Aim: This study aimed to investigate the relationship between biochemical recurrence after radical prostatectomy and CD47 glycoprotein expression level assessed according to immunohistochemical staining pattern.

Material and Methods: Pathologic specimens of 54 patients who underwent retropubic radical prostatectomy at our clinic were stained for CD47. Staining patterns showed a level of expression. Staining patterns of patients with and without biochemical recurrence during follow-up were statistically compared.

Results: The mean age was 64.9±5.5 years, mean preoperative prostate-specific antigen (PSA) was 9.38±4.17 ng/dl, and the mean follow-up time was 45.9±6.5 months. Biochemical recurrence was identified in 15 (28%) patients. The CD47 staining pattern was significantly prevalent in the biochemical recurrence group (p=0.000). Patients with biochemical recurrence had higher Gleason scores in both biopsy specimens and surgical specimens (p=0.000, p=0.000 respectively).

Discussion: Biochemical recurrence frequently develops after radical prostatectomy. Various parameters have been investigated to predict this occurrence. Our study is the first in the literature to demonstrate increased CD47 expression as an independent predictor of biochemical recurrence following radical prostatectomy.

Keywords: Prostate Adenocarcinoma, CD47, Gleason Score, Biochemical Recurrence, Markers

Introduction

Prostate adenocarcinoma (PCa) is a common malignancy in the USA and is the second most common cause of cancer-related deaths in males [1]. There are various therapeutic options in the treatment of prostate cancer. Radical prostatectomy has been recognized as the standard treatment for localized prostate cancer [2, 3]. However, recurrence may occur in some patients after surgery and is known to be associated with a prostate-specific antigen (PSA), Gleason score (GS), and stage of the disease [4]. Biochemical recurrence (BCR) is used as an early indicator of recurrent disease and/or metastasis. BCR is considered as a serum PSA level above 0.2 mg/dl. BCR incidence in a 5-10-year follow-up period is relatively high [5]. Early detection of BCR and even its prediction holds great importance in the clinical prognosis of patients.
A Cluster of Differentiation 47 (CD47) is a transmembrane receptor glycoprotein for the immunoglobulin superfamily. It plays a role as a receptor for Thrombospondin-1 (TSP-1) and Signal Regulating Protein-α (SIRP-α). These two interactions of CD47 have been encountered in various pathologies, including hemostasis, ischemic damage, inflammation, radiation injury, and cancer. CD47 functions as a ligand in its relationship with SIRP-α. SIRP-α is an inhibitory transmembrane receptor and plays a role in regulating the two-way signaling pathway that permits intercellular transmission. The purpose of CD47 as a ligand for this receptor and its “don’t-eat-me” message to phagocytic cells and its increased expression in tumor cells have been demonstrated. There are also publications indicating that increased expression of CD47 is associated with decreased cancer-related survival rates [6].
In this study, we investigated the relationship between BCR relapse occurrence and CD47 staining pattern in pathology specimens in patients who underwent radical prostatectomy for prostate cancer. We hope that our retrospective study, as the first on this topic, will be a contribution to the literature.

