The role of GSTM1 gene polymorphism in pathophysiology, evaluation, and management of constipation of anorectal outlet obstruction.

Constipation of anorectal outlet obstruction may be caused by mechanical or functional causes. This complication is a debilitating disease that needs proper and timely treatment. Many studies have shown that there is a direct link between constipation and intestinal cancer. One of the most effective ways to prevent or diagnose intestinal cancer is through genetic studies. Evaluation of people's polymorphism shows how much they are at risk for cancer. Therefore, in this study, the GSTM1 gene polymorphism was evaluated in patients with constipation of anorectal outlet obstruction to assess better and manage this disease and investigate the possibility of anorectal cancer in these people. In this regard, 40 people with constipation of anorectal outlet obstruction were compared with 40 healthy people. In the case group (patients), in addition to demographic and clinical evaluations, the anorectal manometric test was used to diagnose the pathology of the disease. Results showed that out of 40 patients with constipation of anorectal outlet obstruction, 5 cases (12.5%) had megarectum, 7 cases (17.5%) had anismus, 10 cases (25%) had Hirschsprung's disease, 5 cases (12.5%) had descending perineum syndrome, 6 cases (15%) had rectal prolapse, 4 cases (10%) had enterocele, and 3 cases (7.5%) were with rectocele. Also, the results of GSTM1 gene deletion polymorphism showed that patients with constipation of anorectal outlet obstruction were almost two times more exposed to the null genotype than the control group (P <0.04). Therefore, in people with both constipation of anorectal outlet obstruction and null genotype (i.e., deletion in the GSTM1 gene), because they do not have glutathione-S transferase, they appear to be at higher risk for anorectal cancer than healthy people with the same genotype.

Hazard of Cervical, Oropharyngeal, and Anal Cancers in HIV-Infected and HIV-Uninfected Medicaid Beneficiaries.

BACKGROUND: Human immunodeficiency virus-infected (HIV+) individuals are disproportionately at risk for human papillomavirus (HPV)-associated cancers, but the magnitude of risk estimates varies widely. We conducted a retrospective study using a large U.S.-based cohort to describe the relationship between HIV infection and incident cervical, oropharyngeal, and anal cancers. METHODS: Using 2001-2012 U.S. Medicaid data from 14 states, we matched one HIV+ to three HIV-uninfected (HIV-) enrollees on sex, race, state, age, and year, and followed persons for up to 10 years. We developed Cox proportional hazards models comparing HIV+ to HIV- for time to cancer diagnosis adjusted for demographic and comorbidity attributes. RESULTS: Our cohorts included 443,592 women for the cervical cancer analysis, and 907,348 and 906,616 persons for the oropharyngeal and anal cancer analyses. The cervical cancer cohort had a mean age of 39 years and was 55% Black. The oropharyngeal and anal cancer cohorts were 50% male, had a mean age of 41 years, and were 51% Black. We estimated the following HRs: cervical cancer, 3.27 [95% confidence interval (CI), 2.82-3.80]; oropharyngeal cancer, 1.90 (95% CI, 1.62-2.23; both sexes), 1.69 (95% CI, 1.39-2.04; males), and 2.55 (95% CI, 1.86-3.50; females); and anal cancer, 18.42 (95% CI, 14.65-23.16; both sexes), 20.73 (95% CI, 15.60-27.56; males), and 12.88 (95% CI, 8.69-19.07; females). CONCLUSIONS: HIV+ persons were at an elevated risk for HPV-associated cancers, especially anal cancer. IMPACT: Medicaid claims data corroborate previous estimates based on registries and clinical cohorts.

Systematic review of clinical practice guidelines for colorectal and anal cancer: the extent of recommendations for managing long-term symptoms and functional impairments.

