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Supplementary fig 3 Tumor Regression Grade versus Baseline p-ERK score in Tumor Tissue

supplemental legend

Purpose: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a 5-year survival rate Experimental Design: Peripheral blood was collected from 73 patients presenting with previously untreated metastatic PDAC. Extensive immunologic profiling was conducted to assess relationships between OS and the level of soluble plasma biomarkers or detailed immune cell phenotypes as measured by flow cytometry.Results: Higher baseline levels of the immunosuppressive cytokines IL6 and IL10 were strongly associated with poorer OS (P = 0.008 and 0.026, respectively; HR = 1.16 and 1.28, respectively), whereas higher levels of the monocyte chemoattractant MCP-1 were associated with significantly longer OS (P = 0.045; HR = 0.69). Patients with a greater proportion of antigen-experienced T cells (CD45RO+) had longer OS (CD4 P = 0.032; CD8 P = 0.036; HR = 0.36 and 0.61, respectively). Although greater expression of the T-cell checkpoint molecule CTLA-4 on CD8+ T cells was associated with significantly shorter OS (P = 0.020; HR = 1.53), the TIM3 molecule had a positive association with survival when expressed on CD4+ T cells (P = 0.046; HR = 0.62).Conclusions: These data support the hypothesis that baseline immune status predicts PDAC disease course and overall patient survival. To our knowledge, this work represents the largest cohort and most comprehensive immune profiling of treatment-naïve metastatic PDAC patients to date. Clin Cancer Res; 22(10); 2565–74. ©2015 AACR.

Supplementary fig 1 Flowchart for trial design

Supplementary fig 2 Schema for trial design

Table S1. Antibodies used for flow cytometry Table S2. Monte Carlo cross-validation of continuous measure markers. Table S3. Monte Carlo cross-validation of dichotomous measure markers. Table S4. Pancreatic cancer patient circulating immune cell frequencies Figure S1. Overall survival does not predict plasma MCP-1 levels

Table showing next generation sequencing of tumor samples

Purpose: To broaden access to and implementation of precision medicine in the care of patients with pancreatic cancer, the Know Your Tumor (KYT) program was initiated using a turn-key precision medicine system. Patients undergo commercially available multiomic profiling to determine molecularly rationalized clinical trials and off-label therapies.Experimental Design: Tumor samples were obtained for 640 patients from 287 academic and community practices covering 44 states. College of American Pathologists/Clinical Laboratory Improvement Amendments–accredited laboratories were used for genomic, proteomic, and phosphoprotein-based molecular profiling.Results: Tumor samples were adequate for next-generation sequencing in 96% and IHC in 91% of patients. A tumor board reviewed the results for every patient and found actionable genomic alterations in 50% of patients (with 27% highly actionable) and actionable proteomic alterations (excluding chemopredictive markers) in 5%. Actionable alterations commonly found were in DNA repair genes (BRCA1/2 or ATM mutations, 8.4%) and cell-cycle genes (CCND1/2/3 or CDK4/6 alterations, 8.1%). A subset of samples was assessed for actionable phosphoprotein markers. Among patients with highly actionable biomarkers, those who received matched therapy (n = 17) had a significantly longer median progression-free survival (PFS) than those who received unmatched therapy [n = 18; PFS = 4.1 vs. 1.9 months; HR, 0.47; 95% confidence interval (CI): 0.24–0.94; Padj = 0.03].Conclusions: A comprehensive precision medicine system can be implemented in community and academic settings, with highly actionable findings observed in over 25% of pancreatic cancers. Patients whose tumors have highly actionable alterations and receive matched therapy demonstrated significantly increased PFS. Our findings support further prospective evaluation of precision oncology in pancreatic cancer. Clin Cancer Res; 24(20); 5018–27. ©2018 AACR.

Supplementary Methods, Figures, Tables, and Legends

Supplementary fig 5 Degree of Reduction (%) in Tumor pERK Levels From Baseline to After Trametinib Monotherapy and Correlation With pCR

Supplementary fig 4 Baseline p-ERK score in Tumor Tissue Correlated to RAS/RAF Mutation Status

Purpose:The RAS/RAF/MEK/ERK signaling pathway is critical to the development of colorectal cancers, and KRAS, NRAS, and BRAF mutations foster resistance to radiation. We performed a phase I trial to determine the safety of trametinib, a potent MEK1/2 inhibitor, with 5-fluorouracil (5-FU) chemoradiation therapy (CRT) in patients with locally advanced rectal cancer (LARC).Patients and Methods:Patients with stage II/III rectal cancer were enrolled on a phase I study with 3+3 study design, with an expansion cohort of 9 patients at the MTD. Following a 5-day trametinib lead-in, with pre- and posttreatment tumor biopsies, patients received trametinib and CRT, surgery, and adjuvant chemotherapy. Trametinib was given orally daily at 3 dose levels: 0.5 mg, 1 mg, and 2 mg. CRT consisted of infusional 5-FU 225 mg/m2/day and radiation dose of 28 daily fractions of 1.8 Gy (total 50.4 Gy). The primary endpoint was to identify the MTD and recommended phase II dose. IHC staining for phosphorylated ERK (pERK) and genomic profiling was performed on the tumor samples.Results:Patients were enrolled to all dose levels, and 18 patients were evaluable for toxicities and responses. Treatment was well tolerated, and there was one dose-limiting toxicity of diarrhea, which was attributed to CRT rather than trametinib. At the 2 mg dose level, 25% had pathologic complete response. IHC staining confirmed dose-dependent decrease in pERK with increasing trametinib doses.Conclusions:The combination of trametinib with 5-FU CRT is safe and well tolerated, and may warrant additional study in a phase II trial, perhaps in a RAS/RAF-mutant selected population.

