Surgery (Austin & Northern Health) - Theses
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ItemNo Preview AvailableThe Use of Prehabilitation in Colorectal Cancer Surgery( 2021)Abstract Introduction: Prehabilitation in colorectal cancer surgery is an emerging opportunity in the field of perioperative medicine designed to improve the standard of care. The thesis aim is to identify the current attitudes towards risk stratification and the delivery of prehabilitation programs to colorectal cancer patients. The impact of a “Bundle-of-Care” approach to prehabilitation prior to major GI cancer surgery has not previously been explored. Risk stratification can enable the clinician to differentiate modifiable and non-modifiable risk. Cardiopulmonary exercise testing (CPET) is the gold standard assessment of functional capacity and is therefore the most reproducible risk stratification tool. However, availability of CPET in Australasian Hospitals is limited. Furthermore, the accuracy of traditional CPET parameters is reduced in patients with sarcopenic obesity and chemotoxicity. Conventional CPET focus on VO2 at anaerobic threshold (AT), may be superseded by a holistic approach that analyses multiple physiological and biochemical parameters to not only improve risk prediction, but to optimise reversible patient factors within the prehabilitation window. As part of prehabilitation initiatives, a number of unimodal components have been investigated in isolation. Haematinic prehabilitation to optimize oxygen carrying capacity in circulating blood volume an opportunity for improvement of fitness. Methods: An electronic survey was distributed to all members of the Colorectal Surgical Society of Australia and New Zealand (CSSANZ). A comprehensive review of published trials in preoperative optimisation of GI cancer patients was conducted according to the Preferred Reporting Items or Systematic Review and Meta-Analysis (PRISMA) guidelines. A retrospective cohort of 43 consecutive patients scheduled for major cancer surgery was used to identify if the peakVO2 derived from the patient administered questionnaire, “Duke Activity Severity index (DASI)” would correlate with the CPET peakVO2. A retrospective cohort of 82 consecutive patients was used to investigate novel risk stratification variables. A further retrospective cohort of 65 cancer patients that underwent a ferric carboxymaltose (FCM) infusion prior to surgery were assessed as to the feasibility and potential haematinic optimisation following intervention. Based on the above findings, a protocol was derived for a potential randomized control trial in order to determine if the preoperative functional status (as measured by CPET) of anaemic and/or iron deficient colorectal cancer patients could be improved by preoperative intravenous infusion of FCM. Results: There does not appear to be enough robust data to make specific conclusions based on the systematic review of multimodal prehabilitation in colorectal cancer surgery. There is no harm identified with prehabilitation, however prior to routine integration of multimodal prehabilitation programs into clinical practice, adequately powered trials that utilise CPET, therefore ensuring uniform endpoints would be of benefit. Awareness of objective preoperative risk stratification and prehabilitation amongst CSSANZ members is variable and current utilisation of prehabilitation programs is low. There is growing interest in this area amongst the colorectal community, who regard implementation of prehabilitation programs as technically feasible within the majority of represented institutions. DASI-predicted peakVO2 did overpredict the actual peakVO2 values, with a more significant discrepancy for patients with higher peakVO2. The CPET-derived parameters that were most predictive of reduced overall survival included peakVO2 (corrected to body surface area) and (Ve/VCO2) at anaerobic threshold. Specifically, one in two patients with a preoperative pVO2 <710 ml/kg/m2 and Ve/VCO2 at AT >35 had died within one year of surgery. A preoperative pro-inflammatory state added significant ability to discriminate between survivors and non-survivors. Charlson Co-morbidity Index however, did not discriminate survivors from non-survivors. The overall numbers from the retrospective analysis of FCM infusion did not demonstrate any meaningful conclusions. However, FCM infusion is safe and feasible in this patient population, therefore, the proposed randomized control trial would contribute to the literature on this topic. Conclusion: The “Bundle-of-Care” approach to prehabilitation makes intuitive sense, however robust data is required prior to mass implementation. The survey of CSSANZ members does not demonstrate current use or core knowledge, but there is significant interest. Subjective assessment of functional capacity (such as DASI) is inaccurate and CPET will continue to play an integral role in risk stratification. Specific CPET parameters require further refinement, particularly in sarcopenic patients with significant co-morbidities. Haematinic optimization is safe and would benefit a significant proportion of colorectal cancer patients. A multidisciplinary approach to implementation of prehabilitation programs is key. In order to proceed, it is imperative that early triage of patients to preoperative clinics, identification of reversible comorbid disease, including deconditioning, and implementation of interventions occurs in parallel with the diagnostic work up of the surgical disease.
