Evaluation of Urinalysis-Based Screening for Urothelial Carcinoma in Patients With Lynch Syndrome.

BACKGROUND: Approximately 5% to 10% of patients with Lynch syndrome develop urothelial carcinoma. Current screening recommendations vary and are based on expert opinion. Practices need to be evaluated for clinical effectiveness. Our program utilizes urinalysis as a screening test, followed by additional evaluation of microscopic hematuria. OBJECTIVE: This study aimed to determine the clinical utility of a urinalysis-based screening approach for urothelial cancers in patients with Lynch syndrome. DESIGN: This is a retrospective review of a prospectively maintained cohort. SETTING: Patients with Lynch syndrome were managed at a tertiary referral center. PATIENTS: All patients with a Lynch syndrome diagnosis who had a screening urinalysis done as part of our institutional screening protocol (N = 204) were included. MAIN OUTCOME MEASURES: A single-institution hereditary colorectal cancer syndrome registry was queried for patients with Lynch syndrome who had been screened for urothelial carcinomas by urinalysis. Demographics, genotype, family history of urothelial carcinoma, urinalysis results, and subsequent screenings and final diagnosis were gathered for patients between 2008 and 2017. RESULTS: Two hundred four asymptomatic patients underwent screening by urinalysis. Nineteen patients (9.3%) had microscopic hematuria and were further evaluated with urine cytology, imaging, cystoscopy, and/or Urology consultation. None of the 19 patients with microscopic hematuria had urothelial carcinoma. During the same study period, 5 of 204 (2.4%) patients with Lynch syndrome were diagnosed with urothelial cancer, and all presented with symptoms between screening intervals. LIMITATIONS: This is a retrospective study, and not all patients underwent the same secondary evaluation. CONCLUSIONS: No urothelial carcinomas were detected by screening urinalysis in our cohort of asymptomatic patients with Lynch syndrome. False-positive testing led to extensive, mostly uninformative, workups. If urothelial cancer screening is to continue, more effective screening approaches need to be identified. See Video Abstract at http://links.lww.com/DCR/B702. EVALUACIN DEL CRIBADO BASADO EN ANLISIS DE ORINA PARA CARCINOMA UROTELIAL EN PACIENTES CON SNDROME DE LYNCH: ANTECEDENTES:Aproximadamente el 5-10% de los pacientes con síndrome de Lynch desarrollan carcinoma urotelial. Las recomendaciones actuales de detección varían y se basan en la opinión de expertos. Las prácticas deben evaluarse para determinar su eficacia clínica. Nuestro programa utiliza el análisis de orina como prueba de detección, seguido de una evaluación adicional con hematuria microscópica.OBJETIVO:Determinar la utilidad clínica desde un enfoque de cribado basado en análisis de orina, para cánceres uroteliales en pacientes con síndrome de Lynch.DISEÑO:Revisión retrospectiva de una cohorte mantenida prospectivamente.ENTORNO CLINICO:Pacientes con síndrome de Lynch atendidos en un centro de referencia terciario.PACIENTES:Criterios de inclusión fueron todos los pacientes con diagnóstico de síndrome de Lynch realizándoles un análisis de orina de detección como parte de nuestro protocolo de detección institucional (N = 204).PRINCIPALES MEDIDAS DE VALORACION:Solicitando un registro de síndrome de cáncer colorrectal hereditario de una sola institución para pacientes con síndrome de Lynch previamente evaluados para carcinomas uroteliales mediante análisis de orina. Se recopilaron para los pacientes entre 2008 y 2017, datos demográficos, genotipo, antecedentes familiares de carcinoma urotelial, resultados del análisis de orina, posteriores exámenes de detección posteriores y diagnóstico final.RESULTADOS:Doscientos cuatro pacientes asintomáticos fueron sometidos a cribado mediante análisis de orina. Diecinueve pacientes (9,3%) tenían hematuria microscópica y fueron investigados más a fondo con citología de orina, imágenes, cistoscopia y / o consulta de urología. Ninguno de los 19 pacientes con hematuria microscópica tenían carcinoma urotelial. Durante el mismo período de estudio, 5 de 204 (2,4%) pacientes con síndrome de Lynch fueron diagnosticados con cáncer urotelial y todos presentaron presentando síntomas entre los intervalos de detección.LIMITACIONES:Estudio retrospectivo y no todos los pacientes sometidos a la misma evaluación secundaria.CONCLUSIONES:No se detectaron carcinomas uroteliales mediante análisis de orina de detección en nuestra cohorte de pacientes asintomáticos con síndrome de Lynch. Las pruebas de falsos positivos. Condujeron a estudios exhaustivos y en su mayoría poco informativos. Si se desea continuar con la detección del cáncer de urotelio, es necesario identificar enfoques de detección más efectivos. Consulte Video Resumen en http://links.lww.com/DCR/B702.