Background Roux-en-Y gastric bypass (RYGB) is one of the most effective bariatric procedures. The study aimed to explore the value of lengthening the biliopancreatic limb (BPL) in RYGB compared to the outcome of one-anastomosis gastric bypass (OAGB). Methods This prospective study included morbidly obese patients divided into two groups. The RYGB group (n = 36) was subjected to long biliary limb Roux-en-Y gastric bypass (LPRYGB), and the OAGB Group (n = 36) had one anastomosis gastric bypass. During follow-up, weight, BMI, percentage of excess body weight loss (%EBWL), resolution of obesity-related comorbidities, and quality of life (QoL) were evaluated. Results There was no significant difference in weight and BMI after 3 and 6 months. At 12-month follow-up, weight loss was significantly higher in the OAGB group. After 12 months, the two groups showed significant improvement of comorbid conditions without significant difference between the two groups. The Qol was significantly higher in the LPRYGB group 3, 6, and 12 months after surgery compared to the OAGB group. Conclusions Extending the BPL length in RYGB to 150 cm is as effective as OAGB in remission of comorbidities, including diabetes. It was also equally effective in weight reduction in the short term. OAGB was more efficient in weight reduction and a significantly faster operation. LPRYGB showed a better QoL of life 1 year after surgery. Graphical abstract

OBJECTIVE: The aim was to develop a reliable surgical quality assurance system for 2-stage esophagectomy. This development was conducted during the pilot phase of the multicenter ROMIO trial, collaborating with international experts.SUMMARY OF BACKGROUND DATA: There is evidence that the quality of surgical performance in randomized controlled trials influences clinical outcomes, quality of lymphadenectomy and loco-regional recurrence.METHODS: Standardization of 2-stage esophagectomy was based on structured observations, semi-structured interviews, hierarchical task analysis, and a Delphi consensus process. This standardization provided the structure for the operation manual and video and photographic assessment tools. Reliability was examined using generalizability theory.RESULTS: Hierarchical task analysis for 2-stage esophagectomy comprised fifty-four steps. Consensus (75%) agreement was reached on thirty-nine steps, whereas fifteen steps had a majority decision. An operation manual and record were created. A thirty five-item video assessment tool was developed that assessed the process (safety and efficiency) and quality of the end product (anatomy exposed and lymphadenectomy performed) of the operation. The quality of the end product section was used as a twenty seven-item photographic assessment tool. Thirty-one videos and fifty-three photographic series were submitted from the ROMIO pilot phase for assessment. The overall G-coefficient for the video assessment tool was 0.744, and for the photographic assessment tool was 0.700.CONCLUSIONS: A reliable surgical quality assurance system for 2-stage esophagectomy has been developed for surgical oncology randomized controlled trials.ETHICAL APPROVAL: 11/NW/0895 and confirmed locally as appropriate, 12/SW/0161, 16/SW/0098.TRIAL REGISTRATION NUMBER: ISRCTN59036820, ISRCTN10386621.

Portal vein thrombosis (PVT) is an infrequent, yet potentially lethal, complication of bariatric surgery. The aim of this prospective, non-randomized, cohort study is to compare between laparoscopic sleeve gastrectomy (LSG) and laparoscopic one-anastomosis gastric bypass (LOAGB) in terms of their early postoperative effects on portal venous flow and patency. Forty-nine morbidly obese patients were allocated to one of 2 groups (A or B). Group A patients underwent LSG, whereas group B patients underwent LOAGB. Portal venous Doppler ultrasound scanning was performed preoperatively and 2 weeks postoperatively in all cases, in order to assess the portal venous flow (PVF) in terms of flow direction and peak systolic velocity (PSV); as well as to assess the portal venous patency and exclude PVT. The mean change in PSV (ΔPSV) and the mean percentage change in PSV (%ΔPSV) were determined in both groups. In all cases (group A (n = 26); group B (n = 23)), the direction of PVF was “hepatopetal” both preoperatively and 2 weeks postoperatively. The mean ΔPSV and the mean %ΔPSV were higher in LSG patients “group A” (− 0.84 cm/s and 3.25% respectively) compared with LOAGB patients “group B”(− 0.06 cm/s and 0.27% respectively); P = 0.038 and 0.039 respectively. The mean change in PSV was in the negative direction in both groups, i.e., “deceleration.” No cases of PVT were reported in the study. Laparoscopic sleeve gastrectomy is associated with greater reduction in portal venous peak systolic flow velocity in the early postoperative period, compared with laparoscopic one-anastomosis gastric bypass.

BackgroundMinimally invasive surgery has been steadily growing in popularity. Control of splenic hilar vessels is the most delicate step during laparoscopic splenectomy (LS). In the earlier eras of LS, hilar vessels were controlled using clips and/or ligation. Laparoscopic staples were later introduced and have arguably led to an increase in popularity of LS. They do not abolish potential complications of splenectomy and theoretically represent an added operative cost.In this study, we aimed to assess the safety and efficacy of stapleless LS (using knots, haemostatic devices and clips) compared with the now more conventional stapled LS.MethodsA pilot randomised prospective study was conducted in a university hospital between September 2018 and April 2020. It included 40 patients randomly assigned to two equal groups: (1) 20 patients: stapleless LS and (2) 20 patients: LS using laparoscopic staples.We compared operative time, intra and postoperative complications and postoperative recovery.ResultsThere was no statistically significant difference between both groups across all comparative outcomes.ConclusionBoth techniques are comparable in terms of safety and operative time. In terms of cost efficiency, we recommend more comprehensive analyses of hospital costs.