PURPOSE: Due to increasing numbers of colorectal and anal cancer survivors, more individuals are living with long-term symptoms after treatment. A systematic review was undertaken to assess the extent to which practice guidelines for colorectal and anal cancer provide recommendations for managing long-term symptoms and functioning impairments. METHODS: Four electronic databases and websites of 30 international cancer societies were searched for clinical practice guidelines, consensus statements, or best practice recommendations for colorectal or anal cancer. Quality of included guidelines was evaluated with the Appraisal of Guidelines for Research & Evaluation II tool. Results were narratively summarized. RESULTS: We included 51 guidelines or consensus statements. Recommendations for managing long-term symptoms or functioning impairments were reported in 13 guidelines (25.4%). All 13 recommend a healthy lifestyle, diet, body weight, and physical activity. The ASCO Colorectal Cancer Survivorship Care Guideline is the most comprehensive, including interventions targeting sexual and bowel function to pain and cognitive issues, and also highlights limited evidence for informing management strategies. Other guidelines recommend treating incontinence, chronic diarrhea, and distress, and stress the need for greater awareness for sexual dysfunction, survivorship clinics, and referrals to specific supportive care interventions. CONCLUSIONS: Few clinical practice guidelines include recommendations for managing long-term symptoms and functioning impairments. It is unclear if this is due to limited evidence or absence of management strategies and interventions. Clear recommendations for managing long-term symptoms and functioning to help health professionals in supporting colorectal and anal cancer survivors are needed.

Anal Squamous Intraepithelial Lesions (SILs) in Human Immunodeficiency Virus-Positive Men Who Have Sex With Men: Incidence and Risk Factors of SIL and of Progression and Clearance of Low-Grade SILs.

BACKGROUND: Human immunodeficiency virus (HIV)-positive men who have sex with men (MSM) are at risk of anal squamous cell carcinoma. Data are limited on the natural history of the precursor to this carcinoma, anal squamous intraepithelial lesions (SILs). METHODS: HIV-positive MSM were screened for histopathological SILs by means of high-resolution anoscopy (HRA). For participants without SILs at baseline, we estimated the cumulative incidence and risk factors for SILs. For those with low-grade SILs (LSILs) at baseline, the risk of progression to high-grade SILs (HSILs) and the clearance rate were estimated at the lesion level. RESULTS: Of 807 men without SILs at baseline, 107 underwent follow-up HRA between 1 to 4.5 years later. At the second visit 18 men (16.8%) showed LSIL, and 25 (23.4%) HSIL. Age was associated with incident LSILs (adjusted odds ratio [aOR], 2.10 per 10-year increase in age; P = .01). Of 393 men with LSILs at baseline, 114 underwent follow-up HRA 0.5 to 2.5 years later. Of the 177 LSILs found at baseline, 87 (49.2%) had cleared at the second visit, and 29 (16.4%) had progressed to HSILs. CONCLUSION: Incident LSILs and HSILs were common during follow-up among HIV-positive MSM without dysplasia at baseline. Among men with LSILs at baseline, nearly half of these lesions cleared, and a small portion progressed.

Quality of life in patients treated for anal carcinoma-a systematic literature review.

PURPOSE: Anal cancer is a mainly treated with chemoradiotherapy. A small number of patients undergo salvage surgery. There are few published studies investigating quality of life and functional outcome after treatment for anal cancer. The aim of this review was to explore the literature and identify areas for further research. METHODS: A search was conducted in Medline using MESH terms related to anal cancer and quality of life. Two investigators selected and reviewed articles based on titles and abstracts. Three investigators read and reviewed the included articles and collected relevant data. The included articles were evaluated using the minimum standard checklist, and key findings were summarised in a chart. RESULTS: Some 15 articles, and a total of 802 patients, were deemed eligible. The results differed slightly among the studies. The incidence of symptoms such as fatigue, nausea, insomnia and appetite loss was higher than among healthy volunteers. Bowel function, urinary function and sexual function were negatively affected. Some studies found that, compared with the normal population, anal cancer survivors scored clinically significant worse in the functional scales in QLQ-C30. CONCLUSION: In conclusion, it is apparent that several functional problems affect the quality of life of patients with anal cancer. There are few studies which have investigated quality of life after treatment for anal cancer. Interventions to address issues related to anal cancer treatment may improve long-term quality of life in this patient group. TRIAL REGISTRATION: CRD42017059787.

Role of Epstein-Barr Virus and Human Papillomavirus Coinfection in Oral and Anogenital Carcinogenesis: Potential Tumorigenic Pathways.

