Perioperative outcomes of cytoreductive surgery for tumours of colorectal or appendiceal origin with ovarian involvement.

BACKGROUND AND OBJECTIVES: Ovarian metastases (OM) are a common site for metastases in gastrointestinal tumours with peritoneal disease. This study aimed to evaluate perioperative complications between patients with and without OM following cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for appendiceal/colorectal cancer. METHODS: Female patients undergoing CRS ± HIPEC for appendiceal/colorectal tumours at a single centre from 2009 to 2020 were analysed. Patients were grouped according to presence or absence of OM at the time of CRS. RESULTS: The study included 318 patients, 72 (22.6%) had OM. Operation duration was longer for patients with OM (332 vs. 276 min, p < 0.0001). Patients with OM achieved higher rates of complete cytoreduction (93% vs. 79%, p = 0.006) despite a higher peritoneal carcinomatosis index (13 vs. 7, p < 0.001) and were more likely to require a blood transfusion (32% vs. 19%, p = 0.024) and a stoma (24% vs.10%, p = 0.005). Increasing age and presence of abdominal symptoms were independent predictors of major and all-cause morbidity, respectively. The presence of abdominal symptoms was independently associated with all-cause morbidity in the OM group. CONCLUSION: These results may assist with preoperative counselling. Prospective multicentre datasets are needed to evaluate morbidity in one- versus two-stage approaches for those with abdominal symptoms and OM.

Molecular and genomic characterisation of a panel of human anal cancer cell lines.

Anal cancer is a rare disease that has doubled in incidence over the last four decades. Current treatment and survival of patients with this disease has not changed substantially over this period of time, due, in part, to a paucity of preclinical models to assess new therapeutic options. To address this hiatus, we set-out to establish, validate and characterise a panel of human anal squamous cell carcinoma (ASCC) cell lines by employing an explant technique using fresh human ASCC tumour tissue. The panel of five human ASCC cell lines were validated to confirm their origin, squamous features and tumourigenicity, followed by molecular and genomic (whole-exome sequencing) characterisation. This panel recapitulates the genetic and molecular characteristics previously described in ASCC including phosphoinositide-3-kinase (PI3K) mutations in three of the human papillomavirus (HPV) positive lines and TP53 mutations in the HPV negative line. The cell lines demonstrate the ability to form tumouroids and retain their tumourigenic potential upon xenotransplantation, with varied inducible expression of major histocompatibility complex class I (MHC class I) and Programmed cell death ligand 1 (PD-L1). We observed differential responses to standard chemotherapy, radiotherapy and a PI3K specific molecular targeted agent in vitro, which correlated with the clinical response of the patient tumours from which they were derived. We anticipate this novel panel of human ASCC cell lines will form a valuable resource for future studies into the biology and therapeutics of this rare disease.

Appendiceal pseudomyxoma peritonei: predictors of recurrence and iterative surgery.

AIM: Appendiceal pseudomyxoma peritonei (PMP) is a rare entity, with recurrence rates up to 26% despite optimal cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Evidence specific to PMP originating from non-infiltrative appendiceal mucinous neoplasms (low grade - LAMN and high grade - HAMN) is lacking. The aim of this study was to identify patterns of recurrence and predictive factors for patients appropriate for iterative surgery. METHOD: A bi-institutional retrospective analysis was performed on patients undergoing complete cytoreduction and HIPEC for PMP derived from perforated LAMN or HAMN. Multivariate logistic regression was performed to identify independent predictors for re-do CRS. Five-year overall survival (OS) was stratified according to surgical intervention, and 5-year disease-free survival (DFS) was stratified according to histological PMP grade. Cox regression analysis was performed to identify independent predictors for OS and DFS. RESULTS: Sixty of 239 (25.1%) patients developed peritoneal recurrence between 2007 and 2020. The median time to recurrence was 20.7 months. The risk of disease recurrence was highest with high-grade PMP (P <0.001) and increasing PCI (P <0.001). Patients with high-grade histology from their index procedure and aged over 60 years were less likely to be offered iterative surgery on multivariate analysis. Patients who underwent iterative CRS and HIPEC had a 5-year survival of 100%. CONCLUSION: Iterative CRS and HIPEC is feasible in selected patients with recurrent PMP, displaying good oncological outcomes. Age, index histology and level of abdominal quadrant involvement are predictive of proceeding to re-do surgery.