PURPOSE Up to 25% of pancreatic adenocarcinomas (PDACs) harbor mutations in the homologous recombination DNA damage response (HR-DDR) pathway. Although known to affect responsiveness to DNA-damaging chemotherapy, the prognostic relevance of these mutations is unclear and outcomes in patients with PDAC who harbor HR-DDR mutations beyond BRCA1/2 remain unexplored. METHODS We evaluated 820 patients with PDAC enrolled in the Know Your Tumor program for whom we had collected comprehensive genomic testing results and longitudinal clinical outcomes. Patients were categorized as having resected versus advanced disease, and as having received platinum-based therapy versus being platinum naïve. Tumor genomic profiles were categorized as HR-DDR mutated (HR-DDRmut) or proficient (pHR-DDR) on the basis of the presence of pathogenic mutations of somatic or germline origin in BRCA1/2 or PALB2 (group 1); ATM/ATR/ATRX (group 2); or BAP1, BARD1, BRIP1, CHEK1/2, RAD50/51/51B, or FANCA/C/D2/E/F/G/L (group 3). Overall survival was measured from the date of diagnosis until death. RESULTS Median overall survival (mOS) was similar in all resected patients irrespective of exposure to platinum-based therapy, whereas for platinum-treated patients with advanced disease, mOS was significantly longer for HR-DDRmut versus pHR-DDR (2.37 years v 1.45 years, respectively). Of importance, no difference was identified in platinum-naïve patients. mOS in patients with mutations in all three HR-DDRmut groups was greater than that for pHR-DDR patients, but this difference was lost in platinum-naïve patients. CONCLUSION Patients with advanced HR-DDRmut have improved mOS when treated with platinum-based therapy compared with pHR-DDR patients. In platinum-naïve patients, there is no mOS difference, which suggests that HR-DDR status has no pure prognostic value. These findings support the need to test all patients with advanced PDAC to ensure that HR-DDRmut patients receive the benefit of treatment with platinum-based therapy.

Roux-en-Y gastric bypass (RYGB) is one of the most effective bariatric procedures. The study aimed to explore the value of lengthening the biliopancreatic limb (BPL) in RYGB compared to the outcome of one-anastomosis gastric bypass (OAGB).This prospective study included morbidly obese patients divided into two groups. The RYGB group (n = 36) was subjected to long biliary limb Roux-en-Y gastric bypass (LPRYGB), and the OAGB Group (n = 36) had one anastomosis gastric bypass. During follow-up, weight, BMI, percentage of excess body weight loss (%EBWL), resolution of obesity-related comorbidities, and quality of life (QoL) were evaluated.There was no significant difference in weight and BMI after 3 and 6 months. At 12-month follow-up, weight loss was significantly higher in the OAGB group. After 12 months, the two groups showed significant improvement of comorbid conditions without significant difference between the two groups. The Qol was significantly higher in the LPRYGB group 3, 6, and 12 months after surgery compared to the OAGB group.Extending the BPL length in RYGB to 150 cm is as effective as OAGB in remission of comorbidities, including diabetes. It was also equally effective in weight reduction in the short term. OAGB was more efficient in weight reduction and a significantly faster operation. LPRYGB showed a better QoL of life 1 year after surgery.

Among the controversial points in laparoscopic sleeve gastrectomy (LSG) is how much of the antrum to be resected. This study aimed to evaluate food tolerance after preservation or resection of the antrum during LSG. Prospective randomized study included 50 patients scheduled for LSG. Participants were randomly allocated into one of two groups. In antral resection (AR-LSG) group (n = 25), resection started 2 cm from the pylorus. In antral sparing (AS-LSG) group (n = 25), it started 6 cm from the pylorus. Percentage of excess weight loss (%EWL) and percentage of excess BMI loss (%EBL) were evaluated after 3 and 6 months. Quality of life (QOL) was evaluated by using the Bariatric Analysis and Reporting Outcome System (BAROS). Food tolerance was assessed using the Quality of Alimentation questionnaire. Primary outcome measure was food tolerance and %EWL. Food tolerance was significantly better in the antral sparing group compared to the antral resection group after 3 and 6 months. The two groups were comparable in %EWL and BMI change after 3 and 6 months. Six months after surgery, the majority of patients had a very good quality of life, with no significant difference between the two groups (p = 0.877). There was no significant difference between the two groups in operative time, intraoperative blood loss, and hospital stay. Preservation of the pyloric antrum during LSG is associated with significantly better food tolerance and comparable effect of weight loss up to 6 months postoperatively when compared with total antral resection.

Purpose: To broaden access to and implementation of precision medicine in the care of patients with pancreatic cancer, the Know Your Tumor (KYT) program was initiated using a turn-key precision medicine system. Patients undergo commercially available multiomic profiling to determine molecularly rationalized clinical trials and off-label therapies. Experimental Design: Tumor samples were obtained for 640 patients from 287 academic and community practices covering 44 states. College of American Pathologists/Clinical Laboratory Improvement Amendments–accredited laboratories were used for genomic, proteomic, and phosphoprotein-based molecular profiling. Results: Tumor samples were adequate for next-generation sequencing in 96% and IHC in 91% of patients. A tumor board reviewed the results for every patient and found actionable genomic alterations in 50% of patients (with 27% highly actionable) and actionable proteomic alterations (excluding chemopredictive markers) in 5%. Actionable alterations commonly found were in DNA repair genes (BRCA1/2 or ATM mutations, 8.4%) and cell-cycle genes (CCND1/2/3 or CDK4/6 alterations, 8.1%). A subset of samples was assessed for actionable phosphoprotein markers. Among patients with highly actionable biomarkers, those who received matched therapy (n = 17) had a significantly longer median progression-free survival (PFS) than those who received unmatched therapy [n = 18; PFS = 4.1 vs. 1.9 months; HR, 0.47; 95% confidence interval (CI): 0.24–0.94; Padj = 0.03]. Conclusions: A comprehensive precision medicine system can be implemented in community and academic settings, with highly actionable findings observed in over 25% of pancreatic cancers. Patients whose tumors have highly actionable alterations and receive matched therapy demonstrated significantly increased PFS. Our findings support further prospective evaluation of precision oncology in pancreatic cancer. Clin Cancer Res; 24(20); 5018–27. ©2018 AACR.

