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The incidence of rectal cancer is increasing in patients younger than 50 years. Locally advanced rectal cancer is still treated with neoadjuvant radiation, chemotherapy and surgery, but recent evidence suggests that patients with a complete response can avoid surgery permanently. To define correlates of response to neoadjuvant therapy, we analyzed genomic and transcriptomic profiles of 738 untreated rectal cancers. APC mutations were less frequent in the lower than in the middle and upper rectum, which could explain the more aggressive behavior of distal tumors. No somatic alterations had significant associations with response to neoadjuvant therapy in a treatment-agnostic manner, but KRAS mutations were associated with faster relapse in patients treated with neoadjuvant chemoradiation followed by consolidative chemotherapy. Overexpression of IGF2 and L1CAM was associated with decreased response to neoadjuvant therapy. RNA-sequencing estimates of immune infiltration identified a subset of microsatellite-stable immune hot tumors with increased response and prolonged disease-free survival.

A subset of patients with marginal ulcers after Roux-en-Y gastric bypass (RNYGB) is refractory to medical management. Here we report a retrospective review of a single institution cohort (N = 10) of video- or robotic-assisted thoracoscopic (VATS or RATS) truncal vagotomies performed between 2013 and 2018. All patients had recurrent marginal ulcers following RNYGB complicated by bleeding or perforation, refractory to medical management for a median of 3.5 months prior to undergoing truncal vagotomy. With a median of 23 months’ follow-up, only three patients had continued symptoms (70% symptom resolution) post-operatively. Only one patient who had repeat endoscopy after the procedure had documented endoscopic evidence of recurrent marginal ulcer (83% endoscopic resolution). VATS or RATS truncal vagotomy is a safe and effective method to treat complicated marginal ulceration after RNYGB. After an average duration of unsuccessful medical treatment lasting three months, vagotomy led to successful resolution in 70-83% of patients.

BACKGROUND: Pathologic complete response (pCR) is associated with better prognosis and guides management for patients with advanced rectal cancer. Response rates vary between series for unclear reasons. We examine whether the thoroughness of pathologic assessment explains differences in pCR rates. METHODS: We retrospectively reviewed pathology reports from patients with stage II/III rectal cancer who underwent chemoradiation and resection in a prospective, multicenter trial. We utilized a novel measure for the thoroughness of pathologic assessment by dividing residual tumor size by the number of cassettes evaluated (tumor size to cassette ratio, TSCR), and evaluated whether TSCR is associated with pCR. We validated our findings using a separate cohort. RESULTS: From the trial cohort, 71 of 247 (29%) patients achieved pCR. The pCR rate ranged from 0 to 45% and mean TSCR ranged 0.29 to 0.87 across 12 institutions. Within each institution, a lower TSCR was associated with pCR, demonstrating a higher degree of thoroughness used for tumors that achieved pCR. Moreover, across all samples, low TSCR was independently associated with pCR on multivariable analysis. This finding was corroborated in a separate cohort of 201 tumors evaluated by five pathologists; each pathologist had a lower mean TSCR for pCR calls compared with non-pCR calls. However, the mean TSCR for an institution was not associated with its overall pCR rate. CONCLUSIONS: Pathologists assess rectal cancers that have responded significantly to neoadjuvant therapy more thoroughly. Thoroughness does not appear to explain differences in pCR rates between institutions. Our results suggest pCR is not a sampling artifact.

Somatic mutations in the KRAS oncogene are associated with poor outcomes in locally advanced rectal cancer but the underlying biologic mechanisms are not fully understood. We profiled mRNA in 76 locally advanced rectal adenocarcinomas from patients that were enrolled in a prospective clinical trial and investigated differences in gene expression between KRAS mutant (KRAS‐mt) and KRAS‐wild‐type (KRAS‐wt) patients. We found that KRAS‐mt tumors display lower expression of genes related to the tumor stroma and remodeling of the extracellular matrix. We validated our findings using samples from The Cancer Genome Atlas (TCGA) and also by performing immunohistochemistry (IHC) and immunofluorescence (IF) in orthogonal cohorts. Using in vitro and in vivo models, we show that oncogenic KRAS signaling within the epithelial cancer cells modulates the activity of the surrounding fibroblasts in the tumor microenvironment., Oncogenic KRAS is associated with poor outcomes in locally advanced rectal cancer (LARC) but the underlying biologic mechanisms are not fully understood. We investigated differences in gene expression profiles between KRAS mutant and KRAS wild‐type LARC tumors. We found that KRAS mutant tumors display lower expression of genes related to the tumor stroma and remodeling of the extracellular matrix.

