RP. Long-term effectiveness of repeat corticosteroid injections for trigger finger. J Hand Surg Am. 2017;42(4):227-35.
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Berna Eriten, Serdar Menekşe. Histopathological examination of a1 pulley tissue resected in trigger finger surgery and correlation with clinical results. Ann Clin Anal Med 2025;16(3):187-192
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A retrospective evaluation of patients visiting a family medicine center
Hayriye Şentürk 1, Hümeyra Yaka 2
1 Department of Family Medicine, Family Health Center 47, 2 Department of Family Medicine, Family Health Center Number 48, Konya, Turkey
DOI: 10.4328/ACAM.22559 Received: 2025-01-13 Accepted: 2025-02-10 Published Online: 2025-02-10 Printed: 2025-03-01 Ann Clin Anal Med 2025;16(3):193-196
Corresponding Author: Hayriye Şentürk, Department of Family Medicine, Family Health Center 47, Konya, Turkey. E-mail: hyrybulbul@hotmail.com P: +90 554 632 61 44 Corresponding Author ORCID ID: https://orcid.org/0000-0002-5612-9300
Other Authors ORCID ID: Hümeyra Yaka, https://orcid.org/0000-0002-4973-1774
This study was approved by the Ethics Committee of KTO-Karatay University (Date: 2024-12-30, No: 100449)
Aim: Primary healthcare services form the foundation of health systems due to their potential to address most individuals’ health issues. This study evaluates the demographic characteristics, reasons for admission, and diagnoses of patients visiting a family medicine center.
Material and Methods: This study has a retrospective and descriptive design. The medical records of 1012 patients who visited a family medicine center between December 1, 2024, and December 31, 2024, were reviewed. Data were analyzed using the SPSS 25.0 program.
Results: Among the patients, 59% were female, and 41% were male, with a mean age of 49.7 ± 24.1 years. The most common reasons for admission were prescription refills (58.2%), respiratory tract infections (12.7%), and chronic disease follow-ups (7.8%). The most frequent diagnoses were acute nasopharyngitis (24.3%), essential hypertension (15.8%), and diabetes mellitus (5.1%).
Discussion: This study provides valuable insights into understanding patient profiles in primary healthcare and contributes to family medicine specialty training.
Keywords: Primary Care, Symptoms, Diagnoses
Introduction
Primary healthcare services are the cornerstone of healthcare systems as they serve as individuals’ first point of contact. These services encompass preventive, therapeutic, and rehabilitative practices. According to the World Organization of Family Doctors (WONCA), family medicine is a primary healthcare discipline that serves as the initial medical contact point within the healthcare system. It provides personal and continuous healthcare to individuals, families, and a registered population, regardless of age, gender, or disease [1]. Family physicians deliver holistic, comprehensive, and coordinated care, employing unique consultation processes and problem-solving skills to address the needs of individuals, families, and communities.
Effective primary healthcare operations in modern health systems contribute to sustainability by reducing the burden on advanced healthcare services [2]. The World Health Organization (WHO) identifies primary healthcare as the most effective way to meet a community’s health needs. The 1978 Alma Ata Conference emphasized the importance of primary healthcare, promoting the goal of “Health for All” [3].
In Turkey, the family medicine system implemented since 2005 reflects this approach and aims to enhance accessibility and improve individual and community health. As the initial level of healthcare delivery, family medicine centers can address most health issues. Studies indicate that approximately 80% of health problems can be resolved at the primary care level when effectively implemented [4].
Analyzing the demographic characteristics, reasons for admission, and diagnoses of patients visiting family medicine centers is crucial to improving healthcare quality and developing educational programs. Identifying patient profiles in family medicine centers can also guide health policy development and healthcare worker training. This study aims to reveal patient profiles in primary healthcare to address deficiencies in the field and improve healthcare standards.
Material and Methods
This study has a retrospective and descriptive design. The medical records of 1062 patients who visited a family medicine center between December 1, 2024, and December 31, 2024, were reviewed using the family medicine information management system. Fifty patients with incomplete records were excluded, and the study was completed with 1012 participants.
Data on participants’ age, gender, chronic disease diagnoses, reasons for admission, complaints, symptoms, and prescription statuses were evaluated. Diagnoses were coded using the International Classification of Diseases, 10th Revision, Clinical Modification (ICD-10-CM).
Statistical analyses were conducted using the SPSS 25.0 program. Descriptive statistics (mean, standard deviation, percentage distributions) were calculated, and the Chi-square test was applied for categorical variables. A p-value of <0.05 was considered statistically significant.
Ethical Approval
This study was approved by the Ethics Committee of KTO-Karatay University (Date: 2024-12-30, No: 100449).
Results
The age, gender distribution, and chronic disease diagnoses of the patients are presented in Table 1. Among the 1012 patients in the study, 59% were female and 41% were male, with a mean age of 49.7 ± 24.1 years (Table 1). The youngest patient was 4 months old, while the oldest was 96. Among chronic disease diagnoses, 13.1% of patients were diagnosed with hypertension, 5.1% with diabetes mellitus, 2.2% with coronary artery disease, and 5% with dyslipidemia. When the reasons for admission were analyzed, 58.2% of patients visited for prescription refills, 12.7% for respiratory complaints, 7.8% for chronic disease follow-ups, and 5.7% for blood tests. Other reasons included 4% for reports (e.g., driver’s licenses, mental competence, hunting firearm permits, workplace applications, medication reports, military fitness reports, etc.), 0.2% for trauma, 1.3% for consultation, 0.8% for dermatological issues, 1% for joint and muscle pain, 1.4% for routine child health check-ups, 1.7% for urinary system complaints, 0.9% for pregnancy follow-ups, 0.8% for gastrointestinal system complaints, 0.4% for dental and gum issues, and 3.2% for other complaints (Table 2).
Discussion
This study observed that the admission rate of female patients (59%) was higher than that of male patients. This finding is supported by numerous studies in the literature, which indicate that women have higher access rates to healthcare services. Similar findings have been reported in studies on primary healthcare services, highlighting that women are more likely to monitor their health closely and seek medical care more frequently [2, 5, 6-8]. This can be associated with societal roles that lead women to adopt a more active attitude toward health-related matters [9]. This suggests that collaborating more with women could be beneficial when designing projects to improve health literacy and raise awareness about health issues in the community.
The fact that 58.2% of patients visited for prescription refills emphasizes the importance of regular monitoring and treatment of chronic diseases in primary healthcare [10]. Every patient visiting for a prescription refill also undergoes a general health evaluation, addressing topics such as proper and consistent medication use, side effects, allergies, or difficulties in medication management. In the study by Kara et al., the rate of prescriptions was 47%, while in the study by Aboulghate et al., it was 97.1%, making up the majority of visits [6, 9]. This variation may be influenced by the high prevalence of chronic diseases among participants or the timing of the study during seasons with a higher incidence of illnesses, such as winter. Although this study included December clinic visits, the rate of prescriptions was lower compared to similar studies. This difference could be due to the recently implemented chronic disease screening and follow-up platform in primary healthcare in Turkey. This system requires family physicians to conduct periodic screenings and follow-ups for patients registered in their units and maintain records.
Respiratory complaints ranked second (12.7%) and can be explained by these infections’ prevalence and frequent occurrence in primary healthcare. Similar studies also report respiratory tract infections as one of the most common complaints, ranking first or second [9, 11, 12]. In this study, chronic disease follow-ups ranked third among reasons for admission (7.8%), underscoring the importance of long-term care services provided in primary healthcare [13]. With recent healthcare reforms in Turkey, many chronic disease screenings and follow-ups are now conducted in primary care.
Acute upper respiratory tract infections (19.7%) were the most frequently recorded when the diagnoses were examined. Upper respiratory tract infections such as acute nasopharyngitis are among the most common diseases encountered in primary healthcare. They are globally recognized as some of the most frequent diagnoses in primary care [14]. Among chronic disease diagnoses, diabetes and hypertension ranked first and second, respectively, as seen in similar studies [5]. In this study, essential hypertension ranked second (15.8%), and diabetes ranked third (5.1%), highlighting the significant burden of chronic diseases in the community and their importance in primary healthcare [9]. Similar studies have also reported hypertension as one of the top two diagnoses [9, 11, 12]. Hypertension is a priority among chronic diseases because it is preventable and manageable [15].
Conclusion
In this study, the age, gender distribution, reasons for admission, and diagnoses of patients visiting a family medicine center were analyzed. Including patients and disease groups ranging from 0 to 96 years old within the scope of family medicine demonstrates that it provides comprehensive and inclusive healthcare services for public health. The fact that the most frequent diagnoses recorded were respiratory infections, hypertension, and diabetes indicates the critical role of family medicine in managing infections and chronic diseases. Strengthening primary healthcare services further will benefit public health.
Limitation
The limitations of the study include its short duration of only one month, the variation in disease profiles according to summer and winter seasons, and the fact that it was conducted within the population of a single-family medicine unit.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and Human Rights Statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or compareable ethical standards.
Funding: None
Conflict of Interest
The authors declare that there is no conflict of interest.
References
1. Altuntaş M. The Role of Patient Education Level and Family Medicine Practice in the Diagnosis of Arterial Hypertension. Selcuk Med J. 2019;35(1):31-6.
2. Xavier PB, Silva ÍDS, Dantas THDM, Lopes RH, de Araújo AJ, Figueirêdo RC, et al. Patient satisfaction and digital health in primary health care: A scoping review protocol. Front Public Health. 2024;12:1357688.
3.Yılmaz M, Mayda AS, Yüksel C, Bolu F, Seval O, Bayındır K, et al. Bir Aile Hekimliği Merkezi’ne Başvuran Hastalara Konulan Tanılar [Diagnoses of Patients Referred to a Family Medicine Centre]. J DU Health Sci Inst. 2012;2(3):7-13.
4. Levine DM, Syrowatka A, Salmasian H, Shahian DM, Lipsitz S, Zebrowski JP, et al. The safety of outpatient health care: review of electronic health records. Ann Intern Med. 2024;177:738-48.
5. Parkerson Jr GR, Harrell Jr FE, Hammond WE, Wang XQ. Characteristics of adult primary care patients as predictors of future health services charges. Med Care. 2001;39(11):1170-81.
6. Aboulghate A, Abel G, Lyratzopoulos G, Abdelmohsen A, Hamed AR, Roland M. Patterns of disease presentation and management in Egyptian primary care: findings from a survey of 2458 primary care patient consultation. BMC Fam Pract. 2013;14:1-9.
7. Prazeres F, Santiago L. Prevalence of multimorbidity in the adult population attending primary care in Portugal: A cross-sectional study. BMJ Open. 2015;5(9):e009287.
8. Toçi E, Burazen G, Kamberi H, Jerliu N, Sorensen K, Brand H. Socio-economic correlates of functional health literacy among patients of primary health care in Kosovo. Public Health. 2014;128(9):842-8.
9. Kara İH, Türker Y, Hakan L, Baltacı D. Investigation of demographic features and symptoms at admission of patients who apply to a family health center in city center of Düzce: preliminary study. Duzce Med J. 2015;17(3):115-9.
10. Beasley JW, Hankey TH, Erickson R, Stange KC, Mundt M, Elliott M. How many problems do family physicians manage at each encounter? Ann Fam Med. 2004;2(5):405-10.
11. Şensoy N, Başak O, Gemalmaz A. Family medicine practice and patient profile at Umurlu Family Medicine Center: To what extent does it meet the needs of family medicine field training? Kocatepe Med J. 2009;10:49-56.
12. Ünalan PC, Uzuner A, Çifçili S, Akman M, Apaydın ÇK. Families receiving healthcare services from Marmara University Faculty of Medicine Family Medicine Clinic. MMJ. 2009;22(2):90‐6.
13. Starfield B, Shi L, Macinko J. Contribution of primary care to health systems and health. Milbank Q. 2005;83(3):457-502.
14. Bodenheimer T, Pham HH. Primary care: Current problems and proposed solutions. Health Aff (Millwood). 2010;29(5):799-805.
15. Yeksan M, Ecirli Ş, Telli HH, Çiftçi D, Cirit M, Türk S, et al. Investigation of hypertension prevalence in Konya and its surrounding region. Selcuk Med J. 2001;7(2):177-82.
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Hayriye Şentürk, Hümeyra Yaka. A retrospective evaluation of patients visiting a family medicine center. Ann Clin Anal Med 2025;16(3):193-196
Citations in Google Scholar: Google Scholar
Effect of tube voltage and tube current in abdominal ct scans with principal components analysis and cluster analysis: Phantom study
Güneş Açıkgöz
Department of Medical Services and Techniques, Vocational School of Health Services, Hatay Mustafa Kemal University, Hatay, Turkiye
DOI: 10.4328/ACAM.22560 Received: 2025-01-14 Accepted: 2025-02-17 Published Online: 2025-02-26 Printed: 2025-03-01 Ann Clin Anal Med 2025;16(3):197-202
Corresponding Author: Güneş Açıkgöz, Department of Medical Services and Techniques, Vocational School of Health Services, Hatay Mustafa Kemal University, Hatay, Turkiye. E-mail: gunesboraacikgoz@gmail.com P: +90 546 844 35 75 Corresponding Author ORCID ID: https://orcid.org/0000-0001-9118-3153
Aim: The aim of the study was to investigate the effects of tube current and tube voltage selection on patient dose in adult and pediatric abdominal CT protocols by analyzing them both statistically and with PCA and cluster methods.
Material and Methods: A total of 24 CT phantom scans (12 pediatric and 12 adult) were performed and CTDIvol and DLP values in the dose sheet were recorded. In the scans, 50 mAs, 60 mAs, 80 mAs, and 100 mAs tube currents were used, respectively. For each mAs value, tube voltages of 80 kVp, 110 kVp, and 130 kVp were selected.