Portal vein thrombosis (PVT) is an infrequent, yet potentially lethal, complication of bariatric surgery. The aim of this prospective, non-randomized, cohort study is to compare between laparoscopic sleeve gastrectomy (LSG) and laparoscopic one-anastomosis gastric bypass (LOAGB) in terms of their early postoperative effects on portal venous flow and patency.Forty-nine morbidly obese patients were allocated to one of 2 groups (A or B). Group A patients underwent LSG, whereas group B patients underwent LOAGB. Portal venous Doppler ultrasound scanning was performed preoperatively and 2 weeks postoperatively in all cases, in order to assess the portal venous flow (PVF) in terms of flow direction and peak systolic velocity (PSV); as well as to assess the portal venous patency and exclude PVT. The mean change in PSV (ΔPSV) and the mean percentage change in PSV (%ΔPSV) were determined in both groups.In all cases (group A (n = 26); group B (n = 23)), the direction of PVF was "hepatopetal" both preoperatively and 2 weeks postoperatively. The mean ΔPSV and the mean %ΔPSV were higher in LSG patients "group A" (- 0.84 cm/s and 3.25% respectively) compared with LOAGB patients "group B"(- 0.06 cm/s and 0.27% respectively); P = 0.038 and 0.039 respectively. The mean change in PSV was in the negative direction in both groups, i.e., "deceleration." No cases of PVT were reported in the study.Laparoscopic sleeve gastrectomy is associated with greater reduction in portal venous peak systolic flow velocity in the early postoperative period, compared with laparoscopic one-anastomosis gastric bypass.

Purpose: The RAS/RAF/MEK/ERK signaling pathway is critical to the development of colorectal cancers, and KRAS, NRAS, and BRAF mutations foster resistance to radiation. We performed a phase I trial to determine the safety of trametinib, a potent MEK1/2 inhibitor, with 5-fluorouracil (5-FU) chemoradiation therapy (CRT) in patients with locally advanced rectal cancer (LARC). Patients and Methods: Patients with stage II/III rectal cancer were enrolled on a phase I study with 3+3 study design, with an expansion cohort of 9 patients at the MTD. Following a 5-day trametinib lead-in, with pre- and posttreatment tumor biopsies, patients received trametinib and CRT, surgery, and adjuvant chemotherapy. Trametinib was given orally daily at 3 dose levels: 0.5 mg, 1 mg, and 2 mg. CRT consisted of infusional 5-FU 225 mg/m2/day and radiation dose of 28 daily fractions of 1.8 Gy (total 50.4 Gy). The primary endpoint was to identify the MTD and recommended phase II dose. IHC staining for phosphorylated ERK (pERK) and genomic profiling was performed on the tumor samples. Results: Patients were enrolled to all dose levels, and 18 patients were evaluable for toxicities and responses. Treatment was well tolerated, and there was one dose-limiting toxicity of diarrhea, which was attributed to CRT rather than trametinib. At the 2 mg dose level, 25% had pathologic complete response. IHC staining confirmed dose-dependent decrease in pERK with increasing trametinib doses. Conclusions: The combination of trametinib with 5-FU CRT is safe and well tolerated, and may warrant additional study in a phase II trial, perhaps in a RAS/RAF-mutant selected population.

Treatment with cisplatin and gemcitabine demonstrates a survival benefit in patients with advanced biliary tract cancer (ABTC). However, the weekly administration can add significant toxicities that may prohibit prolonged treatment. Based on previous studies, we implemented a modified biweekly regimen of GC in an attempt to optimize the prescribed regimen with an improved toxicity profile, added convenience to patients while maintaining efficacy. Patients with ABTC were treated with fixed dose rate (FDR) gemcitabine (1,000 mg/m2 /min) and cisplatin 20 mg/m2 on days 1 and 15 of every 28-day cycle. Patients received treatment until time of progression, death, or discontinuation due to intolerance. Collected data included demographics, clinico-pathologic features, toxicities, and survival. Kaplan-Meier curves were used to calculate the median overall survival (OS) and progression free survival (PFS). The study included 107 evaluable pts with unresectable ABTC who received the biweekly regimen. Sites of tumor included gallbladder (21.5%), ampullary (3.7%), and bile duct (74.8%). Median number of cycles was 6 (1-27). Median PFS was 8.34 (6.74, 9.23) months and median OS was 10.32 (9.10, 11.43) months. Most common grade ≥3 adverse events included neutropenia (11%), fatigue (10%), and thrombocytopenia (6.4%). Biweekly FDR GC in ABTC is associated with a more favorable toxicity profile while maintaining efficacy similar to that observed in prior clinical trials. Minimal toxicities were observed despite a prolonged course for many patients. Further prospective trials should consider evaluating the role of biweekly GC regimen in ABTC, including a potentially more favorable platform in novel experimental strategies.

Esophageal cancer (EC) is increasing in prevalence due to rising incidence and improved treatment strategies. Dysphagia is a significant morbidity in patients with EC requiring nutritional intervention. We sought to evaluate outcomes of nutritional interventions for EC patients hospitalized with dysphagia at a population level. The National Inpatient Sample (2002-2012) was utilized to include all adult inpatients (≥18 years of age) with EC and presence of dysphagia and stricture that underwent nutritional interventions including feeding tube (FT) placement, esophageal stenting, or parenteral nutrition (PN). Temporal trends were examined with multivariate analysis performed for mortality, length of stay (LOS), and cost of hospitalization. A total of 509,593 EC patients had 12,205 hospitalizations related to dysphagia. The hospitalization rates doubled over the study period (1.52% vs. 3.28%, p < 0.001). The most common nutritional intervention was FT (27%), followed by esophageal stenting (13%), and PN (11%). PN was more frequently associated with a diagnosis of sepsis (6.1%, p = 0.023) compared to FT (2.5%) or esophageal stenting (1.8%). Multivariate analysis demonstrated FT and esophageal stenting had comparable mortality (OR 1.06, 95% CI: 0.49, 2.32); however, PN was associated with higher mortality (OR 2.37, 95% CI: 1.22, 4.63), cost of hospitalization ($5,510, 95% CI: 2,262, 8,759), and LOS (2.13 days, 95% CI: 0.72, 3.54). This study shows that hospitalizations for EC with dysphagia and related nutritional interventions are increasing. As a single modality, parenteral nutrition should be avoided. Among our esophageal stent and FT population, further studies are necessary to determine adequate interventions based on disease stage.

