Resveratrol is widely promoted as a potential cancer chemopreventive agent, but a lack of information on the optimal dose prohibits rationally designed trials to assess efficacy. To challenge the assumption that "more is better," we compared the pharmacokinetics and activity of a dietary dose with an intake 200 times higher. The dose-response relationship for concentrations generated and the metabolite profile of [(14)C]-resveratrol in colorectal tissue of cancer patients helped us to define clinically achievable levels. In Apc(Min) mice (a model of colorectal carcinogenesis) that received a high-fat diet, the low resveratrol dose suppressed intestinal adenoma development more potently than did the higher dose. Efficacy correlated with activation of adenosine monophosphate-activated protein kinase (AMPK) and increased expression of the senescence marker p21. Nonlinear dose responses were observed for AMPK and mechanistic target of rapamycin (mTOR) signaling in mouse adenoma cells, culminating in autophagy and senescence. In human colorectal tissues exposed to low dietary concentrations of resveratrol ex vivo, we measured enhanced AMPK phosphorylation and autophagy. The expression of the cytoprotective NAD(P)H dehydrogenase, quinone 1 (NQO1) enzyme was also increased in tissues from cancer patients participating in our [(14)C]-resveratrol trial. These findings warrant a revision of developmental strategies for diet-derived agents designed to achieve cancer chemoprevention.
The abdomino-perineal resection of the rectum (APR) was first described in detail, by the eminent English surgeon Sir Ernest Miles in his seminal paper in 1908. He described the steps employed to surgically treat low rectal cancers, which were not amenable to Anterior Resection of the rectum. This operation has been the standard treatment for low rectal cancers for over a hundred years. However, despite the advent of TME, local recurrence and survival have not improved to the same degree as seen in Anterior Resection of rectum. Differences in outcomes were partly related to the anatomical and surgical (technical) challenges operating deep in the pelvis. In recent years, the Extra-Levator APR technique has been shown to improve outcome. In this study we report on the differences in outcome following adoption of Chemo-DXT and ELAPR in our unit.
Method
We used our colorectal cancer database to select cases that qualified i.e. low rectal cancers that underwent APR in a 3 year period. In hospital Radiology and Pathology IT systems were used to collect further data. We compared various measures including circumferential resection margins (CRM). Margin positivity was compared from the pre ELAPR era to that observed in current unit practice of ELAPR.
Results
1. Our findings showed that neoadjuvant treatment downstaged and in some cases “cured” the tumours prior to surgery, radiologically. 2. With Neoadjuvant Chemo-DXT all T4 tumours were shrunk to a lower ypT stage in our Post-ELAPR data. 3. CRM margin positivity had reduced to 9% since the adoption of ELAPR in the unit. Previously it was 20%; thus, an 11% improvementon the previous audit figure or a >50% reduction in CRM positivity.
Conclusion
Our data supports the notion that Neoadjuvant Chemo-DXT and ELAPR can reduce CRM positivity in low rectal cancer and improve prognosis and should form the gold standard treatment of low rectal cancer.
Disclosure of interest
None Declared.
References
Miles WE. A method of performing abdomino-perineal excision for carcinoma of the rectum and of the terminal portion of the pelvic colon (1908). CA Cancer J Clin.1971;21(6):361–364 Heald RJ. The 9Holy Plane9 of rectal surgery. J R Soc Med. 1988;81(9):503–508 Palmer G, et al. Local control and survival after extralevator abdominoperineal excision for locally advanced or low rectal cancer. Colorectal Dis. 2014;16(7): 527–532
Abstract Aims Abdominal VAC dressings are part of the surgical armamentarium in the management of the open abdomen. This study examined the number, indication and outcomes of patients with VAC dressings in a tertiary surgical unit. Methods Retrospective review of the operating theatre database identified all patients with abdominal VAC dressing between February 2016 and July 2021. Medical records were reviewed for demographics, operative, outcome and discharge data. Results 76 patients had abdominal VAC dressings. 40 (53%) were female and 57 (75%) were aged >50 years. For 54 (72%) the primary surgery was an emergency. Major indications for VAC included intra-abdominal sepsis 41 (53.9%) and wound dehiscence 16 (21.1%). Mean VAC changes under GA 2.07 (range 0–10). Mean VAC changes on the ward 2.1 (range 0–11). Mean length of hospital stay 48.6 days (range 4–258). 49 (70%) had the VAC removed in hospital, in this cohort mean duration of VAC therapy was 22 days. 11 (15%) were discharged to community hospitals and 56 (77%) directly home. 4 (5.3%) patients developed entero-atmospheric fistulae, 1 (1.3%) bleeding and 1 (1.3%) wound infection. Conclusions Abdominal VAC therapy is safe. However, it comes with significant immediate and medium-term burdens, in terms of hospital bed days, theatre time and specialist staff input, all of which are costly. Longer term, incisional hernias are associated with morbidity for patients and a financial cost for the Trust. The authors therefore advocate an attempt at early fascial closure where possible, through techniques such as mesh mediated fascial closure.
Human papillomavirus (HPV) testing has been recently introduced as an alternative to cytology for cervical cancer screening. However, since most HPV infections clear without causing clinically relevant lesions, additional triage tests are required to identify women who are at high risk of developing cancer. We performed DNA methylation profiling on formalin-fixed, paraffin-embedded tissue specimens from women with benign HPV16 infection and histologically confirmed cervical intraepithelial neoplasia grade 3, and cancer using a bead-based microarray covering 1,500 CpG sites in over 800 genes. Methylation levels in individual CpG sites were compared using a t-test, and results were summarized by computing p-values. A total of 12 candidate genes (ADCYAP1, ASCL1, ATP10, CADM1, DCC, DBC1, HS3ST2, MOS, MYOD1, SOX1, SOX17 and TMEFF2) identified by DNA methylation profiling, plus an additional three genes identified from the literature (EPB41L3, MAL and miR-124) were chosen for validation in an independent set of 167 liquid-based cytology specimens using pyrosequencing and targeted, next-generation bisulfite sequencing. Of the 15 candidate gene markers, 10 had an area under the curve (AUC) of ≥ 0.75 for discrimination of high grade squamous intraepithelial lesions or worse (HSIL+) from
We reviewed our series of anal squamous cell carcinomas (ASCC) treated over the last two decades.ASCC patients undergoing treatment at the Leicester Royal Infirmary between 1998 and 2016 were selected. Age, gender, pathological tumor characteristics, treatment adopted, the overall survival (OS), cancer-specific survival (CSS), and disease-free survival (DFS) at 5-year follow-up were recorded and calculated.A total of 190 ASCC were reviewed, of these 64.2% (n = 122) received primary radical chemoradiotherapy. Complete response rate was 92.6% (n = 113) and four patients with residual disease underwent a salvage APER. Twenty-eight patients experienced recurrent disease (23.0%) either systemic (n = 8), local (n = 14), or both (n = 6); six had a salvage APER. Complete follow-up data are available for 63.1% patients (77/122). Overall, the locoregional failure rate of primary chemoradiotherapy (residual + recurrent disease) was present in 29 patients (29/122; 23.8%). OS was 41.6% CSS was 69.2% and DFS 60.0% at 5 years follow-up.In our series of ASCC primary chemoradiotherapy had achieved significant initial complete response rates, however, long term-follow ups still present systemic and local recurrences. APR is able to treat 30% of the pelvic recurrences (6/20), the others are either associated with systemic disease or locally inoperable masses.
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