Results: The loading plot obtained the relationships between the variables in the Principal Component 1 (PC1) and Principal Component 2 (PC2) space. PC1 was obtained as 84.67% and PC2 as 14.64%, and the sum of both PCs was observed to constitute 99.31% of the total variance. It was observed that the values obtained with 100 mAs and 130 kVp in CT scans had the highest heavy loadings for PC1. In cluster analysis, it was observed that all the data obtained from CT scans performed with 80 kVp at different mAs values with both adult and pediatric abdomen phantoms were in the same Group.
Discussion: PCA and cluster analysis are advantageous in terms of ease of use and qualitative assessment. PCA method can be used to evaluate the compliance of radiation with standards in scans performed with different CT devices used and to examine multiple parameters simultaneously.
Keywords: Computed Tomography, Volume Ct Dose Index (Ctdivol), Dose Length Product (Dlp), Radiation
Introduction
Computed Tomography (CT) is a modern device used in diagnostic radiology for diagnostic/therapeutic purposes in different age groups. X-ray or ionizing radiation is used in CT scans. Ionizing radiation has the energy to change the structure of cells and molecules in the human body [1].
Based on epidemiological studies, it is known that radiation can cause cancer. Therefore, the increasing use of CT has become an important issue as it will cause harmful effects such as hereditary and genetic diseases [2]. In CT scans, patient exposure to radiation varies depending on the scanning protocols of different institutions [3]. Differences in the make and model of CT scanners, differences in patients (e.g., clinical indication for scanning, patient size, gender, and age), protocol selection of the healthcare personnel obtaining the imaging, and the relevant CT scan parameters cause changes in radiation dose [3]. Performing CT scans by reducing radiation dose while preserving the quality of diagnostic images protects patients from overexposure. Unnecessary radiation exposure is a bigger problem, especially in pediatric patients. The reason is that children’s tissues are more radiosensitive than adults and have a longer lifespan for radiation-induced damage to occur [4]. Therefore, adjusting the scanning parameters according to the body structure of children is an important factor in terms of their exposure to less radiation [5].
Diagnostic reference levels (DRLs) are used in diagnostic radiology to avoid unnecessary radiation [6]. The use of DRLs has reduced dose variation among imaging centers and hospitals to some extent [7]. In addition to DRL, methods such as automatic tube current modulation (ATCM) and iterative reconstruction (IR) are also recommended to reduce patient exposure [8]. However, when it is desired to reduce the radiation dose, image quality should also be taken into consideration. For this purpose, measurements are made using phantoms and the volume CT dose index (CTDIvol) or dose length product (DLP) obtained on the dose page is used as patient exposure indicators [6]. CTDI is the basic dose descriptor in CT and is recorded for a single rotation of the X-ray source. The unit of CTDI is milligray (mGy) [9]. DLP is a parameter obtained by multiplying CTDIvol by the total length and is used to calculate the radiation dose received by the patient. Its unit is expressed as mGy*cm. In order to make generalizations in the evaluation of dose optimization in CT, a lot of data need to be evaluated.
Therefore, machine learning techniques are used to detect outliers from a large data set [10].
Principal Component Analysis (PCA), one of the unsupervised Machine Learning techniques, is a statistical method used to analyze similarities and differences in data qualitatively and quantitatively. It is widely used in different disciplines to reduce the size of multidimensional and interrelated data [11]. Therefore, PCA is a widely adaptable method for analyzing different data sets obtained in different disciplines [12]. In the PCA method, the importance of the data to be analyzed, their weighted averages, and their effects on the outputs can be examined [13].
The aim of the study was to investigate the effects of tube current and tube voltage selection on patient dose in adult and pediatric abdominal CT protocols by analyzing them both statistically and with PCA and cluster methods.
Material and Methods
CT machine and imaging protocol (CT scanning and phantom)
In the study, CT scans were performed using the Somatom Go. Up 16 Slice (Siemens AG, Forchheim, Germany) and abdomen phantom were used (Wire in Air Phantom, Siemens Healthineers, Germany) for CT (Figure 1).
A total of 24 CT phantom scans (12 pediatric and 12 adult) were performed. In the scans, 50 mAs, 60 mAs, 80 mAs, and 100 mAs tube currents were used, respectively. For each mAs value, tube voltages of 80 kVp, 110 kVp, and 130 kVp were selected separately. CTDIvol and DLP values on the dose page were recorded in different abdomen phantom CT scans. Tube voltage selection greater than 130 kVp could not be made in the CT device used in the study.
Statistical Analysis
Descriptive statistics for the features emphasized were expressed as Mean and Standard Deviation (SD). The Kruskal-Wallis test was used to compare the groups in terms of these features. The Spearman Correlation Coefficient was calculated to determine the relationship between the variables. SPSS (IBM SPSS Statistics 24) statistical package program was used for calculations and the statistical significance level was taken as 5%.
Principal Component Analysis and Cluster Analysis
In PCA and cluster analysis, only kVp values were written in parentheses for both adult and pediatric patients to make the data understandable. Patients indicated with 1, 2, 3, and 4 expressed 50, 60, 80, and 100 mAs values, respectively.
In the study, OriginPro 2022 (OriginLab Corporation, Northampton, MA) was used for PCA, cluster analysis, and all data processing.
Ethical Approval
No animal or human studies were carried out by the author for this article. For this reason, the measurements were made with permission from the Private Başarı Hospital without the need for ethics committee approval.
Results
In the study, CT scans were performed at different mAs and kVp values using an abdomen phantom in pediatric and adult patient protocols, and CTDIvol and DLP values were measured on the dose page. While the CTDIvol values obtained at 50 mAs in the pediatric and adult protocols changed, it was detected that these values were the same at 60, 80, and 100 mAs. It was observed that the DLP values changed with the increase of both kVp and mAs values. It was determined that the CTDIvol and DLP values measured in the pediatric patients were higher at the same kVp values.
Statistical analysis
In the study, firstly, Mean±SD was calculated for the features focused on. Kruskal-Wallis test was used to compare the groups in terms of these features and the results obtained are shown in Table 1. A comparison of CTDIvol and DLP values was made according to both mAs values (50 mAs, 60 mAs, 80 mAs, and 100 mAs) and patient type (Adult, Pediatric) (Table 1).
According to mAs values and patients, the Total Mean±SD value for CTDIvol was 4.3658±3.22172 and the Total Mean±SD value for DLP was 175.421±127.5346. The averages of CTDIvol and DLP values measured at different mAs values were found to be statistically significant (p<0.05). In the analysis performed according to patient groups, p=0.936 for CTDIvol value and p=0.769 for DLP value were found.
A comparison of CTDIvol and DLP values obtained at different mAs values (groups) in Adult and Pediatric phantom CT examinations is shown in Table 2. In the comparison of CTDIvol and DLP values detected at different mAs values in pediatric phantom CT examinations, p values were found to be 0.190 and 0.151, respectively. In the comparison of CTDIvol and DLP values found at different mAs values in adult phantom CT examinations, p values were found to be 0.148 and 0.243, respectively (Table 2).
PCA and Cluster analysis
In the study, a total of 24 (12 adult, 12 pediatric) examinations were performed in the CT device at different kVp and mAs values, and the determined CTDIvol and DLP values were shown qualitatively by the PCA method and cluster analysis (Figure 2). The relationships between variables in the Principal Component 1 (PC1) and Principal Component 2 (PC2) space were reached with the loading plot. PC1 was obtained as 84.67%, PC2 as 14.64%, and the sum of both PCs was observed to constitute 99.31% of the total variance. In the loading graph, CTDIvol, DLP, and kVp were seen to have similar heavy loadings for PC2. P4 (130 kVp) and A4 (130 kVp) values obtained with 100 mAs and 130 kVp in pediatric and adult phantom CT scans, were observed to have the highest heavy loadings for PC1 (Figure 2).
In the cluster analysis, the distribution of the data uploaded to the system in 2 different groups is shown in Figure 3. As a result of the analysis, the PC1 and PC2 scores detected and the groups in which the patients were included are shown in Table 3. It was observed that all the data obtained from the CT scans performed with 80 kVp at different mAs values with both Adult and Pediatric abdomen phantoms were in Group 1.
Discussion
Tube voltage (kVp) is a scanning parameter that has an exponential relationship with radiation exposure. While kVp is a parameter that determines image quality, lowering kVp increases image noise [14].
Since contrast and image noise parameters are related to tube current and tube voltage, it is necessary to obtain the lowest radiation dose without compromising the accuracy of diagnosis in CT scans. In addition, tube current and tube voltage should be adjusted according to the size of the patient [15].
CTDIvol and DLP values, which can vary depending on the mAs and kVp values used during a CT scan, are used by CT manufacturers as indicators of the radiation produced during the scan. It also provides valuable information when used to the amount of radiation exposure of patients in different age groups [16].
Brenner et al. [17] put forward that the lifetime CT-attributable cancer death risk for children aged 5 years was approximately 2.5 times higher than the risk for adults aged 30 years in their study. They also compared abdomen and head CT scans and showed that the estimated risks were significantly higher for abdominal CT scans than for head scans.
In the study conducted by Masuda et al. [18], they evaluated the radiation dose and image quality in low-tube-voltage pediatric chest computed tomography angiography (CTA) using the standard tube voltage technique. As a result of the study, they found out that the contrast-to-noise ratio (CNR) index was the same in 80 kVp and 120 kVp imaging. Therefore, they concluded that the radiation dose given to infants undergoing chest CT scans could be reduced without deterioration in image quality.
In a study carried out by Khan et al., they concluded that reducing the tube voltage from 120 kVp to 100 kVp can significantly reduce radiation exposure while maintaining good diagnostic imaging quality [14]. Karmazyn et al. [19] obtained CTDIvol values at various tube voltages using cylindrical water phantoms of different sizes. They also evaluated the effect of patient size on dose and image quality. They suggested that the tube voltage should be reduced from 120 to 80 kVp for infants and 100 kVp for older children.
Wilting et al. [20] revealed that radiation dose can be reduced by adjusting the X-ray beam according to patient size. In the study, the higher values obtained from the scans made with 80 mAs-130 kVp (A3, P3) and 100 mAs-130 kVp (A4, P4) are due to the increase in radiation dose by tube current and tube voltage. As seen from PCA and Cluster analysis, it was noted that especially P4 (130 kVp), that is, the CT scan made with 100 mAs-130 kVp, had the highest PC1 loading. It can be concluded that the results obtained from PCA and Cluster analysis have advantages in terms of both qualitative and quantitative presentation and ease of use. Especially in today’s world where machine learning is increasingly gaining attention, it is seen that there are studies conducted with PCA in Radiology as in other fields. Meineke et al. [10] used machine learning techniques in dose optimization for CT quality assurance and suggested that it could be a useful tool to simplify CT quality assurance.
The PCA method was used to distinguish benign and malignant solitary pulmonary nodules [21], to verify the relationships between MRI (Magnetic Resonance Imaging) features and gene expression profiles in retinoblastoma, and thus to evaluate the reproducibility of radiogenomics in retinoblastoma [22], and to analyze the effectiveness of medical treatments and changes in radiological imaging before and after treatment [23]. Rompado et al. [24] applied the cluster analysis technique to information obtained from the CT dose record archive. They detected that cluster analysis can provide a fast and effective overview of the main combinations of exposure parameters and dose indicator distributions, even if the information is not homogeneous.
It has been stated that conversion factors were created to normalize CTDI vol and DLP according to patient size to estimate the actual absorbed doses in CT scans performed with phantoms and that these values are consistent with the 32 cm phantom. Moreover, CTDIvol and DLP should be reported in the studies performed in accordance with the instructions recommended by the manufacturer for the clinical pediatric body protocol. Therefore, using the same phantom provides an advantage in terms of not causing errors when trying to optimize the protocols [25].
Limitation
This study has some limitations. These limitations are that the study was conducted with a single CT device and the same phantom was used in the measurements. Moreover, the data was obtained from the dose report page.
Conclusion
Changing the kVp and mAs values affects CTDIvol and DLP values in both adult and pediatric patients. The fact that there was no significant difference between the results in the statistical comparison led to the thought that more attention should be paid to pediatric patients due to their small body structure. The reason is that it can be said that the amount of radiation they are exposed to is higher. In addition, it was concluded that PCA and cluster analysis are also advantageous in terms of ease of use and qualitative assessment. It can be stated that the PCA method will be advantageous and usable in terms of evaluating the compliance of radiation with the standards in scans made on different CT devices used and examining multiple parameters at the same time.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and Human Rights Statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or compareable ethical standards.
Funding: None
Conflict of Interest
The authors declare that there is no conflict of interest.
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Ai-powered screening for psoriatic arthritis: A comparative study with existing tools
Ozge Sevil Karstarli Bakay 1, Umut Bakay 2, Tugba Izci Duran 2, Zeynep Dundar Ok 2
1 Department of Dermatology, Faculty of Medicine, Pamukkale University, 2 Department of Rheumatology, Denizli State Hospital, Denizli, Turkiye
DOI: 10.4328/ACAM.22563 Received: 2025-01-15 Accepted: 2025-02-23 Published Online: 2025-02-28 Printed: 2025-03-01 Ann Clin Anal Med 2025;16(3):203-208
Corresponding Author: Ozge Sevil Karstarli Bakay, Department of Dermatology, Faculty of Medicine, Pamukkale University, Denizli, Turkiye. E-mail: ozgekarstarli@hotmail.com P: +90 537 675 54 41 Corresponding Author ORCID ID: https://orcid.org/0000-0002-1523-3187
Other Authors ORCID ID: Umut Bakay, https://orcid.org/0000-0002-1798-4072 . Tugba Izci Duran, https://orcid.org/0000-0003-4428-9873 . Zeynep Dundar Ok, https://orcid.org/0000-0003-0925-2098
This study was approved by the Ethics Committee of Pamukkale University (Date: 2024-07-04, No: E.547543)
Aim: Psoriatic arthritis (PsA) is common in psoriasis patients but is sometimes overlooked. Delayed diagnosis of PsA can lead to joint erosion, axial damage, and impaired physical function. Screening tools are essential for early diagnosis and selecting the right patients for rheumatological evaluation. We aimed to develop a practical and comprehensive screening tool using the ChatGPT and compare its performance with that of validated questionnaires.