Material and Methods

A total of 54 patients who underwent radical prostatectomy for prostate cancer at our clinic were included in this study. Patients with a history of any other malignancies and chemotherapy or radiotherapy were excluded from the study. Patients with primary prostate adenocarcinoma were included in the study. Ultrasound-guided prostate needle biopsy due to elevated PSA or abnormal digital rectal examination had been conducted on all patients. Demographic data, as well as biopsy and pathological assessment of surgical specimens, CD47 staining patterns, and PSA follow-up values, were recorded. Surgical specimens were stained with CD47 only. In the mean follow-up period of 4 years, the statistical relationship of CD47 staining pattern was examined in the BCR recurrence group.
All patients had nonmetastatic prostate cancer, and they underwent retropubic radical prostatectomy. Patients were followed-up every three months for clinical evaluation and PSA measurement. Beckman Coulter brand Unicel DXC 800 Synchron clinical biochemistry system was used to measure PSA with the chemiluminescence method.
CD47 immunohistochemical staining procedure
For the immunohistochemical study of all cases, 4-micron thick sections with paraffin blocks and a rotary microtome were coated with Poly-L-lysine. The avidin-biotin method was used as the immunohistochemical staining system.
Slides of the sections were kept in the incubator at 80ºC for 30 minutes, for melting the paraffin. The slides were removed from the incubator and kept in xylol for 10 minutes. They were then rehydrated by placing them in three different alcohols of densities ranging from 90% to 70% for five minutes. The rehydrated sections were incubated in hydrogen peroxide for five minutes and rinsed with distilled water. The slides were placed in a saline solution containing citrate buffer and microwaved at 850 watts for five minutes and 500 watts for five minutes. Microwaved slides were left to cool in the citrate buffer. The slides were removed and rinsed in distilled water then incubated in phosphate buffer solution (PBS) for two minutes in two batches. Margins of the tissues on the slides were marked with a PAP Pen. The vicinity was dried with blotting paper, and each slide was placed in a covered humidity chamber. CD47 (Dako EnVision Cat. No. 1046) was stained with two drops of antibodies from these dyes onto the slides. They were left covered for 30 minutes and filtered onto blotting paper. They sat for five minutes and were submerged in PBS. The slides were dried, and drops of biotinylated link for streptavidin-HRP/AP (UltraVision Large Volume Detection System of Lab Vision Corporation) were applied and left to sit for 10 minutes. After the biotinylated link for streptavidin-HRP/AP solution was drained, they were left in PBS in two batches for five minutes. The slides were dried, and Streptavidin-HRP solution drops were applied and left for 10 minutes. After draining the streptavidin-HRP solution, PBS was gone for five minutes, and then slides were removed and dried. At this stage, the DAB+ chromogen solution was prepared by dropping two drops of chromogen solution into 1cc DAB (Diamino benzene) substrate, which was dripped on slides and kept for 5-7 minutes. The chromogen slides were filtered and rinsed rapidly with distilled water.
For counterstaining, slides were kept in Mayer hematoxylin for one minute and washed with distilled water. The slides were passed through an alcohol series and dried in the incubator. The slides were removed from the incubator and kept in xylol, applied Entellan drops, and closed with a coverglass.
The slides obtained according to the method described, immunohistochemically prepared for CD47 evaluation, were examined and scored according to the following method under the Olympus brand BX51 microscope. Brown staining of tumor cell nuclei was used as a criterion for CD47 antigen positivity.

Staining assessment was conducted in four categories:

0: No staining in tumor cells

1: < 35% staining in tumor cells

2: 35-70% staining in tumor cells

3: >70% staining in tumor cells

In this evaluation, the lack of staining was considered negative (category 0), while categories 1-3 were considered positive (Figure 1).

Ethical Consideration

The study obtained approval from the Turkey Yüksek Ihtisas Training and Research Hospital Education and Planning Board (No. 4312). The study was planned under the principles of the Helsinki Declaration. Informed written consent was acquired from all patients.

Statistical Analysis

Data obtained in this study were statistically evaluated with SPSS version 22.0 (SPSS IBM, Statistical Package for Social Sciences, Chicago, IL, USA) statistical software. For statistical analysis, the Mann-Whitney U test was used to compare groups with and without BCR according to the categorical, ordinal variable of CD47 expression level. Student’s-t independent test was used to compare numerical data including age, preoperative and postoperative PSA, and follow-up time in groups with a normal distribution. The Mann-Whitney U test was used to compare the Gleason score of biopsies and surgical specimens between the groups. P<0.05 values were considered statistically significant.

Results

The mean age of the 54 patients included in the study was 64.9±5.5 years, mean preoperative PSA was 9.38±4.17 ng/dl, and the mean follow-up time was 45.9±6.5 months. The mean prostate volume was 64.4±21.4 cc (Table 1).
Eight of the patients were T2a (15%), 19 were T2b (35%), and 20 were T2c (37%), and 7 were T3a (13%). T staging of the patients is shown in Figure 2.
Surgical margin positivity was detected in 4 (7.4%) patients. BCR occurred in the follow-up of 15 patients. Thirteen patients were upgraded, and two patients were downgraded according to the assessment of biopsy and surgical specimens. The Gleason score remained unchanged in 39 patients. Five of the 13 patients with the upgrade and ten of the 39 consistent patients developed BCR, while BCR was not observed in the two downgraded patients. Mean CD47 staining was 1.92 in upgraded patients, 1.44 in unchanged patients, and 0.5 in downgraded patients.
There was a statistically significant difference in CD47 staining patterns between the patients who developed BCR (Group 1) and those who did not (Group 2) (p=0.000). Comparison of the groups showed a significant difference between preop and postop PSA, while age and follow-up times were similar (Table 2).
When biopsy GS and surgical GS values were compared separately, there was also a statistically significant difference.
The mean period until patients developed BCR was 24.6 months in six patients with pattern three staining and 31.2 months in nine patients with pattern two stainings. Meantime, until BCR, occurrence was 29.3 months in all patients.

