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A major response to pre-hepatectomy chemotherapy has been associated with improved survival in patients who undergo resection of colorectal liver metastases (CRLM). However, the role of tumor biology, as exemplified by overall and codon-specific KRAS mutational status, in predicting response to chemotherapy is not well defined.Pathologic response was characterized as minor or major depending on the percentage of remnant viable cells (50% vs50%, respectively). Multivariable logistic regression was used to identify factors associated with major response.319 patients met inclusion criteria. 229 patients had a KRAS wild-type (wtKRAS) tumor and 90 harbored KRAS mutations (mutKRAS). A major pathologic response was more commonly noted in patients with wtKRAS compared to mutKRAS (48.5% vs 33.3%, P = 0.01) and wtKRAS status remained independently associated with a major response (P = 0.04). On a codon-specific level, major pathologic response occurred less frequently in those with codon 13 mutations (17.7%) compared to those with codon 12 (35.4%), and other KRAS mutations (33.3%). Importantly, codon 13 mutations were independently associated with minor pathologic response (P = 0.023).Patients with wtKRAS tumors appear to have the highest likelihood of experiencing a major response after preoperative chemotherapy. Future studies in "all-comer" cohorts are needed to confirm these findings and further investigate the response of codon 13 mutations.

To evaluate the changing impact of genetic and clinicopathologic factors on conditional overall survival (CS) over time in patients with resectable colorectal liver metastasis.CS estimates account for the changing likelihood of survival over time and may reveal the changing impact of prognostic factors as time accrues from the date of surgery.CS analysis was performed in 1099 patients of an international, multi-institutional cohort. Three-year CS (CS3) estimates at the "xth" year after surgery were calculated as follows: CS3 = CS (x + 3)/CS (x). The standardized difference (d) between CS3 rates was used to estimate the changing prognostic power of selected variables over time. A d0.1 indicated very small differences between groups, 0.1 ≤ d0.3 indicated small differences, 0.3 ≤ d0.5 indicated moderate differences, and d ≥ 0.5 indicated strong differences.According to OS estimates calculated at the time of surgery, the presence of BRAF and KRAS mutations, R1 margin status, resected extrahepatic disease, patient age, primary tumor lymph node metastasis, tumor number, and carcinoembryonic antigen levels independently predicted worse survival. However, when temporal changes in the prognostic impact of these variables were considered using CS3 estimates, BRAF mutation dominated prognosis during the first year (d = 0.48), whereas surgeon-related variables (ie, surgical margin and resected extrahepatic disease) determined prognosis thereafter (d ≥ 0.5). Traditional clinicopathologic factors affected survival constantly, but only to a moderate degree (0.3 ≤ d0.5).The impact of genetic, surgery-related, and clinicopathologic factors on OS and CS3 changed dramatically over time. Specifically, BRAF mutation status dominated prognosis in the first year, whereas positive surgical margins and resected extrahepatic disease determined prognosis thereafter.

Colorectal liver metastases (CRLM) present an important clinical challenge in both surgical and medical oncology. Despite improvements in management, survival among patients undergoing resection of CRLM is still very variable and there is a paucity of clinical trial data and reliable biomarkers that could guide prognostic forecasts, treatment selection, and follow-up. Fortunately, recent advances in molecular biology and tumor sequencing have identified a number of critical genetic loci and proliferation markers that may hold the key to understanding the biologic behavior of CRLM; specifically, mutations of KRAS, BRAF, TP53, PIK3CA, APC, expression of Ki-67, and the presence of microsatellite instability appear to have a decisive impact on prognosis and response to treatment in patients with CRLM. While the applicability of genetic biomarkers in everyday clinical practice remains conditional on the development of inexpensive bedside sequencing, targeted therapies, and the conduct of appropriate clinical trials, the promise of personalized treatment may be closer to realization than ever before.