Material and Methods: A prospective study was conducted on adult psoriasis patients who had musculoskeletal complaints but were not diagnosed with PsA. Artificial intelligence (AI)-powered PsA screening (AIPS) was developed by selecting questions on peripheral arthritis, axial inflammation, and enthesitis from multivariate analyses conducted via Chat GPT 4.0. The Psoriasis Epidemiology Screening Tool (PEST), the Early Arthritis for Psoriatic Patients Questionnaire (EARP), and the AIPS questionnaires were completed concurrently by all psoriasis patients. All patients were evaluated for PSA diagnosis by three rheumatologists who were blinded to the questionnaire responses.
Results: The study included 199 patients, 115 (57.8%) of whom were female. The mean age was 44.4 ± 13.3 years. PSA was detected in 84 psoriasis patients (42.2%). The sensitivity of the EARP questionnaire, 98%, was greater than those of the AIPS and PEST questionnaires, which had 92% and 83% sensitivity values, respectively. However, the AIPS had a higher specificity at 96% than did the PEST and EARP, with specificities of 91% and 80%, respectively.
Discussion: The AIPS questionnaire is an effective tool for screening for PsA, exhibiting high sensitivity and specificity. Artificial intelligence can help screen patients, saving time and money.
Keywords: Artificial Intelligence, Psoriatic Arthritis Screening Tool, Early Arthritis For Psoriatic Patients, Questionnaire, Chatgpt, Pest, Earp
Introduction
Psoriasis is a common chronic inflammatory papulosquamous skin disease with various clinical presentations. Psoriatic arthritis (PsA) has a higher frequency, reaching 30% in psoriasis patients, and causes dysfunction by turning into severe arthritis [1]. It is estimated that approximately 80% of patients with PsA present to dermatology clinics with cutaneous psoriasis up to 10 years before the onset of arthritis [2]. As a result, the patient is more likely to be seen by a dermatologist before a rheumatologist. Furthermore, a dermatologist’s therapy decision for a psoriasis patient is determined by the presence or absence of PsA [3]. A meta-analysis revealed that the prevalence of undiagnosed PsA in psoriasis patients attending dermatology clinics was 17.4% [4]. PsA diagnosis is challenging due to the variability of symptoms and the lack of serum biomarkers. A comprehensive evaluation by a rheumatologist is essential for an accurate diagnosis of PsA to prevent misdiagnosis and avoid unnecessary treatment [5]. It is therefore crucial to identify psoriasis patients with a higher risk of PsA development to stop the progression of PsA. Clinical predictors of PsA include nail, scalp, and genital psoriasis, obesity, arthralgia, history of uveitis, and having a first-degree relative with PsA [6]. However, it is difficult to determine the presence of PsA by evaluating these predictors independently. Sending every psoriasis patient to a rheumatologist may lead to labor, time, and economic losses, therefore dermatologists need to filter patients and refer patients in need to rheumatologists for early diagnosis of PsA. A potential shift in the practice of dermatologists away from the examination of the musculoskeletal system may present challenges in screening for PsA. In this instance, the utilization of screening tools becomes a crucial aspect. Several screening tools were developed that combine clinical predictors and joint complaints to reduce unnecessary patient referrals to rheumatologists [7-10]. Nevertheless, the current screening tools are time-consuming, complex, and have a high false positive rate, which limits their use in dermatological routines [11].
As healthcare systems globally encounter challenges such as increased costs, restricted access, and rising demand for personalized care, there is growing evidence to suggest that using AI can assist in resolving these issues [12]. In numerous medical disciplines, including dermatology and rheumatology, the utilization of AI for the processing of patient data has the potential to facilitate a more personalized approach to healthcare [13]. Furthermore, AI applications have provided regular monitoring and recommendations to patients as medical assistants in chronic diseases such as diabetes, cardiac, and pulmonary diseases [14].
A Generative Pretrained Transformer (GPT) is a game-changing form of AI that can produce text that closely resembles a human. OpenAI has developed this AI language model, which is known as ChatGPT [15]. It has quickly reached a large number of users, surpassed social media platforms, and has become one of the pioneers of AI [16]. This technology has several healthcare applications that improve patient care, research and planning, and treatment options [15, 16].
The objective of this study was to evaluate the performance of the AI-powered PsA Screening (AIPS) tool, developed by ChatGPT, in detecting psoriatic arthritis (PsA) compared to the validated Psoriasis Epidemiology Screening Tool (PEST) and Early ARthritis for Psoriatic patients (EARP) screening questionnaires.
Material and Methods
This prospective study included participants over 18 years old with musculoskeletal complaints but without a diagnosis of PsA.
Patients with a previous diagnosis of PsA or other rheumatological diseases were excluded from the study. The PEST, EARP, and AIPS questionnaires were tested on 199 psoriasis patients. The diagnosis of psoriasis was based on clinical features and histopathological findings reported by a dermatologist (Ozge Sevil Karstarli Bakay).
We asked ChatGPT to create a custom questionnaire designed to screen for PsA effectively, which was specifically tailored for individuals with psoriasis to either self-administer or share with their healthcare providers. The AIPS comprises questions relevant to peripheral arthritis, axial inflammation, and enthesitis. These questions were selected from multivariate analyses conducted via Chat GPT 4.0. Turkish translations of the PEST and EARP questionnaires are available. Patients were then referred to rheumatologists and examined for clinical signs of axial and peripheral arthritis (enthesopathy, axial spondyloarthritis, and swelling of the fingers and toes). All patients were assessed by three rheumatologists (Umut Bakay, Tugba Izci Duran and Zeynep Dundar Ok) who were blinded to the questionnaire responses. After the initial examination, if PsA was suspected, further investigations (sonography, radiography, and MRI) were performed to confirm the diagnosis. PsA was diagnosed according to the CASPAR (Classification criteria for psoriatic Arthritis) criteria [17].
Evaluation of the PEST, EARP, and AIPS questionnaires
PEST
There are five questions: 1. Have you ever had a swollen joint (or joints)? 2. Has a doctor ever told you that you have arthritis? 3. Do your fingernails or toenails have holes or pits? 4. Have you ever had pain in your heel? 5. Have you ever had a finger or toe completely swollen and painful for no apparent reason?
The total PEST score was calculated as the sum of the ‘yes’ answers. Univariate and multivariate analyses have shown an increased incidence of PsA in patients with a PEST score >3 [13].
EARP
It consists of 10 yes/no questions and the cut-off to be considered positive is 3 or higher.
1. Do your joints hurt? 2. Have you taken anti-inflammatory drugs for joint pain more than twice a week in the last 3 months? 3. Do you wake up at night because of back pain? 4. Do you feel stiffness in your hands for more than 30 minutes in the morning? 5. Do your wrists and fingers hurt? 6. Do your wrists and fingers swell up? 7. Has any finger been sore and swollen for more than 3 days? 8. Is your Achilles tendon swelling? 9. Do your feet or ankles hurt? 10. Do your elbows or hips hurt?
AIPS
1. Joint pain: Have you had any joint pain in the last month? 2. Morning stiffness: Do you experience stiffness or restricted movement in your joints in the morning? 3. Swollen joints: Have you had swollen joints in the past? 4. Swollen fingers or feet: Have you had complete swelling (like a sausage) of your fingers or feet? 5. Nail changes: Have you noticed pits, discoloration, or other abnormalities in your nails? 6. Eye problems: Have you had any eye redness, pain, or blurred vision? Pain at night and in the morning: Does your joint pain get worse at night or in the morning? 8. Family history: Do you have a family history of psoriatic arthritis or any other inflammatory joint disease?
Scoring:
3 or more ‘yes’ answers: This indicates that the patient is at high risk of developing psoriatic arthritis and should be referred for rheumatological assessment.
1-2 ‘Yes’ answers: This indicates that the patient is at moderate risk and should be monitored closely. A rheumatological assessment may be considered if necessary.
0 “Yes” answers: This indicates that the patient is at low risk of psoriatic arthritis. However, an assessment should be made in the light of the patient’s clinical symptoms and medical history.
Statistical Analysis
Data are presented as counts and percentages, mean ± standard deviation, or median (min-max). The normality of the distribution of numerical variables was tested with the Shapiro-Wilk test. The independent-samples t-test and the Mann-Whitney U were used for intergroup comparisons of numerical variables. Categorical data were evaluated with the χ2 test and Fisher exact test.
The receiver operating characteristic (ROC) curves were constructed to investigate the diagnostic performance of EARP, PEST, and the newly developed Chat-GPT questionnaire. The area under the curve (AUC) provided a measure of the overall discriminative ability of the prediction rule. The cut-off value was determined with the Youden index (Youden index = sensitivity + specificity – 1) as it is the cut-off value with the highest AUC and aims to maximize the difference between the true positive rate and the false positive rate. The sensitivity and specificity were determined for several cut-off values of the prediction score. A p-value of <0.05 was considered significant. Statistical analysis was performed with SPSS, version 22.0 (IBM Corp., Armonk, NY, USA).
Ethical Approval
The Ethics Committee of Pamukkale University approved this study (Date: 2024-07-04, No: E.547543).
Results
A total of 199 patients (115 [57.8%] female, with a mean age of 44.4 ± 13.3) were enrolled in the study. The prevalence of PsA based on rheumatologist diagnosis was 42.2% (84 patients). The demographic and clinical data of psoriasis patients are shown in Table 1. Out of the patients, 22.6% (n=45) were diagnosed with fibromyalgia, 15.1% (n=30) with osteoarthritis, 11.1% with disc herniation, and 9% with nonspecific musculoskeletal complaints.
The comparison between patients with PsA and those without it, as diagnosed by the rheumatologist, showed no significant differences in terms of age, gender, duration of psoriasis disease, or family history (p>0.05). It was found that 18 patients diagnosed with PsA by AIPS were not considered to have PsA by the rheumatologist. Furthermore, PsA patients had significantly higher AIPS, PEST, and EARP scores (p < 0.001) (Table 2).
The AIPS (AUC 0.982, p<0.05, 95% confidence interval [CI] 0.967-0.997), PEST (AUC 0.949, p<0.05, 95% CI 0.922-0.975), and EARP (AUC 0.960, p<0.005, 95% CI 0.937-0.984) were identified as predictors of diagnosis of PsA (Figure 1). The AIPS questionnaire demonstrated superior efficacy in predicting the diagnosis of PsA. The Youden index was employed to ascertain the optimal cut-off value for the AIPS score, which was determined to be 4. When the cutoff of 3 was selected for EARP and PEST based on the previous studies[7,8] (7, 8), the calculated sensitivity and specificity by the ROC curve are presented in Figure 1. The sensitivity of 98% observed for EARP was superior to that of AIPS and PEST, which exhibited sensitivity values of 92% and 83%, respectively. On the other hand, the specificity of AIPS (96%) was superior to that of PEST and EARP (91% and 80%, respectively).
Discussion
This study demonstrates that the PsA screening tool developed by ChatGPT, which we called AI-powered PsA Screening (AIPS), outperformed the current and validated questionnaires EARP and PEST in predicting PsA. Another important finding of the study is that 42.2% of psoriasis patients with musculoskeletal complaints were diagnosed with PsA.
We asked ChatGPT to create a PsA screening tool to help psoriasis patients and healthcare professionals. The ’’AIPS’’ questionnaire inquired about morning stiffness and axial-peripheral joint involvement. In addition to the previous questionnaires, it included questions about eye problems and family history of joint disease, which are risk factors for PsA. ChatGPT, similar to other surveys, only asked about nail involvement and did not ask about cutaneous involvement. Interestingly, it did not include questions regarding enthesitis, such as heel pain.
Psoriatic arthritis frequently presents as dactylitis, enthesitis, spondylitis, and peripheral arthritis. In established PsA, persistent joint pain is anticipated with or without morning stiffness lasting longer than thirty minutes [18]. So, it’s unsurprising that the AIPS, like other screening tools, asks about joint pain, swelling, and morning stiffness [7-10]. However, especially in the early stages, joint pain and morning stiffness may not be as noticeable as in other joint diseases such as rheumatoid arthritis or ankylosing spondylitis [18]. Therefore, we speculate that ChatGPT questions characteristics such as eye problems and family history, which are risk factors for PsA and that can be defined by patients themselves, to detect early PsA cases that are not fully clinically established.
Psoriatic disease is a complex inflammatory condition involving skin and joint symptoms, and numerous comorbidities and extra-articular manifestations such as inflammatory bowel disease and uveitis. The prevalence of uveitis is between 2% and 25% of patients with PsA [19]. A recent meta-analysis showed an increased risk of uveitis in cases of psoriasis and PsA, with a higher risk in PsA than in psoriasis. The results of this meta-analysis suggested an overall positive bidirectional association between psoriasis and uveitis [20].
First-degree relative with PsA is a significant predictor of developing PsA in patients with psoriasis. A cohort study revealed that first-degree relatives of patients with PsA were 39 times more likely to develop PsA than those without a family history [21].
