Search

Background: Biliary tract cancers, which arise from the intrahepatic or extrahepatic bile ducts and the gallbladder, generally have a poor prognosis and are rising in incidence worldwide. The standard-of-care treatment for advanced biliary tract cancer is chemotherapy with gemcitabine and cisplatin. Because most biliary tract cancers have an immune-suppressed microenvironment, immune checkpoint inhibitor monotherapy is associated with a low objective response rate. We aimed to assess whether adding the immune checkpoint inhibitor pembrolizumab to gemcitabine and cisplatin would improve outcomes compared with gemcitabine and cisplatin alone in patients with advanced biliary tract cancer. Methods: KEYNOTE-966 was a randomised, double-blind, placebo-controlled, phase 3 trial done at 175 medical centres globally. Eligible participants were aged 18 years or older; had previously untreated, unresectable, locally advanced or metastatic biliary tract cancer; had disease measurable per Response Evaluation Criteria in Solid Tumours version 1.1; and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Eligible participants were randomly assigned (1:1) to pembrolizumab 200 mg or placebo, both administered intravenously every 3 weeks (maximum 35 cycles), in combination with gemcitabine (1000 mg/m2 intravenously on days 1 and 8 every 3 weeks; no maximum duration) and cisplatin (25 mg/m2 intravenously on days 1 and 8 every 3 weeks; maximum 8 cycles). Randomisation was done using a central interactive voice-response system and stratified by geographical region, disease stage, and site of origin in block sizes of four. The primary endpoint of overall survival was evaluated in the intention-to-treat population. The secondary endpoint of safety was evaluated in the as-treated population. This study is registered at ClinicalTrials.gov, NCT04003636. Findings: Between Oct 4, 2019, and June 8, 2021, 1564 patients were screened for eligibility, 1069 of whom were randomly assigned to pembrolizumab plus gemcitabine and cisplatin (pembrolizumab group; n=533) or placebo plus gemcitabine and cisplatin (placebo group; n=536). Median study follow-up at final analysis was 25·6 months (IQR 21·7–30·4). Median overall survival was 12·7 months (95% CI 11·5–13·6) in the pembrolizumab group versus 10·9 months (9·9–11·6) in the placebo group (hazard ratio 0·83 [95% CI 0·72–0·95]; one-sided p=0·0034 [significance threshold, p=0·0200]). In the as-treated population, the maximum adverse event grade was 3 to 4 in 420 (79%) of 529 participants in the pembrolizumab group and 400 (75%) of 534 in the placebo group; 369 (70%) participants in the pembrolizumab group and 367 (69%) in the placebo group had treatment-related adverse events with a maximum grade of 3 to 4. 31 (6%) participants in the pembrolizumab group and 49 (9%) in the placebo group died due to adverse events, including eight (2%) in the pembrolizumab group and three (1%) in the placebo group who died due to treatment-related adverse events. Interpretation: Based on a statistically significant, clinically meaningful improvement in overall survival compared with gemcitabine and cisplatin without any new safety signals, pembrolizumab plus gemcitabine and cisplatin could be a new treatment option for patients with previously untreated metastatic or unresectable biliary tract cancer. Funding: Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA.