Epstein-Barr virus (EBV) and human papillomavirus (HPV) have been implicated in 38% of all virus-related cancers. Over the past three decades, both have been detected in anogenital and head-and-neck squamous cell carcinomas (HNSCC), with evidence of involvement in tumor genesis and progression. Very little has been published on HPV/EBV coinfection. In this chapter, we review the literature on the role of these viruses in oral carcinoma and draw parallels with other HNSCCs and anogenital carcinomas, with emphasis on their interplay and potential signaling pathways. EBV infection seems to create an environment that favors HPV latency, supporting the claim that EBV is a cofactor in HPV-related carcinomas. In turn, under certain circumstances, HPV appears to be able to induce EBV to switch to the latent or replicative state. The main viral oncogenes expressed in these malignancies are EBNA1, EBNA2, LMP1, EBERs, and the high-risk HPV oncogenes E6 and E7. The most well-documented human proteins involved are p53, pRb, p16INK4a, p19ARF, Myc, E-cadherin, ß-catenin, EGFR, MLH1, and COX-2. These proteins are directly associated not only with viral products but also with one another in the development of malignancy. Knowledge of the molecular machinery behind carcinomas coinfected with HPV and EBV may help understand how these viruses trigger carcinogenesis and subsidize the development of new biomarkers of tumor aggressiveness and prognosis, alternative surrogate virus markers, and possible therapeutic targets.

Abnormal neuronal response to rectal and anal stimuli in patients treated with primary radiotherapy for anal cancer.

INTRODUCTION: Sphincter-sparing radiotherapy or chemoradiation (RT/CRT) have become the standard treatments for most patients with anal cancer. Unfortunately, long-term survivors often suffer from severe bowel symptoms indicating sensory dysfunction. The aim of the present study was to characterize the sensory pathways of the brain-gut axis after radiotherapy for anal cancer. METHOD: Cortical evoked potentials (CEPs) were recorded during repeated, rapid balloon distensions of the rectum and anal canal in 13 patients with anal cancer treated with radiotherapy or chemoradiation and in 17 healthy volunteers. Latencies and amplitudes of rectal CEPs were compared between the groups. CEPs from both rectal and anal distensions were examined using single sweep spectral band analysis to determine the relative amplitude of five spectral bands as a proxy of neuronal processing. RESULTS: Groups were comparable by age (62.4 ±â€¯7.8 vs 58.9 ±â€¯8.9, p < 0.32) and gender. Patients had a mean Wexner fecal incontinence score of 5.5 (±3.8) and median LARS Score of 29 (0-39). Rectal CEP latencies were prolonged in patients (F = 11.7; p < 0.001), whereas amplitudes were similar (F = 0.003; p = 0.96). Spectral analysis of CEPs from rectal distensions showed significant differences between groups in theta (4-8 Hz), alpha (8-12 Hz), beta (12-32 Hz) and gamma (32-70 Hz) bands (all p < 0.001) and CEPs from anal distensions showed significant differences in the alpha, beta and gamma bands (all p ≤ 0.002). CONCLUSION: Patients treated with RT/CRT for anal cancer have impaired ano-rectal sensory pathways and abnormal cortical processing. This may play a central role for the pathogenesis of late proctopathy.

Preliminary human application of optical coherence tomography for quantification and localization of primordial follicles aimed at effective ovarian tissue transplantation.

PURPOSE: The purpose of this study was to evaluate the possible clinical application of optical coherence tomography for assessing ovarian reserve in individual specimens of human ovarian tissue for fertility preservation. METHODS: Ovarian tissue examination by optical coherence tomography was performed before ovarian tissue cryopreservation. Three of the four subjects had hematological disease or cancer, and they faced a threat to their fertility due to impending chemotherapy. One patient underwent ovarian tissue extraction for in vitro activation of dormant follicles as fertility treatment. RESULTS: The current full-field optical coherence tomography technique can detect primordial follicles in non-fixed and non-embedded human ovarian tissue. These images are well correlated with histological evaluation and the ovarian reserve test, including follicle counts. CONCLUSION: It was demonstrated that optical coherence tomography could assess localization of primordial follicles and ovarian reserve in specimens of non-fixed human ovarian cortex, although optimization for examination of human ovarian tissue is needed for clinical application. Additionally, this technique holds the possibility of assessing the ovarian reserve of patients with unevaluable ovarian reserve. TRIAL REGISTRATION NUMBER: UMIN000023141.