Evaluation of enthesitis in patients with psoriasis is important for the diagnosis of PsA, but due to the wide range of signs and symptoms that partially overlap or coexist with the clinical features of fibromyalgia, evaluation of enthesitis by history or physical examination alone may be inadequate. Patient-based evaluations are misleading in the diagnosis of enthesitis and evaluation with ultrasound provides more accurate results [22]. Probably, ChatGPT did not include enthesitis-associated questions to increase specificity, since it prepared a patient-based questionnaire.
Following these questions, the AIPS demonstrated an excellent capacity to accurately identify patients with psoriatic arthritis, with a sensitivity of 92% and a specificity of 96%. In comparison, the validated screening tools, namely EARP (sensitivity 98%, specificity 80%) and PEST (sensitivity 83%, specificity 91%), demonstrated satisfactory performance, albeit with slightly lower overall results. In a study comparing four validated screening tools, EARP had the highest sensitivity (91%), similar to ours; the sensitivities of PASE 44, PASE 47, PEST, and ToPAS II were found to be 80%, 76%, 53%, and 44%, respectively. EARP, PASE 44, PASE 47, PEST, and ToPAS II specificities were 88%, 95%, 95%, 95%, and 97% respectively. (23). However, a recent systematic review evaluated eleven validated PsA screening tools, including the EARP and PEST. It was found that existing screening tools were not supported by very high-quality evidence of content validity. The main problem they identified with the screening tools was that they lacked items that accurately reflected the full spectrum of the disease to perform a true screening in patients with probable or intact PsA, and there was insufficient information to support item reduction methods [24].
It has been reported that in patients with psoriasis, 47% of those in the initial diagnosis period and approximately 80% of those who have completed the five-year disease period present with accompanying musculoskeletal complaints. However, not all these cases are associated with PsA. Other pathologies, such as fibromyalgia and osteoarthritis, can also manifest with these symptoms. In addition, half of the patients who did not have PsA at the time of diagnosis developed PsA symptoms later [25]. In the present study, only patients with psoriasis and musculoskeletal complaints were included, and 42.2% of these patients were diagnosed with psoriatic arthritis by rheumatologists. This result indicates that musculoskeletal complaints should not be taken lightly, but that not every patient requires rheumatologist evaluation. Furthermore, dermatologists should incorporate this approach into their routine evaluations, bearing in mind that even if these patients are not diagnosed with PSA, some may develop PsA symptoms in the future. AI is a promising tool for dermatologists, offering a way to detect potential cases of PsA in their busy clinical routines. In our study, AIPS incorrectly diagnosed 18 patients as having PsA despite the absence of PsA. It is important to note that artificial intelligence is not infallible and may err in its assessments. This potential shortcoming can be addressed in the future through the advancement of technology or a re-evaluation of the patient at each examination.
Artificial intelligence will certainly bring advantages to healthcare, but it may also lead to ethical and social challenges. Furthermore, it is important to consider that AI algorithms cannot apply a holistic approach to clinical scenarios and cannot fully consider the psychological and social aspects of human nature that are usually considered by skilled healthcare professionals [12].
Limitation
The study’s limitation is a relatively small number of patients. However, its prospective design and multidisciplinary nature are its strengths.
Conclusion
Musculoskeletal complaints in patients with psoriasis do not necessarily indicate the presence of PsA, so it is not always necessary to refer these patients to a rheumatologist. Implementing appropriate screening tools has the potential to reduce economic costs and time loss. AIPS developed by ChatGPT, with 92% sensitivity and 96% specificity, suggests that artificial intelligence is a promising topic in this regard and worth working on.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and Human Rights Statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or compareable ethical standards.
Funding: None
Conflict of Interest
The authors declare that there is no conflict of interest.
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17. Taylor W, Gladman D, Helliwell P, Marchesoni A, Mease P, Mielants H, et al. Classification criteria for psoriatic arthritis: Development of new criteria from a large international study. Arthritis Rheum. 2006;54(8):2665-73.
18. Savage L, Tinazzi I, Zabotti A, Laws PM, Wittmann M, McGonagle D. Defining pre-clinical psoriatic arthritis in an integrated dermato-rheumatology environment. J Clin Med. 2020;9(10):3262.
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20. Li CR, Chen L, Wang LF, Yan B, Liang YL, Luo J, et al. Association between uveitis and psoriatic disease: A systematic review and meta-analysis based on the evidence from cohort studies. Int J Ophthalmol. 2020;13(4):650-9.
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The protective effect of alpha lipoic acid against 6-mercaptopurine-induced testicular damage in pre-pubertal and pubertal rats
Umit Yilmaz 1, Semir Gul 2
1 Department of Physiology, Faculty of Medicine, Karabuk University, Karabuk, 2 Department of Histology and Embryology, Faculty of Medicine, Tokat Gaziosmanpasa University, Tokat, Turkey
DOI: 10.4328/ACAM.22570 Received: 2025-01-18 Accepted: 2025-02-19 Published Online: 2025-02-25 Printed: 2025-03-01 Ann Clin Anal Med 2025;16(3):209-213
Corresponding Author: Umit Yilmaz, Department of Physiology, Faculty of Medicine, Karabuk University, Karabuk, Turkey. E-mail: umityilmaz@karabuk.edu.tr P: +90 370 418 92 02 Corresponding Author ORCID ID: https://orcid.org/0000-0003-0248-3483
Other Authors ORCID ID: Semir Gul, https://orcid.org/0000-0002-4668-9603
This study was approved by the Ethics Committee of Karabük University Experimental Animal (Date: 2024-09-03, No: 2024/09/15)
Aim: This study aimed to investigate the protective effect of alpha lipoic acid (ALA) against the toxicity caused by 6-mercaptopurine (6-MP), which is used in the treatment of childhood cancers, in the testicular tissue of pre-pubertal and pubertal rats.
Material and Methods: In this study, thirty-six Wistar Albino male rats, approximately 28-day old, were used and divided into 6 groups (n=6). According to the groups, 6-MP (10 mg/kg/day) and ALA (100 mg/kg/day) were administered to the rats orally for 14 days by dissolving them in physiological saline. The rats in Group 1 (Control), Group 2 (6-MP), and Group 3 (6-MP+ALA) were decapitated after 14 days of gavage. Group 4 (Control), Group 5 (6-MP), and Group 6 (6-MP+ALA) were decapitated after waiting for 14 more days to reach puberty after 14 days of gavage. Histopathological changes in the testicular tissue were evaluated by hematoxylin and eosin staining. Johnsen’s scores were also compared between groups. In the immunofluorescence analysis, the apoptotic index of the cells was determined by staining with cleaved caspase-3.
Result: According to our results, 6-MP administered to pre-pubertal and pubertal rats decreased seminiferous tubule diameter and seminiferous epithelial thickness, but did not affect seminiferous epithelial thickness/diameter ratio. In the testicular tissue of ALA-treated groups, this damage caused by 6-MP was found to be reversed. In addition, 6-MP decreased the Johnsen’s score, but the Johnsen’s score recovered significantly in the ALA-treated groups. The apoptotic index increased in the pre-pubertal group treated with 6-MP and decreased in the group treated with ALA.
Discussion: 6-MP may cause damage to the testis of pre-pubertal rats, and ALA may protect against this damage.
Keywords: 6-Mercaptopurine, Alpha Lipoic Acid, Puberty, Testis, Toxicity
Introduction
The pre-pubertal testes are not immune to chemotherapy, and prolonged exposure to chemotherapy can cause chromatin aberrations and DNA damage in sperm and germ cells [1]. Cancer treatment with chemotherapy reduces sperm count and can even lead to azoospermia, which can last for several years or become permanent [2]. There is still little information on the effects of many chemotherapy drugs on the prepubertal testis, and most of the available data are mainly from adult studies [3]. The 6-mercaptopurine (6-MP) is a safe and cost-effective drug that has been used in humans for the treatment of several types of cancer as well as autoimmune diseases [4]. 6-MP, an antimetabolite, competes with purine derivatives for the enzyme hypoxanthine-guanine phosphoribosyl transferase and is incorporated into DNA during synthesis. This phenomenon has been shown to cause cytotoxicity that kills cancer cells while damaging healthy cells. In some childhood cancer survivors, 6-MP has been reported to cause caspase 3 activation and loss of Leydig cell function, depending on the dose of exposure [5]. Early spermatocytes are more susceptible to 6-MP exposure compared to late and post-meiotic cells [6]. Alpha lipoic acid (ALA) is an important molecule in physiological systems containing thiol groups and has antioxidant activity. ALA, a cofactor of the mitochondrial multienzyme dehydrogenase complex, exhibits antioxidant effects such as regeneration of vitamin E, ascorbic acid and glutathione when applied exogenously. ALA exhibits free radical scavenging effects in metal chelation and inhibition of lipid peroxidation [7].
Chemotherapy-related toxicity is a major concern for younger cancer patients, who have higher survival rates. A common long-term adverse effect of cancer treatment in children is infertility. Testicular dysfunction is common during adolescence after chemotherapy, and there is currently no known treatment to prevent this damage [8-10]. Antimetabolites such as 6-MP are used to treat a variety of cancers, but their treatment-related adverse effects on male reproductive function are also overlooked. The aim of the current study was to address the increasing concern about long-term side effects, particularly infertility, among cancer survivors. Therefore, this study aimed to investigate the protective effect of ALA against the toxicity caused by 6-MP, which is used in the treatment of childhood cancers, in the testicular tissue of pre-pubertal and pubertal rats.
Material and Methods
Animal care
In this study, thirty-six Wistar Albino male rats, approximately 28day old (pre-pubertal male rats), were used and divided into 6 groups (n=6). During the experiments, the animals were kept in an environment with a temperature of 21±1ºC and a 12-hour light/dark period and were fed with normal tap water and standard rat chow ad libitum. The 6-MP (Biochemical CAS number: 6112-76-1, Sigma-Aldrich, USA) and ALA (Biochemical CAS No: 1077-28-7, Abcam, UK) were administered orally (gavage) to animals by dissolving them in physiological saline for 14 days.
According to the literature, puberty in male rats begins around 40-45 days and ends at 70-77 days of age. Between 56-70 days of age is considered late puberty/adolescence [11]. Therefore, the study started with 28-day old rats. Group-1, Group-2 and Group-3 were decapitated after 14 days of gavage, that is, when the rats were 42 days old. Group-3, Group-4 and Group-5 were decapitated after waiting for them to reach puberty, that is, after 14 days of gavage, after waiting for another 14 days, when the rats were 56 days old.
Experimental groups and experimental design
Group 1 (Control): Rats in this group were not administered 6-MP or ALA. Only the same amount of solvent, saline solution, was administered orally (gavage). Rats in this group were decapitated 14 days after the start of the experiment. Group 2 (6-MP): Rats in this group were administered orally (gavage) 6-MP (10 mg/kg/day) [12] for 14 days [13]. Rats were decapitated after 14 days of gavage. Group 3 (6-MP+ALA): Rats in this group were administered orally (gavage) 6-MP (10 mg/kg/day) [12] and ALA (100 mg/kg/day) [7] for 14 days [13]. Rats were decapitated after 14 days of gavage. Group 4 (Control): Rats in this group were not administered 6-MP or ALA. Only the same amount of saline solution with solvent was given orally (gavage). The rats in this group were allowed to reach puberty and were decapitated 28 days after the start of the experiment. Group 5 (6-MP): The rats in this group were administered orally (gavage) 6-MP (10 mg/kg/day) [12] for 14 days [13]. After 14 days of 6-MP administration, the rats were allowed to reach puberty for 14 days and were decapitated at the end of the 28th day. Group 6 (6-MP+ALA): The rats in this group were administered orally (gavage) 6-MP (10 mg/kg/day) [12] and ALA (100 mg/kg/day) [7] for 14 days [13]. After 14 days of 6-MP and ALA administration, the rats were allowed to reach puberty for 14 days and were decapitated at the end of the 28th day.
Histopathological analysis
Testicular tissues were kept in 10% formaldehyde solution at room temperature for 24 hours and then used in histopathological and histomorphometry analyses. After 24 hours of fixation, testicular tissues were divided into two equal parts and subjected to manual tissue processing, and the testicular tissues that completed processing were embedded in paraffin. From the paraffin-embedded testis blocks, 4 µm thick sections were cut on poly-L-lysine slides using a microtome. The sections were stained with hematoxylin and eosin (HE) for histomorphology measurements. Seminiferous tubule diameter, epithelial thickness measurements and Johnsen’s scoring were performed on HE-stained testicular tissue sections. For diameter measurements, the shortest axis of 50 randomly selected seminiferous tubules were determined and measured at two different depths. In 50 seminiferous tubules with smooth contours in each section, seminiferous epithelial thickness was measured in two different areas from the basal lamina to the lumen, including Sertoli and germ cells. The diameter of the seminiferous tubules, the thickness of the seminiferous epithelium and the ratio of the thickness of the seminiferous epithelium to the diameter of the seminiferous tubules were calculated separately for each group. In addition, Johnsen’s scoring was performed on HE-stained sections. For this purpose, 20 seminiferous tubule sections from randomly selected transfers were analyzed in each section [14]. A light microscope (Nikon Eclipse E200), DS-Fi-1 camera (Nikon Instruments Inc., Melville, NY) and NIS-Elements BR 2.30 image analysis system (Nikon Corp., Tokyo, Japan) were used for analysis.
