Evolution of the management of retrorectal masses: A retrospective cohort study.

AIM: Retrorectal masses are abnormalities located anatomically in the retrorectal space. A significant proportion are asymptomatic with no malignant potential while others cause symptoms due to mechanical pressure or malignant infiltration. We reviewed and categorised the retrorectal masses encountered over a 30-year time period in a specialist colorectal hospital and describe our management algorithm for consideration by other multidisciplinary teams (MDT). METHODS: This was a retrospective analysis of consecutive patients referred between 1984-2019. A detailed review of clinical presentation, imaging features, postoperative histology and impact on morbidity and anorectal function is reported. RESULTS: A total of 143 patients with median age of 46 years and female preponderance (74%) were reviewed. The commonest presenting symptom was pain (46%) and all malignant cases had symptoms (n = 17). Over the last decade, more asymptomatic patients have presented with a retrorectal mass (33%, p = 0.04) and more patients are opting for surveillance rather than resection (33%, p = 0.013). Increasing age and lesion size were associated with malignancy (p < 0.05). Radiological features associated with malignancy included: solid/heterogeneous component, lobulated borders or locally invasive. Following surgery, complications included chronic pain (40%), poor wound healing (23%) and bowel dysfunction (10%). CONCLUSIONS: The management of retrorectal masses remains complex. There are features, both clinical and radiological, that can help determine the best management strategy. Management should be in a high-volume tertiary centre and preferably through a complex rectal cancer MDT. Long-term sequelae such as chronic pain must be highlighted to patients. We advocate the establishment of an international registry to further record and characterise these rare, potentially troublesome lesions.

Once-only flexible sigmoidoscopy screening in prevention of colorectal cancer: a multicentre randomised controlled trial.

BACKGROUND: Colorectal cancer is the third most common cancer worldwide and has a high mortality rate. We tested the hypothesis that only one flexible sigmoidoscopy screening between 55 and 64 years of age can substantially reduce colorectal cancer incidence and mortality. METHODS: This randomised controlled trial was undertaken in 14 UK centres. 170 432 eligible men and women, who had indicated on a previous questionnaire that they would accept an invitation for screening, were randomly allocated to the intervention group (offered flexible sigmoidoscopy screening) or the control group (not contacted). Randomisation by sequential number generation was done centrally in blocks of 12, with stratification by trial centre, general practice, and household type. The primary outcomes were the incidence of colorectal cancer, including prevalent cases detected at screening, and mortality from colorectal cancer. Analyses were intention to treat and per protocol. The trial is registered, number ISRCTN28352761. FINDINGS: 113 195 people were assigned to the control group and 57 237 to the intervention group, of whom 112 939 and 57 099, respectively, were included in the final analyses. 40 674 (71%) people underwent flexible sigmoidoscopy. During screening and median follow-up of 11.2 years (IQR 10.7-11.9), 2524 participants were diagnosed with colorectal cancer (1818 in control group vs 706 in intervention group) and 20 543 died (13 768 vs 6775; 727 certified from colorectal cancer [538 vs 189]). In intention-to-treat analyses, colorectal cancer incidence in the intervention group was reduced by 23% (hazard ratio 0.77, 95% CI 0.70-0.84) and mortality by 31% (0.69, 0.59-0.82). In per-protocol analyses, adjusting for self-selection bias in the intervention group, incidence of colorectal cancer in people attending screening was reduced by 33% (0.67, 0.60-0.76) and mortality by 43% (0.57, 0.45-0.72). Incidence of distal colorectal cancer (rectum and sigmoid colon) was reduced by 50% (0.50, 0.42-0.59; secondary outcome). The numbers needed to be screened to prevent one colorectal cancer diagnosis or death, by the end of the study period, were 191 (95% CI 145-277) and 489 (343-852), respectively. INTERPRETATION: Flexible sigmoidoscopy is a safe and practical test and, when offered only once between ages 55 and 64 years, confers a substantial and longlasting benefit. FUNDING: Medical Research Council, National Health Service R&D, Cancer Research UK, KeyMed.

Does the timing of comorbidity affect colorectal cancer survival? A population based study.