Ileocolic anastomosis after right hemicolectomy: stapled end-to-side, stapled side-to-side, or handsewn?

PURPOSE: Anastomotic leak (AL) following ileocolic anastomosis is a cause of significant morbidity and mortality. Stapled end-to-side (ESA), stapled side-to-side (SSA), and handsewn anastomoses (HSA) are commonly performed techniques. There is however conflicting data on the superiority of one technique over the other. The aim of this study was to compare the outcomes of ESA against SSA and HSA. METHODS: This retrospective cohort study was conducted at a tertiary colorectal unit. All patients who underwent an ileocolic anastomosis from October 2008 to May 2020 were included. Exclusion criteria were missing data on anastomotic technique or clinicopathological variables. Primary outcomes were AL and anastomotic bleeding (AB). Secondary outcomes were length of stay (LoS) and return of gut function. RESULTS: A total of 1390 patients met the inclusion criteria. A total of 976 (70%) ESA, 308 (22%) SSA, and 108 (8%) HSA were performed. AL occurred in 17/1390 (1.2%) patients, and 54/1390 (3.9%) had AB. On adjusted analysis, ESA experienced a lower AL when compared with SSA (OR 4.93, p = 0.005), with a trend towards a lower AL when compared to HSA (OR 2.6, p = 0.27). There was no difference in AB between all techniques: ESA vs. SSA (OR 1.07 p = 0.84), and ESA vs. HSA (OR 0.24 p = 0.76). Both stapled techniques were associated with a shorter return to gut function compared to HSA; 3.3 vs. 4.2 days (p < 0.001). There was no difference in LoS. CONCLUSION: ESA has the lowest leak rate when compared to other anastomotic techniques without any increased risk of anastomotic bleeding.

Lower peripouch fat area is related with increased frequency of pouch prolapse and floppy pouch complex in inflammatory bowel disease patients.

BACKGROUND: Pouch prolapse is a rare pouch complication which often leads to pouch failure in inflammatory bowel disease (IBD) patients. Its exact cause remains unknown. Floppy pouch complex (FPC) was defined as the presence of any one of the following pouch disorders: pouch prolapse, afferent limb syndrome (ALS), redundant loop, and pouch folding. We aimed to explore the role of peripouch fat area in the occurrence of pouch prolapse and FPC. METHODS: Pouch patients with available pouchoscopy and abdominal CT scans who were followed up between 2011 and 2017 in Cleveland Clinic were reviewed. Peripouch fat was measured on CT images. RESULTS: Of the 93 included patients, 31 were females; 87 had J pouches and 6 had S pouches. The median duration of pouch was 8.0 (interquartile range [IQR] 5.0-16.5) years. A total of 18 cases (19.4%, 18/93) were identified as FPC, including 12 pouch prolapse, 5 ALS, 1 redundant loop, and 3 pouch folding. Patients with pouch prolapse had lower peripouch fat area (13.6 (9.3-18.5) vs. 27.6 (11.0-46.2)cm2, P = 0.022) than those without. Patients with FPC had lower peripouch fat area (15.4 (11.4-20.6) vs. 27.6 (11.0-46.9)cm2, P = 0.040) than those without. Univariate and multivariate analyses demonstrated that lower peripouch fat area, lower weight, and family history of IBD were independent predictors of pouch prolapse and FPC. CONCLUSIONS: A lower peripouch fat area was observed in inflammatory bowel disease patients with pouch prolapse and FPC. Longitudinal studies are needed to further elucidate the role of peripouch fat in the pathogenesis of pouch prolapse and FPC.