There is no consensus on the ideal small bowel length that should be bypassed in laparoscopic one-anastomosis gastric bypass (OAGB). This study aimed to compare the safety and efficacy of conventional versus distal techniques of laparoscopic OAGB. This randomized controlled trial involved 60 adults with morbid obesity scheduled for laparoscopic OAGB randomly assigned to one of the two techniques; conventional technique (fixed anastomosis 200 cm from the ligament of Treitz) and distal technique (anastomosis 400 cm from the ileocecal valve). Total small bowel length (TSBL) was measured in all cases. Quality of life was assessed using the Gastrointestinal Quality of Life Index (GIQLI). Outcome measures were excess body weight loss percentage (EBWL%), resolution of associated comorbidities, frequency of nutritional deficiencies, and quality of life. No patients were lost to follow-up. The two groups were comparable in TSBL, EBWL%, and complete resolution of comorbidities up to 12 months. The percentage of afferent loop length to TSBL was significantly higher in the distal group (p

Among the controversial points in laparoscopic sleeve gastrectomy (LSG) is how much of the antrum to be resected. This study aimed to evaluate food tolerance after preservation or resection of the antrum during LSG.Prospective randomized study included 50 patients scheduled for LSG. Participants were randomly allocated into one of two groups. In antral resection (AR-LSG) group (n = 25), resection started 2 cm from the pylorus. In antral sparing (AS-LSG) group (n = 25), it started 6 cm from the pylorus. Percentage of excess weight loss (%EWL) and percentage of excess BMI loss (%EBL) were evaluated after 3 and 6 months. Quality of life (QOL) was evaluated by using the Bariatric Analysis and Reporting Outcome System (BAROS). Food tolerance was assessed using the Quality of Alimentation questionnaire. Primary outcome measure was food tolerance and %EWL.Food tolerance was significantly better in the antral sparing group compared to the antral resection group after 3 and 6 months. The two groups were comparable in %EWL and BMI change after 3 and 6 months. Six months after surgery, the majority of patients had a very good quality of life, with no significant difference between the two groups (p = 0.877). There was no significant difference between the two groups in operative time, intraoperative blood loss, and hospital stay.Preservation of the pyloric antrum during LSG is associated with significantly better food tolerance and comparable effect of weight loss up to 6 months postoperatively when compared with total antral resection.

Background Molecular profiling is increasingly used to match patients with metastatic cancer to targeted therapies, but obtaining a high-quality biopsy specimen from metastatic sites can be difficult. Methods Patient samples were received by Perthera to coordinate genomic, proteomic and/or phosphoproteomic testing, using a specimen from either the primary tumour or a metastatic site. The relative frequencies were compared across specimen sites to assess the potential limitations of using a primary tumour sample for clinical decision support. Results No significant differences were identified at the gene or pathway level when comparing genomic alterations between primary and metastatic lesions. Site-specific trends towards enrichment of MYC amplification in liver lesions, STK11 mutations in lung lesions and ATM and ARID2 mutations in abdominal lesions were seen, but were not statistically significant after false-discovery rate correction. Comparative analyses of proteomic results revealed significantly elevated expression of ERCC1 and TOP1 in metastatic lesions. Conclusions Tumour tissue limitations remain a barrier to precision oncology efforts, and these real-world data suggest that performing molecular testing on a primary tumour specimen could be considered in patients with pancreatic adenocarcinoma who do not have adequate tissue readily available from a metastatic site.

Background Biliary tract cancers (BTCs) are uncommon and are associated with a dismal prognosis. Combinations of gemcitabine and platinum chemotherapy (gemcitabine and platinum-based therapy [GP]) form the standard approach for treating advanced BTC. To characterize the spectrum of mutations and to identify potential biomarkers for a GP response in BTC, this study evaluated the genomic landscape and assessed whether mutations affecting DNA repair were associated with GP resistance. Methods Pretreatment, formalin-fixed, paraffin-embedded samples from 183 BTC patients treated with GP were analyzed. Cox regression models were used to determine the association between mutations, progression-free survival (PFS), and overall survival (OS). Results When genes with an incidence > 10% were considered, no individual gene was independently predictive of a GP response. In patients with unresectable BTC who received GP as their first-line therapy, the joint status of cyclin-dependent kinase inhibitor 2A (CDKN2A), tumor protein 53 (TP53), and AT-rich interaction domain 1A (ARID1A) was associated with PFS (P = .0004) and OS (P ≤ .0001). Patients with mutations in CDKN2A and TP53 were identified as a poor-prognosis cohort with a median PFS of 2.63 months and a median OS of 5.22 months. Patients with mutant ARID1A, regardless of the single-mutation status of TP53 or CDKN2A, had similar outcomes. A patient who exhibited mutations in all 3 genes had a median PFS of 20.37 months, and OS was not reached. Conclusions In the largest exploratory analysis of this kind for BTC, 3 prevalent, mutually exclusive mutations represent distinct patient cohorts. These mutations are prognostic and may represent a predictive biomarker for a GP response. Prospective studies to validate these findings are needed, and they should include the incorporation of therapies that exploit the genomic instability observed with these mutations in BTC. Cancer 2016;122:3657-66. © 2016 American Cancer Society.

OBJECTIVES The objectives of this systematic review and pooled analysis were to examine long-term survival, morbidity, and mortality following surgical resection of gastric cancer hepatic metastases and to identify prognostic factors that improve survival. BACKGROUND Patients with hepatic metastases from gastric cancer are traditionally treated with palliative chemotherapy. METHODS A systematic literature search was undertaken (1990 to 2015). Publications were included if they studied more than 10 patients undergoing hepatectomy for hepatic metastasis from gastric adenocarcinoma in the absence of peritoneal disease or other distant organ involvement. The primary outcome was the hazard ratio (HR) for overall survival. The influence of liver metastasis related factors; multiple vs single and metachronous vs synchronous upon survival was also assessed. RESULTS The median number of resections for the 39 studies included was 21 (range 10 to 64). Procedures were associated with a median 30-day morbidity of 24% (0% to 47%) and mortality of 0% (0% to 30%). The median 1-year, 3-year, and 5-year survival were 68%, 31%, and 27%, respectively. Survival was improved in Far Eastern compared with Western studies; 1-year (73% vs 59%), 3-year (34% vs 24.5%), and 5-year (27.3% vs 16.5%). Surgical resection of hepatic metastases was associated with a significantly improved overall survival (HR = 0.50; P < 0.001). Meta-analysis confirmed the additional survival benefit of solitary compared with multiple hepatic metastases (odds ratio = 0.31; P = 0.011). CONCLUSIONS The observed improved survival rates following the resection of hepatic metastasis from gastric adenocarcinoma in selected patients merit a prospective study to formally address the survival benefits and the influence on quality of life of such approach.