Immunofluorescence analysis
Sections of 4 µm thickness were cut from the paraffin-embedded tissue blocks on positively charged microscope slides. For deparaffinization, sections were passed through xylene (5 min x 3), 100% alcohol (3 min), 96% alcohol (3 min), 80% alcohol (3 min), 70% alcohol (3 min), distilled water and then PBS. Sections were incubated with 5% normal donkey serum cat no: GTX30972 (GeneTex, USA) for 15 minutes. After incubation, the tissue sections were spotted on the slide using a hydrophobic pen and rabbit clonal primary antibody cleaved caspase-3 (1:200) catalogue no: E-AB-30004 (Elabscience, USA) was added and incubated overnight at +4°C. After washing with PBS for 10 minutes x 3, the sections were incubated with anti-rabbit Alexa Fluor 594 (1:200) cat no: ab150076 (Abcam, UK) secondary antibody for 1 hour at room temperature in the dark. After washing with PBS buffer for 10 min x 3 times, the sections were cover slipped with DAPI (diamidin-2-phenylindole dihydrochloride) cat no: GTX30920 (GeneTex, USA) containing coverslip. The sections were digitally photographed with a fluorescent microscope (Nikon Eclipse E600, Nikon Corp., Tokyo, Japan).
Statistical analysis
Statistical analyses were conducted on IBM SPSS Statistics 24.0 for Windows software. Normal distribution was determined with the Kolmogorov-Smirnov test. One-way analysis of variance (One-way ANOVA) was employed to compare the variables between the groups. Multiple comparisons were conducted with the appropriate post-hoc tests (Tukey or Tamhane’s test). The findings were expressed as means ± standard deviations (SD), and p <0.05 was accepted as statistical significance.
Ethical Approval
This study was conducted with approval from the Karabük University Experimental Animal Ethics Committee (Date: 2024-09-03, No: 2024/09/15). Animal care and all applications were carried out at the Karabük University Experimental Medicine Application and Research Center as specified in the ethics committee protocol. All animals were treated ethically in accordance with the Guide for the Care and Use of Laboratory Animals.
Results
Histopathological results
The seminiferous tubule diameter of group 2 treated with 6-MP decreased compared to group 1 and group 3 (p<0.001). However, the seminiferous tubule diameter of group 3 treated with prophylactic ALA increased compared to group 2 and was statistically similar to group 1 (p<0.001). Similarly, the seminiferous tubule diameter of group 5 receiving 6-MP decreased compared to group 4 and group 6, but in group 6 receiving prophylactic ALA, the seminiferous tubule diameter increased compared to group 5 and was statistically similar to group 4 (p<0.001). The seminiferous epithelial thickness of group 2 receiving 6-MP decreased compared to group 1 and group 3 (p<0.001). However, the seminiferous epithelial thickness of group 3 receiving ALA as a prophylactic agent increased compared to group 2 and was statistically similar to group 1 (p<0.001). Similarly, the seminiferous epithelial thickness of group 5 treated with 6-MP decreased compared to group 4 and group 6 (p<0.001). The seminiferous epithelial thickness of group 6, which received ALA as a prophylactic agent, increased compared to group 5 and was statistically similar to group 4 (p<0.001). The groups were compared in terms of thickness/diameter and there was no statistical difference between group 1, group 2 and group 3, and between group 4, group 5 and group 6 (p>0.05) (Table 1 and Figure 1).
Johnsen’s score
The Johnsen score of group 2 given 6-MP decreased compared to group 1 and group 3 (p<0.001). However, the Johnsen’s score of group 3, which received ALA as a prophylactic, increased compared to group 2 and was statistically similar to group 1 (p<0.001). Similarly, Johnsen’s score of group 5 given 6-MP decreased compared to group 4 and group 6, but in group 6 given ALA as prophylactic, Johnsen’s score increased compared to group 5 and was statistically similar to group 4 (p<0.001) (Figure 2).
Apoptotic index
Caspase 3 is often activated to catalyze the cleavage of certain downstream molecules. This ultimately leads to DNA fragmentation and programmed cell death (apoptosis) [15]. In our study, immunofluorescence staining of cleaved caspase-3 was evaluated as an apoptotic index. The level of cleaved caspase-3 was increased in group 2 treated with 6-MP compared to group 1 and group 3 (p<0.002). However, the level of cleaved caspase-3, which is considered an apoptotic index, was increased in group 3 receiving ALA as a protective agent compared to group 2 and was statistically similar to group 1 (p<0.001). Comparing groups 4, 5 and 6 for cleaved caspase-3 levels, which is considered an apoptotic index, there was no statistical difference between groups (p>0.05) (Table 2 and Figure 3).
Discussion
Because 6-MP interferes with purine metabolism, particularly in rapidly growing and dividing cells, it raises concerns about spermatogenesis and pregnancy outcome. Although studies in rodents have reported that exposure to high doses of 6-MP significantly inhibits male reproduction, experimental data on the effect of low doses on fertility and reproductive outcome are still lacking [16]. Therefore, our study was designed to evaluate the protective effects of ALA against 6-MP toxicity on testicular tissue of pre-pubertal male rats.
In mice treated with 6-MP (2, 5 and 8 mg/kg), sperm morphology and sperm production in the seminiferous tubules were not affected. However, pregnancy rates in female mice mated with these mice were inversely correlated with increasing doses of 6-MP, indicating latent sperm damage [16]. Chronic low-dose 6-MP treatment was shown to have no effect on testicular weight, seminiferous tubule stage quantification, number of mature spermatids and serum testosterone levels in rats [17]. Panghal et al. investigated the toxicity of 6-MP administered for one week and intermittently for three weeks in the testicular tissue of juvenile rats. In their results, they reported that one-week and intermittent 3-week exposure cycles to 6-MP did not change the testis-to-body weight ratio but decreased the epididymis-to-body weight ratio in a dose-dependent manner, but this change was insignificant. It has also been reported that 6-MP causes structural abnormalities in the basement membrane, reduction in the spermatogonia and spermatid population, degeneration of the seminiferous tubules and enlargement of the interstitial space. It has also been shown to reduce seminiferous tubule diameter and Johnsen’s score. In addition, 6-MP has been shown to decrease sperm count, sperm motility and the number of sperm with normal head morphology [12]. In childhood cancer survivors, 6-MP has been reported to cause Leydig cell failure. Furthermore, in a mouse model, 6-MP has been shown to induce caspase 3 activation and cause Leydig cell loss [5].
Recent studies have shown that ALA plays a protective role in the testis against damage caused by anticancer drugs [18], various toxic agents [19-23], ionizing radiation [24] or ischemia-reperfusion [25]. In our study, the protective effect of ALA against the damage caused by 6-MP administered to pre-pubertal rats before or after puberty was investigated. According to our results, 6-MP administered to pre-pubertal rats decreased the seminiferous tubule diameter and seminiferous epithelial thickness of pre-pubertal and pubertal rats but did not alter the ratio of seminiferous epithelial thickness to diameter . In the testicular tissue of ALA-treated groups, this damage caused by 6-MP was found to be reversed. In addition, 6-MP decreased the Johnsen’s score, but the Johnsen’s score almost recovered in the ALA-treated groups. In our study, cleaved caspase-3 levels were evaluated to determine the apoptotic index, and it was found that the apoptotic index increased in the 6-MP treated groups and decreased in the ALA treated groups. In conclusion, 6-MP may have induced oxidative stress/DNA damage by inducing the formation of oxidant substances in reproductive cells, and cells may have been induced to undergo apoptosis to recover from this stress. ALA may also have a protective effect against 6-MP-induced damage in the testes of rats.
Limitation
A limitation of our study is the absence of biochemical analyses.
Conclusion
There is a paucity of studies in the literature investigating the effects of 6-MP on reproductive cells/functions following its use before puberty. Therefore, our study is an important contribution to the literature. The results of our study suggest that 6-MP may cause damage to the testes of pre-pubertal rats and that ALA may have a protective effect against this 6-MP-induced damage.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and Human Rights Statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or compareable ethical standards.
Funding: None
Conflict of Interest
The authors declare that there is no conflict of interest.
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Umit Yilmaz, Semir Gul. The protective effect of alpha lipoic acid against 6-mercaptopurine-induced testicular damage in pre-pubertal and pubertal rats.Ann Clin Anal Med 2025;16(3):209-213
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Preoperative and postoperative evaluation of patients undergone appendectomies either in spinal or general anesthesia
İsa Caner Aydın 1, Saadet Kılıç 2, Emine Özdemir 3
1 Department of Gastroenterologic Surgery, Ministry of Health Zonguldak Atatürk State Hospital, Zonguldak, 2 Department of General Surgery, Ministry of Health Bozüyük State Hospital, Bilecik, 3 Department of Anesthesia, Ministry of Health Yunus Emre State Hospital, Eskişehir, Türkiye
DOI: 10.4328/ACAM.22571 Received: 2025-01-19 Accepted: 2025-02-17 Published Online: 2025-02-26 Printed: 2025-03-01 Ann Clin Anal Med 2025;16(3):214-220
Corresponding Author: İsa Caner Aydın, Department of Gastroenterologic Surgery, Ministry of Health Zonguldak Atatürk State Hospital, Zonguldak, Türkiye. E-mail: isacaneraydin@hotmail.com P: +90 537 935 37 03 Corresponding Author ORCID ID: https://orcid.org/0000-0003-2434-0045
Other Authors ORCID ID: Saadet Kılıç, https://orcid.org/0000-0001-9490-7487 . Emine Özdemir, https://orcid.org/0000-0001-6655-4477
This study was approved by the Ethics Committee of Zonguldak Bülent Ecevit University, Faculty of Medicine (Date: 2024-12-19, No: 2024/22/10)
Aim: The Coronavirus 2019 (COVID-19) pandemic has changed healthcare practices, leading to heightened protective measures and conservative management strategies. In acute appendicitis (AA) cases, conservative surgical and anesthetic approaches, such as spinal anesthesia, were increasingly adopted. However, studies focusing specifically on conventional appendectomy during the pandemic remain limited.
Material and Methods: 126 patients underwent open appendectomy in a single center retrospectively analyzed. Patients are categorized based on COVID status and anesthesia administrations. Cox regression tests were utilized for analyzing factors affecting longer hospitalization.
Results: Major complications (9.8% vs. 25.0%, p=0.044) and ileus development (0.0% vs. 4.1%, p=0.038), CRP levels (23.64 ± 23.54 vs. 64.42 ± 69.41; p<0.001), time to initiate oral feeding (1.24 ± 0.91 vs. 1.54 ± 1.74; p=0.018), length of hospital stay (1.74 ± 1.30 vs. 2.17 ± 3.48; p=0.021), and surgical durations (35.39 ± 6.74 vs. 37.08 ± 12.93; p=0.016) were frequent in COVID-19 positive patients. CRP levels (39.98 ± 54.20 vs. 26.13 ± 26.80; p=0.003), time to initiate oral feeding (1.50 ± 1.60 vs. 1.17 ± 0.65; p=0.002) and length of hospital stay (2.00 ± 2.87 vs. 1.71 ± 0.93; p=0.002) were more frequent in general anesthesia. General anesthesia (OR: 32.337; p<0.001), advanced age (OR: 1.089; p<0.001), perforation (OR: 15.906; p=0.005), and the development of major complications (OR: 33.056; p=0.005) were independent risk factors for prolonged hospital stay in multivariate analysis.
Discussion: Open Appendectomy under spinal anesthesia was found to be a safe option in patients with AA which also protects both patients and healthcare professionals and lowers hospitalization stays.
Keywords: COVID-19, Acute Appendicitis, Appendectomy, Anesthesia
Introduction
The Coronavirus Disease 2019 (COVID-19) pandemic, since its onset in 2020, has caused significant changes in the behaviors and attitudes of both patients and healthcare professionals. During the pandemic, many outpatient services were temporarily suspended to reduce contact and limit the number of visits, while protective measures were heightened. Patients, on the other hand, developed an instinct to avoid seeking hospital care unless their symptoms were unbearable [1-3].
In cases of acute appendicitis (AA), which represents the highest emergency surgical workload in general surgery, more conservative approaches were adopted by both surgical and anesthesia teams [4, 5]. Surgical teams prioritized conservative management strategies, such as close monitoring and antibiotic therapy, while anesthesia teams increasingly preferred sedation or spinal anesthesia instead of general anesthesia [6-8].
During the pandemic, numerous studies were published on appendicitis cases in which these approaches were adopted. While these studies have evaluated laparoscopic appendectomy, literature focusing on conventional appendectomy remains limited. This study aims to determine the impact of anesthesia method selection on perioperative and postoperative outcomes in acute appendicitis cases treated at a public hospital designated as a “pandemic hospital” during the pandemic period.
Material and Methods
Study Design
The study was designed based on patients who presented with acute appendicitis and underwent conventional appendectomy during the pandemic period between 2020 and 2021. Monocentric data collection began after obtaining ethical approval. Since this was a retrospective study, the requirement for informed consent was waived by the ethics committee.
Inclusion Criteria
The study included patients aged 18 years or older who underwent emergency surgery for AA using conventional methods. Only patients whose surgeries were completed via McBurney modified McBurney (Lanz or Langer incision), or Rockey-Davis incisions were included. Additionally, patients who were directly scheduled for surgery without clinical follow-up after admission were also included.
Exclusion Criteria
Patients initially managed with medical follow-up despite suspicion of AA and later operated on, those younger than 18 years, patients who underwent exploratory laparotomy or conversion to median laparotomy after the initial incision, and patients diagnosed with phlegmonous appendicitis who only had a drain placed with interval appendectomy planned were excluded from the study. Additionally, patients with incomplete data required for the study were also excluded.
Preoperative Variables
Appendectomy records were extracted from operating room logs throughout the pandemic. Preoperative data collected for these patients included COVID-19 antigen positivity, COVID-19 Reporting and Data System (CO-RADS) scores from computed tomography scans, C-reactive protein (CRP) levels, and oxygen saturation at the time of admission [9-11].