Routine mutation profiling for resected lung cancers is not widespread despite an increasing array of targeted therapies. We report the incidence of epidermal growth factor receptor mutations (EGFRmu+) in resected lung adenocarcinomas and their outcomes at a large North American cancer center to characterize this population now eligible for targeted adjuvant therapy.Among 1036 pulmonary resections performed between 2015 and 2019, 647 patients (62%) had adenocarcinomas that underwent molecular profiling by next-generation sequencing. Clinical and pathologic characteristics, along with survival, were analyzed.EGFRmu+ were identified in 238 patients (37%). Patients with EGFRmu+ were more likely to be Asian than those with EGFR wild-type (79/238 [33%] vs 37/409 [9%], respectively; P.001) and more likely to be never-smokers (115/238 [48%] vs 73/409 [18%], P.001). However, most patients with EGFRmu+ in our cohort were White (45%) and had a history of smoking (52%). A statistically nonsignificant trend was observed toward improved 3-year overall survival for pathologic stage IB to III cancers with EGFRmu+ (91% vs 77%, P = .09). Patients with pathologic stage IB lung cancers with EGFRmu+ had a 97% rate of 3-year disease-free survival, with only 1 recurrence in the first 3 years of follow-up. EGFR mutation subtype was not associated with survival differences.Although Asians and never-smokers comprised a disproportionately large group of patients with lung adenocarcinomas with EGFRmu+, most EGFR mutations within our cohort were found in patients who were White or with a smoking history, supporting a routine rather than selective approach to mutation profiling. Patients with surgically resected stage IA and IB lung adenocarcinomas enjoy excellent survival regardless of their mutational status.

Tracheobronchomalacia and airway obstruction from severely dilated pulmonary arteries in tetralogy of Fallot with absent pulmonary valve (TOF-APV) has been associated with high rates of respiratory failure and mortality (15% to 25%). It is not known whether aggressive pulmonary artery (PA) or direct airway intervention during early definitive cardiac repair improves outcomes.A retrospective observational study was made of all patients undergoing surgical repair for TOF-APV at our center between 2006 and 2018.Twenty patients underwent repair at a median age of 51 days and PA Z-scores of 8.1. Twelve patients had a valve implanted, 6 of whom required reoperation for valve replacement at a median of 9 months (range, 3 to 28) compared with 8 who had initial transannular patch, and only 1 patient required subsequent valve replacement (P.05). Seven patients had central PAs replaced with thin-walled Gore-Tex (WL Gore, Flagstaff, AZ) grafts; none of these required PA reoperation during a median follow-up of 26.5 months, whereas 3 of 13 patients who did not have PA replacement with Gore-Tex required subsequent PA reoperation (P.05). Concomitant airway interventions (eg, tracheobronchopexy/plasty) were performed in 4 patients and none required subsequent airway interventions, whereas 2 patients not having initial airway intervention required subsequent tracheopexy (P.05). Three patients in the cohort eventually required tracheostomy (15%), and 2 patients died (10%; on postoperative days 30 and 326); none had received initial airway intervention.Pulmonary artery replacement and aggressive direct airway management at initial definitive repair of cardiac TOF-APV can be performed safely with acceptable survival outcomes and low rates of airway and PA reintervention.

