Necrotizing Fasciitis: Expect the unexpected.

INTRODUCTION: Necrotizing fasciitis is a rapidly progressive and potentially fatal soft tissue infection. A wide spectrum of aerobic and nonaerobic organisms has been implicated as the causative pathogen. Necrotizing Fasciitis due to Salmonella serovars have previously been implicated both with and without a prodromal diarrheal illness, but mono-microbial Salmonella NF is very rare. CASE PRESENTATION: We have discussed the case of a 67-year-old man who presented with necrotizing fasciitis of the perianal region in the emergency department of our hospital. He underwent serial debridement and a defunctioning colostomy, tissue and blood cultures revealed Salmonella Newport as the culprit microorganism. He received antibiotic therapy tailored to the organism and was discharged on recovery. He currently awaits a reversal of his colostomy. DISCUSSION: Necrotizing fasciitis infections are rapidly progressive and potentially lethal, a high index of suspicion and aggressive surgical debridement supplemented with culture sensitive antibiotics is essential. Salmonella Newport has recently been implicated in diarrheal illness, associated with consumption of minced beef in the US. To the best of our knowledge, no previous reports of NF have been published related to Salmonella newport. The unexpected growth of this organism from tissue cultures and the excellent response to treatment prompted us to highlight this case as the first report of its type in the medical literature. CONCLUSION: Necrotizing soft tissue infections are associated with considerable morbidity and mortality, and delayed recognition and treatment can have severe implications. Necrotizing fasciitis due to Salmonella serovars has been reported with Group B and C however no previous reports of NF have been reported with this serovar.

Conditional Survival in Patients With Rectal Cancer and Complete Clinical Response Managed by Watch and Wait After Chemoradiation: Recurrence Risk Over Time.

OBJECTIVE: Analyze conditional recurrence-free survival (cRFS) for rectal cancer patients with complete clinical response (cCR) after neoadjuvant chemoradiation (nCRT) managed nonoperatively after each year without recurrence. SUMMARY BACKGROUND DATA: Select patients with cCR after nCRT have been managed nonoperatively. Risk factors for local recurrence, the need for prolonged follow-up, and the risk of recurrence over time are not well defined. METHODS: Retrospective review of patients with rectal cancer cT2-4N0-2M0 treated with nCRT. Mean follow-up was 64 months. Patients who achieved cCR were managed nonoperatively. cRFS was used to investigate the evolution of recurrence-odds, as patients remain recurrence-free after completion of nCRT. Three-year cRFS was estimated at "x" years after completion of nCRT based on the formula cRFS3 = RFS(x+3)/RFS(x). RESULTS: One hundred ninety-seven patients with cCR after nCRT were included. Overall survival and recurrence-free survival (RFS) at 5 years were 81.9% (95% CI 74.0%-87.6%) and 60.4% (95% CI 52.5%-67.4%) respectively. Using cRFS estimates, the probability of remaining disease-free for an additional 3 years if the patient survived without disease at 1, 3, and 5 years, was 77.4% (95% CI 68.8%-83.8%), 91.0% (95% CI 81.9%-95.7%), and 94.3% (95% CI 82.9%-98.2%), respectively. In contrast, actuarial RFS rates for similar intervals were 79.1% (95% CI 72.5%-84.2%), 64.2% (95% CI 56.5%-70.8%), and 60.4% (95% CI 52.5%-67.4%). After 2 years disease-free, 3 year cRFS became similar for T2 and T3 cancers. In contrast, patients undergoing extended nCRT became less likely to develop recurrences only after initial 2 years of successful organ-preservation. CONCLUSIONS: Conditional survival suggests that patients have significantly lower risks (≤10%) of developing recurrences after 2 years of achieving cCR following nCRT.

Oncological and Survival Outcomes in Watch and Wait Patients With a Clinical Complete Response After Neoadjuvant Chemoradiotherapy for Rectal Cancer: A Systematic Review and Pooled Analysis.

OBJECTIVE: The aim of this study was to evaluate the oncological and survival outcomes of a Watch and Wait policy in rectal cancer after a clinical complete response (cCR) following neoadjuvant chemoradiotherapy. BACKGROUND: The detection of a cCR after neoadjuvant treatment may facilitate a nonoperative approach in selected patients. However, the long-term safety of this strategy remains to be validated. METHOD: This is a systematic review of the literature to determine the oncological outcomes in Watch and Wait patients. The primary outcome was the cumulative rate of local regrowth, success of salvage surgery, and incidence of metastases. We also evaluated survival outcomes. A pooled analysis of manually extracted summary statistics from individual studies was carried out using inverse variance weighting. RESULTS: Seventeen studies comprising 692 patients were identified; incidence of cCR was 22.4% [95% confidence interval (CI),14.3-31.8]. There were 153 (22.1%) local regrowths, of which 96% (n = 147/153) manifested in the first 3 years of surveillance. The 3-year cumulative risk of local regrowth was 21.6% (95% CI, 16.0-27.8). Salvage surgery was performed in 88% of patients, of which 121 (93%) had a complete (R0) resection. Fifty-seven metastases (8.2%) were detected, and 35 (60%) were isolated without evidence of synchronous regrowths; 3-year incidence was 6.8% (95% CI, 4.1-10.2). The 3-year overall survival was 93.5% (95% CI, 90.2-96.2). CONCLUSION: In rectal cancer patients with a cCR following neoadjuvant chemoradiotherapy, a Watch and Wait policy appears feasible and safe. Robust surveillance with early detection of regrowths allows a high rate of successful salvage surgery, without an increase in the risk of systemic disease, or adverse survival outcomes.