A Changing Spectrum of Colorectal Cancer Biology With Age: Implications for the Young Patient.

BACKGROUND: The methylator pathway of colorectal carcinogenesis, characterized by CpG island hypermethylation and BRAF mutations, accounts for ≈25% of colorectal cancers. Because these cancers tend to be right sided and because DNA methylation in the right colon increases with age, we expect an increasing proportion of right-sided cancer over time. Conversely, we expect young patients (age <50 y) to have less methylated and fewer right-sided cancers OBJECTIVE:: The purpose of this study was to analyze the distribution and genetic traits of colorectal cancer from different age groups. DESIGN: This was a retrospective cohort study. SETTING: The study was conducted at a high-volume tertiary referral center. PATIENTS: Patient samples included those from our colorectal cancer biobank of resected colorectal cancer specimens. MAIN OUTCOME MEASURES: Tumor CpG island hypermethylation, microsatellite instability, and mutations in KRAS and BRAF oncogenes were analyzed in resected specimens and stratified by age and tumor location. Comparisons included age >50 or <50 years and decade of diagnosis (≤50, 51-60, 61-70, 71-80, and >81 y). Patients with IBD or hereditary syndromes were excluded. RESULTS: A total of 497 colorectal cancers were analyzed (266 men and 231 women); 57 patients (11.5%) were ≤50 years of age. No young cancers (0/57) were hypermethylated compared with 97 (22%) of 440 cancers of patients aged >50 years (p < 0.001). An increasing percentage of tumors were CpG island phenotype high with each decade of age at diagnosis. No cancers in patients <50 years of age were microsatellite unstable compared with 91 (23.6%) of 346 for those >50 years of age. No young cancers contained a BRAF mutation compared with 46 (10.6%) of 434 in older cancers (p < 0.001). KRAS mutations were less common in young cancers compared with older cancers (13/57 (22.8%) vs 126/410 (30.7%); p < 0.01). Eleven (19.3%) of 57 young cancers were proximal compared with 228 (51.8%) of 440 (p < 0.001) older cancers. LIMITATIONS: This study was limited by its retrospective design. CONCLUSIONS: The lack of CpG island methylator phenotype tumors in young patients is consistent with the dominant left-sided cancer distribution seen in the young and focuses efforts to understand and prevent cancer in this age group on causes of chromosomal instability. See Video Abstract at http://links.lww.com/DCR/A709.

Clinical significance of multiple gene detection with a 22-gene panel in formalin-fixed paraffin-embedded specimens of 207 colorectal cancer patients.

BACKGROUND: Simultaneous detection of multiple molecular biomarkers is helpful in the prediction of treatment response and prognosis for colorectal cancer (CRC) patients. METHODS: A 22-gene panel consisting of 103 hotspot regions was utilized in the formalin-fixed paraffin-embedded (FFPE) tissue samples of 207 CRC patients, using the next-generation sequencing (NGS)-based multiplex PCR technique. Those 22 genes included AKT1, ALK, BRAF, CTNNB1, DDR2, EGFR, ERBB2, ERBB4, FBXW7, FGFR1, FGFR2, FGFR3, KRAS, MAP2K1, MET, NOTCH1, NRAS, PIK3CA, PTEN, SMAD4, STK11, and TP53. RESULTS: Of the 207 patients, 193 had one or more variants, with 170, 20, and 3 having one, two, and three mutated genes, respectively. Of the total 414 variants identified in this study, 384, 25, and 5 were single-nucleotide variants, deletion, and insertion. The top four frequently mutated genes were TP53, KRAS, PIK3CA, and FBXW7. There was high consistency between the results of NGS-PCR technique and routine ARMS-PCR in KRAS and BRAF mutation detection. Univariate and multivariate analyses demonstrated that advanced TNM stage, elevated serum CEA, total variants number ≥ 2, AKT1 and PTEN mutation were independent predictors of shorter DFS; poor differentiation, advanced TNM stage, total variants number ≥ 2, BRAF, CTNNB1 and NRAS mutation were independent predictors of shorter OS. CONCLUSIONS: It is feasible to detect multiple gene mutations with a 22-gene panel in FFPE CRC specimens. TNM stage and total variants number ≥ 2 were independent predictors of DFS and OS. Detection of multiple gene mutations may provide additional prognostic information to TNM stage in CRC patients.