Additionally history of diabetes, were recorded. Preoperative anesthesia evaluations included American Society of Anesthesiology (ASA) scores and body mass index (BMI) values [12, 13].
Surgery Data
Anesthesia was administered using previously described techniques for both spinal and general anesthesia. During the COVID-19 pandemic, spinal anesthesia was preferred whenever possible. General anesthesia was performed in patients with failed spinal anesthesia, a history of lumbar surgery, or those using anticoagulants [14]. All surgeries were initiated using McBurney, modified McBurney (Lanz or Langer incision), or Rockey-Davis incisions. Depending on the patients’ adhesions and presentation, mesocolic or retrocolic dissection was performed to access the appendix base. The base of the appendix was ligated with double-layer silk sutures and subsequently resected. In patients with abscesses, the cavity was irrigated and aspirated. All patients received 2 grams of cefazolin 60 minutes before the surgical incision. Postoperatively, the peritoneal and muscular layers were closed with polyglactin 910 sutures, the fascial layer was repaired with polydioxanone sutures, and the skin was closed with sharp, non-absorbable monofilament sutures.
Oral feeding was initiated after the return of bowel gas passage in the postoperative period. Postoperative management included only analgesics, antiemetics, and fluid replacement. In patients with perforations and significantly elevated CRP levels, metronidazole therapy was started at a dose of 500 mg twice daily. For COVID-19-positive patients, additional treatments were administered according to the Ministry of Health’s suggested guidelines at the time [15].
Surgical duration, intraoperative bleeding or abscess presence, and perforated cases were extracted from the surgical records. Additionally, postoperative data, including ileus development, time to oral feeding, fistula formation, superficial incisional surgical site infections, intra-abdominal abscess formation, readmissions, length of hospital stay, and major morbidity were recorded. Major morbidities were defined as complications classified as grade 3 or higher according to the Clavien-Dindo classification [16].
Statistics
IBM® SPSS® (Statistical Package for the Social Sciences) version 27 (IBM Corp. Armonk, NY, USA) used for statistical analysis. The distribution of numerical data was performed using the Kolmogorov–Smirnov test with the normal distribution results. Qualitative data were presented as frequency and percentage. Continuous measurements were presented as mean and standard deviation (sd). The chi-square test is used for comparisons involving categorical variables. The relationship between continuous parameters with COVID status or anesthesia type was analyzed through the application of the independent t-test. For the analysis of factors influencing longer hospitalization; multivariate Cox regression tests were conducted. A significance level of 0.05 was considered for all tests.
Ethical Approval
This study was approved by the Ethics Committee of Zonguldak Bülent Ecevit University, Faculty of Medicine (Date: 2024-12-19, No: 2024/22/10).
Results
The study was conducted by compiling data from patients who underwent emergency appendectomy at the Ministry of Health Besni State Hospital between March 2020 and June 2021. Two surgeons and one anesthesiologist were involved in the surgical procedures in this single-center study. Data from a total of 126 surgical patients were collected.
When patients were evaluated based on their COVID-19 status, the majority of COVID-19-positive patients were classified as ASA 3E, while most COVID-19-negative patients were categorized as ASA 1E (p=0.022). In CO-RADS assessments, the frequencies of CO-RADS 4 and 5 were significantly higher in COVID-19-positive patients compared to COVID-19 negative patients (5.8% vs. 33.3% and 0.0% vs. 4.1%, respectively; p<0.001). In admission parameter evaluations, arterial oxygen saturation (SO2) levels were lower in COVID-19-positive patients (16.6% vs. 37.5%; p=0.011). Major complications (9.8% vs. 25.0%, p=0.044) and ileus development (0.0% vs. 4.1%, p=0.038) were also more frequent in COVID-19-positive patients. CRP levels were significantly higher in COVID-19-positive patients (23.64 ± 23.54 vs. 64.42 ± 69.41; p<0.001). Additionally, the time to initiate oral feeding (1.24 ± 0.91 vs. 1.54 ± 1.74; p=0.018), length of hospital stay (1.74 ± 1.30 vs. 2.17 ± 3.48; p=0.021), and surgical durations (35.39 ± 6.74 vs. 37.08 ± 12.93; p=0.016) were longer in COVID-19 positive patients. Other parameters showed similar distributions (Table 1).
When patients were evaluated based on the chosen anesthesia method, overweight (35.4% vs. 20.5%) and obese patients (14.5% vs. 6.4%) were more frequently observed in the general anesthesia group (p=0.037). Among perioperative findings, perforated appendicitis (31.2% vs. 11.5%; p=0.006) and bleeding cases (8.3% vs. 0.0%; p=0.010) were more common in the general anesthesia group. CRP levels were higher in the general anesthesia group (39.98 ± 54.20 vs. 26.13 ± 26.80; p=0.003), and both the time to initiate oral feeding (1.50 ± 1.60 vs. 1.17 ± 0.65; p=0.002) and length of hospital stay (2.00 ± 2.87 vs. 1.71 ± 0.93; p=0.002) were longer. However, surgical durations were similar between the two groups (36.87 ± 10.03 vs. 35.00 ± 6.88; p=0.099). Other variables were evenly distributed between the groups (Table 2).
To evaluate length of hospital stay, regression analysis was conducted using both the parameters found to be significant in each group and other known influencing factors from the literature, such as fistula at the appendix base, surgical duration, and surgical site incisions [17-21]Univariate analysis identified general anesthesia use (OR: 4.211; p<0.001), age (OR: 1.038; p=0.015), elevated CRP levels (OR: 0.989; p=0.031), surgical duration (OR: 0.947; p=0.031), the presence of perforation (OR: 4.857; p=0.001), and the development of major complications (OR: 8.211; p=0.002) as significant risk factors. Variables found to be significant were included in a multivariate analysis, which demonstrated that general anesthesia use (OR: 32.337; p<0.001), advanced age (OR: 1.089; p<0.001), perforation (OR: 15.906; p=0.005), and the development of major complications (OR: 33.056; p=0.005) were independent risk factors for prolonged hospital stay (Table 3).
Discussion
Our study shows similar perioperative findings and postoperative follow-up data were observed compared to patients who underwent general anesthesia in cases where appendectomy was performed under spinal anesthesia, While morbidity rates were comparable between the two groups, patients receiving spinal anesthesia had shorter hospital stays. Our study demonstrated that, during the COVID-19 pandemic, the preference for spinal anesthesia in appendectomies contributed to reduced hospital stays, thereby lowering the workload and potentially reducing morbidity for both patients and healthcare workers. This suggests that spinal anesthesia can be a suitable option for appendectomy in appropriate patients.
The COVID-19 pandemic has left striking impacts not only on medical history but also on modern world history. Throughout the pandemic, many physicians and healthcare professionals worked selflessly to manage the crisis. In our country, physicians took on the care of COVID-19 patients outside their specialties during the crisis management process. Beyond this increased workload, the global effects of the pandemic disrupted international trade, causing delays in the supply of medications and medical devices [22, 23].
Conventional appendectomy is increasingly being replaced by laparoscopic appendectomy in modern surgical practice. However, during global crises like the COVID-19 pandemic, where the availability and supply of medical equipment may be disrupted, conventional appendectomy remains a reliable alternative. It can be easily performed with a single surgical set and basic sutures, ensuring its continued relevance in resource-limited situations [2, 4].
When evaluating other studies in the literature, one study comparing the pre-pandemic and post-pandemic periods reported an increase in complicated appendicitis cases from 8.0% to 33.9% after the pandemic. Although this shift aimed to prioritize the safety of both patients and healthcare professionals by managing cases more conservatively, the study found that the incidence of perforated and phlegmonous appendicitis was higher post-pandemic. Additionally, hospital stays for appendectomy patients were shown to be longer after the pandemic [2].
During the pandemic, studies on appendectomy primarily focused on patients operated on under spinal anesthesia, often evaluating laparoscopic surgeries or combining two surgical techniques. A multicenter analysis from Italy reported that the conversion rate to open surgery in patients with complications was 2.4 times higher, and open surgery was performed 2.24 times more frequently [24]. In a single-center study conducted in Turkey, 588 patients presenting with acute appendicitis were included, and an increase in conversion from laparoscopy to open surgery was observed in cases of perforated appendicitis. Both studies demonstrated that hospital stays were prolonged in cases of perforated appendicitis [25]. Similarly, our study also showed that perforated appendicitis significantly prolonged the length of hospital stay.
Studies comparing only open appendectomy cases are limited. There is only one case series that specifically evaluates these patients. In that series, no major complications were reported among the 11 operated cases, and hospital stays were described as short. Similarly, our study demonstrated that general anesthesia does not increase major complications or prolong hospital stays, consistent with the findings of this series. However, unlike the previous study, our research included a larger patient population. Additionally, by including patients with positive COVID-19 antigen tests or CO-RADS imaging findings, our study uniquely evaluated outcomes specific to the pandemic context [4].
Limitation
Our study has several limiting factors. First, it was designed as a retrospective study. Due to the restricted availability of medical equipment during the pandemic, laparoscopic surgery cases were excluded because of technical limitations at the center where the study was conducted. Lastly, the exact onset times of patients’ symptoms were unknown and therefore could not be included in the analysis. As a strength, the study exclusively focused on a single surgical method, evaluated in a single center by the same surgical team, ensuring consistency in the findings. Also as a technique comparison; interval appendectomy or medical approach patients weren’t included which contributes to a more homogenous patient cohort.
Conclusion
Open appendectomy performed under spinal anesthesia demonstrates similar morbidity rates to those under general anesthesia while resulting in shorter hospital stays. Although open appendectomy has largely been replaced by laparoscopy in modern practice, it remains a safe and reliable option under spinal anesthesia during crisis periods, such as the COVID-19 pandemic, when access to minimally invasive techniques may be limited or delayed.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and Human Rights Statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or compareable ethical standards.
Funding: None
Conflict of Interest
The authors declare that there is no conflict of interest.
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İsa Caner Aydın, Saadet Kılıç, Emine Özdemir. Preoperative and postoperative evaluation of patients undergone appendectomies either in spinal or general anesthesia. Ann Clin Anal Med 2025;16(3):214-220
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Relationship between knee osteoarthritis severity and novel peripheral inflammatory markers
Alper Uysal 1, Uğur Güngör Demir 1, Ali Nail Demir 2, Hacer Paksoy Karateke 3
1 Department of Physical Medicine and Rehabilitation, Mersin City Training and Research Hospital, Mersin, 2 Department of Rheumatology, Mersin City Training and Research Hospital, Mersin, 3 Department of Physical Medicine and Rehabilitation, Adana City Training and Research Hospital, Adana, Turkiye
DOI: 10.4328/ACAM.22574 Received: 2025-01-20 Accepted: 2025-02-20 Published Online: 2025-02-22 Printed: 2025-03-01 Ann Clin Anal Med 2025;16(3):221-226
Corresponding Author: Hacer Paksoy Karateke, Department of Physical Medicine and Rehabilitation, Adana City Training and Research Hospital, Adana, Turkiye. E-mail: hacerpaksoy1@gmail.com P: +90 505 011 50 40 Corresponding Author ORCID ID: https://orcid.org/0009-0004-5790-6759
Other Authors ORCID ID: Alper Uysal, https://orcid.org/0000-0002-4114-1649 . Uğur Güngör Demir, https://orcid.org/0000-0002-5084-7280 Ali Nail Demir, https://orcid.org/0000-0001-5713-4120
This study was approved by the Ethics Committee of Mersin University (Date: 2024-10-16, No: 988)
Aim: Osteoarthritis (OA) is a degenerative joint disease influenced by inflammatory processes. This study aimed to investigate the relationship between inflammatory markers and OA severity.
Material and Methods: This retrospective study included patients aged ≥40 with knee OA, classified using the Kellgren–Lawrence (KL) grading system. Data from 167 individuals were divided into three groups: Group 1 included 50 healthy individuals (KL grade 0), Group 2 comprised 56 with mild OA (KL grades 1–2), and Group 3 included 61 with severe OA (KL grades 3–4). Peripheral inflammation was assessed through hemogram-derived parameters, including platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), platelet-to-neutrophil ratio (PNR), neutrophil-lymphocyte-platelet ratio (NLPR), systemic immune response index (SIRI), systemic immune inflammation index (SII), and systemic inflammation aggregate index (SIAI).
Results: Demographic characteristics were similar across groups (p > 0.05). Neutrophil count, monocyte count, NLR, LMR, PNR, NLPR, SII, SIRI, and SIAI showed significant differences (p < 0.05). PNR and SIRI values differed significantly among the three groups across all pairwise comparisons. SIRI exhibited a weak positive correlation with KL grades (r = 0.240, p = 0.009), while PNR showed a weak negative correlation (r = -0.273, p = 0.003). ROC (Receiver Operating Characteristic) analysis showed moderate discriminatory power for SIRI and PNR with AUCs (Area Under the Curve) of 0.762 and 0.740, respectively.
Discussion: This study indicates a potential link between OA and systemic inflammation. SIRI and PNR may be useful markers for assessing OA severity.
Keywords: Inflammatory Markers, Systemic Immune Response Index (Siri), Platelet-To-Neutrophil Ratio (Pnr), Systemic Immune Inflammation Index (Sii), Neutrophil-To-Lymphocyte Ratio (Nlr), Knee Osteoarthritis.
Introduction
For a long time, osteoarthritis (OA) was primarily regarded as a degenerative condition affecting cartilage. However, growing evidence now suggests that inflammation is pivotal in the disease’s pathogenesis [1]. Recent research has demonstrated that inflammation may be associated with both the progressive breakdown of cartilage and the manifestation of symptoms such as pain, synovial swelling, palpable joint swelling, and the development of OA. It was indicated that cytokines in the knee joint originate from the systemic circulation and locally, as the cartilage, synovium, or infrapatellar fat can serve as a source [2]. Moreover, a study published in 2023 suggested that the development and progression of OA in patients with Parkinson’s disease (PD) may be associated with chronic inflammation [3].