Colorectal cancer in younger adults from a Bi-National Colorectal Cancer Audit registry.

BACKGROUND: The incidence of colorectal cancer (CRC) in younger adults (<50 years old) is rising worldwide, at a rate of 1% per annum since mid-1980s. The clinical concern is that younger adults may have more advanced disease leading to poorer prognosis compared to their older cohort due to lack of screening. Therefore, the aim of this study is to assess the incidence and short-term outcomes of colorectal cancer in younger adults. METHODS: This is a retrospective study from a prospectively maintained bi-national database from 2007 to 2018. RESULTS: There were 1540 younger adults diagnosed with CRC, with a rise from 5.8% in 2007 to 8.4% in 2018. Majority had lower American Society of Anaesthesiologists (ASA) scores (89%), rectal cancers (46.1%) and higher tumour stage (65.4%). As a consequence, they were likely to have higher circumferential resection margin positivity (6%, P = 0.02) and to receive adjuvant chemotherapy (57.1%, P < 0.001) compared to their older cohort. Multivariate analysis showed disadvantaged socioeconomic status (odds ratio (OR) 3.3, 95% confidence interval (CI) 1.37-7.94, P < 0.001) and increasing tumour stage (OR 14.9, 95% CI 1.89-116.9, P < 0.001) were independent predictors for circumferential resection margin positivity whereas being female (OR 0.71, 95% CI 0.53-0.95, P = 0.02), higher ASA score (OR 175.3, 95% CI 26.7-1035.5, P < 0.001), urgent surgery (OR 2.75, 95% CI 1.84-4.11, P < 0.001) and anastomotic leak (OR 5.02, 95% CI 3.32-7.58, P < 0.001) were predictors of inpatient mortality. CONCLUSION: There is a steady rise in the incidence of colorectal cancer in younger adults. Both physicians and younger adults should be aware of the potential risk of colorectal cancer (CRC) and appropriate investigations performed so not to delay the diagnosis.

An Evolutionarily Conserved Function of Polycomb Silences the MHC Class I Antigen Presentation Pathway and Enables Immune Evasion in Cancer.

Loss of MHC class I (MHC-I) antigen presentation in cancer cells can elicit immunotherapy resistance. A genome-wide CRISPR/Cas9 screen identified an evolutionarily conserved function of polycomb repressive complex 2 (PRC2) that mediates coordinated transcriptional silencing of the MHC-I antigen processing pathway (MHC-I APP), promoting evasion of T cell-mediated immunity. MHC-I APP gene promoters in MHC-I low cancers harbor bivalent activating H3K4me3 and repressive H3K27me3 histone modifications, silencing basal MHC-I expression and restricting cytokine-induced upregulation. Bivalent chromatin at MHC-I APP genes is a normal developmental process active in embryonic stem cells and maintained during neural progenitor differentiation. This physiological MHC-I silencing highlights a conserved mechanism by which cancers arising from these primitive tissues exploit PRC2 activity to enable immune evasion.

Prognostic Impact of Tumor-Infiltrating Lymphocytes in Primary and Metastatic Colorectal Cancer: A Systematic Review and Meta-analysis.

BACKGROUND: There is increasing literature emerging on the significance of tumor-infiltrating lymphocytes in colorectal cancer. However, there have been inconsistent findings, secondary to small patient numbers and varied methods for identifying these lymphocytes. OBJECTIVE: The aim of this study was to determine the prognostic and predictive power of tumor-infiltrating lymphocytes in colon, rectal (in neoadjuvant setting), and metastatic colorectal cancer. DATA SOURCES: A comprehensive search of PubMed and Embase was undertaken from January 2006 to December 2016. STUDY SELECTION: The inclusion criteria included a description of the tumor-infiltrating lymphocyte subset(s) assessed with reporting of associated short- and long-term outcomes. MAIN OUTCOME MEASURES: The main outcome measures, were disease-free and overall survival. RESULTS: A total of 25 studies were included, 15 for primary colorectal cancer (4719 patients), 7 for locally advanced rectal cancer (727 patients), and 3 studies for metastatic colorectal cancer (418 patients). High CD3, CD8, FoxP3, and CD45RO densities were associated with improved overall survival for primary colorectal cancer, with pooled estimated HRs of 0.88, 0.81, 0.70, and 0.63 (all p < 0.001) respectively. Furthermore, in locally advanced rectal cancer, the levels of CD8 cells were a significant predictor of good tumor regression grade after chemoradiotherapy. LIMITATIONS: The retrospective nature of included studies and the significant interstudy heterogeneity were limitations. CONCLUSIONS: There is increasing evidence that tumor-infiltrating lymphocytes play an important role in predicting prognosis in colorectal cancer and tumor regression after neoadjuvant chemoradiotherapy in locally advanced rectal cancer. Clinical researchers are now in a unique position to build on this work to identify robust predictive markers to stratify patients not only to currently available therapies but also to immunotherapy, which has demonstrated success in improving patient outcomes.