OBJECTIVES: Comorbid conditions in colorectal cancer patients can influence both clinical eligibility for treatment and survival. We aimed to evaluate the effect of comorbidity on 1 year survival from colorectal cancer, and to assess whether this effect varied with the timing of the comorbidity in relation to the cancer diagnosis. STUDY DESIGN AND SETTING: A population based cohort of 29,563 colorectal cancer patients diagnosed between 1997 and 2004 in the North West of England was evaluated. The excess hazard of death up to 1 year after diagnosis was estimated using deprivation and region specific life tables to adjust for background mortality. Results were adjusted for age and stage at diagnosis. RESULTS: Comorbid conditions diagnosed during the period 18 to 6 months before the diagnosis of colorectal cancer were strongly associated with lower survival at 1 year. Stage and age remained the strongest predictors of cancer related mortality even after adjustment for comorbidity. CONCLUSIONS: Administrative data provide a good estimate of the prevalence of most comorbid conditions but may be biased for some comorbid conditions that can be contra-indicators for cancer treatment. The time window in which a comorbid condition occurs in relation to the cancer diagnosis should be taken into account. Adjustment should be carried out, where possible, to provide more robust and clinically appropriate comparisons of population based cancer patient survival.

The influence of circumferential resection margins on long-term outcomes following rectal cancer surgery.

PURPOSE: Circumferential resection margin involvement after rectal cancer surgery is associated with local recurrence and decreased survival, but definitions of "safe" margins vary. This study assessed the influence of various circumferential margins on long-term outcome from rectal cancer surgery. METHODS: Data were extracted from a rectal cancer database of patients undergoing rectal resection at a tertiary referral center between 1971 and 1996. The influence of circumferential margins on five-year local recurrence and cancer-specific survival were assessed using Cox regression. RESULTS: Circumferential margin measurements were available from 435 patients (median follow-up, 70.4 months). Cancer-specific survival at five years was 80.8%, 69.2%, 59.2%, and 34.1% for tumors with a circumferential resection margin of >10 mm, 3-10 mm, 2 mm, and < or =1mm, respectively (P < 0.001). Local recurrence at five years was 9.0%, 14.7%, and 25.8% for margins >10 mm, 2-10 mm, and < or =1 mm, respectively (P = 0.001). Independent predictors of cancer-specific mortality were circumferential margins of < or =1 mm vs. >10 mm (odds ratio = 3.38, P = 0.014) or 2 mm (odds ratio = 2.24, P = 0.029), Dukes Stage (C2 vs. A: odds ratio = 15.18, P < 0.001), and vascular invasion (present vs. absent: odds ratio = 1.51, P = 0.033). Local recurrence was predicted by a margin of < or =1 mm (odds ratio = 2.29, P = 0.041), gender (female vs. male: odds ratio = 0.25, P = 0.002), Dukes Stage (C2 vs. A: odds ratio = 28.89, P = 0.003), and vascular invasion (extramural vs. none: odds ratio = 2.04, P = 0.024). CONCLUSION: Circumferential margins < or =2 mm are associated with significantly reduced cancer-specific survival, and margins < or =1 mm with increased local recurrence, when other factors are accounted for, challenging the assumption that a circumferential resection margin of < or =1 mm is safe.

Pooled Analysis of external-beam RADiotherapy parameters in phase II and phase III trials in radiochemotherapy in Anal Cancer (PARADAC).

PURPOSE: Concomitant external-beam radiochemotherapy (5-fluorouracil-mitomycin C) has become the standard of care in anal cancer since the '90s. A pooled analysis of individual patient data from 7 major trials was performed quantifying the effect of radiation therapy (RT)-related parameters on the outcome of patients with anal cancer. MATERIALS AND METHODS: Pooling databases from combined modality trials, the impact of RT parameters (total dose, gap duration, OTT: overall treatment time) on outcome including locoregional failure (LRF), 5-year progression free survival (PFS) and toxicities were investigated. Individual patient data were received for 10/13 identified published studies conducted from 1987 to 2008 (n = 3031). A Cox regression model was used (landmark = 3 months after RT for first follow-up). RESULTS: After data inspection indicating severe heterogeneity between trials, only 1343 patients from 7/10 studies received were analysed (the most recent ones, since 1994; median follow-up = 4.1 years). A higher overall 5-year LRF rate [22.8% (95% confidence interval [CI] 22.3-27.3%)] significantly correlated with longer OTT (p = 0.03), larger tumour size (p < 0.001) and male gender (p = 0.045). Although significant differences were not observed, subset analyses for LRF (dose range: 50.4-59 Gy) seemed to favour lower doses (p = 0.412), and when comparing a 2-week gap versus 3 (dose: 59.4 Gy), results suggested 3 weeks might be detrimental (p = 0.245). For a 2-week gap versus none (dose range: 55-59.4 Gy), no difference was observed (p = 0.89). Five-year PFS was 65.7% (95% CI: 62.8-68.5%). Higher PFS rates were observed in women (p < 0.001), smaller tumour sizes (p < 0.001) and shorter OTT (p = 0.025). Five-year overall survival [76.7% (95% CI: 73.9%-79.3%)] correlated positively with female gender (p < 0.001), small tumour size (p = 0.027) and short OTT (p = 0.026). Descriptive toxicity data are presented. CONCLUSION: For patients receiving concurrent external-beam doublet chemoradiation, a longer OTT seems detrimental to outcome. Further trials involving modern techniques may better define optimal OTT and total dose.