Little is known about anorectal function and quality of life after chemoradiation followed by local excision, which is an alternative to total mesorectal excision for selected patients with early rectal cancer.The purpose of this study was to prospectively assess anorectal function and health-related quality of life of patients with T2N0 rectal cancer who were treated with an alternative approach.This was a prospective, phase II trial.The study was multicentric (American College of Surgeons Oncology Group trial Z6041).Patients with stage cT2N0 rectal adenocarcinomas were treated with an oxaliplatin/capecitabine-based chemoradiation regimen followed by local excision.Anorectal function and quality of life were assessed at enrollment and 1 year postoperatively with the Fecal Incontinence Severity Index, Fecal Incontinence Quality of Life scale, and Functional Assessment of Cancer Therapy-Colorectal Questionnaire. Results were compared, and multivariable analysis was performed to identify predictors of outcome.Seventy-one patients (98%) were evaluated at enrollment and 66 (92%) at 1 year. Compared with baseline, no significant differences were found on Fecal Incontinence Severity Index scores at 1 year. Fecal Incontinence Quality of Life results were significantly worse in the lifestyle (p0.001), coping/behavior (p0.001), and embarrassment (p = 0.002) domains. There were no differences in the Functional Assessment of Cancer Therapy overall score, but the physical well-being subscale was significantly worse and emotional well-being was improved after surgery. Treatment with the original chemoradiation regimen predicted worse depression/self-perception and embarrassment scores in the Fecal Incontinence Quality of Life, and male sex was predictive of worse scores in the Functional Assessment of Cancer Therapy overall score and trial outcome index.Small sample size, relatively short follow-up, and absence of information before cancer diagnosis were study limitations.Chemoradiation followed by local excision had minimal impact on anorectal function 1 year after surgery. Overall quality of life remained stable, with mixed effects on different subscales. This information should be used to counsel patients about expected outcomes.

Purpose To validate the finding of an association between single nucleotide polymorphisms (SNPs) and toxicity during chemoradiotherapy (CRT) in rectal cancer patients, in an independent population. Methods and Materials The cohort consisted of 165 patients who received CRT for rectal cancer from 2006 to 2012. Prospectively recorded toxicity information, graded according to the Common Terminology Criteria for Adverse Events version 3.0, was retrieved from the medical record. Additionally, a subset of 52 patients recorded their gastrointestinal symptoms weekly during CRT, using the 7-item Bowel Problems Scale. Deoxyribonucleic acid was extracted from normal tissue in the proctectomy specimens and screened for 3 SNPs: XRCC1 R399Q, XPD K751Q, and TGFβ1 R25P. Univariable and multivariable logistic regression models were constructed. Results The median radiation dose was 50.4 Gy, and all patients received concurrent chemotherapy. Toxicities measured by the Common Terminology Criteria for Adverse Events were closely associated with patient-reported outcomes for the patients who completed the 7-item Bowel Problems Scale. Grade ≥3 toxicity occurred during CRT in 14 patients (8%). All 14 patients had either XRCC1 R399Q or TGFβ1 R25P polymorphisms. The TGFβ1 R25P polymorphism was significantly associated with grade ≥3 toxicity (odds ratio [OR] 3.47, P =.04) and, in patients who completed the Bowel Problems Scale, with grade ≥4 toxicity (OR 5.61, P =.02). The latter finding persisted in a multivariable logistic regression model controlling for ethnicity, age, and sex (adjusted OR 1.83, P =.02). Conclusions We have validated the correlation between the TGFβ1 R25P SNP and acute toxicity during CRT in an independent cohort using both clinician- and patient-reported toxicity. The information from our study could be used as a basis to formulate a prospective trial testing the utility of this SNP as a biomarker of acute toxicity during neoadjuvant treatment in locally advanced rectal cancer.