The interaction between BRAF mutation and microsatellite instability (MSI) status in determining survival outcomes after adjuvant 5FU based chemotherapy in stage III colon cancer.

PURPOSE: The predictive role of biomarkers in colon cancer is still being defined. The aim of this study is to determine the interaction between BRAF mutation and microsatellite instability (MSI) status in determining survival benefit after adjuvant 5-FU based chemotherapy in stage III colon cancer. METHODS: We performed a retrospective cohort study including all curatively resected stage III colon cancer cases over a 33-year period. A clinicopathological database was collated (adjuvant chemotherapy, age, gender, obstruction, perforation, tumor location, grade, mucin, nodal stage, extramural vascular, and perineural invasion). BRAF (V600E) mutation testing was performed and MSI status established by immunohistochemistry for mismatch repair proteins and molecular testing for National Cancer Institute panel markers. Patients were categorized into four groups for comparison: MSS and BRAF-ve (termed " traditional"), MSI and BRAF-ve (termed " presumed Lynch"), MSI and BRAF+ve (termed " sporadic MSI"), and MSS and BRAF+ve (termed " other BRAF"). The primary endpoint was cancer specific survival. Interaction testing was conducted to determine whether there were different responses to chemotherapy between groups. RESULTS: A total of 686 unselected cases met inclusion criteria and had tissue available, of which 15.7% had BRAF mutation (BRAF+ve) and 13.8% had MSI. Thirty-nine percent received chemotherapy. Overall, adjuvant chemotherapy produced a cancer specific survival benefit (HR 0.66, 95% CI, 0.49-0.88, P < 0.01). On adjusted analysis, neither BRAF nor MSI status were individually predictive of survival benefit. On adjusted analysis specifically of the chemotherapy effect in each subgroup, only patients in the presumed Lynch (HR 0.260, 95% CI, 0.09-0.80, P < 0.01) and other BRAF groups (HR 0.45, 95% CI, 0.23-0.87, P < 0.01) had a significant survival benefit from chemotherapy. On interaction testing of subgroups, adjusting for all the clinicopathological parameters, only patients in the presumed Lynch group (HR 0.277, 95% CI, 0.10-0.75, P < 0.01) gained a differentially greater benefit from chemotherapy than other groups. CONCLUSIONS: In this historical cohort, MSI testing is predictive of response to adjuvant chemotherapy in stage III colon cancer, but only when results are interpreted in combination with BRAF. This supports the role of routine testing for these biomarkers.

Comparisons of the surgical outcomes and medical costs between transferred and directly admitted patients diagnosed with intestinal obstruction in an American tertiary referral center.