Malignant transformation of normal cells is associated with the evolution of genomic alterations. This concept has led to the development of molecular testing platforms to identify genomic alterations that can be targeted with novel therapies. Next generation sequencing (NGS) has heralded a new era in precision medicine in which tumor genes can be studied efficiently. Recent developments in NGS have allowed investigators to identify genomic predictive makers and hereditary mutations to guide treatment decision. The application of NGS in gastrointestinal cancers is being extensively studied but continues to face substantial challenges. In our review, we discuss various NGS platforms and highlight their role in identifying familial mutations and markers of response or resistance to cancer therapy. We also provide a balanced discussion of the challenges that limit the routine use of NGS in clinical practice.

The objectives of this national study were to examine the short-term safety and long-term survival benefit associated with surgical resection of hepatic metastases from gastric cancer. Patients from the Hospital Episode Statistics database were classified by disease and treatment approach. Gastric cancer: 1. Without liver metastases treated by gastrectomy (GG). 2. With liver metastases treated by gastrectomy and hepatectomy (GGH). 3. With liver metastases treated by gastrectomy without hepatectomy (GGNH). 4. With liver metastases treated with no surgery (GNS). Propensity score matching and multivariable analyses were used to compensate for differences in some baseline characteristics. During the study period, 87,482 were patients diagnosed with gastric cancer, of whom 13,841 underwent partial or total gastrectomy. Of those who underwent gastrectomy, 336 had a diagnosis of liver metastases and 78 of these had a hepatectomy. Propensity-matched analysis showed no significant differences in 30- or 90-day mortality between the GGH and GG groups. The GGH group had significantly improved 1-year mortality (35.9 % vs. 50.0 %, p = 0.049) and 5-year mortality (61.5 % vs. 75.7 %, p = 0.031) compared to the GGNH group, and compared to the GNS group, the GCH group had 1-year mortality (35.9 % vs. 84.6 %, p

Colorectal cancer is the second leading cause of cancer death in the USA. It is estimated that approximately 132,700 patients are diagnosed with, and more than 49,700 are expected to die of colorectal cancer each year. For many years, 5-fluorouracil was the only treatment option for patients with metastatic colorectal cancer but, over the last decade, the introduction and the US FDA approval of irinotecan, oxaliplatin and several monoclonal antibodies that target the VEGF and EGF receptor have markedly changed the therapeutic landscape. Most recently, regorafenib, ramucirumab and the novel orally active TAS-102 have also become available, presenting even more therapeutic options. In this review, we focus on emerging systemic therapy options for the management of advanced/metastatic colorectal cancer, particularly in the second-line/salvage settings, highlighting existing scientific evidence for the activity of, as well as future perspectives on, these more novel treatments.

4641 Background: Approximately 90% of PDAC tumors are driven by activating KRAS mutations. The biological and clinical impact of common KRAS variants (e.g. G12D, G12V, G12R) and less common variants (e.g. G12C, Q61H, Q61R) remains largely unknown despite the emergence of variant-specific treatment strategies. Methods: We retrospectively analyzed real-world outcomes from 1475 PDAC pts who underwent molecular profiling via the Know Your Tumor program. Overall survival (OS) and progression-free survival (PFS) were analyzed by choice of 1st line standard therapies. Outcomes in pts with specific KRAS mutations were compared against the KRAS G12D cohort using Cox regression. Based on our prior data, tumor profiles with actionable molecular findings (DDR mutations or other drivers) were evaluated separately. Results: The prognostic/predictive value of specific KRAS variants revealed differences in real-world outcomes (Table). OS was greater in pts with KRAS G12V and G12R variants, as was PFS on 5FU-Based Therapy (e.g. FOLFIRINOX) but not for Gemcitabine/nab-Paclitaxel. Opposing trends were noted for KRAS Q61. Pts with KRAS wild type tumors as well as both actionable subgroups also had an improved OS. Conclusions: In this large national dataset, we demonstrate that KRAS mutation status and specific variants appear to be prognostic as well as predictive in pancreatic cancer. [Table: see text]

735 Background: Molecular profiling (MP) for PDAC has gained increased acceptance and we previously demonstrated that targeting actionable mutations can improve patient (pt) outcomes. However, the correlations of diverse patterns of molecular alterations with outcomes following SOC Tx are largely unknown. Methods: We analyzed longitudinal outcomes of 1355 PDAC pts who underwent MP and received SOC Tx. “Persona” types were established based on the molecular characteristics of each pt using unsupervised clustering, as well as a supervised review defined by our molecular tumor board, following classifications reported in previous studies. Progression-free survival (PFS) for each type was assessed based on the choice of first-line Tx (i.e. FOLFIRINOX [FFX] vs. gemcitabine + nab-paclitaxel [GA]). Statistical comparisons were made against all other types within a specific Tx group. Results: The prognostic/predictive value of the persona types for 1st-line Tx revealed distinct differences in outcomes (Table). As expected, the DDR deficiency type was associated with a significantly improved PFS for pts treated with FFX but not for GA. In addition, pts in the cell cycle type had a worse PFS compared to other persona types for both FFX and GA. Using this platform, we will further subdivide the persona types into molecular subtypes and associate these with pt outcomes. Conclusions: Our analyses demonstrate that specific molecular persona types exist in PDAC pts and can be linked to Tx outcomes. Ultimately, knowing the persona type/subtype early in a pt’s Tx course may help personalize Tx to improve outcomes. [Table: see text]