Background Burnout has been linked to poor job satisfaction, increased medical errors, and is prevalent among healthcare professionals. We sought to characterize burnout and distress among US cardiothoracic surgical (CTS) trainees. Methods A 19-question survey was sent to CTS trainees in collaboration with the Thoracic Surgery Residents Association. We queried sociodemographic variables, balance/quality of life (QOL), and indicators of depression and regret. We included questions along the emotional exhaustion, depersonalization, and personal accomplishment subscales of the Maslach Burnout Inventory. Results The survey was sent to 531 CTS trainees across 76 institutions and there were 108 responses (20.3%). Over 50% of respondents expressed dissatisfaction with balance in their professional life and over 40% screened positively for signs of depression. Over 25% (n=28) of respondents would not complete CTS training again, given a choice. More than half met criteria for burnout on emotional exhaustion and depersonalization subscales. CTS residents with children were more likely to express regret towards pursuing CTS training. A greater proportion of women than men reported poor levels of balance/QOL during training as measured by missed health appointments, negative impact on relationships, and self-perception. Similarly, those in the final three years of training were more likely to report poor levels of balance/QOL. Conclusions High rates of burnout, regret, and depression are present among US CTS trainees. Efforts to promote trainee well-being and implement interventions that support those at high risk for burnout are warranted, to benefit trainees as well as the patients they serve., Graphical abstract

Locally advanced rectal cancer (LARC) is treated with chemoradiation prior to surgical excision, leaving residual tumors altered or completely absent. Integrating layers of genomic profiling might identify regulatory pathways relevant to rectal tumorigenesis and inform therapeutic decisions and further research. We utilized formalin-fixed, paraffin-embedded pre-treatment LARC biopsies (n=138) and compared copy number, mRNA, and miRNA expression with matched normal rectal mucosa. An integrative model was used to predict regulatory interactions to explain gene expression changes. These predictions were evaluated in vitro using multiple colorectal cancer cell lines. The Cancer Genome Atlas (TCGA) was also used as an external cohort to validate our genomic profiling and predictions. We found differentially expressed mRNAs and miRNAs that characterize LARC. Our integrative model predicted the upregulation of miR-92a, miR-182, and miR-221 expression to be associated with downregulation of their target genes after adjusting for the effect of copy number alterations. Cell line studies using miR-92a mimics and inhibitors demonstrate that miR-92a expression regulates IQGAP2 expression. We show that endogenous miR-92a expression is inversely associated with endogenous KLF4 expression in multiple cell lines, and that this relationship is also present in rectal cancers of TCGA. Our integrative model predicted regulators of gene expression change in LARC using pre-treatment FFPE tissues. Our methodology implicated multiple regulatory interactions, some of which are corroborated by independent lines of study, while others indicate new opportunities for investigation.

© 2015 Elsevier Ltd. Background: Local excision is an organ-preserving treatment alternative to transabdominal resection for patients with stage I rectal cancer. However, local excision alone is associated with a high risk of local recurrence and inferior survival compared with transabdominal rectal resection. We investigated the oncological and functional outcomes of neoadjuvant chemoradiotherapy and local excision for patients with stage T2N0 rectal cancer. Methods: We did a multi-institutional, single-arm, open-label, non-randomised, phase 2 trial of patients with clinically staged T2N0 distal rectal cancer treated with neoadjuvant chemoradiotherapy at 26 American College of Surgeons Oncology Group institutions. Patients with clinical T2N0 rectal adenocarcinoma staged by endorectal ultrasound or endorectal coil MRI, measuring less than 4 cm in greatest diameter, involving less than 40% of the circumference of the rectum, located within 8 cm of the anal verge, and with an Eastern Cooperative Oncology Group performance status of at least 2 were included in the study. Neoadjuvant chemoradiotherapy consisted of capecitabine (original dose 825 mg/m2 twice daily on days 1-14 and 22-35), oxaliplatin (50 mg/m2 on weeks 1, 2, 4, and 5), and radiation (5 days a week at 1·8 Gy per day for 5 weeks to a dose of 45 Gy, followed by a boost of 9 Gy, for a total dose of 54 Gy) followed by local excision. Because of adverse events during chemoradiotherapy, the dose of capecitabine was reduced to 725 mg/m2 twice-daily, 5 days per week, for 5 weeks, and the boost of radiation was reduced to 5·4 Gy, for a total dose of 50·4 Gy. The primary endpoint was 3-year disease-free survival for all eligible patients (intention-to-treat population) and for patients who completed chemotherapy and radiation, and had ypT0, ypT1, or ypT2 tumours, and negative resection margins (per-protocol group). This study is registered with ClinicalTrials.gov, number NCT00114231. Findings: Between May 25, 2006, and Oct 22, 2009, 79 eligible patients were recruited to the trial and started neoadjuvant chemoradiotherapy. Two patients had no surgery and one had a total mesorectal excision. Four additional patients completed protocol treatment, but one had a positive margin and three had ypT3 tumours. Thus, the per-protocol population consisted of 72 patients. Median follow-up was 56 months (IQR 46-63) for all patients. The estimated 3-year disease-free survival for the intention-to-treat group was 88·2% (95% CI 81·3-95·8), and for the per-protocol group was 86·9% (79·3-95·3). Of 79 eligible patients, 23 (29%) had grade 3 gastrointestinal adverse events, 12 (15%) had grade 3-4 pain, and 12 (15%) had grade 3-4 haematological adverse events during chemoradiation. Of the 77 patients who had surgery, six (8%) had grade 3 pain, three (4%) had grade 3-4 haemorrhage, and three (4%) had gastrointestinal adverse events. Interpretation: Although the observed 3-year disease free survival was not as high as anticipated, our data suggest that neoadjuvant chemoradiotherapy followed by local excision might be considered as an organ-preserving alternative in carefully selected patients with clinically staged T2N0 tumours who refuse, or are not candidates for, transabdominal resection. Funding: National Cancer Institute and Sanofi-Aventis.