A rectal cancer feasibility study with an embedded phase III trial design assessing magnetic resonance tumour regression grade (mrTRG) as a novel biomarker to stratify management by good and poor response to chemoradiotherapy (TRIGGER): study protocol for a randomised controlled trial.

BACKGROUND: Pre-operative chemoradiotherapy (CRT) for MRI-defined, locally advanced rectal cancer is primarily intended to reduce local recurrence rates by downstaging tumours, enabling an improved likelihood of curative resection. However, in a subset of patients complete tumour regression occurs implying that no viable tumour is present within the surgical specimen. This raises the possibility that surgery may have been avoided. It is also recognised that response to CRT is a key determinant of prognosis. Recent radiological advances enable this response to be assessed pre-operatively using the MRI tumour regression grade (mrTRG). Potentially, this allows modification of the baseline MRI-derived treatment strategy. Hence, in a 'good' mrTRG responder, with little or no evidence of tumour, surgery may be deferred. Conversely, a 'poor response' identifies an adverse prognostic group which may benefit from additional pre-operative therapy. METHODS/DESIGN: TRIGGER is a multicentre, open, interventional, randomised control feasibility study with an embedded phase III design. Patients with MRI-defined, locally advanced rectal adenocarcinoma deemed to require CRT will be eligible for recruitment. During CRT, patients will be randomised (1:2) between conventional management, according to baseline MRI, versus mrTRG-directed management. The primary endpoint of the feasibility phase is to assess the rate of patient recruitment and randomisation. Secondary endpoints include the rate of unit recruitment, acute drug toxicity, reproducibility of mrTRG reporting, surgical morbidity, pathological circumferential resection margin involvement, pathology regression grade, residual tumour cell density and surgical/specimen quality rates. The phase III trial will focus on long-term safety, regrowth rates, oncological survival analysis, quality of life and health economics analysis. DISCUSSION: The TRIGGER trial aims to determine whether patients with locally advanced rectal cancer can be recruited and subsequently randomised into a control trial that offers MRI-directed patient management according to radiological response to CRT (mrTRG). The feasibility study will inform a phase III trial design investigating stratified treatment of good and poor responders according to 3-year disease-free survival, colostomy-free survival as well as an increase in cases managed without a major resection. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT02704520 . Registered on 5 February 2016.

Expression of DNA double-strand break repair proteins ATM and BRCA1 predicts survival in colorectal cancer.

PURPOSE: The double-strand break (DSB) is the major DNA lesion leading to chromosomal aberrations and faithful repair is crucial for maintaining genomic instability. Very little is known about the expression of DNA DSB repair proteins in colorectal cancer. To address this issue, we examined the expression pattern of DSB repair key proteins ATM, BRCA1, BRCA2, Ku70, and Ku80 and their putative role in patients survival in a large series of colorectal cancer. EXPERIMENTAL DESIGN: 342 sporadic colorectal cancer were subjected to immunohistochemistry by using specific antibodies for the various proteins investigated. Staining results were compared with clinicopathologic data, patient survival, as well as expression of mismatch repair proteins MLH1 and MSH2. RESULTS: The expression pattern of both ATM and BRCA1 predicted survival in all colorectal cancer patients as well as in the small subgroup of patients that received adjuvant therapy. Low expression of ATM and BRCA1 was associated with loss of MLH1 or MSH2 expression. CONCLUSIONS: This is the first study to show a relationship between the expression of DNA DSB repair proteins ATM and BRCA1 and survival in colorectal cancer patients. Studies in tumors from large randomized trials are now necessary to validate our pilot data and establish the clinical usefulness of the immunohistochemical assay in predicting response to a particular adjuvant therapy regimen. Furthermore, our results indicate a possible link between expression of DNA mismatch repair and DNA DSB repair proteins in sporadic colorectal cancer, which warrants further investigation.

The septin-binding protein anillin is overexpressed in diverse human tumors.

Anillin is an actin-binding protein that can bind septins and is a component of the cytokinetic ring. We assessed the anillin expression in 7,579 human tissue samples and cell lines by DNA microarray analysis. Anillin is expressed ubiquitously but with variable levels of expression, being highest in the central nervous system. The median level of anillin mRNA expression was higher in tumors than normal tissues (median fold increase 2.58; 95% confidence intervals, 2.19-5.68, P < 0.0001) except in the central nervous system where anillin mRNA levels were lower in tumors. We developed a sensitive reverse transcription-PCR strategy to show that anillin mRNA is expressed in cell lines and in cDNA panels derived from fetal and adult tissues, thus validating the microarray data. We compared anillin with Ki67 mRNA expression and found a significant linear relationship between anillin and Ki67 mRNA expression (Spearmann r approximately 0.6, P < 0.0001). Anillin mRNA expression was analyzed during tumor progression in breast, ovarian, kidney, colorectal, hepatic, lung, endometrial, and pancreatic tumors and in all tissues there was progressive increase in anillin mRNA expression from normal to benign to malignant to metastatic disease. Finally, we used anti-anillin sera and found nuclear anillin immunoreactivity to be widespread in normal tissues, often not correlating with proliferative compartments. These data provide insight into the existence of nonproliferation-associated activities of anillin and roles in interphase nuclei. Thus, anillin is overexpressed in diverse common human tumors, but not simply as a consequence of being a proliferation marker. Anillin may have potential as a novel biomarker.