Recurrent common bile duct stones as a late complication of endoscopic sphincterotomy.

BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) with endoscopic sphincterotomy (ES) has become well established as a modality for the management of common bile duct stones (CBDS), especially in the setting of associated cholangitis. Our study aims to determine the rate of long term morbidity of recurrent CBDS post ES. METHODS: A retrospective analysis of patients who underwent ERCP and ES (ERCP+ES) was undertaken on a prospectively maintained database from 1998 to 2012 at the Northern Hospital, Melbourne. Primary CBDS were defined as those detected at least 6 months after complete clearance of the CBD. Prior cholecystectomy was a requirement for inclusion and patients with primary CBD stones in the setting of an intact sphincter were excluded. RESULTS: A total of 1148 patients underwent ERCP, of which 573 had an ES. Fifty-one patients underwent an ES prior to developing primary CBDS (8.9%). The time to recurrence ranged from 6 months to 15 years (mean 3.3 years). The number of procedures per patient ranged from 2 to 11, with 51% requiring 3 or more ERCPs. Factors associated with primary CBDS recurrence included a dilated CBD > 12 mm, stricture of the major papilla post ES to 2 - 5 mm and presence of the ampulla within or on the edge of a duodenal diverticulum. CONCLUSION: The results demonstrate that ERCP + ES has an inherent long-term complication of recurrent primary CBDS formation. While this can be managed with repeat ERCP, the advent of laparoscopic bile duct exploration should lead us to re-examine the role of ERCP + ES in younger patients.

Risk Factors Associated With Circumferential Resection Margin Positivity in Rectal Cancer: A Binational Registry Study.

BACKGROUND: Rectal cancer outcomes have improved with the adoption of a multidisciplinary model of care. However, there is a spectrum of quality when viewed from a national perspective, as highlighted by the Consortium for Optimizing the Treatment of Rectal Cancer data on rectal cancer care in the United States. OBJECTIVE: The aim of this study was to assess and identify predictors of circumferential resection margin involvement for rectal cancer across Australasia. DESIGN: A retrospective study from a prospectively maintained binational colorectal cancer database was interrogated. SETTINGS: This study is based on a binational colorectal cancer audit database. PATIENTS: Clinical information on all consecutive resected rectal cancer cases recorded in the registry from 2007 to 2016 was retrieved, collated, and analyzed. MAIN OUTCOME MEASURES: The primary outcome measure was positive circumferential resection margin, measured as a resection margin ≤1 mm. RESULTS: A total of 3367 patients were included, with 261 (7.5%) having a positive circumferential resection margin. After adjusting for hospital and surgeon volume, hierarchical logistic regression analysis identified a 6-variable model encompassing the independent predictors, including urgent operation, abdominoperineal resection, open technique, low rectal cancer, T3 to T4, and N1 to N2. The accuracy of the model was 92.3%, with an receiver operating characteristic of 0.783 (p < 0.0001). The quantitative risk associated with circumferential resection margin positivity ranged from <1% (no risk factors) to 43% (6 risk factors). LIMITATIONS: This study was limited by the lack of recorded long-term outcomes associated with circumferential resection margin positivity. CONCLUSIONS: The rate of circumferential resection margin involvement in patients undergoing rectal cancer resection in Australasia is low and is influenced by a number of factors. Risk stratification of outcome is important with the increasing demand for publicly accessible quality data. See Video Abstract at http://links.lww.com/DCR/A512.