PURPOSE: Intestinal obstruction is a leading cause of patient mortality and the most common reason for emergent operation in colorectal surgery. The influence of inter-hospital transfer on patients' outcomes varies greatly in different diseases. We aimed to compare the surgical outcomes and medical costs between transferred and directly admitted patients diagnosed with intestinal obstruction in an American tertiary referral center. METHODS: All intestinal obstruction patients operated in Cleveland Clinic from Jan 2012 to Dec 2016 were collected from a prospectively maintained database. Preoperative characteristics; surgical outcomes, including intraoperative complication, postoperative complication, readmission, reoperation, and postoperative 30-day mortality; and medical cost were collected. All parameters were compared between two groups before and after propensity score match. Multivariate logistic analysis was used to explore risk factors of surgical outcomes. RESULTS: A total of 576 patients were included, with 75 in the transferred group and 501 in the directly admitted group. Before match, the transferred patients had longer waiting interval from admission to surgery (p < 0.001), more contaminated or infected wounds (p = 0.02), different surgical procedures (p = 0.02), and similar surgical outcomes and total medical cost (all p > 0.05), compared with the directly admitted group. Multivariate analysis showed that inter-hospital transfer was not an independent predictor of any surgical outcome. After matching to balance the preoperative characteristics between two groups, no significant differences were identified in all surgical outcomes and total medical cost between two groups (all p > 0.05). CONCLUSIONS: Compared with directly admitted patients, transferred intestinal obstruction patients are associated with similar surgical outcomes and similar medical costs.

Surgical management of splenic flexure cancer: is there an optimal technique? A bi-national registry analysis.

BACKGROUND: Splenic flexure tumours (SFC) are uncommon and present at more advanced disease stages. The optimal surgical technique for SFC remains controversial. We sought to compare the short-term outcomes of a left hemicolectomy (LHC) versus an extended resection (subtotal colectomy, STC) for SFCs. METHODS: A retrospective analysis using the Binational Colorectal Cancer Audit (BCCA) registry was performed. All patients with SFC who underwent elective or emergency surgery for a SFC between 2010 and 2021 were included. Primary outcomes included short-term inpatient complications. Secondary outcomes included survival outcomes. RESULTS: Six hundred and ninety-nine patients underwent resections for SFCs. A LHC was more common, performed in 64.1%. Patients having a LHC were significantly older, with proportionally more LHCs done laparoscopically. Overall grade III/IV complications were similar between both operations. Prolonged ileus and return to theatre were significantly higher in patients undergoing a STC. On multivariate analysis, anastomotic leak and overall grade III/IV complications were not independently associated with the type of operation. There was no difference in medial survival based on type of operation. Higher tumour stage (Stage III/IV) were independently associated with worse survival. CONCLUSION: Segmental and extended resections are both oncologically sound procedures for SFCs. Segmental resections are associated with lower rates of prolonged ileus.

Does intra-operative humidification with warmed CO2 reduce surgical site infection in open colorectal surgery? A randomized control trial.

BACKGROUNDS: Surgical site infections (SSI) are a significant cause of postoperative morbidity and mortality, contributing to a considerable financial burden on the healthcare system. Insufflation of the open surgical wound with warm, humidified carbon dioxide (CO2 ) is a novel measure aimed to reduce SSI. The local atmosphere of warm, humidified CO2 within the open surgical wound is proposed to decrease airborne contamination, bacterial growth, desiccation, and heat loss while improving tissue oxygenation and perfusion. This randomized controlled trial evaluates the impact of the HumiGard™ surgical humidification system on the incidence of SSI in patients undergoing open colorectal surgery. METHODS: We conducted a multi-site single-blinded randomized control trial on patients undergoing elective or emergency laparotomy at a single tertiary Colorectal Surgery service. The primary outcome measure was the incidence of SSI, with secondary outcomes including ICU length of stay (LOS), total LOS and mean core temperature. RESULTS: Patients who received HumiGard™ had a lower incidence of SSI, although this did not reach statistical significance (4.5% for treatment group versus 13.0% for control group; P = 0.092). There was no significant difference in ICU LOS or total LOS between cohorts. The HumiGard™ group had a higher mean core temperature than the control at the end of surgery (P < 0.001). CONCLUSION: The present study could not confirm that utilization of warm, humidified CO2 with HumiGard™ reduces SSI in open colorectal surgery. Further research is indicated to validate and extend these findings.

Right hemicolectomy for colon cancer: does the anastomotic configuration affect short-term outcomes?