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ItemProcurement-related liver injury: an analysis of the incidence, risk factors and consequences at the Victorian Liver Transplant Unit( 2020)Introduction Liver transplantation is an established treatment for liver failure, and its success relies on the quality of the donated organ. A systematic review on the topic of procurement-related liver injury (PRLI) showed that studies on PRLI are few, with widely variable methodologies and results, and may not apply to modern day practice. This is the first Australian study examining risk factors and consequences of PRLI. Method The Victorian Liver Transplant database was examined for PRLI from deceased liver donors from 2010 to 2017. Information regarding the donor, surgery and subsequent transplantation was obtained. PRLI details were retrieved from the “organ retrieval report form” (ORRF). Risk factors and complications for PRLI were obtained and analyzed. Results 420 transplants were included in this study. There were 46 injuries in 45 livers equating to an injury rate of 10.7%. Aberrant anatomy increased the risk of PRLI (OR 3.68 CI 1.84 – 7.35, p<0.001). Surgeon experience of less than 172 cases increased the risk of PRLI (OR 5.96, CI 1.29 – 27.51, p=0.02). On subgroup analysis aberrant anatomy increased the risk of vascular injury and lower surgeon experience increased the risk of parenchymal injury. There was no difference in patient or graft survival for injured grafts with the exception of reduced graft survival at 3 months for injuries requiring repair or modification (78.6% vs. 93.3%, p=0.028). Complication rates were the same in the presence of PRLI. Conclusion This study shows that PRLI is common, and that aberrant anatomy and surgeon inexperience increase the risk of injury. Similar outcomes for transplantation despite the presence of PRLI indicate that injuries are being appropriately managed in the Australian setting.
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ItemThe effects of cannabinoid derivatives on pancreatic cancer( 2019)Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignant solid tumours and its treatment has not been efficiently improved during the last decade. The overall 5-year survival rate of pancreatic cancer is 9%, which is expected to become the second major cause of cancer-related mortality by 2030. Chemotherapy has been used as the main treatment of choice in the majority of patients bearing either locally advanced or metastatic tumours. Gemcitabine alone or gemcitabine-based combination chemotherapy is commonly used worldwide for the treatment of pancreatic cancer. The poor treatment response to chemotherapy might be related to a dense stroma that is associated with these cancers. However, more effective treatment techniques and novel targets are urgently needed to improve the treatment response. Plant-derived cannabinoids have been used for medical purposes for over a thousand years. The main active cannabinoid components are tetrahydrocannabinol (THC) and cannabidiol (CBD) that are obtained from Cannabis sativa and Cannabis indica. THC exerts its effects via a receptor dependent mechanism, while CBD can act through a receptor and receptor independent mechanisms. CBD can modulate the adverse effects of THC such as its psychoactive effects. To date, three cannabinoids receptors have been identified, CB1, CB2, and GPR55, which are located on the cell membrane and members of the G-protein coupled receptor (GPCR) family. Cannabinoid receptors play an important role in biological and pathological activities such as inflammation, oxidative stress, metabolism, fibrosis, appetite control, memory and emotion. The main aims of this study were to look at the expression of cannabinoid receptors in pancreatic cancer cell lines and pancreatic cancer specimens, detect the correlation of cannabinoid receptors expression with patient’s outcome, determine the effect of cannabinoids alone or in combination with chemotherapy on pancreatic cancer cells in vivo and in vitro. Methods: Western blot assay, SRB-assay, immunohistochemistry staining, wound healing assay and an animal model were the main methods used in this study. Results: The expression of CB1 and CB2 receptors were shown in all the human and murine pancreatic cancer cell lines, stellate cells, and the gemcitabine resistant cell lines. The significant correlation between high expression of GPR55 and worsened PDAC patients’ outcome were demonstrated. In addition, the positive surgical margin and moderate to dense stromal status are associated with a poorer and prolonged survival in patients, respectively. Both CBD and THC dose-dependently inhibited cell proliferation of pancreatic cancer cells, although CBD was more effective than THC. All the different combination ratios of CBD to THC showed significant effects on the inhibition of cancer cell proliferation compared with a single treatment of drugs, although a 1:1 ratio of THC to CBD demonstrated the maximal inhibitory effect on cell proliferation and migration. Synergistic inhibition was observed for combined THC and CBD treatments, and when THC/CBD was combined. with gemcitabine (combination index < 1; using the Chou-Talalay method). In this study, cannabis oil, which contained a 1:1 ratio of CBD to THC