While the evidence supporting chronic systemic inflammation in OA pathogenesis continues to grow, the literature remains inconsistent. Several studies have examined specific inflammatory markers for their potential in assessing OA-related inflammation. For instance, studies in recent years have shown that markers such as NLR and PLR may not effectively indicate low-grade inflammation in knee OA [4, 5]. Additionally, findings from a 2023 study suggest no significant correlation between SII and either radiographic grading or functional outcomes in knee OA [6]. These results imply that conventional markers, such as NLR and PLR, may not fully capture the complex inflammatory profile of knee OA, and highlight the need for alternative, cost-effective markers that can assist in monitoring OA progression and prognosis.
This retrospective study investigated the relationship between OA severity and inflammatory markers derived from hemogram-based parameters, which reflect low-grade inflammation, alongside radiographic imaging. Our study aimed to identify a potential alternative marker for assessing OA diagnosis and severity by examining these relationships.
Material and Methods
Study Design and Scope
This retrospective study was conducted at the Rheumatology and Physical Medicine and Rehabilitation Clinics of Mersin City Training and Research Hospital, using patient data collected between July 1, 2023, and September 30, 2024. A total of 167 participants over the age of 40, who were examined for knee OA, had anteroposterior and lateral knee X-rays taken at the time of their visit, and had available hemogram results, were included in the study.
In this study, the diagnosis of knee OA was based on radiographic findings using the KL classification, a widely accepted tool for grading OA severity [7]. Although clinical symptoms were not directly included due to the retrospective design, patient files, previous radiological imaging, laboratory parameters, International Classification of Diseases, 10th Revision (ICD-10) codes, and medication history (to the extent available or accessible) were reviewed to ensure accurate OA diagnosis and to exclude systemic or inflammatory joint diseases.
The participants were categorized into three groups according to their KL grades: Group 1 consisted of 50 healthy individuals (KL grade 0), Group 2 comprised 56 patients with lower KL grades (grades 1 and 2), and Group 3 comprised 61 patients with higher KL grades (grades 3 and 4).
Exclusion criteria included OA related to trauma (e.g., fractures or dislocations identified through ICD-10 diagnosis codes or imaging methods) or infection (e.g., septic arthritis or osteomyelitis), systemic inflammatory disease, systemic infectious disease, pregnancy, malignancy, and the use of medications that could affect platelet, neutrophil, or lymphocyte counts. Additionally, if identified, patients within 6 weeks of recovery from acute infectious conditions such as influenza or enteritis were also excluded.
Assessment of OA Severity
Radiographic grading of gonarthrosis was performed using the KL score: Grade 0 (no detectable signs of OA on X-ray), Grade 1 (possible joint space narrowing (JSN) and slight osteophyte development), Grade 2 (clearly visible osteophytes with probable JSN), Grade 3 (definite JSN, numerous osteophytes, bone sclerosis, and potential bone distortion), and Grade 4 (prominent osteophytes, severe JSN, significant bone sclerosis, and clear bone distortion) [7].
Determination of Inflammatory Parameters
Peripheral inflammation in this study was evaluated using hemogram-derived parameters, including PLR, NLR, LMR, and PNR. Additionally, SIRI was determined based on the formula: neutrophil count * monocyte count/lymphocyte count. SII was determined using the following equation: NLR * platelet count. SIAI was computed as follows: neutrophil count * monocyte count * platelet count/lymphocyte count. NLPR was derived from the following equation: neutrophil count * 100 / lymphocyte count * platelet count [8, 9].
Statistical Analyses
All analyses were performed using IBM SPSS Statistics version 22.0, with a significance threshold set at p < 0.05. Data distributions were initially examined using the Shapiro-Wilk test. Continuous variables were presented as mean ± standard deviation (SD) for normally distributed data or as median (minimum–maximum) for non-normally distributed data. Categorical variables were expressed as frequencies and percentages. Group comparisons used One-Way ANOVA or Kruskal-Wallis H Test, with post-hoc tests for significant results. Pearson’s Chi-Square Test was used for categorical variables. Spearman’s correlation coefficient (r) was used to evaluate the association between KL grade and laboratory parameters. Correlation strength was interpreted as follows: very weak (r < 0.20), weak (0.20–0.39), moderate (0.40–0.59), strong (0.60–0.79), and very strong (r ≥ 0.80) [10]. Receiver Operating Characteristic (ROC) curve analyses were conducted to assess the diagnostic performance of SIRI and PNR for OA diagnosis and severity.
Ethical Approval
This study was approved by the Ethics Committee of Mersin University (Date: 2024-10-16, No: 988). As the study was retrospective, informed consent from participants was not required, and it does not conflict with the ethical guidelines of the Declaration of Helsinki.
Results
A total of 167 participants were divided into three groups: 50 healthy (KL 0), 56 with mild OA (KL 1–2), and 61 with severe OA (KL 3–4). Demographic characteristics, including age and gender, were similar across the three groups (p > 0.05) (Table 1). Laboratory parameters such as platelet count, lymphocyte count, and PLR were also similar among the groups (p > 0.05).
In contrast, certain laboratory parameters such as neutrophil count, monocyte count, NLR, LMR, PNR, NLPR, SII, SIRI, and SIAI showed significant differences between the groups. NLR and SIAI values in Group 2 and Group 3 were statistically similar to each other but significantly higher than those in Group 1 (p = 0.002 and p < 0.001, respectively). LMR, SII, and NLPR values were statistically different between Group 1 and Group 3, but no significant differences were observed between Group 1 and Group 2 or Group 2 and Group 3 (p < 0.001, p = 0.025, and p = 0.001, respectively). Neutrophil count, PNR, and SIRI values differed significantly across all pairwise group comparisons (p < 0.001 for each parameter). Monocyte count in Groups 1 and 2 was statistically similar but significantly lower than in Group 3 (p < 0.001) (Table 1). The study’s findings indicate a weak positive correlation between SIRI and KL grade (r = 0.240, p = 0.009). In contrast, PNR demonstrated a weak negative correlation with KL grade (r = -0.273, p = 0.003) (Table 2).
The scatter plot demonstrates a weak positive correlation between SIRI and KL grade, with SIRI values showing a slight increase as KL grade progresses (Figure 1A). The scatter plot illustrates a weak inverse relationship between PNR and KL grade, with PNR values tending to decline progressively as KL grade advances (Figure 1B).
In differentiating between OA and healthy controls, the ROC analysis for SIRI (Figure 2A) demonstrated an AUC of 0.762, with a p-value of < 0.001 and a 95% confidence interval ranging from 0.682 to 0.842. For the PNR (Figure 2B), the ROC analysis revealed an AUC of 0.740, with a p-value of < 0.001 and a 95% confidence interval ranging from 0.658 to 0.823.
In distinguishing between high and low grades of OA, the ROC analysis for SIRI revealed an AUC of 0.635, with a p-value of 0.012 and a 95% confidence interval ranging from 0.534 to 0.736 (Figure 3A). In differentiating between high and low grades of OA, the ROC analysis for PNR yielded an AUC of 0.655, with a p-value of 0.004 and a 95% confidence interval ranging from 0.554 to 0.756 (Figure 3B).
Discussion
This study identified significant differences in some inflammatory markers between OA patients and healthy controls, with significant associations between KL grade and these inflammatory markers. SIRI showed a weak positive correlation with KL grade, suggesting increased systemic inflammation with OA severity, while PNR had a weak negative correlation, indicating its decline with severity. ROC analysis demonstrated the moderate discriminatory power of SIRI and PNR in diagnosing OA and assessing its progression.
Emerging evidence from recent studies increasingly supports the view that alterations in inflammatory factors are closely associated with the development and progression of OA [3, 11]. Uysal et al.’s 2023 study examined the link between inflammation and OA in PD patients, considering the impact of balance deterioration over time. The findings indicated that chronic systemic inflammation in PD patients is associated with the onset and progression of OA. Specifically, PD patients showed elevated CRP and NLR levels compared to healthy individuals, suggesting the presence of low-grade chronic inflammation. In the early stages of PD, patients showed thicker distal femoral cartilage (DFCT) than healthy controls, probably due to cartilage swelling or edema, a potential marker of early OA. The study accounted for balance, demonstrating that OA development in the early stages of PD was independent of balance issues, as balance was preserved in the early stages of PD. However, as PD advanced, cartilage thickness decreased, and balance deteriorated, indicating OA progression in later stages, which may result from both chronic inflammation and worsening balance levels [3].
Under conditions of inflammation and stress, neutrophil and platelet counts increase, while lymphocyte levels tend to decrease [5, 12]. The observed increase in monocyte levels may result from the progression of immune responses. Monocytes are activated through inflammasome-mediated pathways, and chronic low-grade activation of the inflammasome is thought to contribute to OA progression. In contrast, the reduction in lymphocyte counts may reflect their migration to zones of inflammation [13, 14]. Gao et al. showed that patients with knee OA had higher MLR, NLR, and PLR values compared to the control group and indicated that the MLR and NLR act as reliable indicators of knee OA severity [13].
Some studies have reported that elevated blood NLR and PLR levels are associated with knee OA [15, 16]; however, other studies have found no significant increase in these markers [4, 5]. A systematic review and meta-analysis identified an association between both NLR and PLR with the presence of OA and showed that only NLR demonstrated a correlation with disease severity [17]. Zhang et al. reported that NLR, PLR, and SII were positively associated with an increased risk of OA, whereas LMR was inversely associated with OA risk. Moreover, they reported that while NLR was linked to an increased risk of overall OA, no statistical correlation was found with the risk of knee OA [18]. Salamanna et al. suggested that an elevated PLR is linked to a greater probability of moderate to severe OA and that tracking this biomarker could support early identification and effective management of OA severity [19]. In our study, NLR values in both mild and severe OA patient groups were higher compared to the control group. Additionally, SII values were higher in the severe OA patient group than in the control group. In contrast to the findings of Salamanna et al. [19], our study showed that PLR was similar among the groups. These discrepancies across studies could be attributed to differences in study design, patient populations, sample sizes, and methodologies used to assess inflammatory markers. Additionally, factors such as the stage of OA, the presence of comorbidities, variations in local and systemic inflammatory responses, and the status of smoking or Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) use might contribute to these inconsistent findings. However, LMR was identified as being inversely associated with OA risk in our study, similar to the findings in the study by Zhang et al. [18].
Additionally, data on the association between SIRI and OA risk remain limited, whereas the relationship between PNR, a novel inflammatory marker, and the risk of OA has not been previously reported. However, PNR has proven highly effective in identifying and predicting other inflammation-associated disorders.
For example, PNR has been found to inversely correlate with the severity of systemic inflammatory skin diseases [20]. Liu et al. observed that PNR levels were reduced in patients with lupus nephritis who did not have an infection, compared to levels in healthy controls [21]. Wei et al. observed that NPR (inverse of P/N) levels were elevated in patients with infective endocarditis, a condition characterized by inflammation of the endocardium and heart valves. Additionally, they found that elevated NPR was associated with both in-hospital and long-term mortality in these patients [22]. However, until now, the potential of PNR to predict knee OA has not been investigated. In the present study, PNR values differed significantly across all pairwise group comparisons. Specifically, PNR values were higher in the control group compared to both the mild and severe OA groups. Additionally, a negative correlation was observed between KL grade and PNR, indicating that PNR decreased progressively as OA severity increased. ROC analysis further demonstrated the predictive value of PNR in differentiating between OA severity levels and healthy controls.
Xue et al. found a significant positive relationship between OA and SIRI and suggested that both SII, particularly at higher levels and SIRI may act as valuable markers in OA research, underscoring the need for further investigation in this field [11]. Another study suggested that SIRI is an innovative and accessible inflammatory marker that may aid in predicting OA risk in adults [23]. In our study, SIRI values differed significantly across all pairwise group comparisons, with the highest values observed in the severe OA group and the lowest in the control group. Furthermore, SIRI levels were positively correlated with KL grade, while PNR levels demonstrated a negative correlation with KL grade. This evidence highlights the potential role of these markers in assessing OA diagnosis and severity.
The retrospective design and the small sample size were the primary limitations of our study. Additionally, the study lacked data on body mass index, smoking habits, and comorbidities, which are known to influence inflammatory markers [24, 25]. Due to the retrospective nature of the study, data on treatments like NSAIDs were limited, which may affect inflammatory markers. Another limitation of the study was the exclusion of well-established markers of systemic inflammation, such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP).
Conclusion
Elevated SIRI and decreased PNR levels in the mild osteoarthritis group compared to the healthy group, as well as their progressive changes in the severe osteoarthritis group, highlight a relationship between systemic inflammation and OA severity. While these results suggest that SIRI and PNR may hold potential in assessing OA severity, the limited data on their predictive role underscores the need for further investigation to clarify their utility in identifying the diagnosis and severity of OA.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and Human Rights Statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or compareable ethical standards.
Funding: None
Conflict of Interest
The authors declare that there is no conflict of interest.