BACKGROUND: Accurate prediction of prognosis for patients with intrahepatic cholangiocarcinoma (ICC) remains a challenge. We sought to define a preoperative risk tool to predict long-term survival after resection of ICC. STUDY DESIGN: Patients who underwent hepatectomy for ICC at 1 of 16 major hepatobiliary centers between 1990 and 2015 were identified. Clinicopathologic data were analyzed and a prognostic model was developed based on the regression beta-coefficients on data in training set. The model was subsequently assessed using a validation set. RESULTS: Among 538 patients, most patients had a solitary tumor (median tumor number 1; interquartile range 1 to 2) and median tumor size was 5.7 cm (interquartile range 4.0 to 8.0 cm). Median and 5-year overall survival was 39.0 months and 39.0%, respectively. On multivariable analyses, preoperative factors associated with long-term survival included tumor size (hazard ratio [HR] 1.12; 95% CI 1.06 to 1.18), natural logarithm carbohydrate antigen 19-9 level (HR 1.33; 95% CI 1.22 to 1.45), albumin level (HR 0.76; 95% CI 0.55 to 0.99), and neutrophil to lymphocyte ratio (HR 1.05; 95% CI 1.02 to 1.09). A weighted composite prognostic score was constructed based on these factors: [9 + (1.12 x tumor size) + (2.81 x natural logarithm carbohydrate antigen 19-9) + (0.50 x neutrophil to lymphocyte ratio) + (-2.79 x albumin)]. The model demonstrated good performance in the testing (area under the curve 0.696) and validation (0.691) datasets. The model performed better than both the T categories (area under the curve 0.532) and the cumulative stage classifications in the American Joint Committee on Cancer staging manual, 8th edition (area under the curve 0.559). When assessing risk of death within 1 year of operation, a risk score >= 25 had a positive predictive value of 59.8% compared with a positive predictive value of 35.3% for American Joint Committee on Cancer staging manual, 8th edition T4 disease and 31.8% for stage IIIB disease. CONCLUSIONS: Postsurgical long-term outcomes could be predicted using a composite weighted scoring system based on preoperative clinical parameters. The preoperative risk model can be used to inform patient to provider conversations and expectations before operation. (C) 2017 by the American College of Surgeons. Published by Elsevier Inc. All rights reserved.

Background: While several prognostic models have been developed to predict long-term outcomes in resectable intrahepatic cholangiocarcinoma (ICC), their prognostic discrimination remains limited. The addition of tumor markers might improve the prognostic power of the classification schemas proposed by the AJCC 8th edition and the Liver Cancer Study Group of Japan (LCSGJ). Methods: The prognostic discrimination of the AJCC and the LCSGJ were compared before and after the addition of CA 19-9 and CEA, using Harrell's C-index, net reclassification improvement (NRI) and the integrated discrimination improvement (IDI) in an international, multi-institutional cohort. Results: Eight hundred and five surgically treated patients with ICC that met the inclusion criteria were identified. On multivariable analysis, CEA5 ng/mL, 100IU/mL CA 19-9< 500IU/mL and CA 19-9500 IU/mL were associated with worse overall survival. The C-index of the AJCC and the LCSGJ improved from 0.540 to 0.626 and 0.553 to 0.626, respectively following incorporation of CA 19-9 and CEA. The NRI and IDI metrics confirmed the superiority of the modified AJCC and LCSGJ, compared to the original versions. Conclusion: The inclusion of preoperative CA 19-9 and CEA in the AJCC and LCSGJ staging schemas may improve prognostic discrimination among surgically treated patients with ICC. info:eu-repo/semantics/publishedVersion

Non-invasive intraductal papillary mucinous neoplasm (IPMN) with high-grade dysplasia and IPMN-associated invasive pancreatic ductal adenocarcinoma (PDAC) are frequently included under the term "malignancy". The goal of this study is to clarify the difference between these two entities.From 1996 to 2013, data of 616 patients who underwent pancreatic resection for an IPMN were reviewed.The median overall survival for patients with IPMN with high-grade dysplasia (92 months) was similar to survival for patients with IPMN with low/intermediate-grade dysplasia (118 months, p = 0.081), and superior to that of patients with IPMN-associated PDAC (29 months, p 0.001). IPMN-associated PDAC had lymph node metastasis in 53%, perineural invasion in 58%, and vascular invasion in 33%. In contrast, no lymph node metastasis, perineural or vascular invasion was observed with high-grade dysplasia. None of the patients with IPMN with high-grade dysplasia developed recurrence outside the remnant pancreas. In stark contrast 58% of patients with IPMN-associated PDAC recurred outside the remnant pancreas. The rate of progression within the remnant pancreas was significant in patients with IPMN with high-grade (24%) and with low/intermediate dysplasia (22%, p = 0.816).Non-invasive IPMN with high-grade dysplasia should not be considered a malignant entity. Compared to patients with IPMN with low/intermediate-grade dysplasia, those with high-grade dysplasia have an increased risk of subsequent development of PDAC in the remnant pancreas.