and other cannabinoid components has been used for in vitro and in vivo experiments. The effects of this oil on pancreatic cancer cell proliferation and migration was less than either the pure CBD or THC alone. Moreover, cannabis oil alone or in combination with gemcitabine did not significantly inhibit tumour growth in a xenograft model. Bioavailability and absorption patterns of this oil are unknown and further studies are required. Conclusion: Cannabinoid receptors are highly expressed in pancreatic cancer cell lines. The high intensity of GPR55 was correlated with poor patients’ outcome. The 1:1 ratio of THC to CBD provided a significant inhibitory effect on pancreatic cancer proliferation and migration. Combination of cannabinoids with gemcitabine had a synergistic effect on pancreatic cancer inhibition in in vitro study. The cannabis oil used in our in vitro study showed a lesser effect on blocking proliferation and migration of cancer cells than purified THC and CBD. We could not determine the clinically significant effect on pancreatic cancer in our in vivo study using cannabis oil. No absorption characteristics of studied cannabis oil have been reported, therefore more in vivo bioavailability studies are required for the future work.
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ItemCommunication, technology and instruments in the modern contemporary setting of urology( 2018)The 2017 Sensis Social Media Report demonstrated an increase in Australians being involved in Social Media Platform. About 84% of Australians access the Internet on a daily basis with higher usage among the age group under 30 year old and less common among people age group of 40 and over. Delivering accurate medical information to patients or caregivers is essential in any medical practice. Having free access healthcare information with the unknown potential of having inaccurate medical information or unmoderated website for quality control while online consumers with health information-seeking behaviour could lead to false health information. Technological innovation has aided the growth in the healthcare industry. The wide expansion of modes of communication and surgical equipments, especially in urology has definitely changed the practice in the past few decades. It is one of the surgical specialty that has increasingly become a technology-driven specialty. With new innovative surgical instruments aiming to improve the outcomes for patients and the ease of accessibility of communication technology in medical practice has certainly improved in various ways within the healthcare setting. Technology has been part of medical and surgical practice and this continue to change the way medicine would be practice in the future. With regards to surgical instruments, the advancement of endoscopic procedures have shown to be a huge advantage in the surgical practice. Although it does not involve all types of surgery but it has been a turning point in some surgical cases. For example, open surgery was the conventional method of treating benign prostatic hyperplasia (BPH) but new treatments have been developed over the years without going through major surgery. BPH is a common condition for men as they get older which causes prostate enlargement which leads lower urinary tract symptoms (LUTS). The BPH prevalence examined in several autopsy studies showed that 20% for men stated to develop in their 40s, reaching between 50% to 60% for men in their 60s, and from 80% to 90% for men in their 70s and 80s. BPH If left untreated, this will eventually lead to blockage of the urinary tract, causing problems to bladder, urinary tract or kidney. The current "gold standard" of treating BPH surgically is transurethral resection of the prostate (TURP) using endoscopic method to remove prostate tissue. Although this method is an effective treatment clearing obstructive prostate tissue, the main side effects include bleeding. Laser surgical therapy for BPH was introduced for more than 20 years. To this date, there are various types of laser therapy that are readily available for surgical treatment of BPH with the unique properties of each laser to allow accurate treatment of BPH. The GOLIATH study demonstrated the GreenLightTM laser was noninferior to TURP in terms of the outcomes and had better results in length of catheterisation and length of hospital stay. The impact of technology in any surgical setting with the aim to improve outcomes in treating any disease while minimizing the risk of complication, or improving has changed significantly. With the rapid evolution of this of technology in the surgical field, however,needs thorough research to ensure high standards of care is delivered when utilizing latest surgical instruments. Essentially, the background outlined here not only highlights the core aim of this thesis: to observe the trend and understand the impact of technology in the current surgical practice. Given that this is will be a broad perspective, this thesis will be focusing on two parts, that is, one related to modes of communication using online technology and how it benefits the users and observing the risks involved. The other part of the thesis will be related to advancement of surgical instruments in urological surgery and the outcomes from the new equipments.