Angiogenesis and hypoxic factors in colorectal cancer.

Colorectal cancer is a common cause of cancer death in the developed world. Angiogenesis is a key factor in the growth and dissemination of malignant disease, including colorectal cancer, with significant implications for its clinical management. Over the past few years, significant inroads have been made into understanding the mechanisms and processes of angiogenesis in various malignancies. It is postulated that, with a greater understanding of the angiogenic mechanisms that govern tumor growth, anti-angiogenic compounds may be introduced to combine with conventional means to combat the growth and spread of malignant disease. This review discusses the mechanisms involved in tumor angiogenesis, highlighting its influence in colorectal cancer.

Activation of AKT and nuclear accumulation of wild type TP53 and MDM2 in anal squamous cell carcinoma.

Human papilloma virus (HPV) infection is considered as an important aetiological factor for anal squamous cell carcinoma (ASCC) but is not sufficient for tumour progression. This carcinoma is poorly understood at the molecular level. Using the largest cohort of cases to date we investigated the molecular mechanisms underlying ASCC development, in particular the roles of TP53, MDM2 and AKT. Viral infection in our cohort occurred at high frequency (73%, 94/128) with HPV16 accounting for the majority (86%, 81/94) of infected cases. Only 4% (5/119) of ASCCs showed TP53 (exons 5-8) mutations, but a high frequency (91%, 100/110) of nuclear protein expression of TP53 was observed. There was a significant association (p < 0.001) between nuclear accumulation of TP53 and MDM2 protein although no MDM2 mutations were found, and copy number was normal. Cellular accumulation of phosphorylated-AKT was observed in 66% (82/125) of ASCCs and an association demonstrated between nuclear accumulation of MDM2 and activated AKT (p < 0.001). We observed a high frequency of copy number gain at PIK3CA (47%), and some coding sequence mutations (4%). Amplification of PIK3CA was associated with presence of phosphorylated-AKT (p= 0.008). There was no association between virus infection and TP53 nuclear accumulation (p = 0.5). However, a significant association was found between infection and MDM2 nuclear staining, and between infection and activated AKT (p = 0.04, p = 0.01, respectively). We propose that activation of AKT, possibly through the PI3K-AKT pathway, is an important component of ASCC tumorigenesis that contributes to MDM2 and TP53 accumulation in the nucleus.

Can histopathologic assessment of circumferential margin after preoperative pelvic chemoradiotherapy for T3-T4 rectal cancer predict for 3-year disease-free survival?

PURPOSE: This study set out to determine the impact of a positive circumferential resection margin (CRM) (R1-R2) and pathologic downstaging on local recurrence and survival in patients with borderline resectable or unresectable rectal adenocarcinoma treated with neoadjuvant chemoradiotherapy (CRT). METHODS AND MATERIALS: A total of 150 patients with locally advanced rectal cancer were treated with long-course neoadjuvant CRT using low-dose folinic acid and 5-fluorouracil. CRT was followed 6-12 weeks later by surgical excision. The CRM rate and incidence, site, and pattern of local and systemic recurrences were recorded. The median follow-up was 25 months. RESULTS: The overall median survival was 37 months, with a 5-year overall survival rate of 34%. Of the 150 patients, 122 underwent curative resection; 12% had a complete pathologic response, and downstaging to pT1-T2 occurred in an additional 16%. A negative CRM (R0) was achieved in 65% overall (98 of 150). Local recurrence occurred in 10% of those with R0 resection and 62% of those with R1-R2 resections. Distant metastases occurred in 29% of those with R0 resections and 75% of those with R1-R2 resections. The 3-year disease-free and 3-year overall survival rate was 9% and 25% and 52% and 64%, respectively, for patients with and without a histologically positive CRM. CONCLUSION: After 5-fluorouracil-based CRT, a positive CRM predicted for a high risk of subsequent local recurrence and a 3-year disease-free survival rate of only 9%. For this reason, the CRM should be considered a major prognostic factor and should be validated in future trials as an early alternative clinical endpoint.