Salvage Surgery for Locoregional Failure in Anal Squamous Cell Carcinoma.

BACKGROUND: Anal squamous cell carcinoma is a rare cancer with a high cure rate, making research into the treatment of locoregional failure difficult. OBJECTIVE: The purpose of this study was to examine factors related to local treatment failure and determine the outcomes of patients undergoing local salvage resection. DESIGN: This was a retrospective cohort study. SETTING: This study was conducted at a quaternary referral center. PATIENTS: Patients with anal squamous cell carcinoma treated with chemoradiotherapy between January 1983 and December 2015 were included. MAIN OUTCOME MEASURES: The influence of patient-, tumor-, and treatment-related factors on the primary outcome measures of locoregional failure, overall survival, and disease-free survival were investigated. RESULTS: Of 467 patients with anal squamous cell carcinoma, 63 experienced locoregional failure with 41 undergoing salvage resection. Twenty-seven patients (38%) had persistent disease and 36 (62%) developed locoregional recurrence. Multivariate analysis identified tumor stage (HR, 3.16; p < 0.002) as an independent predictor of locoregional failure. Thirty abdominoperineal resections and 11 pelvic exenterations were undertaken with no surgical mortality. At a median follow-up of 20 months (range, 4-150 months), 5-year overall and disease-free survival for the salvage cohort was 51% and 47%. Margin positivity was an independent predictor for relapse post-salvage surgery on multivariate analysis (HR, 20.1; p = 0.027). Nineteen patients (48%) developed further relapse, which included all 10 patients with a positive resection margin, 3 of whom underwent re-resection. Of the 19 patients with relapse, 3 remain alive and 2 have persistent disease. LIMITATIONS: Limitations include the retrospective nature of the database, the prolonged time period of the study, and episodes of incomplete data. CONCLUSIONS: Advanced T stage is an independent predictor of local failure in anal squamous cell carcinoma. Most patients can be salvaged, with a positive resection margin being a strong predictor of further relapse and poor outcome. See Video Abstract at http://links.lww.com/DCR/A515.

Colonoscopic surveillance: quality, guidelines and effectiveness.

Colonoscopic surveillance in patients with a personal or family history of colorectal carcinoma or colonic polyps represents a significant workload for endoscopy services. Effective colonoscopic surveillance relies on quality endoscopic examination and appropriate surveillance interval. This review will discuss quality in colonoscopy and review guidelines for surveillance.

Inhibiting the system xC-/glutathione axis selectively targets cancers with mutant-p53 accumulation.

TP53, a critical tumour suppressor gene, is mutated in over half of all cancers resulting in mutant-p53 protein accumulation and poor patient survival. Therapeutic strategies to target mutant-p53 cancers are urgently needed. We show that accumulated mutant-p53 protein suppresses the expression of SLC7A11, a component of the cystine/glutamate antiporter, system xC-, through binding to the master antioxidant transcription factor NRF2. This diminishes glutathione synthesis, rendering mutant-p53 tumours susceptible to oxidative damage. System xC- inhibitors specifically exploit this vulnerability to preferentially kill cancer cells with stabilized mutant-p53 protein. Moreover, we demonstrate that SLC7A11 expression is a novel and robust predictive biomarker for APR-246, a first-in-class mutant-p53 reactivator that also binds and depletes glutathione in tumours, triggering lipid peroxidative cell death. Importantly, system xC- antagonism strongly synergizes with APR-246 to induce apoptosis in mutant-p53 tumours. We propose a new paradigm for targeting cancers that accumulate mutant-p53 protein by inhibiting the SLC7A11-glutathione axis.

Outcome and Salvage Surgery Following "Watch and Wait" for Rectal Cancer after Neoadjuvant Therapy: A Systematic Review.

