Spectrum of somatic mutational features of colorectal tumors in ancestrally diverse populations.

Ancestrally diverse and admixed populations, including the Hispanic/Latino/a/x/e community, are underrepresented in cancer genetic and genomic studies. Leveraging the Latino Colorectal Cancer Consortium, we analyzed whole exome sequencing data on tumor/normal pairs from 718 individuals with colorectal cancer (128 Latino, 469 non-Latino) to map somatic mutational features by ethnicity and genetic ancestry. Global proportions of African, East Asian, European, and Native American ancestries were estimated using ADMIXTURE. Associations between global genetic ancestry and somatic mutational features across genes were examined using logistic regression. TP53 , APC , and KRAS were the most recurrently mutated genes. Compared to non-Latino individuals, tumors from Latino individuals had fewer KRAS (OR=0.64, 95%CI=0.41-0.97, p=0.037) and PIK3CA mutations (OR=0.55, 95%CI=0.31-0.98, p=0.043). Genetic ancestry was associated with presence of somatic mutations in 39 genes (FDR-adjusted LRT p<0.05). Among these genes, a 10% increase in African ancestry was associated with significantly higher odds of mutation in KNCN (OR=1.34, 95%CI=1.09-1.66, p=5.74×10 -3 ) and TMEM184B (OR=1.53, 95%CI=1.10-2.12, p=0.011). Among RMGs, we found evidence of association between genetic ancestry and mutation status in CDC27 (LRT p=0.0084) and between SMAD2 mutation status and AFR ancestry (OR=1.14, 95%CI=1.00-1.30, p=0.046). Ancestry was not associated with tumor mutational burden. Individuals with above-average Native American ancestry had a lower frequency of microsatellite instable (MSI-H) vs microsatellite stable tumors (OR=0.45, 95%CI=0.21-0.99, p=0.048). Our findings provide new knowledge about the relationship between ancestral haplotypes and somatic mutational profiles that may be useful in developing precision medicine approaches and provide additional insight into genomic contributions to cancer disparities. Significance: Our data in ancestrally diverse populations adds essential information to characterize mutational features in the colorectal cancer genome. These results will help enhance equity in the development of precision medicine strategies.

Return to intended oncologic therapy after colectomy for stage III colon adenocarcinoma: Does surgical approach matter?

AIM: Return to intended oncologic treatment (RIOT) is an important paradigm for surgically resected cancers requiring multimodal treatment. Benefits of minimally invasive colectomy (MIC) may allow earlier initiation of adjuvant chemotherapy (ACT) and have associated survival benefits. We sought to determine if operative approach affects RIOT timing in resected stage III colon cancer. METHODS: NCDB identified pathological stage III colon adenocarcinoma patients who underwent resection and received ACT. Propensity score matching and kernel density estimation compared operative approaches and conversion impact on intervals to RIOT. RESULTS: A total of 15,132 open colectomies (OC) versus 14,107 MIC were included. MIC patients had two-days shorter median length of stay (LOS) (4 vs. 6 days; p < 0.001), one-week shorter median time to RIOT (6 vs. 7 weeks; p = 0.015) comparing 12,867 matched pairs. There was no difference in time interval to RIOT between the LC versus RC, converted MIC vs. OC groups. MIC was a favourable predictor of earlier RIOT (HR 1.14 [1.07-1.22]; p < 0.001). CONCLUSION: MIC in stage III colon cancer is associated with a shorter time to RIOT when compared to OC. Since timely initiation of ACT may influence cancer outcome, MIC may be oncologically preferable. Prospective studies are needed to assess RIOT and survival outcomes in stage III colon cancer.

Tumor Response-speed Heterogeneity as a Novel Prognostic Factor in Patients With Metastatic Colorectal Cancer.