Although evidence has repeatedly shown transanal excision (TAE) to be an oncological compromise compared with standard resection for early rectal cancers, the use of TAE and other local approaches has steadily increased over the past decade. This trend is especially evident for cT1 tumors. An increased risk of local recurrence and worse disease-free survival and overall survival are balanced by the markedly decreased surgical risk associated with TAE, as well as its potential benefit with respect to patient values and priorities. The most pressing questions when considering TAE for early-stage rectal cancers revolve around patient selection. How accurate is our clinical staging? How do we weigh the relative risks and benefits of transanal approaches for each patient? How does a local excision alter the subsequent clinical course and options in managing early rectal cancer? In case of recurrence, how successful is salvage surgery? In this review, we provide an update on the use of transanal surgery for patients with cT1 rectal cancer, focusing on patient selection, technique, and outcomes.

Neoadjuvant therapy has been a keystone supporting the advances we have made in the treatment of rectal cancer. The reason for maximizing tumor response to neoadjuvant treatment is clear: as response improves, the consideration of less invasive treatment options such as local excision and “watch-and-wait” (nonoperative) strategies can be explored. Tumor response is closely correlated with long-term oncologic outcome, and the optimization of tumor response to neoadjuvant therapy is thought to improve long-term outcomes as well [1–3]. Maximizing neoadjuvant treatment response is therefore expected to have profound effects on both oncologic outcomes and quality of life.

IMPORTANCE: The watch-and-wait (WW) strategy aims to spare patients with rectal cancer unnecessary resection. OBJECTIVE: To analyze the outcomes of WW among patients with rectal cancer who had a clinical complete response to neoadjuvant therapy. DESIGN, SETTING, AND PARTICIPANTS: This retrospective case series analysis conducted at a comprehensive cancer center in New York included patients who received a diagnosis of rectal adenocarcinoma between January 1, 2006, and January 31, 2015. The median follow-up was 43 months. Data analyses were conducted from June 1, 2016, to October 1, 2018. EXPOSURES: Patients had a clinical complete response after completing neoadjuvant therapy and agreed to a WW strategy of active surveillance and possible salvage surgery (n = 113), or patients underwent total mesorectal excision and were found to have a pathologic complete response (pCR) at resection (n = 136). MAIN OUTCOMES AND MEASURES: Kaplan-Meier estimates were used for analyses of local regrowth and 5-year rates of overall survival, disease-free survival, and disease-specific survival. RESULTS: Compared with the 136 patients in the pCR group, the 113 patients in the WW group were older (median [range], 67.2 [32.1-90.9] vs 57.3 [25.0-87.9] years, P