Simple Summary The most prevalent type of hereditary colorectal cancer is called Lynch syndrome and it is characterized by a tumor phenotype called microsatellite instability (MSI). This disease is a consequence of germline (inheritable) variants in any of the four mismatch repair (MMR) DNA genes, being their identification essential to ensure their appropriate diagnosis and implementation of preventive measurements. Nevertheless, only 50% of patients with MSI and suspected Lynch syndrome actually carry a germline pathogenic variant in an MMR gene that explains the clinical entity. The remaining 50% are termed Lynch-like syndrome, and their causes remain unknown. In this work, we tried to elucidate the molecular mechanisms that underlie this rare entity in a group of early-onset Lynch-like syndrome colorectal cancer, through whole-exome sequencing of germline and tumor samples. We observed that one-third of these patients have somatic alterations in genes associated with the MMR system and that these could be the mechanism causing their unexplained MSI. Furthermore, we found that patients who showed biallelic somatic alterations also carried germline variants in new candidate genes associated with DNA repair functions and that this could be, partly, the cause of the early onset in this cohort. Abstract Lynch-like syndrome (LLS) is an increasingly common clinical challenge with an underlying molecular basis mostly unknown. To shed light onto it, we focused on a very young LLS early-onset colorectal cancer (CRC) cohort (diagnosis ≤ 40 y.o.), performing germline and tumor whole-exome sequencing (WES) of 15 patients, and additionally analyzing their corresponding tumor mutational burden (TMB) and mutational signatures. We identified four cases (27%) with double somatic putative variants in mismatch repair (MMR) core genes, as well as three additional cases (20%) with double MSH3 somatic alterations in tumors with unexplained MSH2/MSH6 loss of expression, and two cases (13%) with POLD1 potential biallelic alterations. Average TMB was significantly higher for LLS cases with double somatic alterations. Lastly, nine predicted deleterious variants in genes involved in the DNA repair functions and/or previously associated with CRC were found in nine probands, four of which also showed MMR biallelic somatic inactivation. In conclusion, we contribute new insights into LLS CRC, postulating MSH3 and POLD1 double somatic alterations as an underlying cause of a microsatellite instability (MSI) phenotype, proposing intrinsic biological differences between LLS with and without somatic alterations, and suggesting new predisposing candidate genes in this scenario.

Early-onset (

Muscle function and its correlation with body composition and weight loss have not been studied deeply in pancreas and gastrointestinal cancers. This research aims to determine the skeletal muscle function and its relationship with body compartments, significant weight loss, and performance status (ECOG) 0-2 in a population with advanced digestive cancers. A cross-sectional study was designed to determine the relationship between muscular function, weight loss, and body composition. Patients with advanced digestive adenocarcinomas were evaluated. Muscle strength was examined by hand grip technique and body composition by bioimpedance analysis. Values of hemoglobin and albumin were measured in plasma. A sample of 81 patients was included. They had adenocarcinoma of stomach (n = 9), pancreas (n = 28), or colorectum (n = 44). With regard to skeletal muscle function, sub-maximal strength increased when percentage of weight loss decreased (p = 0.002) or when any of the following variables increased: skeletal muscle (p

Pancreatic cancer is a malignancy of great impact in developed countries and is having an increasing impact in Latin America. Incidence and mortality rates are similar for this cancer. This is an important reason to offer to the patients the best treatments available. During the Latin American Symposium of Gastroenterology Oncology (SLAGO) held in Viña del Mar, Chile, in April 2015, a multidisciplinary group of specialists in the field met to discuss about this disease. The main conclusions of this meeting, where practitioners from most of Latin American countries participated, are listed in this consensus that seek to serve as a guide for better decision making for patients with pancreatic cancer in Latin America.

Introduction : diabetes mellitus (DM) is considered to be a risk factor for the development of pancreatic ductal adenocarcinoma (PDAC). Objectives : describe the prevalence of DM and of impaired fasting glucose (IFG) at the diagnosis of PDAC, among patients assisted in a gastroenterological reference center. Analyze differences in personal and nutritional characteristics in patients with both PDAC and DM; with both PDAC and IFG; and with PDAC but neither DM nor IFG. Determine the time lapse between the diagnosis of DM and the diagnosis of PDAC. Materials and methods : between October 2019 and March 2020, we analyzed 465 clinical records of PDAC-diagnosed patients over 18 years, from Oncology and Nutrition Sections. Results : 171 clinical records (36.7%) showed both PDAC and DM; 294 clinical records (63.2%) showed PDAC but not DM. In 45.1% of the former, the interval between the diagnosis of DM and that of PDAC was 10 years, respectively.