Control of blue mold (Penicillium expansum) by fludioxonil in apples (cv Empire) under controlled atmosphere and cold storage conditions.

A reduced risk fungicide, fludioxonil, was tested for its efficacy against blue mold caused by thiabendazole-resistant and -sensitive Penicillium expansum (Link) Thom in apples under three storage conditions. In a co-treatment, fludioxonil and inoculum were applied together to test the protective activity of the fungicide on wounds that had been aged for 1 or 2 days. The fungicide was also tested for its curative activity in post-inoculation treatment on apples that had been inoculated for 1 or 2 days. Fludioxonil was very effective as co-treatment and as post-inoculation treatment. At a concentration of 300 mg litre(-1), fludioxonil gave complete control of post-harvest blue mold caused by the thiabendazole-resistant and -sensitive P expansum for 105 days in controlled atmosphere (CA) storage at 2 (+/-1) degrees C, for 42 days in common cold storage at 4 (+/-1) degrees C and also in a shelf-life study for 6 days at 20 (+/-1) degrees C. Comparison on the effect of fludioxonil in CA storage and common cold storage showed that higher concentrations of fungicide were needed in cold storage than in CA storage. Fludioxonil at a concentration of 450 mg litre(-1), gave 98 and 92% control of blue mold of apples in the simulated shelf-life studies after CA and common cold storages, respectively. Fludioxonil has a potential to be incorporated in the fungicide resistance management strategies for control of blue mold in apples stored for 105 days.

"Mind the gap"--the impact of variations in the duration of the treatment gap and overall treatment time in the first UK Anal Cancer Trial (ACT I).

PURPOSE: The United Kingdom Coordinating Committee on Cancer Research anal cancer trial demonstrated the benefit of combined modality treatment (CMT) using radiotherapy (RT), infusional 5-fluorouracil, and mitomycin C over RT alone. The present study retrospectively examines the impact of the recommended 6-week treatment gap and local RT boost on long-term outcome. METHODS AND MATERIALS: A total of 577 patients were randomly assigned RT alone or CMT. After a 6-week gap responders received a boost using either additional external beam radiotherapy (EBRT) (15 Gy) or iridium-192 implant (25 Gy). The effect of boost, the gap between initial treatment (RT alone or CMT) and boost (Tgap), and overall treatment time (OTT) were examined for their impact on outcome. RESULTS: Among the 490 good responders, 436 (89%) patients received a boost after initial treatment. For boosted patients, the risk of anal cancer death decreased by 38% (hazard ratio [HR]: 0.62, 99% CI 0.35-1.12; p=0.04), but there was no evidence this was mediated via a reduction in locoregional failure (LRF) (HR: 0.90, 99% CI 0.48-1.68; p=0.66). The difference in Tgap was only 1.4 days longer for EBRT boost, compared with implant (p=0.51). OTT was longer by 6.1 days for EBRT (p=0.006). Tgap and OTT were not associated with LRF. Radionecrosis was reported in 8% of boosted, compared with 0% in unboosted patients (p=0.03). CONCLUSIONS: These results question the benefit of a radiotherapy boost after a 6-week gap. The higher doses of a boost may contribute more to an increased risk of late morbidity, rather than local control.

Anal cancer in renal transplant patients.

PURPOSE: A comprehensive literature review was performed to examine the prevalence of anal cancer, anal intraepithelial neoplasia (AIN) and anal human papillomavirus (HPV) infection in renal transplant recipients who are at risk of anal cancer due to iatrogenic immunosuppression. METHODS: Pertinent articles were identified from searches performed on the National Center for Biotechnology Information database using the following keywords: anal cancer, AIN, screening, renal transplant (or kidney transplant), organ transplant recipients and post-transplant malignancies. RESULTS: The prevalence of AIN is 20% in renal transplant patients. The prevalence of anal HPV infection in established transplant patients is 47%, and the prevalence of anal HPV infection in new transplant patients is 23%. The relative risk for anal cancer in renal transplant patients is 10. CONCLUSIONS: As compared to HIV-positive male patients who practise anal intercourse, renal transplant patients showed a modest rise in relative risk for anal cancer. Screening programmes to detect AIN in HIV-positive patients who practise anal intercourse have been introduced on a preliminary basis in sexual health clinics in the US and may become standard practise in this population. The case for screening in renal transplant patients is unclear and would merit further investigation, especially with reference to the prevalence of anal HPV infection in this population. It may transpire that renal transplant patients would benefit more from HPV prophylaxis rather than screening for AIN.