Background The aims of this study were to create a model of peritoneal carcinomatosis in patients with gastric cancer and to evaluates outcomes in patients with gastric cancer treated using surgery and hyperthermic intraperitoneal chemotherapy (HIPEC). Methods A single-institution cohort of patients with gastric cancer was analyzed according to the development of gastric cancer with peritoneal carcinomatosis (GCPC). Variables were evaluated using regression analysis. Kaplan-Meier analysis was used to evaluate outcomes after surgical resection, cytoreductive surgery, and HIPEC. Results Age ≤60 years and local tumor stage (T3/T4) were significantly associated with GCPC (odds ratio, 3.95 and 3.94, respectively). Thirty-six-month survival was 57% for patients without peritoneal disease and 39% for patients with GCPC. There was no significant trend of improved survival after surgical management or HIPEC. Conclusions Age ≤60 years and T3/T4 tumor stage are risk factors for GCPC. Intermediate-term survival of patients with GCPC treated with surgical resection or cytoreductive surgery and HIPEC was not improved, though future research should address the possible benefits of aggressive approaches to the treatment of GCRC.

BackgroundThe response of rectal cancers to neoadjuvant chemoradiation (CRT) is variable, but tools to predict response remain lacking. We evaluated whether KRAS and TP53 mutations are associated with pathologic complete response (pCR) and lymph node metastasis after adjusting for neoadjuvant regimen.MethodsRetrospective analysis of 229 pretreatment biopsies from patients with stage II/III rectal cancer was performed. All patients received CRT. Patients received 0-8 cycles of FOLFOX either before or after CRT, but prior to surgical excision. A subset was analyzed to assess concordance between mutation calls by Sanger Sequencing and a next-generation assay.ResultsA total of 96 tumors (42%) had KRAS mutation, 150 had TP53 mutation (66%), and 59 (26%) had both. Following neoadjuvant therapy, 59 patients (26%) achieved pCR. Of 133 KRAS wild-type tumors, 45 (34%) had pCR, compared with 14 of 96 (15%) KRAS mutant tumors (p=.001). KRAS mutation remained independently associated with a lower pCR rate on multivariable analysis after adjusting for clinical stage, CRT-to-surgery interval and cycles of FOLFOX (OR 0.34; 95% CI 0.17-0.66, p&nbsp

696 Background: A pathologic complete response (pCR) after neoadjuvant therapy and surgical excision is associated with a better prognosis and guides the management of patients with locally advanced rectal cancer. It is not known whether the thoroughness of pathologic assessment correlates with the finding of pCR. Methods: We introduce a surrogate measure for the thoroughness of pathologic assessment by taking the ratio of maximum residual tumor size and the number of cassettes prepared from the tumor: the Tumor Size to Cassette Ratio (TSCR). We retrospectively reviewed pathology reports from 259 patients with Stage II/III rectal cancer enrolled in a multicenter prospective clinical trial to determine whether TSCR is associated with pCR. Results: Of 247 included patients, 71 (29%) had a pCR. The pCR rate ranged from 0-45% and TSCR ranged from 0.0004 to 1.67 across the twelve trial sites. TSCR was significantly associated with pCR on univariable analysis. On multivariable analysis, TSCR remained significantly associated with pCR (odds ratio of 0.05; 95% CI 0.008-0.302) after adjusting for clinical stage, tumor size, distance from anal verge, radiation dose, and the number of neoadjuvant cycles of FOLFOX received. Conclusions: Pathologists tend to assess rectal cancer specimens with a pCR more thoroughly, but the thoroughness of pathologic assessment of residual tumor specimens varies between institutions. The thoroughness of pathologic assessment is associated with pCR. This raises the need for further standardization in the assessment of rectal cancer specimens after neoadjuvant chemoradiation.