OBJECTIVES: Right hemicolectomy is a common colorectal operation for resection of cancers of the right colon. The ileocolic anastomosis may be created using a stapled end-to-side, stapled side-to-side or handsewn technique. Anastomotic leak and post-operative bleeding are uncommon but serious causes of morbidity and mortality, while post-operative ileus contributes to prolonged length of stay. The aim of this study was to evaluate differences in short-term outcomes between different anastomotic configurations following right hemicolectomy for colon cancer. METHODS: We conducted a retrospective study using data from the Bowel Cancer Outcomes Registry (BCOR), including 94 hospitals across Australia and New Zealand, of all patients who underwent right hemicolectomy or extended right hemicolectomy for colon cancer with formation of a primary anastomosis between 2007 and 2021. RESULTS: We included 8164 patients in the analysis. There was no significant difference in rates of anastomotic leak and anastomotic bleeding based on anastomotic technique. A stapled end-to-side anastomosis was associated with a lower rate of post-operative ileus than stapled side-to-side anastomosis (6.5% vs. 7.2%; P = 0.03). CONCLUSION: Both handsewn and stapled anastomosis techniques may be utilized for oncologic right hemicolectomy, with comparable rates of anastomotic leak and post-operative bleeding. Stapled end-to-side anastomosis resulted in lower rates of prolonged ileus compared to stapled side-to-side anastomoses.

Mechanical bowel preparation with pre-operative oral antibiotics in elective colorectal resections: an Australian single institution experience.

BACKGROUND: Anastomotic leaks (AL) and surgical site infections (SSI) are serious complications after colorectal resection. Studies have shown the benefits of pre-operative oral antibiotics (OAB) with mechanical bowel preparation (MBP) in reducing AL and SSI rates. We aim to investigate our experience with the short-term outcomes of AL and SSI following elective colorectal resections in patients receiving OAB with MBP versus MBP only. METHODS: A retrospective analysis was performed from our database for patients who underwent elective colorectal resection between January 2019 and November 2021. Prior to August 2020, OAB was not used as part of MBP. After 2020, Neomycin and Metronidazole were used in conjunction with MBP. We evaluated differences in AL and SSI between both groups. RESULTS: Five hundred and seventeen patients were included from our database with 247 having MBP while 270 had OAB and MBP. There was a significantly lower rate of AL in patients receiving MBP and OAB as compared to MBP alone (0.4% versus 3.0%, P-value = 0.03). The SSI rate at our institution was 4.4%. It was lower in patients with MBP and OAB as compared to MBP alone, but this was not clinically significant (3.3% versus 5.7%, P-value = 0.19). CONCLUSION: The association in the reduction of AL with the addition of OAB to the MBP protocol seen here reinforces the need for future randomized controlled trials in the Australasian context. We recommend colorectal institutions in Australian and New Zealand consider OAB with MBP as part of their elective colorectal resection protocol.

Radical vs. Local Excision in Rectal Carcinoma T1N0M0: Recurrence and Mortality Rates.

Local transanal excision of early rectal carcinoma is an appealing treatment because of its low morbidity rates and better functional results than radical resection. However, this treatment approach is controversial due to its association with local recurrence when compared to the latter. This review aims to compare the local recurrence and mortality rates of local vs. radical excision in patients with T1N0M0 rectal carcinoma, based on data in the literature in the last 20 years. A PubMed, Cochrane, and Google Scholar search of published literature in the last 20 years was performed. A total of 12 studies were identified. Three were prospective, one was a population-based propensity matching study, one was a nationwide cohort study, one was a meta-analysis, and the remaining studies were retrospective/observational. The mean local recurrence rate within five years from the studies selected for local excision (LE: 12.8%) was nearly double that of radical excision (RAD: 5.0%). The five-year mean survival rate for both LE and RAD groups from the studies selected was 86%, which was equal for both groups. The main predictors of poor outcomes were older age and the presence of two or more comorbid conditions. There is a consensus amongst studies that LE is associated with inferior oncological outcomes such as postoperative complications and recurrence when compared to RAD. The higher local recurrence rates in LE are attributed to occult lymph node disease and inadequate adjunctive therapy due to suboptimal staging. There is no difference in the five-year survival rate when compared to RAD. A longer follow-up period is needed to determine whether the survival rates diverge after five years.