El adenocarcinoma de páncreas (CP) es una enfermedad altamente desafiante con una tasa de supervivencia a 5 años de menos del 5%. Aunque la mayoría de los pacientes presentan enfermedad avanzada, los mejores resultados se observan en aquellos sometidos a resección de su tumor primario en centros especializados. Se considera resecable al diagnóstico; en el 15% de los casos y con tratamiento adyuvante (TA) determina una supervivencia mediana de 24 a 28 meses. El objetivo fue conocer la evolución oncológica de los mismos. El estudio es retrospectivo, observacional y multicéntrico. Se evaluaron pacientes incluidos en la plataforma virtual RITA (Registro Institucional de Tumores de Argentina) diseñada por el Instituto Nacional del Cáncer para tumores hepato-hilio-pancreáticos entre el 1/06/13 y el 31/07/16 con diagnóstico de CP tratados con cirugía seguido de algún TA, que asistieron a los centros participantes. De un total de 337 pacientes, 50 fueron sometidos a cirugía seguida de TA. El 48% fueron hombres. La edad media fue de 60 años. El 90% (45) presentó un PS 0/1 y el 98% adenocarcinoma. Se destaca que el 70% (35) presentó estadio II, seguido del 18% (9) con estadio I. El 70% (35) fue tratado con esquema de quimioterapia adyuvante. La mediana de supervivencia fue 27.3 meses. A pesar de las limitaciones en el número de la muestra, la heterogeneidad en los tratamientos y el análisis retrospectivo, los resultados finales de nuestro estudio son similares a los datos de la literatura.

Early-onset (50 years-old) nonpolyposis nonfamilial colorectal cancer (EO NP NF CRC) is a common clinical challenge. Although Lynch syndrome (LS) is associated with EO CRC, the frequency of this syndrome in the EO NF cases remains unknown. Besides, mismatch repair deficient (MMRd) CRCs with negative MMR gene testing have recently been described in up to 60% of cases and termed "Lynch-like syndrome" (LLS). Management and counseling decisions of these patients are complicated because of unconfirmed suspicions of hereditary cancer. To define the prevalence of MMR deficient CRCs, LS and LLS in patients with EO NP NF CRC, we recruited 102 patients with a first diagnosis of NP NF CRC ≤ 50 years old during 2003-2009 who underwent genetic counseling at our institution in Argentina. Tumor immunohistochemical (IHC) MMR for protein expression and microsatellite instability (MSI) status were evaluated, and in those with loss of MLH1 expression by IHC, somatic BRAF V600E mutation and both somatic and germline MLH1 methylation levels were studied. Tumors characterized as MMRd without somatic BRAF mutation nor MLH1 methylation were sent for germline analysis. Twenty one (20.6%) tumors were MMRd. Fourteen of 16 putative LS cases underwent germline testing: 6 pathogenic mutations were identified and 8 cases had no identifiable pathogenic mutations. The prevalence of LS and LLS in this cohort was 5.8% (6/102) and 7.8% (8/102), respectively. As a conclusion we found that 20% of patients with EO NP NF CRC have MMRd tumors, and at least half of these are likely to have LLS.

Your article is protected by copyright and allrights are held exclusively by Springer Science+Business Media New York. This e-offprint isfor personal use only and shall not be self-archived in electronic repositories. If you wishto self-archive your article, please use theaccepted manuscript version for posting onyour own website. You may further depositthe accepted manuscript version in anyrepository, provided it is only made publiclyavailable 12 months after official publicationor later and provided acknowledgement isgiven to the original source of publicationand a link is inserted to the published articleon Springer's website. The link must beaccompanied by the following text: "The finalpublication is available at link.springer.com”.

Pancreatic cancer is a malignancy of great impact in developed countries and is having an increasing impact in Latin America. Incidence and mortality rates are similar for this cancer. This is an important reason to offer to the patients the best treatments available. During the Latin American Symposium of Gastroenterology Oncology (SLAGO) held in Vina del Mar, Chile, in April 2015, a multidisciplinary group of specialists in the field met to discuss about this disease. The main conclusions of this meeting, where practitioners from most of Latin American countries participated, are listed in this consensus that seek to serve as a guide for better decision making for patients with pancreatic cancer in Latin America.

3561 Background: Controversies exist about the proper management of pts with clinical complete tumor regression after preoperative therapy. A non-operative management (NOM) of selected patients has...