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ItemConsiderations for surgical intervention in metastatic cancer to the spine: evaluation of risk factors for pathologic fracture and spinal cord compression, and analysis of pre-operative scoring systems for the prognostication and treatment of patients with spinal metastases( 2014)The spine has structural load bearing and neural-protective functions, and tumour growth and bony destruction caused by spinal metastases results in pathologic fracture and cord compression, causing pain, neurological deficit, impaired function and quality of life. Surgery is the only method to immediately stabilise the spine and decompress the spinal cord. Survival prognosis is one of the key factors in selecting patients for surgery, and there are a number of scoring systems aimed at prognostication and treatment decision making for patients with spinal metastases, however these differ in the parameters assessed and prognostic value. The ability to predict those patients with spinal metastases most likely to progress to pathological fracture or develop spinal cord compression may simplify the surgical decision-making process and enable earlier surgical intervention, with the potential to prevent permanent neurological deficit and disability and maintain function and quality of life for the remainder of the patient's life. This thesis considers the complexities of treatment decision making for patients with spinal metastases, with two major aims: 1) An evaluation of patient risk factors and radiological parameters associated with pathological fracture and metastatic epidural spinal cord compression, and 2) Validation of survival prognostication of current pre-operative prognostic scoring systems, in order to optimise the treatment decision-making process. The methodology involved retrospective assessment of clinical and radiological parameters of 72 patients with spinal metastases who had undergone decompressive and/or stabilisation surgery for pathological fracture and/or metastatic epidural spinal cord compression or nerve root compression. The items assessed for association with pathological fracture or metastatic epidural spinal cord compression were: tumour size, location, type and lesion morphology, disease burden, pain and function. Pre-operative scores were calculated for each patient, and the prognostic value of each scoring system evaluated by comparison of predicted and actual survival. The results showed that tumour size within the vertebral body, vertebral endplate and three-column involvement, tumour growth rate, multiple vertebral metastases, and pain were associated with increased risk for pathological fracture. Vertebral posterior element and costovertebral joint involvement by tumour, primary tumour growth rate and presence of visceral metastases were associated with metastatic epidural spinal cord or nerve root compression. All patients with pathological fracture had at least one of three risk factors – pain; >25% tumour occupancy of vertebral body; and endplate or 3-column involvement – and incidence of pathological fracture increased with higher number of risk factors. The Revised Tokuhashi, Bauer, Modified Bauer, and Tomita scoring systems were the most reliable for survival prediction. It is concluded that these risk factors should be considered in the decision-making process for surgery for spinal metastases. Patients with spinal metastases causing pain, greater than 25% occupancy of the vertebral body and involving the vertebral endplate or all three columns should be considered for prophylactic or therapeutic decompressive and stabilization surgery. As a component of comprehensive treatment planning, we recommend the use of Revised Tokuhashi, Modified Bauer, and Tomita scoring systems due to their favourable survival prognostic accuracy and clearly outline of treatment strategy according to prognostic group.
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ItemThe Effect of Co-stimulation Blockade on Survival of Xenogeneic Pancreatic Beta-cells( 2014)Diabetes mellitus is a chronic disease affecting millions of people worldwide. Currently, the only potential cure is through pancreatic transplantation, either as whole organ or with pancreatic islet cells. However, the morbidity associated with immunosuppression and the scarcity of donor organs do not support the common practice of pancreatic transplantation. Both these factors can potentially be addressed by xenotransplantation of genetically modified cells that are capable of attenuating the immune system. The costimulation pathway of the immune system was the focus of this project, in particular blockade of the ICOS (inducible costimulation molecule) and CTLA-4 (cytotoxic T lymphocyte associated antigen 4) pathways to prolong xenograft survival. To address the problem of diabetes as well as investigate the efficacy of costimulation blockade on xenograft survival, rat insulinoma (beta) cell lines (INS-1E) stably expressing either ICOS-Ig or CTLA4-Ig were generated. The secreted proteins were demonstrated to be biologically active in xenogeneic mixed lymphocyte reactions by their ability to inhibit lymphocyte proliferation. Unfortunately, the in vivo effect of these transgenic INS-1E cells on xenograft survival was unable to be determined because of their failure to establish as tumours due to the slow growth rate of these cells following subcutaneous injection into BALB/c mice. The aim of the second part of this project was to assess the effect of rationally mutated ICOS-Ig on xenograft survival. PIEC (pig iliac endothelial cells) stably expressing ICOS-Ig with single (K52/S and S76/E) and combined (K52/S + S76/E) amino acid mutations were generated. In vitro, compared to wild type ICOS-Ig, the mutants with single amino acid substitutions showed stronger binding avidity to ICOS ligand. This increase in binding avidity however did not translate into superior inhibition of lymphocyte proliferation compared to wild type ICOS-Ig in xenogeneic mixed lymphocyte reactions. Similarly in vivo, the PIECs secreting mutated forms of ICOS-Ig did not prolong xenograft survival after subcutaneous injection of these cells into BALB/c mice. These data suggest that despite their higher avidity, the ICOS-Ig mutants are not biologically more superior than wild type ICOS-Ig both in vitro and in vivo.