Background: Blockade of the vascular endothelial growth factor (VEGF) pathway shows evidence of activity in gastro-oesophageal (GE) and oesophageal cancer. We investigated the efficacy of sunitinib, a multikinase VEGF inhibitor, in patients with relapsed/refractory GE/oesophageal cancer. Methods: This was a single-stage Fleming phase II study. The primary end point was progression-free survival (PFS) at 24 weeks. If five or more patients out of a total of 25 were free of progressive disease at 24 weeks, sunitinib would be recommended for further study. Patients received sunitinib 37.5 mg orally daily and imaged every 6 weeks. Exploratory correlative analysis included serum growth factors, tumour gene expression and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Results: Twenty-five evaluable patients participated in the study. Progression-free survival at 24 weeks was 8% (n=2 patients; confidence interval (CI): 95% 1.4–22.5%), and the duration of best response for the patients was 23 and 72 weeks. Ten patients (42%) had stable disease (SD) for >10 weeks. Overall response rate is 13%. Median PFS is 7 weeks (95% CI: 5.6–11.4 weeks) and the median overall survival is 17 weeks (95% CI: 8.9–25.3 weeks). Most common grade 3/4 toxicities included fatigue (24%), anaemia (20%) thrombocytopenia (16%), and leucopenia (16%). No patients discontinued therapy due to toxicity. Serum VEGF-A and -C levels, tumour complement factor B (CFB) gene expression, and DCE-MRI correlated with clinical benefit, defined as SD or better as best response. Conclusion: Sunitinib is well tolerated but only a select subgroup of patients benefited. Serum VEGF-A and -C may be early predictors of benefit. On this study, patients with clinical benefit from sunitinib had higher tumour CFB expression, and thus has identified CFB as a potential predictor for efficacy of anti-angiogenic therapy. These findings need validation from future prospective trials.

The cell cycle is a highly conserved and tightly regulated biological system that controls cellular proliferation and differentiation. The cell cycle regulatory proteins, which include the cyclins, the cyclin-dependent kinases (CDKs), and the CDK inhibitors, are critical for the proper temporal and spatial regulation of cellular proliferation. Conversely, alterations in cell cycle regulatory proteins, leading to the loss of normal cell-cycle control, are a hallmark of many cancers, including gastrointestinal cancers. Accordingly, overexpression of CDKs and cyclins and by contrast loss of CDK inhibitors, are all linked to gastrointestinal cancers and are often associated with less favorable prognoses and outcomes. Because of the importance that the cell cycle regulatory proteins play in tumorigenesis, currently there is a broad spectrum of cell-cycle inhibitors under development that, as a group, hold promise as effective cancer treatments. In support of this approach to cancer treatment, the growing availability of molecular diagnostics techniques may help in identifying patients who have driving abnormalities in the cell-cycle machinery and are thus more likely to respond to cell-cycle inhibitors. In this review, we discuss the prevalence of cell-cycle abnormalities in patients with gastrointestinal cancers and provide a preclinical and clinical overview of new agents that target cell-cycle abnormalities with a special emphasis on gastrointestinal cancers.

Treatment with cisplatin and gemcitabine demonstrates a survival benefit in patients with advanced biliary tract cancer (ABTC). However, the weekly administration can add significant toxicities that may prohibit prolonged treatment. Based on previous studies, we implemented a modified biweekly regimen of GC in an attempt to optimize the prescribed regimen with an improved toxicity profile, added convenience to patients while maintaining efficacy. Patients with ABTC were treated with fixed dose rate (FDR) gemcitabine (1,000 mg/m

Gastroesophageal (GE) malignancies make up a significant and growing segment of newly diagnosed cancers. Approximately 80% of patients who have GE cancers die within 5 years of diagnosis, which means that effective treatments for these malignancies need to be found. Currently, targeted therapies have a minimal role in this disease group. Intensive study of the molecular biology of GE cancers is a relatively new and ongoing venture, but it has already led to a significant increase in our understanding of these malignancies. This understanding, although still limited, has the potential to enhance our ability to develop targeted therapies in conjunction with the ability to identify actionable gene mutations and perform genomic profiling to predict drug resistance. Several cell surface growth factor receptors have been found to play a prominent role in GE cancer cell signaling. This discovery has led to the approval of 2 agents within the last few years: trastuzumab, an anti-human epidermal growth factor receptor 2 (HER2) monoclonal antibody used in the first-line treatment of HER2-positive GE cancers, and ramucirumab, an anti-vascular endothelial growth factor receptor 2 (VEGFR2) monoclonal antibody that is currently used in later lines of therapy. This review discusses the current state of molecular testing in GE cancers, along with the known molecular biology and current and investigational treatments. The development of trastuzumab and ramucirumab represents a significant advance in our ability to make use of GE tumor molecular profiles. As our understanding of the impact of molecular aberrations on drug effectiveness and disease outcomes increases, we anticipate improved therapy for patients with GE cancers.

Type 2B von Willebrand disease (VWD) accounts for fewer than 5% of all VWD patients. In this disease, mutations in the A1 domain result in increased von Willebrand factor (VWF) binding to platelet GPIbα receptors, causing increased platelet clearance and preferential loss of high molecular weight VWF multimers. Diagnosis is complicated because of significant clinical variations even among patients with identical mutations. Platelet transfusion often provides suboptimal results since transfused platelets may be aggregated by the patients' abnormal VWF. Desmopressin may cause a transient decrease in platelet count that could lead to an increased risk of bleeding. Replacement therapy with factor VIII/VWF concentrates is the most effective approach to prevention and treatment of bleeding in type 2B VWD.

The incidence of esophageal cancer has risen dramatically in the Western world. Although surgical resection of esophageal tumors is considered the cornerstone of curative approaches in localized esophageal cancer, approximately 40% of patients who undergo chemoradiation followed by surgery will experience a recurrence. Additionally, surgical resection is not a viable option for many patients with locally advanced unresectable disease, poor general condition or whose condition deteriorated following chemoradiation. Several investigators have, therefore, attempted to evaluate the outcomes of definitive chemoradiation in patients with localized or locally advanced esophageal cancer. The outcomes of concurrent chemoradiation remain a matter of debate given the heterogenous study design and treatment regimens used in recent trials. Understanding the clinical benefit of chemoradiation is essential prior to recommending it as an alternative to surgery. In our review, we present the most recent studies evaluating the role of chemoradiation to better define the clinical outcomes of patients with special attention to overall survival.