Phase I-III development of the EORTC QLQ-ANL27, a health-related quality of life questionnaire for anal cancer.

BACKGROUND AND PURPOSE: There is currently no health-related quality of life (HRQoL) measure specific to anal cancer. Our objective was to develop an anal cancer HRQoL module to supplement the EORTC QLQ-C30 questionnaire using EORTC Quality of Life Group Guidelines. MATERIALS AND METHOD: In order to generate a list of HRQoL issues facing anal cancer patients treated with chemoradiotherapy (CRT), we systematically reviewed the literature and conducted semi-structured interviews with patients and health care professionals (HCPs). Our list was then operationalised into questions using the EORTC Item Library. The provisional question list was pilot tested alongside the EORTC QLQ-C30 with patients from 11 centres across 8 countries. RESULTS: From our literature review and interviews with 43 patients, we generated a list of 197 issues. The list was then refined to 134 issues and reviewed by 34 HCPs and 10 patients. This review resulted in the retention of 65 issues which were used in the draft questionnaire tested by 100 patients. Our analyses led to the modification and removal of questions resulting in a 27 item questionnaire, the EORTC QLQ-ANL27. CONCLUSION: We have developed a 27 item questionnaire to supplement the EORTC QLQ-C30, for use with patients treated for anal cancer. This has been pilot tested and is now available upon request for use in clinical trials as well as clinical practice in 8 languages (http://groups.eortc.be/qol/).

Syndemic synergy of HPV and other sexually transmitted pathogens in the development of high-grade anal squamous intraepithelial lesions.

BACKGROUND: Anal intraepithelial neoplasia is associated with high-risk human papillomavirus (hrHPV) as a precursor to anal cancer. However, factors other than hrHPV are likely to be involved and further study of cofactors is required because of the possibility of syndemic interactions. METHODS: Three hundred and fourteen patients underwent 457 operations. Histopathology and hrHPV testing using the Digene Hybrid Capture 2 (HC 2) method were performed. Demographic factors and sexually transmissible infections (STIs) were recorded. RESULTS: Results showed that hrHPV alone was associated with HSIL (OR = 4.65, p < 0.001). None of the other STIs were alone associated with HSIL but amplification of risk was found when hrHPV infection occurred with HIV (OR = 11.1); syphilis (OR = 5.58); HSV 2 (OR = 7.85); gonorrhoea (OR = 6.45) and some other infections. CONCLUSIONS: These results suggest that hrHPV is a sufficient cause of anal HSIL. Seropositivity for HIV, HSV 2, T. pallidum, HBV and HCV and a history of gonorrhoea or chlamydia exert a powerful amplifying factor increasing the risk of HSIL above the risk with hrHPV alone. Other co-factors which are associated with an increased risk of HSIL are increased age, male gender, MSM behaviour and self-reported history of more than 50 sexual partners. This pattern of disease in patients with warts is characteristic of a syndemic with potential serious increased risk of anal carcinoma.

The role of pharmacologic modulation of autophagy on anal cancer development in an HPV mouse model of carcinogenesis.

Autophagy is an intracellular, catabolic process that maintains cellular health. We examined the response of pharmacologic modulation of autophagy in an HPV mouse model of anal carcinogenesis. K14E6/E7 mice were treated with the topical carcinogen DMBA weekly and assessed for tumors over 20 weeks. Concurrently, they were given either chloroquine or BEZ235, to inhibit or induce autophagy, respectively. Time to tumor onset was examined. Immunofluorescence (IF) was performed for LC3ß and p62 to examine autophagy. All DMBA treated K14E6/E7 mice developed anal cancer, contrary to zero of the no DMBA treated mice. Chloroquine plus DMBA resulted in a significant decrease in the time to tumor onset compared to K14E6/E7 treated with DMBA. Only 40% BEZ235 plus DMBA treated mice developed anal cancer. Autophagic induction with DMBA and BEZ235, and autophagic inhibition with chloroquine were confirmed via IF. Anal carcinogenesis can be inhibited or induced via pharmacologic modulation of autophagy.

Anal Intraepithelial Neoplasia.