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ItemIdentification of genetic changes in prostate tissue of men with prostate cancer from multiple breast cancer families( 2013)Introduction: Male BRCA2 mutation carriers are at higher risk of developing aggressive prostate cancer. My research looks at DNA changes in prostate cancer specimens from men positive for a BRCA2 mutation. The first project involves DNA analysis of HG PIN tissue to look for loss of heterozygosity (LOH) in those carriers of a BRCA2 mutation. The purpose of looking for LOH in HG PIN of BRCA2 positive carriers is to ascertain if this tissue is a genomic predictor for tumorigenesis in this population. We also considered that whole exome copy-number analysis (CNA) of prostate cancer tissue, as well as HG PIN and normal prostate tissue from these BRCA2 men, may provide additional insight. Another inheritable mutation associated with prostate cancer is the HOXB13 mutation. We explored our cohort of prostate cancer men from breast cancer-rich families for the incidence of this mutation and impact on survival. We also investigated the incidence of the HOXB13 mutation in breast cancer women from breast cancer-rich families. Patients and Methods: Ten BRCA2 positive participants, from the kConFab cohort of high-risk breast cancer families, were identified , with access to archival prostate tissue specimens. Loss of heterozygosity (LOH) at the BRCA2 gene was examined using mutation specific PCR and sequencing of DNA from laser microdissected HG PIN. We also dispatched 15 DNA samples to Affymetrix for CNA: 9 prostate adenocarcinoma tissue DNA samples with 4 matched normal prostate tissue samples and 2 matched HG PIN samples. This data was analysed using specific software for microarray genetic analysis. For the HOXB13 study, the G84E variant was screened for using high resolution melting analysis in germ-line DNA in the index case or youngest affected member of 898 high-risk breast cancer families and in 1097 population controls. Results: Within this cohort of 10 pathogenic BRCA2 carriers, no patient displayed LOH at the mutation locus within HG PIN, irrespective of whether or not corresponding adenocarcinoma DNA displayed LOH. For the CNA project, our samples showed common sites of amplification at 8q, as well as deletions at 10q and 13q. Six out of 898 multi-case breast cancer families had carriers of the HOXB13 G84E variant: three families had either a single or multi-case family history of prostate cancer (3/99) and three had a personal and family history of breast cancer (3/799). Conclusion: Although HGPIN is considered a precursor to cancer, as no LOH was observed, this assay does not provide a genetic marker that may be considered a positive predictor of tumorigenesis in BRCA2 carriers. Regarding the CNA study, this is the first genomic analysis of this specific patient group, with our results have validated previous results of CNA in prostate cancer, as well as demonstrating the highly heterogenous nature of copy-number changes in this subset of patients. We confirm an association of the HOXB13 G84E variant with good prognosis prostate cancer in non BRCA1 or BRCA2 breast cancer families but we found no evidence for an increased risk of familial breast cancer.