Discussion

Studies in recent years have identified prostate adenocarcinoma as the most common malignancy [7]. It accounts for 15% of all cancers, with more than 1.1 million new diagnoses per year [8]. In autopsy studies, the incidence was 5% under the age of 30, while it was 60% over the age of 80 [9]. Its incidence is higher in developed societies such as North America, Northern and Western Europe [10]. The introduction of PSA’s clinical use has led to better early diagnosis rates as well as improved surgical techniques, fewer complications, and increased survival rates with advanced follow-up protocols. Radical prostatectomy remains the gold standard in the treatment of organ-localized disease [2]. BCR rates at the end of a 10-year follow-up period ranged between 35-50% [5]. BCR may be an early sign of recurrent primary disease or metastasis. It should also be kept in mind that BCR may not necessarily be associated with clinical recurrence, progression, or disease-specific mortality, but may result from indolent prostate cancer or postoperative benign tissue. Predicting BCR remains helpful in reducing morbidity and mortality associated with the disease.
Numerous studies have been conducted on preoperative PSA levels, histological grade, positive surgical margins, and clinical-stage to predict disease-related death [11]. Studies show postoperative recurrence associated with prostate-specific antigen (PSA), Gleason score (GS), and disease stage [4]. Positive surgical margins (PSM) are also an independent risk factor for recurrent disease and/or metastasis. Many studies also indicate PSM as an independent risk factor of BCR. PSM is detected in up to 30% of cases after radical prostatectomy [12]. While PSM may not necessarily lead to clinical disease, it is a problem that must be well-managed.
CD 47 is a cell surface glycoprotein that acts as a counter receptor for SIRP-α, playing a role in the immune system’s recognition of the body’s cells. CD 47 also independently functions as a signal receptor to regulate the cell’s response to stress. CD 47, also known as integrin-related protein or Rh-related protein, was first described as a protein lacking in erythrocytes of patients with Rh (-) hemolytic anemia [13].
CD47 has two main functions. The first is its interaction with SIRPα on phagocytic cells resulting in the generation of a “don’t-eat-me” signal towards erythrocytes carrying CD47 at the minimum required concentration, therefore preventing their disposal from circulation. Cells carrying trace amounts or chemically modified CD47 are marked for elimination by phagocytes, while malignant cells with increased CD47 levels are resistant to elimination. The second main role of CD47 is its mechanism as a signal receptor. CD47 binds to TSP-1, generating a signal, and regulating intracellular calcium increase, cyclic nucleotide, integrin, cell status with growth factor signaling, viability, and resistance to stress [14].
Increased expression of CD47 occurs in many human malignancies. Some studies indicate that elevated expression can be used as a diagnostic marker and negative prognostic factor [6]. Based on a similar elevation in hematopoietic stem cells, increased CD47 expression has been reported as a marker that protects cancer stem cells from being eliminated by phagocytes [15].
There are studies in which CD47 expression is associated with poor prognosis and disease progression [16, 17]. Negative effects on survival have been reported in different tumors such as lung, blood, and liver [18, 19]. In addition, there are studies in the literature in which increased CD47 expression in different tumor types was determined as an independent risk factor for recurrence [20, 21]. There is no study in the literature regarding CD47 expression in prostate cancer. This study was conducted to determine whether or not a CD47 expression level can be used as an indicator of BCR. Many studies have investigated the prediction of BCR. A portion of these studies is clinical, while a large number are also laboratory-based.
In a study by Sun et al., the predictive value of microRNA-126 towards BCR was investigated in 128 patients, in whom decreased miRNA-126 expression level was associated with an increased BCR risk [22]. Joung et al. investigated prostate-specific membrane antigen (PSMA) in 124 patients and indicated that serum PSMA levels could be used as a BCR marker [23]. Bauman et al. found that decreased CD147 expression was an independent risk factor for BCR [24]. Shahait et al. conducted a study on 117 patients and reported that increased Ki-67 expression in surgical margin cells was an independent marker for BCR [25].