Anal squamous cell cancer (SCC) is a relatively uncommon cancer in the United States. Anal SCC has long been associated with human immunodeficiency virus (HIV) positivity and/or men who have sex with men. The incidence of anal SCC has been increasing in both genders regardless of HIV status. Few clinicians are aware that white women, when not controlling for gender and sexual preference together, have the highest incidence of anal SCC. Anal intraepithelial neoplasia (AIN), dysplastic cells of the anal canal due to human papilloma virus infection, is believed to be the precursor to anal SCC. A vaccination has been approved by the Federal Drug Administration (FDA) for the prevention of high-risk human papilloma virus infections in presexually active girls and boys. Currently, there are no consensus guidelines for AIN screening, treatment or follow-up. Although anal SCC is treatable when caught early, treatment is often associated with significant morbidity. The purpose of this paper is to raise awareness of anal SCC and its precursor, AIN, in the non-HIV+ and non-MSM populations, and discuss means by which to decrease the incidence of anal SCC in all populations.

Anal adenocarcinoma presenting as a non-healing ischiorectal wound.

We describe the diagnosis and management of a patient with a progressively enlarging, non-healing ischiorectal wound. This patient was further evaluated with radiological investigations which showed the presence of a large left ischiorectal fossa mass. Histology confirmed this mass as an anal adenocarcinoma. Anal Adenocarcinoma is a rare condition that can arise from chronic inflammatory states. Treatment requires an abdomino-perineal resection with neoadjuvant therapy, and the goal of surgery is to achieve clear resection margins.

[Assessment of Functional Results after Sphincter-Preserving Surgery in Elderly Patients with Low Rectal Cancer].

The aim of this study was to evaluate postoperative dysfunction and potential problems after a sphincter-preserving operation in elderly patients with low rectal cancer. METHODS: Between 2000 and 2012, 307 consecutive patients with low rectal cancer underwent curative sphincter-preserving surgery. We evaluated postoperative anal and urinary dysfunction in 190 patients who responded to a questionnaire by mail. RESULTS: After a median follow-up of 5.7 years, there was no significant difference between the elderly and a younger group in the Wexner incontinence score. Poor anal function assessed by modified FIQL was significantly associated with the elderly. Poor urinary function assessed by the IPSS score was significantly associated with the elderly, diabetes mellitus, and autonomic nerve preservation(AN2-3). CONCLUSION: From the viewpoint of urinary function, sphincter-preserving surgery with all autonomicnerve preservation(AN4)should be considered for elderly people and patients with diabetes.

Anal canal carcinoma treatment results: the experience of a single institution.

BACKGROUND AND OBJECTIVES: Prior to the mid-1980s, the treatment of choice for anal cancer was abdominoperineal resection. Currently, combined chemoradiation is the standard of care. Or objective was to analyze results of treatment for anal canal carcinoma treated with combined chemoradiation. DESIGN AND SETTING: Retrospective review of data in local cancer registry at King Faisal Specialist Hospital and Research Centre (KFSHRC) from a 12-year period (1993 to 2005). METHODS: We identified patients with confirmed diagnosis of anal canal squamous cell carcinoma. RESULTS: Of 40 patients identified, 33 were considered eligible for our analysis. All patients were treated by concurrent chemoradiation with mandatory treatment break (MTB) There were 10 (30%) local recurrences. Five-year progression-free survival (PFS) was 50.9%; overall survival (OS) at 5 years was 73.4%. Patients with stage II disease had a median PFS period of 10 years, with no relapses until their last follow-up. There was no statistically significant difference in PFS between patients with stage IIIA disease and those with stage IIIB disease-44.7% and 45%, respectively (P=.8). Five-year PFS according to 'T' stages was as follows: T1, 66%; T2, 71%; T3, 59%; T4, 30% (P>.05). The 5-year colostomy-free survival (CFS) for all patients was 74%. Distant metastases were observed in 4 patients. CONCLUSION: Combined chemoradiation in treatment of anal cancer is effective in terms of local control and sphincter preservation. Five-year estimates of PFS, OS, as well as CFS, in patients treated with a MTB were surprisingly comparable to those determined in most non-MTB series. However, we reported a higher local failure rate, for which we are reevaluating our treatment protocol.