Management options for rectal variceal bleeding in the setting of hepatic encephalopathy.

Bleeding related to rectal varices associated with portal hypertension is rare but life-threatening, and requires prompt treatment. We reviewed the literature for patients with this complex presentation and current recommendations, and commented on a case at our institution of a 68-year-old man with Child-Pugh B alcoholic liver cirrhosis and hepatic encephalopathy who presented with profuse life-threatening rectal variceal bleeding. Treatment options for rectal varices in patients with hepatic encephalopathy were reviewed and a management algorithm was devised from current knowledge in the literature. We suggest endoscopic management, and if unsuccessful then to proceed to angioembolization and/or balloon-occluded retrograde transvenous obliteration, which may be used in conjunction with surgical management. The chosen therapeutic option may depend on the clinical condition of the patient, the cause of portal hypertension and clinical expertise or facilities available. Given that transjugular intra-hepatic portosystemic shunting is contraindicated in patients with hepatic encephalopathy, management of life-threatening rectal variceal bleeding should be multimodal.

Is colorectal cancer associated with altered bowel habits in young patients?

BACKGROUND: There is a rising incidence in young-onset colorectal cancer, with these patients falling outside of routine screening programmes. The aim of the study is to characterize the nature of altered bowel habits in young patients who are diagnosed with colorectal cancer. METHODS: A retrospective audit was conducted of adult patients younger than 45 years admitted under a Colorectal Surgery unit (Dandenong Hospital, Victoria) from 2011 to 2019 for the resection of colorectal cancer. We compared the patients' self-characterization of their bowel habits (from the medical record) with clinical and pathological data. RESULTS: A total of 75 patients were identified, aged between 18 and 45 years, who had surgical resection of colonic or rectal adenocarcinoma between 2011 and 2019. Forty-two (56%) presented with altered bowel habit (irregular bowel habit n = 13, 17%; constipation n = 13, 17%; diarrhoea n = 23, 31%). Constipation approached significance in association with left-sided colonic cancer. Fatigue approached significance in association with right-sided colonic cancers, which were less likely to present with bleeding or constipation, and approached significance in being less likely to present with diarrhoea. Rectal cancers were more likely to present with bleeding. CONCLUSION: Constipation was associated with left-sided colonic cancers, while right-sided colonic cancers were less likely to present with either constipation or diarrhoea. Our findings reinforce the need for clinicians to consider colorectal cancer as a differential diagnosis in young patients with altered bowel habits, or in patients with fatigue in the absence of specific bowel symptoms. Further prospective research is needed to further define bowel habits in this cohort.

CoA Synthase (COASY) Mediates Radiation Resistance via PI3K Signaling in Rectal Cancer.

Neoadjuvant radiation is standard of care for locally advanced rectal cancer. Response to radiation is highly variable and directly linked with survival. However, there currently are no validated biomarkers or molecular targets to predict or improve radiation response, which would help develop personalized treatment and ideally targeted therapies. Here, we identified a novel biomarker, coenzyme A synthase (COASY), whose mRNA expression was consistently elevated in radioresistant human rectal cancers. This observation was validated in independent patient cohorts and further confirmed in colorectal cancer cell lines. Importantly, genetic overexpression and knockdown yielded radioresistant and sensitive phenotypes, respectively, in vitro and in vivo. COASY-knockdown xenografts were more vulnerable to radiation, showing delayed tumor growth, decreased proliferation, and increased apoptosis. Mechanistically, COASY protein directly interacted with the PI3K regulatory subunit PI3K-P85α, which increased AKT and mTOR phosphorylation, enhancing cell survival. Furthermore, shRNA COASY knockdown disrupted downstream PI3K pathway activation and also hindered DNA double-strand break repair, which both led to improved radiosensitivity. Collectively, this work reveals for the first time the biological relevance of COASY as a predictive rectal cancer biomarker for radiation response and offers mechanistic evidence to support COASY as a potential therapeutic target. SIGNIFICANCE: COASY is a novel radiotherapy response modulator in rectal cancer that regulates PI3K activation and DNA repair. Furthermore, COASY levels directly correlate with radiation response and serve as a predictive biomarker.