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ItemManagement of young patients with colorectal cancer( 2013)Introduction: Young Patients with Colorectal Cancer (CRC) pose diagnostic and management challenges. A young age denotes an increased risk of a familial syndrome. The thesis aim was to identify how colorectal surgeons manage young colorectal cancer based on the likelihood of hereditary colorectal cancer. We sought to investigate the reliability of endoscopic biopsies, how compliance with post- operative surveillance guidelines influenced the metachronous colorectal cancer rate, and how quality of life was altered by the extent of colectomy. Young CRC patients’ views to varying aspects of colorectal surgery were also tested. Methods: Scenario based electronic surveys were sent to members of the Colorectal surgical society of Australia and New Zealand (CSSANZ), American Society of Colorectal Surgeons (ASCRS) and Association of Coloproctology of Great Britain and Ireland (ACPGBI). DNA mismatch repair protein immunohistochemical testing was compared between matched pairs of preoperative and postoperative samples in patients with known Lynch syndrome. Subsequently, the effect of radiation on the reliability of this technique was tested in a cohort age less than 50. The influence of compliance with post surgical surveillance intervals on metachronous colon cancers was studied in patients with known Lynch syndrome. The influence of an extended colectomy on QOL and bowel function was tested using the Short form- 36 (SF 36) form. Patients’ perspectives and priorities to various aspects of their care including extent of colectomy were tested. Results: A wide spectrum of practices were identified between countries, although the majority would offer an extended colectomy in the presence of known Lynch syndrome, not all would test for this prior to index colectomy. Lynch syndrome could be reliability tested using endoscopic biopsies, and post radiation samples were reliable providing viable tumor was left. Compliance with postoperative surveillance guidelines did not obviate the risk of second primary colorectal cancer, although the stage of disease was less. Short term and medium term quality of life and bowel function were similar between total colectomy and segmental colectomy groups. Young patients would prefer an extended colectomy to reduce the risk of future CRC despite the risk of worsening bowel function. Conclusion: Lynch syndrome can be identified from endoscopic biopsies using DNA MMR immunohistochemical testing and an extended colectomy should be strongly considered in such patients when diagnosed at a young age. Bowel function and quality of life are not dramatically affected by this approach, and young patients are willing to adopt this approach even with the prospect of worse bowel function. Further education among colorectal surgeon society members is required.
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ItemCharacterisation of the remnant foreskin: implications for HIV transmission in circumcised men( 2010)Human Immunodeficiency Virus (HIV) prevention remains one of the world’s top public health and development priorities, and male circumcision is the only biomedical intervention that has achieved level 1 scientific evidence for effectiveness in HIV prevention. Three randomised controlled trials have provided strong evidence that adult male circumcision confers significant protection against HIV infection, with a reduction in the relative risk of at least fifty percent. During surgical circumcision, a sleeve of preputial skin is removed and a cuff of skin around the base of the glans penis remains, forming the remnant foreskin. It is thought that the protective affect of circumcision can be attributable to the surgical removal of the inner foreskin epithelium, the main entry site of HIV into the penis. Current accepted wisdom is that the inner foreskin epithelium is abundantly supplied with HIV-1 target cells, is poorly keratinised, at risk of microscopic tears, exposed to vaginal secretions during intercourse, has a higher degree of susceptibility to HIV infection when compared to the outer foreskin, and provides a moist environment that might sustain the viability of pathogens. The aim of this study was to characterise the remnant foreskin (R), in comparison to the penile shaft skin (S) and the inner foreskin (I), and determine its role in the transmission of HIV. Tissue biopsies were obtained from the remnant foreskin and penile shaft skin of 10 circumcised men undergoing elective vasectomy and from the inner foreskin of 10 uncircumcised men undergoing elective circumcision. Biopsies were stained for Langerhans’ cells and keratin, and the number of Langerhans’ cells/mm2 and the thickness of the epithelium and stratum corneum was measured at each site. This study has shown that what was previously accepted wisdom regarding the keratin thickness of the inner foreskin is incorrect. Instead, our results revealed no significant difference in epithelial (RvS: p=0.38; IvS: p=0.53; RvI: p=0.82) or keratin (RvS: p=0.32; IvS: p=0.15; RvI: p=0.66) thickness between the three sites. In keeping with current evidence, we found that the inner foreskin has a high density of Langerhans’ cells. We found that the remnant foreskin has a significantly smaller amount of Langerhans’ cell within its epithelial, in comparison to both the penile shaft skin and the inner foreskin. In fact, relative to the inner foreskin, there is an astonishing scarcity of Langerhans’ cells in the remnant foreskin. There was significantly fewer Langerhans’ cells in the remnant foreskin compared to the inner foreskin (p=0.00001) and penile shaft skin (p<0.01), and significantly more Langerhans’ cells in the inner foreskin than the penile shaft skin (p<0.02). We believe that the reduced transmission of HIV seen in circumcised men is not because of a difference in keratin thickness between the inner foreskin and other penile skin, as has been previously accepted wisdom, but could be due to the surgical removal of HIV-1 target cells (Langerhans’ cells) in the inner foreskin and the subsequent development of the remnant foreskin, a tissue with a remarkable scarcity of Langerhans’ cells.