Conclusion

In conclusion, our study found that increased CD47 expression level after radical prostatectomy was an independent risk factor for BCR. A low number of patients and short follow-up time were limitations of our study; however, it is important to note that our study is the first topic in the literature.

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 comparable ethical standards. No animal or human studies were carried out by the authors for this article.

Funding: None

Conflict of interest

None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.

References

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2. Han M, Partin AW, Piantadosi S, Epstein JI, Walsh PC. Era specific biochemical recurrence-free survival following radical prostatectomy for clinically localized prostate cancer. J Urol. 2001;166(2):416-9.
3. Marra G, Valerio M, Heidegger I, Tsaur I, Mathieu R, Ceci F, et al. Management of Patients with Node-positive Prostate Cancer at Radical Prostatectomy and Pelvic Lymph Node Dissection: A Systematic Review. Eur Urol Oncol. 2020;3(5):565-81.
4. Ishizaki F, Hara N, Koike H, Kawaguchi M, Tadokoro A, Takizawa I, et al. Prediction of pathological and oncological outcomes based on extended prostate biopsy results in patients with prostate cancer receiving radical prostatectomy: a single institution study. Diagn Pathol. 2012;7:68.
5. Freedland SJ, Humphreys EB, Mangold LA, Eisenberger M, Dorey FJ, Walsh PC, et al. Risk of prostate cancer-specific mortality following biochemical recurrence after radical prostatectomy. JAMA. 2005;294(4):433-9.
6. Willingham SB, Volkmer JP, Gentles AJ, Sahoo D, Dalerba P, Mitra SS, et al. The CD47signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors. Proc Natl Acad Sci U S A. 2012;109(17):6662-7
7. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69-90
8. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136(5):E359-86.
9. Bell KJ, Del Mar C, Wright G, Dickinson J, Glasziou P. Prevalence of incidental prostate cancer: A systematic review of autopsy studies. Int J Cancer. 2015;137(7):1749-57.
10. Haas GP, Delongchamps N, Brawley OW, Wang CY, de la Roza G. The worldwide epidemiology of prostate cancer: perspectives from autopsy studies. Can J Urol. 2008;15(1):3866-71.
11. Roehl KA, Han M, Ramos CG, Antenor JA, Catalona WJ. Cancer progression and survival rates following anatomical radical retropubic prostatectomy in 3,478 consecutive patients: Long-term results. J Urol. 2004;172(3):910-4.
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15. Jaiswal S, Jamieson CH, Pang WW, Park CY, Chao MP, Majeti R. CD47 is upregulated on circulating hematopoietic stem cells and leukemia cells to avoid phagocytosis. Cell. 2009;138(2):271-85.
16. Tuo Hu , Huashan Liu , Zhenxing Liang , Fengwei Wang , Chi Zhou , Xiaobin Zheng , et al. Tumor-intrinsic CD47 signal regulates glycolysis and promotes colorectal cancer cell growth and metastasis. Theranostics. 2020;10(9):4056-72.
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Aim: An experimental study was designed to find an anatomical correlation between the area of the hindfoot, height and weight of an individual.

Material and Methods: Medical students of preclinical years were recruited into the study and their footprints were taken on a predesigned A4-sized paper. The foot was divided by geometrical tools into three regions: forefoot, midfoot and hindfoot area. The area of the hindfoot was calculated using the specific image-J software after standardizing the metric units into pixels.

Result: Analysis through SPSS showed a strong relationship between the studied parameters.

Discussion: As per our knowledge, this is the first study defining the hindfoot surface area and correlating it with the height and weight of the individual. A strong association was found between the studies parameters that may be useful in predicting complications related to obesity in near future.