Introduction Recent studies have outlined an increase in the incidence rates of rectal cancer among adults aged 50 and younger, a group for whom average-risk screening is not a standard of care. Controversies still exist regarding its features and prognosis. Methods Between February-2007 and December-2011, 578 rectal cancer pts were registered and discussed in our multidisciplinary team “Co-Recto”. A retrospective cohort analysis was performed in a subset of adults aged ≤50 years, focusing on clinical and demographic parameters, preoperative assessment, therapeutic approach, tumor response and pattern of disease recurrence. Results 140/578 (24.2%) pts were aged between 18-50 years, of whom 82 (58%) were identified as being aged ≤40 at presentation. Median age was 37 years, 73/140 (52%) were female. Only 35/140 (25%) had medical insurance. The mean time from symptoms onset to diagnosis was 6 months (1-34 months). The most frequent tumor location was lower rectum: 74/140 (53%). Median distance from the anal verge was 50 mm (10–150 mm). Levator muscle - external anal sphincter were involved in 26/140 pts (18%). 26/140 (18%) tumors were single-ring cells- mucinous adenocarcinoma. Regarding colorectal cancer high-risk conditions, 9/140 (6.5%) pts had familial adenomatous polyposis and 8/140 (6%) had inflammatory bowel disease. Lynch syndrome was assessed in 23/140 (16%) pts with microsatellite instability (MSI) analysis and/or immunohistochemistry (IHQ) analysis of mismatch repair (MMR) proteins MLH1, MSH2, MSH6 and PMS2. 22/23 (96%) pts had MMR proficient tumors; in 1/23 pts (4%) a germinal mutation in PMS2 was identified (Lynch syndrome). 10/23 pts were also screened for the two most prevalent MUTYH mutations: G393D and Y176C, identifying biallelic MUTYH mutations in 1 case. 19/140 (13.5%) pts had already undergone elective surgery before discussion in “Co-Recto”, and 121/140 (86.5%) were assessed preoperatively in “Co-Recto” to decide the best therapeutic approach. Clinical staging at diagnosis was I: 6(5%), II 18(15%), III 66(54%) and IV: 31(26%). A curative intent therapeutic approach was done in 90/121 (74%). Neoadjuvant treatment was delivered in 61/90 (68%): induction chemotherapy 49/61 (80%), chemoradiotherapy mostly based on capecitabine 58/61 (95%), and chemotherapy alone followed by TME surgery 3/61 (5%). 2/61 pts with clinical complete response by MRI were considered for a watch and wait strategy, pathological complete response rate was 19% (11/59). After a median follow up of 23 months (2-54m), the recurrence rate was: local 2/61 (3.2%), distant 4/61 (6.5%), and both (1/61). Conclusion In our experience, young-onset rectal cancer frequently presents with locally advanced and/or metastatic disease, requiring more aggressive treatments. Distant relapses often occur. Known hereditary syndromes seem to have a low prevalence. We highlight the challenge of reviewing current screening strategies to warrant a proper and early diagnosis in young patients.

e14521 Background: Thestandard treatment for biliary tract cancer is gemcitabine plus platinum, but median progression-free survival (PFS) is only 5-8 months (m) (Valle et al, NEJM 2010). Gene expression or somatic mutations may influence the clinical phenotype, which will affect decisions on individualized treatment. Methods: We retrospectively analyzed tissue blocks from 54 advanced or metastatic cholangiocarcinoma, gallbladder or ampulllary cancer patients (p) treated with single-agent gemcitabine or gemcitabine plus carboplatin or cisplatin. Using RT-PCR, we analyzed the mRNA expression levels of oncogenes, tumor suppressors and DNA repair genes (BRCA1, RRM1, AEG-1, RAP80, SPINK1 and FBXW7) and correlated results with PFS, overall survival (OS) and response. In addition, FBXW7 hotspot mutations were assessed. Results: p characteristics: 72% females; median age, 60 (40-87). Only FBXW7 expression correlated with PFS and OS. When FBXW7 levels were dichotomized at the median value, PFS was 4.2 m for p with low levels vs 12.6 m for p with high levels (p=0.02). When FBXW7 expression was divided by terciles, PFS was 4.9 m for p in the lowest tercile, 7.6 for p in the intermediate tercile, and 26.9 m for p in the highest tercile (p=0.08). OS was 6.2 m for p in the lowest tercile, 8 m for p in the intermediate tercile, and not reached for p in the highest tercile. No other significant correlation was observed between expression levels of the other genes examined and PFS or OS. Only AEG-1 expression correlated with response (p=0.05). No FBXW7 hotspot mutations were detected. Conclusions: Although we did not find the FBXW7 hotspot mutations previously described in biliary tract cancer, FBXW7 mRNA expression significantly influenced PFS and OS. A separate cohort of p is being analyzed to validate the prognostic role of FBXW7.