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Alper Uysal, Uğur Güngör Demir, Ali Nail Demir, Hacer Paksoy Karateke. Relationship between knee osteoarthritis severity and novel peripheral inflammatory markers. Ann Clin Anal Med 2025;16(3):221-226
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Postoperative patient satisfaction and oncological outcomes of Grisotti flap vs. total mastectomy: A retrospective analysis
Halit Özgül 1, Ömer Çelik 2, Burak Şakar 2, Ali Çelik 2, Osman Zekai Öner 2
1 Department of General Surgery, Memorial Antalya Hospital, 2 Department of General Surgery, Faculty of Medicine, University of Health Sciences, Antalya Training and Research Hospital, Antalya, Turkey
DOI: 10.4328/ACAM.22578 Received: 2025-01-22 Accepted: 2025-02-23 Published Online: 2025-02-28 Printed: 2025-03-01 Ann Clin Anal Med 2025;16(3):227-231
Corresponding Author: Ömer Çelik, Department of General Surgery, Faculty of Medicine, University of Health Sciences, Antalya Training and Research Hospital, Antalya, Turkey. E-mail: omercelik@windowslive.com P: +90 505 752 39 66 Corresponding Author ORCID ID: https://orcid.org/0000-0002-4006-2527
Other Authors ORCID ID: Halit Özgül, https://orcid.org/0009-0006-6457-9738 . Burak Şakar, https://orcid.org/0000-0002-0079-2517 . Ali Çelik, https://orcid.org/0009-0005-2789-6091 . Osman Zekai Öner, https://orcid.org/0000-0002-7241-7863
This study was approved by the Ethics Committee of University of Health Sciences Antalya Training and Research Hospital (Date: 2024-12-19, No: 20/30)
Aim: This study aimed to compare Grissoti flap tecnique technique and total mastectomy regarding postoperative patient satisfaction, oncological outcomes, and recurrence rates in patients with centrally located breast tumors.
Material and Methods: A retrospective analysis was conducted on 45 patients who underwent either the Grisotti flap technique (n=15) or total mastectomy (n=30) from August 2021 and January 2024. Demographic, clinicopathological, and prognostic data were analyzed, including tumor stage, surgical margins, recurrence rates, and BREAST-Q scores for breast satisfaction , psychosocial well-being, and sexual well-being.
Results: Patients in the Grisotti group were younger (mean age47.6±11.4 vs. 57.2±6.31 years, p=0.004) and had smaller tumors (median size 15 mm vs. 30 mm, p=0.006). Breast satisfaction (84 vs. 71, p<0.001), psychosocial well-being (80 vs. 70, p<0.001), and sexual well-being scores (81.5 vs. 66, p<0.001) were significantly higher in the Grisotti group. There were o significant differences were observed in local recurrence, axillary dissection, or re-excision rates between the two groups.
Discussion: The Grisotti flap technique demonstrated superior patient satisfaction and psychosocial outcomes while maintaining oncological safety comparable to that of mastectomy. The Grisotti flap tecnique offers a viable alternative to mastectomy, particularly in patients prioritizing aesthetic outcomes. Future studies with larger cohorts are needed to confirm these findings.
Keywords: Grisotti Flap Technique, Mastectomy, Breast Cancer, Patient Satisfaction, Oncological Outcomes
Introduction
Breast cancer is one of the most common types of cancer among women and remains a significant cause of morbidity and mortality worldwide [1, 2]. Modern breast cancer surgery aims not only to achieve effective tumor excision but also to optimize aesthetic and functional outcomes [3]. In this context, oncoplastic surgical approaches play a critical role in ensuring both cancer control and aesthetic balance [4].
Grisotti oncoplastic surgical technique was developed to provide aesthetic reshaping of defects resulting from the excision of tumors located near the nipple-areola complex [5]. This method aims to preserve the anatomical and functional characteristics of the breast tissue while simultaneously ensuring optimal oncological outcomes [6].
Mastecomy is a common procedure involving complete breast removal, often followed by reconstruction. It is preferred in cases where the tumor is extensive, breast-conserving surgery is not feasible, or the patient is at high risk [7–9]. Both surgical methods yield different outcomes based on criteria such as postoperative patient satisfaction, adequacy of surgical resection margins, and long-term recurrence rates. However, studies directly comparing these parameters between Grisotti technique and mastectomy remain limited in the literature.
This study aims to compare Grisotti oncoplastic surgical technique and mastectomy in terms of postoperative patient satisfaction, adequacy of oncological excision margins, and recurrence rates. The study seeks to elucidate the clinical efficacy and patient-centered outcomes of these two surgical approaches.
Material and Methods
We retrospectively analyzed 106 patients treated for centrally located breast tumors at our clinic from August 2021 to January 2024 with either total mastectomy or the Grisotti flap technique. Demographic and clinical data, including gender, age, surgical method applied, and postoperative outcomes, were obtained from the institutional database.
A total of 45 patients were included in the study. The analysis comprised 15 patients who underwent Grisotti flap technique (Group 1) and 30 patients who underwent total mastectomy (Group 2). A comparison was made between the two groups (Figure 1).
The clinicopathological and prognostic data collected in the study included parameters such as age, tumor T and N stages, preferred surgical method, surgical resection status, margin positivity, and local recurrence. In accordance with our standard clinical procedures, the BREAST-Q questionnaire was administered to patients who had completed surgical operations and adjuvant therapy at least six months prior to the study, and informed consent was obtained from all participants. To ensure comprehension in Turkish, the original Swedish version of the questionnaire underwent a validated translation process.
The BREAST-Q questionnaire is a patient-reported outcome measure designed to assess the impact of breast reconstruction surgeries on patient satisfaction. The modules used in this study were as follows:
1. Satisfaction with Breasts: A 16-item scale assessing satisfaction with breast shape, symmetry, sensation, and appearance.
2. Psychosocial Well-being: A 10-item scale evaluating self-confidence in social settings and the extent to which individuals feel equal to or normal compared to other women.
3. Sexual Health: A 6-item scale addressing the impact of breast appearance and surgical intervention on sexual life.
Responses from each scale were combined and converted into standardized scores ranging from 0 to 100, which were analyzed using the official scoring system of the BREAST-Q [10].
The exclusion criteria for the study were as follows:
1. Missing clinicopathological or follow-up data
2. Presence of multicentric or multifocal breast cancer, inflammatory breast cancer, or distant metastases
3. Occurrence of minor complications (e.g., infection, hematoma, seroma)
4. Absence of centrally located breast tumors
5. Conditions contraindicating radiotherapy
6. History of undergoing symmetry surgery
7. Incomplete completion of the questionnaire or non-participation in the survey
8. Comorbidities (collagen collective tissue disease, rheumatoid arthritis, etc)
Ethical Approval
This study was approved by the Ethics Committee of the University of Health Sciences Antalya Training and Research Hospital (Date: 2024-12-19, No: 20/30). The research was conducted in accordance with the ethical principles outlined in the Declaration of Helsinki, adhering strictly to research and publication ethics guidelines.
Results
The study included 45 patients (median age: 52 years, range: 34-77). Of these, 15 (33.3%) underwent the Grisotti flap technique, and 30 (66.6%) underwent mastectomy. Regarding tumor stage, 5 patients (11.1%) were classified as stage 1A, 5 patients (11.1%) as stage 2A, 19 patients (42.2%) as stage 2B, 10 patients (22.2%) as stage 3A, 1 patient (2.2%) as stage 3B, and 5 patients (11.1%) as stage 3C. The mean follow-up duration was 19.7±4.36 months, and the median body mass index (BMI) of the patients was 26.1 kg/m² (IQR: 22-35). The median BREAST-Q score for satisfaction with breast appearance was 74 (range: 40-90), for psychosocial well-being was 72 (range: 42-86), and for sexual well-being was 68 (range: 46-92) (Table 1). Differences in age, tumor size, and pathological subtypes between patients undergoing Grisotti technique and mastectomy were evaluated. The mean age of patients in the Grisotti group was 47.6 ± 11.4 years, whereas the mean age in the mastectomy group was
57.2 ± 6.31 years. This difference was statistically significant (p = 0.004). The median pathological tumor size was 15 mm (IQR: 11-29) in Grisotti group and 30 mm (IQR: 25-48.8) in the mastectomy group, showing a significant difference (p=0.006). Regarding pathological subtypes, 86.7% of patients (13 individuals) in Grisotti group and 86.7% of patients (26 individuals) in the mastectomy group were classified as having ductal carcinoma, with no statistically significant difference in subtype distribution (p=0.223).
No significant differences were observed between the groups concerning axillary dissection, re-excision, or DCIS rates. However, the rate of DCIS was calculated as 66.7% in Grisotti group and 33.3% in the mastectomy group (p=0.056). These findings suggest that Grisotti technique and mastectomy may differ in terms of patient profiles and pathological characteristics (Table 2).
Significant differences were found in the BREAST-Q scores between patients in Grisotti and mastectomy groups. The median satisfaction score with breast appearance was 84 (IQR: 82–86) in Grisotti group and 71 (IQR: 68–74) in the mastectomy group, with this difference being statistically significant (p<0.001). In terms of psychosocial well-being, Grisotti group had a median score of 80 (IQR: 78–82.5), compared to 70 (IQR: 66.5–72) in the mastectomy group (p<0.001). Sexual well-being scores were also significantly higher in Grisotti group, with a median of 81.5 (IQR: 80–82.5) compared to 66 (IQR: 62–68) in the mastectomy group (p<0.001). These findings suggest that Grisotti technique yields better outcomes in terms of patient satisfaction and well-being compared to mastectomy (Table 3).
Discussion
The Grisotti flap technique is increasingly preferred for treating NAC involvement and
centrally located breast tumors due to its ability to provide a wide resection area.Additionally, the preservation of breast shape using dermoglandular flaps allows this method to offer significant superiority in terms of aesthetic and functional outcomes [11, 12]. In our study, we demonstrated that Grisotti technique provides both oncologically safe and cosmetically satisfactory results in patients with NAC involvement or tumors located close to this region.
Traditionally, mastectomy was the first choice for centrally located breast cancers. However, the development of oncoplastic techniques and the widespread use of volume-preserving surgeries in recent years have led to a significant decline in the popularity of mastectomy [13]. Studies have shown no significant differences in oncological outcomes between mastectomy and breast-conserving techniques [14]. Similarly, research comparing mastectomy with oncoplastic techniques has reported no significant differences in oncological outcomes, strongly recommending oncoplastic techniques for both oncological and cosmetic advantages [15]. In a multicenter study by Davies et al., similar findings were observed, and patients were encouraged to choose oncoplastic breast-conserving surgery over mastectomy [16].
Various techniques are available for centrally located breast cancers, including methods like the melon slice and Grisotti flap techniques for tumors involving or close to the nipple-areola complex [17, 18]. A study by Teh et al. examining the 5-year experience of Asian women undergoing Grisotti flap technique for centrally located breast cancers reported high cosmetic satisfaction [19]. Similarly, other long-term studies on oncoplastic breast-conserving surgery have demonstrated excellent cosmetic outcomes with Grisotti flap technique [20, 21]. In their study on Grisotti flap technique applied to central breast cancers, Dabiri et al. emphasized its ease of application, high cosmetic satisfaction, and low complication rates, concluding that it is a viable option [22]. Additionally, Kılıç et al. found that oncoplastic techniques combined with Grisotti flap are preferable to mastectomy in terms of both oncological and cosmetic outcomes for selected advanced-stage breast cancer cases [23].
In our study, we compared the oncological outcomes and BREAST-Q satisfaction survey scores between patients who underwent Grisotti flap technique and those who had mastectomy for tumors involving or near the NAC. The average “Satisfaction with Breasts” score was 84% in Grisotti group, compared to 71% in the mastectomy group, where the unilateral loss of breast tissue was a factor. This difference was statistically significant. Similarly, the “Psychosocial Well-Being” score was 80% in Grisotti group and 70% in the mastectomy group, with Grisotti group showing a statistically significant advantage. The “Sexual Well-Being” score was also significantly higher in Grisotti group, which may be associated with reduced feelings of insecurity due to the preservation of breast tissue.
In terms of oncological outcomes, no statistically significant differences were observed between the groups regarding re-excision and local recurrence rates. Adequate resection margins achieved in patients undergoing Grisotti flap technique contributed to favorable oncological results. Additionally, the mean age of patients in Grisotti group was significantly lower, which may be linked to the increased aesthetic concerns in younger patients.
Conclusion
Grisotti flap technique emerges as an effective option for treating NAC involvement or centrally located tumors, offering both oncological safety and aesthetic success. Our study demonstrates that this technique is significantly superior to mastectomy in terms of patient satisfaction, psychosocial well-being, and sexual health. The absence of differences in oncological outcomes between the two methods supports the preference for Grisotti flap technique in appropriate patient groups with aesthetic concerns. These findings may pave the way for future studies evaluating Grisotti flap technique in larger patient populations.
Limitation
This study has several limitations. Firstly, its retrospective design inherently introduces potential biases and limits the ability to establish causal relationships. Additionally, the relatively small sample size and single-center design may restrict the generalizability of the findings. Another limitation is that only two surgical techniques—mastectomy and oncoplastic surgery with the Grisotti method—were compared, while other breast-conserving techniques were not included in the analysis. Furthermore, surgeries were performed by different surgical teams, which may have introduced variability in operative techniques and postoperative outcomes. The relatively short follow-up period may have also limited the ability to comprehensively assess long-term outcomes, such as recurrence rates and patient satisfaction. Finally, the reliance on subjective data for psychosocial and sexual health evaluations introduces potential bias, as these outcomes can be influenced by individual perceptions and cultural differences. These limitations should be considered when interpreting the results of this study.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and Human Rights Statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or compareable ethical standards.
Funding: None
Conflict of Interest
The authors declare that there is no conflict of interest.
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Download attachments: 10.4328.ACAM.22578
Halit Özgül, Ömer Çelik, Burak Şakar, Ali Çelik, Osman Zekai Öner. Postoperative patient satisfaction and oncological outcomes of Grisotti flap vs. total mastectomy: A retrospective analysis. Ann Clin Anal Med 2025;16(3):227-231
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