PURPOSE: Differential tumor response to therapy is partially attributed to tumor heterogeneity. Additional efforts are needed to identify tumor heterogeneity parameters in response to therapy that is easily applicable in clinical practice. We aimed to describe tumor response-speed heterogeneity and evaluate its prognostic value in patients with metastatic colorectal cancer. PATIENTS AND METHODS: Individual patient data from Amgen (NCT00364013) and Sanofi (NCT00305188; NCT00272051) trials were retrieved from Project Data Sphere. Patients in the Amgen 5-fluorouracil, leucovorin, oxaliplatin (FOLFOX) arm were used to establish response-speed heterogeneity. Its prognostic value was subsequently validated in the Sanofi FOLFOX arms and the Amgen panitumumab+FOLFOX arm. Kaplan-Meier method and Cox proportional hazards models were used for survival analyses. RESULTS: Patients with high response-speed heterogeneity in the Amgen FOLFOX cohort had significantly shorter ( P <0.001) median progression-free survival (PFS) of 7.27 months (95% CI, 6.12-7.96 mo) and overall survival (OS) of 16.0 months (95% CI, 13.8-18.2 mo) than patients with low response-speed heterogeneity with median PFS of 9.41 months (95% CI, 8.75-10.89 mo) and OS of 22.4 months (95% CI, 20.1-26.7 mo), respectively. Tumor response-speed heterogeneity was a poor prognostic factor of shorter PFS (hazard ratio, 4.17; 95% CI, 2.49-6.99; P <0.001) and shorter OS (hazard ratio, 2.57; 95% CI, 1.64-4.01; P <0.001), after adjustment for other common prognostic factors. Comparable findings were found in the external validation cohorts. CONCLUSION: Tumor response-speed heterogeneity to first-line chemotherapy was a novel prognostic factor associated with early disease progression and shorter survival in patients with metastatic colorectal cancer.

The impact of socioeconomic status on survival in stage III colon cancer patients: A retrospective cohort study using the SEER census-tract dataset.

BACKGROUND: The impact of socioeconomic status (SES) has been described for screening and accessing treatment for colon cancer. However, little is known about the "downstream" effect in patients who receive guideline-concordant treatment. This study assessed the impact of SES on cancer-specific survival (CSS) and overall survival (OS) for stage III colon cancer patients. METHODS: The SEER Census Tract-Level SES Dataset from 2004 to 2015 was used to identify stage III colon adenocarcinoma patients who received curative-intent surgery and adjuvant chemotherapy. The predictor variable was census tract SES. SES was analyzed as quintiles. The outcome variables were OR and CSS. Statistical analysis included chi square tests for association, Kaplan-Meier, Cox, Fine and Gray regression for survival analysis. RESULTS: In total, 27,222 patients met inclusion criteria. Lower SES was associated with younger age, Black or Hispanic race/ethnicity, Medicaid/uninsured, higher T stage, and lower grade tumors. CSS at the 25th percentile was 54 months for the lowest SES quintile and 80 for the highest. Median OS was 113 months for the lowest SES quintile and not reached for highest. The 5-year CSS rate was 72.4% for the lowest SES quintile compared to 78.9% in the highest (p < 0.001). The 5-year OS rate was 66.5% for the lowest SES quintile and 74.6% in the highest (p < 0.001). CONCLUSION: This is the first study to evaluate CSS and OS in an incidence-based cohort of stage III colon cancer patients using a granular, standardized measure of SES. Despite receipt of guideline-based treatment, SES was associated with disparities in CSS and OS.

Treatment-induced evolutionary dynamics in nonmetastatic locally advanced rectal adenocarcinoma.