BACKGROUND: Currently there is no reliable test to predict pathological complete response following neoadjuvant chemoradiotherapy for rectal cancer. However, there is increasing interest in using clinical complete response as a surrogate marker, allowing a subset of patients with locally advanced rectal cancer to be allocated into a "watch and wait" pathway. Little is known about the oncological safety of the "watch and wait" approach or the rate of salvage surgery in cases of tumor regrowth. This information is critical for the implementation of this approach. OBJECTIVE: The aim of this study is to assess the rate of salvage surgery and associated oncological outcomes for patients who develop a tumor regrowth with the "watch and wait" approach. DATA SOURCES: Relevant studies were identified through PubMed, Embase, and Google Scholar search. STUDY SELECTION: A systematic review was undertaken of studies assessing patients selected for the "watch and wait" approach according to PRISMA guidelines. MAIN OUTCOME MEASURES: The associated tumor regrowth, salvage surgery, and disease-free and overall survival rates were assessed. RESULTS: Five retrospective and 4 prospective observational studies were included into the analysis, with a total of 370 patients in the "watch and wait" group, of which 256 (69.2%) had persistent clinical complete response. Of those who had tumor regrowth, salvage surgery was possible in 83.8%. There was no difference in overall survival and disease-free survival between patients who received immediate surgery and the "watch and wait" group. LIMITATIONS: The limitations of this study include its retrospective nature and small sample size. Furthermore, there is significant heterogeneity between study protocols, including the short median follow-up, given that tumor regrowth and distant metastasis may manifest at a later time point. CONCLUSION: The majority of patients with tumor regrowth can be salvaged with definite surgery after "watch and wait." However, there is insufficient evidence to draw firm conclusions on the oncological safety of this approach; therefore, it is currently not the standard of care for locally advanced rectal cancer.

Abdominal wall metastasis following open nephroureterectomy for upper tract urothelial carcinoma in a patient with Lynch syndrome.

A 74-year-old man developed the rare complication of an abdominal wall metastasis following open nephroureterectomy for upper tract urothelial carcinoma (UTUC). This occurred in the setting of synchronous contralateral ureteric and metachronous colorectal carcinomas. Immunohistochemistry demonstrated loss of the mutS homolog 6 (MSH6) mismatch repair (MMR) protein in the metastatic abdominal wall and colonic lesions, which in conjunction with meeting the Amsterdam II criteria, is strongly suggestive of Lynch syndrome (LS). Surgical resection of the recurrence was performed with clear margins and neither recurrence nor spread during short-term follow-up.

Primary squamous cell carcinoma of the rectum: An update and implications for treatment.

AIM: To provide an update on the aetiology, pathogenesis, diagnosis, staging and management of rectal squamous cell carcinoma (SCC). METHODS: A systematic review was conducted according to the preferred reporting items for Systematic Reviews and Meta-Analyses guidelines. A comprehensive search of Ovid MEDLINE was performed with the reference list of selected articles reviewed to ensure all relevant publications were captured. The search strategy was limited to the English language, spanning from 1946 to 2015. A qualitative analysis was undertaken examining patient demographics, clinical presentation, diagnosis, staging, treatment and outcome. The quantitaive analysis was limited to data extracted on treatment and outcomes including radiological, clinical and pathological complete response where available. The narrative and quantitative review were synthesised in concert. RESULTS: The search identified 487 articles in total with 79 included in the qualitative review. The quantitative analysis involved 63 articles, consisting of 43 case reports and 20 case series with a total of 142 individual cases. The underlying pathogenesis of rectal SCC while unclear, continues to be defined, with increasing evidence of a metaplasia-dysplasia-carcinoma sequence and a possible role for human papilloma virus in this progression. The presentation is similar to rectal adenocarcinoma, with a diagnosis confirmed by endoscopic biopsy. Many presumed rectal SCC's are in fact an extension of an anal SCC, and cytokeratin markers are a useful adjunct in this distinction. Staging is most accurately reflected by the tumour-node-metastasis classification for rectal adenocarcinoma. It involves examining locoregional disease by way of magnetic resonance imaging and/or endorectal ultrasound, with systemic spread excluded by way of computed tomography. Positron emission tomography is integral in the workup to exclude an external site of primary SCC with metastasis to the rectum. While the optimal treatment remains as yet undefined, recent studies have demonstrated a global shift away from surgery towards definitive chemoradiotherapy as primary treatment. Pooled overall survival was calculated to be 86% in patients managed with chemoradiation compared with 48% for those treated traditionally with surgery. Furthermore, local recurrence and metastatic rates were 25% vs 10% and 30% vs 13% for the chemoradiation vs conventional treatment cohorts. CONCLUSION: The changing paradigm in the treatment of rectal SCC holds great promise for improved outcomes in this rare disease.