A 49-year-old man presented with chest pain and was found to have hemorrhage and drainage from a chest wound secondary to disseminated tuberculosis involving the sternum and ankle. He then developed acute hemorrhage from an innominate artery pseudoaneurysm originating just below a severely diseased sternoclavicular junction. A staged approach was used to manage his pathology given the life-threatening bleeding and his debilitated condition. He underwent endovascular stent grafting to exclude the pseudoaneurysm, followed by aggressive debridement of the affected sternal area.

Background: Treatment for locally advanced rectal cancer (LARC) consists of neoadjuvant chemoradiotherapy (NCRT) followed by radical excision. Patients with tumors carrying a mutant KRAS are less likely to respond to NCRT compared to KRAS wild type tumors. We hypothesized that an RNA-based signature differentiating KRAS mutant and wild type patients could serve as an indicator of the biological process associated with response to NCRT. We found that the RNA-based signature is enriched for stromal and immune genes. Furthermore, the stromal component of the signature is a predictor of response to NCRT. Methods: Tumors from 120 LARC patients enrolled in a multicenter phase 2 trial studying response to NCRT were tested for KRAS status by Sanger Sequencing or Memorial Sloan Kettering (MSK)-IMPACT assay and gene expression was quantified by sequencing. Colorectal cancer (CRC) patients from MSK (n = 95) and TCGA (n = 261), previously annotated for KRAS mutation status and gene expression, were used for validation. A KRAS-inducible mouse model and CRC patient-derived xenografts (PDXs) were utilized to determine the cell of origin for the gene expression signature. Stromal enrichment was assessed with the ESTIMATE stromal gene signature. Immunohistochemistry (IHC) was completed for Periostin (POSTN), a stromal marker from the RNA-signature. Variant Allele Frequency (VAF) was used to measure the abundance of KRAS, TP53 and Adenomatous Polyposis Coli (APC) mutant alleles in tumors, and was quantified by targeted exome sequencing with the MSK-IMPACT assay. Results: Analysis of the KRAS-associated gene signature showed significant stromal inactivation in KRAS mutant patients. The signature was validated in the MSK and TCGA cohorts. The stromal signature was recapitulated in a KRAS inducible mouse model. Human CRC PDXs in mouse indicated that the signature arose from murine stroma and not human epithelium. Consistent with the stromal signature, IHC for POSTN, a stromal marker, was significantly lower in the KRAS mutant tumors compared with the KRAS wild type tumors (p Conclusions: This study shows that a KRAS mutation in CRC is associated with a lower expression of a stromal signature and that this signature is derived from the tumor microenvironment. This study indicates that CRC KRAS mutant tumors and a stromal subtype are closely related. Understanding this relationship may play a key role in elucidating the mechanism by which a KRAS mutant tumor is resistant to standard therapy. Citation Format: Raphael Pelossof, Moshe Elkatebts, Oliver Chow, Lauren Fairchild, Kevin O’Rourke, Jesse J. Smith, Chin-Tung Chen, Samuel Brook, Maurizio Scaltriti, Jinru Shia, Philip Paty, Christina Leslie, Scott Lowe, Jose Baselga, Julio Garcia-Aguilar. KRAS mutation status is associated with stromal inactivation in colorectal cancer and predicts poor response to neoadjuvant chemoradiotherapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4078.