Multi-modal treatment of non-metastatic locally advanced rectal adenocarcinoma (LARC) includes chemotherapy, radiation, and life-altering surgery. Although highly effective for local cancer control, metastatic failure remains significant and drives rectal cancer-related mortality. A consistent observation of this tri-modality treatment paradigm is that histologic response of the primary tumor to neoadjuvant treatment(s), which varies across patients, predicts overall oncologic outcome. In this chapter, we will examine this treatment response heterogeneity in the context of evolutionary dynamics. We hypothesize that improved understanding of eco-evolutionary pressures rendering small cancer cell populations vulnerable to extinction may influence treatment strategies and improve patient outcomes. Applying effective treatment(s) to cancer populations causes a "race to extinction." We explore principles of eco-evolutionary extinction in the context of these small cancer cell populations, evaluating how treatment(s) aim to eradicate the cancer populations to ultimately result in cure. In this chapter, we provide an evolutionary rationale for limiting continuous treatment(s) with the same agent or combination of agents to avoid selection of resistant cancer subpopulation phenotypes, allowing "evolutionary rescue." We draw upon evidence from nature demonstrating species extinction rarely occurring as a single event phenomenon, but rather a series of events in the slide to extinction. We posit that eradicating small cancer populations, similar to small populations in natural extinctions, will usually require a sequence of different external perturbations that produce negative, synergistic dynamics termed the "extinction vortex." By exploiting these unique extinction vulnerabilities of small cancer populations, the optimal therapeutic sequences may be informed by evolution-informed strategies for patients with LARC.

Endoscopic Feature and Response Reproducibility in Tumor Assessment after Neoadjuvant Therapy for Rectal Adenocarcinoma.

BACKGROUND: The watch-and-wait approach may be safe for selected rectal cancer patients who achieve a complete clinical response after neoadjuvant treatment. Endoscopic examination is critical in determining completeness of tumor response but has not been systematically studied. METHODS: Two cross-sectional surveys, each containing endoscopic photos of rectal cancers treated with neoadjuvant therapy, were distributed to surgeons. The first survey assessed the reproducibility of eight endoscopic criteria using 41 unique endoscopic photos. The percentage of surgeons selecting each of the prespecified endoscopic criteria for each photo was calculated to determine the reproducibility of endoscopic criteria in assessing treatment and tumor response grade across multiple surgeons. The second survey included endoscopic pairs of pre- and post-neoadjuvant treatment photos of 17 patients. The surgeons were assigned a tumor response grade (clinical complete response [cCR], near complete clinical response [nCR], incomplete [iCR] clinical response), and percentages of correct diagnostic assignment were calculated. RESULTS: The findings showed significant inter- and intra-surgeon variation in the selection of predefined endoscopic features used to grade tumor response as well as significant inter- and intra-surgeon variation in the selection of the tumor response grade (cCR, nCR, or iCR). However, individual endoscopic features and tumor response grades clustered together, suggesting consistency in tumor response interpretation. Surgeons were more accurate in identifying patients with a complete response (82%) than in identifying patients with an incomplete response (68%). CONCLUSIONS: Despite inter- and intra-surgeon variation, endoscopic features were well-selected in terms of tumor response grade, suggesting consistency in endoscopic interpretation. Surgeons tended to underestimate the degree of tumor response, identifying complete responses more accurately than incomplete responses.

Tumor immune infiltration estimated from gene expression profiles predicts colorectal cancer relapse.

A substantial fraction of patients with stage I-III colorectal adenocarcinoma (CRC) experience disease relapse after surgery with curative intent. However, biomarkers for predicting the likelihood of CRC relapse have not been fully explored. Therefore, we assessed the association between tumor infiltration by a broad array of innate and adaptive immune cell types and CRC relapse risk. We implemented a discovery-validation design including a discovery dataset from Moffitt Cancer Center (MCC; Tampa, FL) and three independent validation datasets: (1) GSE41258 (2) the Molecular Epidemiology of Colorectal Cancer (MECC) study, and (3) GSE39582. Infiltration by 22 immune cell types was inferred from tumor gene expression data, and the association between immune infiltration by each cell type and relapse-free survival was assessed using Cox proportional hazards regression. Within each of the four independent cohorts, CD4+ memory activated T cell (HR: 0.93, 95% CI: 0.90-0.96; FDR = 0.0001) infiltration was associated with longer time to disease relapse, independent of stage, microsatellite instability, and adjuvant therapy. Based on our meta-analysis across the four datasets, 10 innate and adaptive immune cell types associated with disease relapse of which 2 were internally validated using multiplex immunofluorescence. Moreover, immune cell type infiltration was a better predictors of disease relapse than Consensus Molecular Subtype (CMS) and other expression-based biomarkers (Immune-AICMCC:238.1-238.9; CMS-AICMCC: 241.0). These data suggest that transcriptome-derived immune profiles are prognostic indicators of CRC relapse and quantification of both innate and adaptive immune cell types may serve as candidate biomarkers for predicting prognosis and guiding frequency and modality of disease surveillance.