Keywords: Area, Body Mass Index, BMI; Hindfoot, Foot Arch, Obesity

Introduction

Foot and ankle injuries are among the most severe in daily life and sports [1]. The complicated foot-ankle complex consists of 26 bones moving ground reaction forces to the lower extremity. The rear-foot is often subjected to injury and deformity due to its role in receiving and transmitting such forces to and from the rest of the body.
One of the seven articulating bones that make up the tarsus is calcaneus. The calcaneus along with the talus forms the skeleton called the hindfoot bone. The part of calcaneus that is in contact with the ground is commonly called “Heel” that articulates mainly with the talus and cuboid bones. Numerous ligaments and muscles bind themselves to the calcaneus and aid with its role in biomechanics of human bipedals. The calcaneus acts as an attachment point for a powerful tendon (Achilles tendon), which aids in standing, walking, running and jumping and the plantar flexion of the foot. The calcaneus also serves as a point of attachment for the muscles, which move the toes.
In a simplified fashion, the subtalar joint can be divided into two parts: anterior and posterior. However, it is important to note that not only the articulating surfaces of the calcaneus and the navicular bone support the talar head, but also the ‘spring’ ligament. This network of ligaments plays an important role in stabilizing the talar head. The insufficiency of this structure can lead to deformity of the acquired flat foot.
The size and shape of the three facets of the calcaneus differ among individuals. Both the anterior and middle facets are concave, while the posterior facets are convex [2]. The posterior facets are larger than the middle and anterior facets and are separated by the interosseous calcaneal ligament from the other two facets [3].
In the past, several studies were conducted to search for the relation between the foot structure and the body mass index (BMI). Though those researching a relationship between the individual foot areas and the index of body mass were scanty. Many of those researches indicated a certain relationship between the arches of the foot and the BMI [4].
The current paper evaluates another hypothesis that an individual’s hindfoot area is directly proportional to one’s body mass index in the given context information.

Material and Methods

A theoretical, quantitative and experimental analysis was planned to verify the hypothesis. The scientific proposal was submitted for approval to the Ethics Committee. The data collection began after the approval of the study. The subjects’ confidentiality was thoroughly protected in the report.
The data collection included documenting the individual’s weight, height and foot imprint. Any individual with any foot infection, deformity and foot injury was excluded. The rationale of the research, to investigate the relationship between the foot pattern and the structure of the body, was clarified to the volunteers. The procedure obtained verbal consent and the intention was thoroughly explained to the subjects, beforehand.
An A4-sized paper with fixed measured calibrations printed was used to take the ink embossed footprints of the subjects. In addition to a space for writing the weight and height of the person, the paper had numbered square boxes of 1cm2. For recording the weight and height, respectively, an electronic weighing scale was used with the embedded stadiometer.
A customized thick foam pad was used as a stamping pad. This pad was pasted into a tray with a pasting solution and soaked with office stamp ink that is used for normal thumb impressions.
Weight was measured in kilograms at the beginning of the experiment, while height was noted in centimeters for each person. The subject’s body mass index (BMI) was then measured and noted using the standard formula as shown below:
BMI = Weight (in kilograms) / Height (in square centimeters).
The subjects were asked to better soak the sole of their feet in the ink by pressing and standing barefoot on the ink-soaked foot-pad; they were then asked to step out of the foam pad and emboss their foot on the A4 size paper mentioned above. The foot ink prints thus taken, were then let to air dry on the paper.
Next, the exact outline of the footprint was then delicately drawn by hand with a dark marker in the dried footprint. The long axis of each sample was drawn to standardize the alignment. The middle of the middle finger was used as a guide for this purpose. The extent of the foot area that needed to be measured has been marked using the mathematical square package. The long axis of the foot was then split into three equal regions; the perpendiculars were drawn using the same square set to outline the three regions of the foot, namely: fore-foot (F), mid-foot (M) and rear or hind-foot (R) (Figure 1).
Next, at a high resolution, these papers were scanned in color and saved as JPEG files. In the “FIJI” image software, which is an advanced version of the “ImageJ2” software, these files were opened. A fixed unit of length (3 cm) was standardized into the pixels on the opened images. The area for each divided region of the foot was measured using the free hand drawing tool of the image-J program, and the mean reading in square centimeters was registered.
Using SPSS tools, reported data were analyzed and p-values were determined by applying a single sample t-test for the variables. A p-value ≤ 0.05 was taken as a significant level of difference in the calculated results.