Background: Treatment with nab-paclitaxel with gemcitabine demonstrates a survival advantage when compared with single-agent gemcitabine. However, the combination is associated with significant toxicities, leading to a high rate of drug discontinuation. We implemented a modified regimen of gemcitabine and nab-paclitaxel (mGNabP) in an attempt to minimize toxicities while maintaining efficacy. Methods: A total of 79 evaluable patients with metastatic pancreatic adenocarcinoma (mPC) treated with a modified regimen of gemcitabine (1000 mg/m2) and nab-paclitaxel (125 mg/m2) on days 1, 15 of every 28-day cycle were identified from our prospective database. A total of 57 patients received this regimen as first-line treatment and were evaluated for toxicities, progression-free survival (PFS), and overall survival (OS). Overall, 22 patients with advanced or metastatic PC treated with the modified regimen outside the first-line setting were only evaluated for toxicities. Results: The median OS and PFS were 10 months [95% confidence interval (CI) 5.9–13 months] and 5.4 months (95% CI 4.1–7.4 months) for patients that received the modified regimen as first-line therapy. Neurotoxicity occurred in 27% with only 1.6% of patients experiencing grade ⩾3 toxicity. The incidence of grade ⩾3 neutropenia was 19%, resulting in growth factor support in 12% of patients. This rate was similar in patients who received the modified regimen for first-line treatment of mPC versus the overall group. Conclusions: A modified regimen of biweekly nab-paclitaxel with gemcitabine is associated with a lower cost, acceptable toxicity profile and appears to be relatively effective in pancreatic cancer. Prospective randomized studies confirming its potential benefits compared with standard weekly mGNabP are warranted.

4138 Background: Initial results from the KYT program demonstrated that 27% of PDACs harbor highly actionable molecular alterations (herein labelled “actionable biomarkers”), defined as biomarkers that predict for a high response rate to appropriately targeted tx, in any cancer type. Within this cohort, the median progression-free survival on molecularly-matched tx was 2 months longer than unmatched tx. Here, we present OS data emphasizing the 125 pts with “actionable biomarkers” who did or did not receive molecularly-matched tx. Methods: PanCAN and Perthera have coordinated tumor molecular profiling through commercial labs (NGS/IHC panels) for PDAC pts since 2014. Results are reviewed by a molecular tumor board, and tx options are prioritized based on the actionable biomarkers, in the context of the pt’s tx history. Pts are followed longitudinally to track physician tx choices and survival outcomes. Cox regression was used to assess differences in OS (measured from date of diagnosis until death). Results: Of 1053 pts who received a Perthera Report, 25% had “actionable biomarkers”. OS analyses across 454 pts with adequate tx history are shown in the Table below. Notably, pts with “actionable biomarkers” who received a molecularly-matched tx had a significantly increased OS compared to those with “actionable biomarkers” but who did not receive molecularly-matched tx. Subgroup analyses related to tx history and specific molecular pathways that warrant further investigation will be discussed. Conclusions: When the ~25% of PDAC pts whose tumors harbored “actionable biomarkers” received molecularly-matched tx, they had a better OS. These findings support the need to test all pts with PDAC, and just as importantly, to maximize access to molecularly-matched tx for appropriate pts, to achieve the best pt outcomes. [Table: see text]

191 Background: Up to 17% of PDAs harbor mutations in the DDR pathway. However, the purely prognostic relevance of these mutations is unclear. Furthermore, outcomes in response to platinum-based therapies in PDA pts harboring mutations in a broad range of DDR genes, particularly beyond BRCA1/2 and PALB2, remain unexplored. Methods: We evaluated PDA pts enrolled in the KYT registry for whom we collected cancer related exome sequencing and clinical outcomes. Pts were categorized as resected and advanced (LAPC and metastatic pts), and tumor genomic profiles were categorized as DDR mutated (DDRmut) based on the presence of pathogenic alterations in BRCA1/2, PALB2 (Group 1), ATM, ATR, ATRX (Group 2), or BAP1, BARD1, BRIP1, CHEK1/2, RAD50/51/51B, or FANCA/C/D2/E/F/G/L (Group 3). Tumors harboring no DDR mutations were labelled DDR proficient (pDDR). Median overall survival (OS) was measured from the date of diagnosis until death. Results: The OS was similar in all resected pts, irrespective of exposure to platinum therapy (see Table). However, for the pts with advanced disease, OS was significantly longer for DDRmut vs. pDDR pts, particularly in the platinum-treated group; but no such difference was identified in the platinum-naïve pts. Detailed outcomes for the 3 Groups will be presented, but in general the OS in pts with mutations in all 3 DDRmut Groups was greater than for the pDDR pts; but again this difference was lost in the platinum-naïve pts. Conclusions: Advanced DDRmut pts have an improved OS when treated with platinums, compared to pDDR pts. But, in the absence of platinum-based therapy, there is no OS difference observed in DDRmut vs. pDDR pts, suggesting that DDR status has no pure prognostic value. These findings support the need to test all pts with advanced PDA, to ensure that DDRmut pts are treated with platinum-based therapy. [Table: see text]

SUMMARY RAS proteins belong to the MAPK network, an essential pathway for maintenance of normal vital processes such as proliferation and differentiation. RAS mutations are observed in 30–50% of colorectal carcinomas. The MAPK pathway and RAS proteins are part of a complex system that mediate signaling from the EGF receptors (EGFRs). Our review discusses the most recent evidence highlighting the role of KRAS mutations in patients who are offered anti-EGFR therapy. Furthermore, we discuss emerging evidence of the role of other predictive markers such as PI3K, PTEN, BRAF, NRAS, MET, IGFR-1 and p53 in patients who are receiving anti-EGFR therapy.