Endoscopic and MRI response evaluation following neoadjuvant treatment for rectal cancer: a pictorial review with matched MRI, endoscopic, and pathologic examples.

A nonoperative management strategy, or Watch-and-Wait, following neoadjuvant therapies of locally advanced rectal adenocarcinoma is increasingly considered for select patients. Yet, standardized tumor response assessment to best select and surveil suitable patients remains an unmet clinical challenge. Endoscopic and MRI currently provide the most reliable tumor response estimations. However, resources illustrating variable tumor responses to neoadjuvant therapies remain limited. This pictorial review aims to provide detailed and annotated examples of common endoscopic and MRI findings of rectal cancer treatment response, while also emphasizing their respective diagnostic shortcomings and consequently, the necessity for a multidisciplinary approach to optimally manage these patients.

The Impact of Histologic Subtype on Receipt of Adjuvant Chemotherapy and Overall Survival in Stage III Colon Cancer: a Retrospective Cohort Analysis.

BACKGROUND: The impact of adjuvant chemotherapy (AT) on resected colon adenocarcinoma based on histologic subtype is poorly defined and extrapolated from patients with advanced disease. We evaluated the receipt and effect of AT on overall survival stratified by histologic subtype-mucinous, non-mucinous, and signet ring adenocarcinomas. METHODS: A retrospective cohort study from 2004 to 2015 was conducted using the National Cancer Database. Patients with colon adenocarcinoma who underwent curative resection with pathologic stage III were included. Appendiceal and rectal tumors were excluded. The predictor variable was histologic subtype, and outcome variables were overall survival and receipt of AT. RESULTS: Absolute survival was increased for mucinous, non-mucinous, and signet ring tumors with receipt of AT (88.1, 108.9, and 38.1 months, respectively). In multivariable analysis, there was no difference in overall survival for mucinous patients relative to non-mucinous patients. In subgroup analysis, a modest survival advantage for non-mucinous patients relative to the mucinous patients was observed (HR, 0.92; 95% CI, 0.89-0.95). In multivariable modeling, non-mucinous and signet ring adenocarcinoma had decreased odds of receipt of AT relative to mucinous adenocarcinoma patients. CONCLUSIONS: Histologic subtype is an important prognostic factor for overall survival for stage III colon adenocarcinoma. Although the magnitude of the benefit of AT may vary in stage III curatively resected patients, it has a substantial survival benefit across all histologic subtypes. Based on these observations, there is no indication that patients with stage III mucinous adenocarcinoma of the colon should not receive AT. All patients with resected stage III colon cancer should be referred for AT regardless of histologic subtype.

Early Urinary Catheter Removal Following Pelvic Colorectal Surgery: A Prospective, Randomized, Noninferiority Trial.

BACKGROUND: Because of the potential increased incidence of acute urinary retention, optimal timing of urinary catheter removal after major pelvic colorectal surgery remains unclear. OBJECTIVE: This study aims to compare the incidence of urinary retention following early catheter removal on postoperative day 1 vs standard catheter removal on day 3. DESIGN: This is a randomized, noninferiority trial. SETTING: This study was conducted at an urban teaching hospital. PATIENTS: Patients undergoing colorectal surgery below the peritoneal reflection were selected. INTERVENTIONS: A 1:1 randomization to early or standard catheter removal was performed. Patients in the early arm were administered an α-antagonist (prazosin 1 mg oral) 6 hours before catheter removal. MAIN OUTCOME MEASURES: The primary outcome measured was the incidence of acute urinary retention. RESULTS: One hundred forty-two patients were randomly assigned to early (n = 71) or standard (n = 71) catheter removal. Mean age was 44.8 ± 16.9 years, and the study cohort included 54% men. The most common operations were IPAA (66%) and low anterior resection (18%). The overall rate of retention was 9.2% (n = 13), with no difference between early (n = 6; 8.5%) or standard (n = 7; 9.9%) catheter removal (RR, 0.86; 95% CI, 0.30-2.42). The risk difference was -1.4% (95% CI, -8.3 to 11.1), confirming noninferiority. The rate of infection was significantly lower in early vs standard catheter removal (0% vs 11.3%; p = 0.01). Length of stay was significantly shorter after early vs standard catheter removal (4 days, interquartile range = 3-6 vs 5 days, interquartile range = 4-7; p = 0.03). LIMITATIONS: Patients and investigators were not blinded; a nonselective oral α-antagonist was used. CONCLUSIONS: Following pelvic colorectal surgery, early urinary catheter removal, when combined with the addition of an oral α-antagonist, is noninferior to standard urinary catheter removal and carries a lower risk of symptomatic infection and shorter hospital stay. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov (NCT01923129). See Video Abstract at http://links.lww.com/DCR/A738.