Results

Extrapolation of the data using SPSS showed a strong correlation between the two parameters. The calculated p -value came out to be 0.00 showing the highly significant difference between the means of the two calculated parameters. The mean BMI was closer to, but slightly above normal. The hindfoot area was found to have a low deviation from the mean and hence significant.

Discussion

Foot pain is a common complaint which affects nearly one in four adults after the age of 45 [6]. Obesity is a contributing factor in foot pain development [7], and elevated body mass index (BMI) is closely correlated with both chronic plantar heel pain and non-specific foot pain [8]. In addition, the feet of obese people are structurally and physically different from their non-obese counterparts, manifesting as thicker, broader and heavier, along with flatter-foot postures, reduced joint motion range and increased plantar peak pressures [9, 10].
This study investigated associations between weight status and normal plantar surface area among youth and specially calculated the heel region. The limitation of this study was that the number of participants was not enough.
Prosperity with the mechanization of nations brings with it a sedentary lifestyle in which the morbid person enters a cascade of obesity, contributing to, but not limited to hypertension, diabetes, etc., and many related diseases. A new class of patients has emerged in the recent past that can be termed as suffering from lifestyle diseases.
In our study, we have attempted to equate body size of the individuals with an important anatomical region of the foot skeleton. We hope that this simplest data can be converted into useful predictors of the imminent risk factors for obesity-related diseases using basic calculations. Furthermore, in this study, hindfoot surface area is investigated according to BMI to obtain data for future use in the fields of physiotherapy intervention, assistive devices, and shoes that address foot diseases.
Studies have shown that people with obesity show an increase in non-uniform plantar pressures, with midfoot and forefoot areas of highest pressure relative to non-obese people [10–12]. Provided that obesity is strongly associated with plantar heel pain [13, 14], increased plantar pressure became discordant where the pain was strongly associated with unnecessary pressure. Paradoxically, as opposed to monitors, people with chronic heel pain show reduced load under the heel [15].
Musculoskeletal pain has a bidirectional relationship with both obesity [16] and depression [17], whereas depression and obesity frequently intensify each other [18]. Such associations, however, are not restricted to weight-bearing joints with a reported association between elevated BMI and symptomatic hand osteoarthritis [19], indicating that metabolic mechanisms, including systemic inflammation [20], can underpin the relationship between obesity and joint pain [21].
The Western Pacific Regional Committee of the WHO on a new BMI for Asians identified 23kg/m2 or higher as overweight, and 25 kg/m2 or higher as obesity [22]. It is associated with increased body fat, BMI, and waist measurements, which adversely affect daily and physical activity activities [23]. The incidence of degenerative foot diseases is also growing with rising life expectancy, and diabetic foot disease is also growing with increasing numbers of patients with diabetes [24]. Plantar pressure is also assessed in patients with pain, diabetes or rheumatism to overcome foot problems [25].
In addition, several comparative studies have been performed on plantar pressure and balance in patients suffering from different diseases, but not many of them have been on foot changes in the general population. One of the drawbacks of this analysis is its modest sample size. Further future research involving more cohorts of different ages may improve reliability with a variety of outcomes.

Conclusion

The findings of this study can be used as basic evidence for exercise programs in order to increase the level of spontaneity in the obesity community by increasing the hindfoot level, or for studies on reducing foot swaying.
Clinically, our findings imply that barring progressive metabolic changes that may precipitate type II diabetes and associated neuropathy, youth with obesity. Further clinical studies on patient populations are needed to validate these conclusions, as well as to determine whether and how they can be precisely applied to different populations. Our findings could prove valuable in various areas of application. However, despite limitations, the results of this study provided preliminary information for future prospective, randomized clinical trials with larger samples. In addition, to the best of our knowledge, this is the first study defining the hindfoot surface area and correlating it with the height and weight of the individual.

Acknowledgment

The author acknowledges the efforts of Mr. Hassan Mohammad Iqbal, lecturer of the anatomy, college of medicine, Northern Border University for all his extended help during this project.

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 comparable ethical standards. No animal or human studies were carried out by the authors for this article.

Funding: None

Conflict of interest

None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.

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