628 Background: KRAS mutation in colorectal cancer (CRC) is characterized by an altered transcriptional profile when compared to wild-type KRAS tumors. The list of differentially expressed genes overlaps significantly with a stromal fibroblast activation (SFA) signature present across multiple carcinomas. We have reported low expression of SFA genes in KRAS mutant CRC compared to KRAS wild type tumors. Here we sought to confirm the variation of the SFA signature with KRAS mutation and infer its origin in the stromal component of the tumor using experimental models. Methods: The SFA signature was assessed in an inducible-KRAS murine CRC model using RNA-sequencing, and in a CRC cell line with and without a transduced KRAS mutant vector by microarray analysis. Finally, RNA-sequencing of CRC patient-derived xenografts (PDXs) was used to determine whether the SFA signature was being expressed in the tumor epithelium or the surrounding stroma by leveraging the ability to align sequenced reads to the mouse and human genomes separately. Results: The SFA signature was identified in the inducible-KRAS mouse model, matching human cohort observations of decreased SFA gene expression in KRAS mutant CRC. On the other hand, KRAS transduction did not recapitulate the SFA signature in a CRC cell line, suggesting that the presence of stroma may be required for the expression of the SFA signature. Finally, RNA-seq reads for SFA signature genes in CRC PDXs immediately after implantation aligned primarily to the human genome but in later passages of the same PDXs aligned only to the mouse genome. These data suggest that the SFA transcriptional program is associated with the stroma rather than the epithelial tumor cells. Conclusions: KRAS mutation in CRC is associated with a gene expression signature derived from the tumor stroma. These findings suggest that KRAS mutation in the epithelial tumor cells may impact the tumor microenvironment in CRC.

509 Background: Nonoperative management (NOM) of rectal cancer following a clinical complete response (cCR) to neoadjuvant therapy is a non-standard approach. We review our experience with NOM to evaluate safety and efficacy. Methods: A retrospective review of prospectively collected data between 2006 and 2014 was conducted. We compared patients completing neoadjuvant therapy for stage I to III rectal cancers who: a) achieved cCR and were treated with NOM, or b) underwent standard total mesorectal excision (TME) and achieved a pathologic complete response (pCR). Kaplan-Meier estimates and the log-rank test were used. Results: Seventy-three patients underwent NOM after cCR. From 369 rectal resections performed, 72 (20%) achieved pCR and form the comparison group. Median follow-up across both groups was 3.3 years. Rectal preservation was achieved in 56 (77%) of the patients treated with NOM. Of the 19 NOM patients with local regrowth, 18 were salvaged successfully with standard TME (n=16) or local excision (n=2), with one patient pending a salvage operation (n=1). No significant differences were noted in the number of distant recurrences between the NOM and pCR groups. Four-year disease-specific survival and overall survival between the two groups were not significantly different. Conclusions: In this highly selected group of patients with cCR to neoadjuvant treatment, NOM with surgical salvage of local tumor regrowth achieved local control in all patients. The oncologic outcome for NOM patients at 4 years was comparable to patients with pCR after rectal resection. These data continue to suggest that NOM does not compromise oncologic outcome, and that preservation of the rectum is achieved in a majority of patients. [Table: see text]

e14656 Background: Gastric cancer (GC) contributes significantly to the burden of cancer death in the United States. Unfavorable prognosis in patients with gastric cancer and peritoneal carcinomatosis (GCPC) is well-documented. In this study, a model predictive of GCPC is proposed, and outcomes in patients with GCPC treated with surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) are assessed. Methods: A single-institution analysis of 112 patients treated for GC between the years 2000 and 2011 was performed. Demographic and clinical-pathologic criteria were entered into univariate and multivariate analyses, to identify criteria independently predictive of GCPC. Overall survival in each cohort was determined via Kaplan-Meier analysis. Results: GCPC developed in 28/112 (25%) of GC patients. Several variables were associated with GCPC by univariate analysis (age, p = 0.018; tumor stage, p = 0.004; tumor location, p = 0.046), but only age (≤60) and tumor stage (T3/T4) were independently predictive of GCPC by multivariate analysis (HR = 3.949, p = 0.024; HR = 3.942, p = 0.049, respectively). Intermediate-term survival was not significantly impacted in nine GCPC patients treated with HIPEC (65% 1-year, 39% 3-year without HIPEC; vs. 73% 1-year, 39% 3-year with HIPEC, p = NS). Conclusions: A model to identify gastric cancer patients at highest risk for GCPC is proposed. Although intermediate term survival in a small number of GCPC patients (9) treated with HIPEC is not significantly improved, emerging experience with increased follow-up with HIPEC in larger cohorts is needed. Earlier application of HIPEC targeted at patients at highest risk may be feasible in utilizing a model predictive of GCPC.