Background While previously believed to be mutually exclusive, concomitant mutation of Kirsten rat sarcoma viral oncogene homolog (KRAS)- and V-raf murine sarcoma b-viral oncogene homolog B1 (BRAF)-mutated colorectal carcinoma (CRC), has been described in rare instances and been associated with advanced-stage disease. The present case series is the first to report on the implications of concurrent KRAS/BRAF mutations among surgically treated patients, and the largest set of patients with surgically treated colorectal liver metastasis (CRLM) and data on KRAS/BRAF mutational status thus far described. Case series We present cases from an international, multi-institutional cohort of patients that underwent hepatic resection for CRLM between 2000-2015 at seven tertiary centers. The incidence of KRAS/BRAF mutation in patients with CRLM was 0.5% (4/820). Of these cases, patient 1 (T2N1 primary, G13D/V600E), patient 2 (T3N1 primary, G12V/V600E) and patient 3 (T4N2 primary, G13D/D594N) succumbed to their disease within 485, 236 and 79 days respectively, post-hepatic resection. Patient 4 (T4 primary, G12S/G469S) was alive 416 days after hepatic resection. Conclusion The present case series suggests that the incidence of concomitant KRAS/BRAF mutations in surgical cohorts may be higher than previously hypothesized, and associated with more variable survival outcomes than expected.

Varying definitions of resection margin clearance are currently employed among patients with colorectal cancer liver metastases (CRLM). Specifically, a microscopically positive margin (R1) has alternatively been equated with an involved margin (margin width = 0 mm) or a margin width 1 mm. Consequently, patients with a margin width of 0-1 mm (sub-mm) are inconsistently classified in either the R0 or R1 categories, thus obscuring the prognostic implications of sub-mm margins.Six hundred thirty-three patients who underwent resection of CRLM were identified. Both R1 definitions were alternatively employed and multivariable analysis was used to determine the predictive power of each definition, as well as the prognostic implications of a sub-mm margin.Five hundred thirty-nine (85.2%) patients had a margin width ≥ 1 mm, 42 had a sub-mm margin width, and 52 had an involved margin (0 mm). A margin width ≥ 1 mm was associated with improved survival vs. a sub-mm margin (65 vs. 36 months; P = 0.03) or an involved margin (65 vs. 33 months; P 0.001). No significant difference in survival was detected between patients with involved vs. sub-mm margins (P = 0.31). A sub-mm margin and an involved margin were both independent predictors of worse OS (HR 1.66, 1.04-2.67; P = 0.04, and HR 2.14, 1.46-3.16; P 0.001, respectively) in multivariable analysis. Importantly, after combining the two definitions, patients with either an involved margin or a sub-mm margin were associated with worse OS in multivariable analysis (HR 1.94, 1.41-2.65; P 0.001).Patients with involved or sub-mm margins demonstrated a similar inferior OS vs. patients with a margin width 1 mm. Consequently, a uniform definition of R1 as a margin width 1 mm should perhaps be employed by future studies.

While previously believed to be mutually exclusive, concomitant mutation of Kirsten rat sarcoma viral oncogene homolog (KRAS)- and V-raf murine sarcoma b-viral oncogene homolog B1 (BRAF)-mutated colorectal carcinoma (CRC), has been described in rare instances and been associated with advanced-stage disease. The present case series is the first to report on the implications of concurrent KRAS/BRAF mutations among surgically treated patients, and the largest set of patients with surgically treated colorectal liver metastasis (CRLM) and data on KRAS/BRAF mutational status thus far described.We present cases from an international, multi-institutional cohort of patients that underwent hepatic resection for CRLM between 2000-2015 at seven tertiary centers. The incidence of KRAS/BRAF mutation in patients with CRLM was 0.5% (4/820). Of these cases, patient 1 (T2N1 primary, G13D/V600E), patient 2 (T3N1 primary, G12V/V600E) and patient 3 (T4N2 primary, G13D/D594N) succumbed to their disease within 485, 236 and 79 days respectively, post-hepatic resection. Patient 4 (T4 primary, G12S/G469S) was alive 416 days after hepatic resection.The present case series suggests that the incidence of concomitant KRAS/BRAF mutations in surgical cohorts may be higher than previously hypothesized, and associated with more variable survival outcomes than expected.

Severe reflux-induced esophagitis is a condition characterized by esophageal inflammation caused by acid and biliary reflux. The process leads to different degrees of esophageal damage with respective clinical presentations, which range from acute pain and severe debilitating dysphagia to life-threatening adenocarcinoma. Early intervention is essential in order to avoid irreversible damage, and since symptoms alone are not always reliable to identify progression of disease, it is important to monitor patients with predisposing risk factors. Depending on the severity of the disease, several options for treatment are available, ranging from medication to endoscopic and surgical therapy.