Prognostic significance of BRAF mutation alone and in combination with microsatellite instability in stage III colon cancer.

PURPOSE: The prognostic significance of biomarkers in colorectal cancer is still being defined. This study aimed to determine the prognostic significance of BRAF mutation alone and in combination with microsatellite instability (MSI), in stage III colon cancer. METHODS: Curatively resected stage III colon cancers were studied from a 33-year period. Clinicopathological data were collated (adjuvant chemotherapy, age, gender, obstruction, perforation, tumour location, grade, presence of mucin, nodal stage, extramural vascular, and perineural invasion). MSI status was established and molecular testing for BRAF (V600E) was performed. Four mutation categories were examined: "traditional" (microsatellite stable [MSS]/BRAF -ve), "presumed Lynch" (MSI/BRAF -ve), "sporadic MSI" (MSI/BRAF +ve), and "other BRAF" (MSS/BRAF +ve). These factors were correlated with cancer-specific survival. RESULTS: In total, 686 unselected cases met our inclusion criteria, of which 15.7% had a BRAF mutation and 13.8% showed MSI. In the adjusted analysis, neither BRAF mutation nor MSI mutation were independently prognostic. On univariate analysis, survival in presumed Lynch cancers was similar to traditional cancers (5-year survival: 62% and 61%, respectively). While there was no difference in cancer-specific survival between sporadic MSI and other BRAF, both these tumour group had poorer outcome when compared to traditional or presumed Lynch cancers. Adjusted analysis of the four groups, however, showed that none of the subgroups were independently prognostic. CONCLUSION: BRAF-mutated cancers demonstrated a trend toward poorer outcomes, however, when adjusted for clinicopathological factors and chemotherapy, BRAF mutation was not found to be an independent prognostic biomarker in stage III colon cancer, even when combined with MSI.

Peripouch Fat Area Measured on MRI Image and Its Association With Adverse Pouch Outcomes.

Background: There are no published studies on the impact of peripouch fat on pouch outcomes in inflammatory bowel disease (IBD) patients. Methods: Patients with pelvic MRI-DIXON scans from our prospectively maintained Pouch Database between 2002 and 2016 were evaluated. Peripouch fat area was measured on MRI-DIXON-F images at the middle height level of the pouch (area M) and the highest level of the pouch (area H). Results: Of all 1863 patients in the database, 197 eligible patients were included in this study. The median of area M was 52.4 cm2, so the 197 patients were classified into 2 groups: group 1 (Area-M <52.4 cm2) and group 2 (Area-M ≥52.4 cm2). Compared with group 1, group 2 was found to have thicker perianal fat, more Caucasian and more males. Group 2 also had a higher Area-H, more weight, height, and body mass index, along with greater age at IBD diagnosis, age at pouch construction and pouch age, and a higher frequency of total pouch complication (86.7% versus 66.7%, P = 0.001), chronic pouch complication (68.4% versus 51.5%, P = 0.016), and chronic antibiotic-refractory pouchitis (16.3% versus 7.1%, P = 0.043). Multivariate logistic analysis showed that Area-M was an independent risk factor for chronic antibiotic-refractory pouchitis (odds ratio [OR]: 1.025; 95% confidence interval [CI]: 1.007-1.042, P = 0.005). The 22 patients with 2 or more pelvic MRI-DIXON scans were further classified into 2 groups by the change from the initial to latest MRI-DIXON scans. Patients with Area-M increase ≥10% and Area-M/height increase ≥10% were found to have shorter pouch survivals than those with increase <10%. Conclusions: A new method was established for measuring peripouch fat using pelvic MRI-DIXON-F image. Our study suggests that accumulation of peripouch fat may be associated with poor outcomes in selected IBD patients suspected of inflammatory or mechanical disorders of the pouch. Whether this association is causal warrants further investigation.