Extradigital glomus tumor as a cause of chronic perianal pain.

Glomus tumor is a rare perivascular benign tumor arising from the Sucquet-Hoyer canal of the normal glomus body, most commonly in the digital areas. We report a serving soldier with such a tumor in an atypical site, the perianal region, presenting with episodic shooting pain. Total surgical excision was performed. Histopathology revealed a well-circumscribed tumor composed of clusters of monotonous polygonal cells surrounding capillary-sized blood vessels. Tumor cells also showed immunopositivity for smooth muscle antigen and vimentin. Following excision, the patient was completely relieved of pain and there was no recurrence on follow-up for 6 months.

Long-term functional and quality of life outcomes of patients after repair of large perianal skin defects for Paget's and Bowen's disease.

INTRODUCTION: The assessment of long- term functional and quality of life outcomes of these patients following repair of large defects after surgical excision has not been reported. METHODS: Between 1992 and 2004, at two institutions, 18 patients underwent repair of a perianal defect for Paget's disease (n = 8) or Bowen's disease (n = 10) and were alive with intestinal continuity at last follow-up. Patients were mailed the fecal incontinence quality of life scale (FIQL) and the SF-36. RESULTS: Fourteen patients (78%) responded. Median follow-up for responders was 5 years. Mean age was 65 years with 12 females. Subcutaneous skin flaps (11) and split-thickness skin grafts (three) were used to repair the perianal defects, which were circumferential in 11 patients (79%). Nine patients reported incontinence and completed the FIQL. The FIQL scores of patients reporting incontinence were lower for lifestyle, coping/behavior, and embarrassment but not significantly different for depression compared to patients without incontinence. SF-36 scores of the patients were not significantly different from the normative population. CONCLUSION: Functional results after repair of large perianal defects are acceptable and overall quality of life (QOL) is similar to the normative population although a large proportion of patients have some form of incontinence that impacts certain aspects of their QOL.

[Progress in diagnostics of anorectal disorders. Part I: anatomic background and clinical and neurologic procedures]. / Fortschritte in der Diagnostik anorektaler Erkrankungen. Teil I: Anatomische Grundlagen sowie klinische und neurologische Verfahren.

Diagnostics and therapy of anorectal disorders are still questions of surgery. Exact knowledge of functional anatomy and precise clinical examination constitute the basis for the resulting therapeutic strategies. Three-dimensional endosonography and technical advances in flexible endoscopy using high-resolution chromoendoscopy and narrow-band imaging enable exact staging and diagnosis, even of malignancies in earliest stages. Furthermore new in-vivo staining methods combined with high-resolution imaging facilitate the discrimination of inflammatory and neoplastic lesions, which often lead to diagnostic difficulties in chronic inflammatory bowel disease. Developments in neurologic testing, including surface electromyography and sacral nerve stimulation, complement the diagnostic armamentarium.

Analysis of centrosome overduplication in correlation to cell division errors in high-risk human papillomavirus (HPV)-associated anal neoplasms.

High-risk HPV-associated anal neoplasms are difficult to treat and biomarkers of malignant progression are needed. A hallmark of carcinogenic progression is genomic instability, which is frequently associated with cell division errors and aneuploidy. The HPV-16 E7 oncoprotein has been previously shown to rapidly induce centriole and centrosome overduplication and to cooperate with HPV-16 E6 in the induction of abnormal multipolar mitoses. Based on this function, it has been suggested that HPV-16 E7 may act as a driving force for chromosomal instability. However, a detailed analysis of centrosome overduplication in primary HPV-associated neoplasms has not been performed so far. Here, we determined the frequency of centrosome overduplication in HPV-associated anal lesions using a recently identified marker for mature maternal centrioles, Cep170. We detected centrosome overduplication in a small but significant fraction of cells. Remarkably, centrosome overduplication, but not aberrant centrosome numbers per se or centrosome accumulation, correlated significantly with the presence of cell division errors. In addition, our experiments revealed that in particular pseudo-bipolar mitoses may play a role in the propagation of chromosomal instability in high-risk HPV-associated tumors. These results provide new insights into the role of centrosome aberrations in cell division errors and encourage further studies on centrosome overduplication as a predictive biomarker of malignant progression in HPV-associated anal lesions.