Trauma sternotomy for presumed haemopericardium with incidental coccidioidal pericarditis.

BACKGROUND: Disseminated cocciodiomycosis with extrapulmonary disease occurs in less than 1% of infected patients, with few cases involving the pericardium reported in the literature. A subxiphoid window in a focussed assessment with sonography for trauma is a fast and reliable study for detecting haemopericardium in the haemodynamically unstable injured patient. METHODS: Case report and literature review. CASE REPORT: A 50-year old man presented in extremis following a stab wound to the right thoracoabdominal region with a positive pericardial ultrasound. At the time of emergent sternotomy, the pericardial effusion appeared non-traumatic and not the cause of haemodynamic instability. Lung, diaphragm, liver and transverse colon lacerations were controlled by laparotomy. He was discovered to have extensive adenopathy within the mediastinum, porta hepatis, and lesser sac, which after histopathologic examination, demonstrated granulomatous lymphadenitis consistent with disseminated cocciodiomycosis. CONCLUSIONS: This case report describes the first reported "incidental" pericardial effusion in a haemodynamically unstable patient sustaining a thoracoabdominal stab wound discovered on a positive ultrasound study. Emergent operative exploration and subsequent workup determined the pericardial fluid to be of infectious origin, rather than traumatic. With the incidence of cocciodiomycosis within endemic geographic regions significantly rising, coccidioidal pericarditis may become an increasingly relevant cause of fluid detected on noninvasive pericardial examination.

Superior mesenteric artery syndrome following sleeve gastrectomy: case report, review of the literature, and video on technique for surgical correction.

Superior mesenteric artery (SMA) syndrome is a rare condition in which the duodenum is compressed between the SMA and aorta. This often occurs following extreme weight loss and has been reported in the bariatric population. We present the first reported case of SMA syndrome following sleeve gastrectomy. The patient underwent laparoscopic duodenojejunostomy and recovered uneventfully. The following is a review of the literature and detailed operative approach in the attached video.

Fulminant clostridium difficile colitis: comparing computed tomography with histopathology: are they concordant?

A Total abdominal colectomy (TAC) is recommended for fulminant Clostridium difficile colitis (FCDC) because intraoperative assessment of diseased segments is inaccurate. To determine whether computerized tomography (CT) provides an accurate assessment of disease, we examined the concordance between CT and histopathologic colitis distribution in patients undergoing TAC for FCDC. The ileocolon was divided into seven distinct segments. Of 20 patients meeting criteria, the median interval between preoperative CT and TAC was 1.5 days (range, 0 to 23 days), and mortality was 65 per cent. The CT distribution of colitis was pancolitis in 12 patients and segmental in eight. Nine of the 12 patients with CT pancolitis had histologic pancolitis (75% concordance). Four of the eight patients with CT-diagnosed segmental disease had histologic segmental disease (50% concordance). For patients with FCDC, the distribution of colitis on CT agrees with the histopathologic extent of disease in the majority of patients. However, discordance between CT and histologic extent of disease was present in 25 to 50 per cent of patients. Therefore, the recommendation for TAC rather than segmental resection for FCDC remains justified.