Through exomic sequencing of 32 intrahepatic cholangiocarcinomas, we discovered frequent inactivating mutations in multiple chromatin-remodeling genes (including BAP1, ARID1A and PBRM1), and mutation in one of these genes occurred in almost half of the carcinomas sequenced. We also identified frequent mutations at previously reported hotspots in the IDH1 and IDH2 genes encoding metabolic enzymes in intrahepatic cholangiocarcinomas. In contrast, TP53 was the most frequently altered gene in a series of nine gallbladder carcinomas. These discoveries highlight the key role of dysregulated chromatin remodeling in intrahepatic cholangiocarcinomas.

The American Joint Committee on Cancer (AJCC) Staging Manual represents the standard for classifying patients with pancreas and hepatobiliary cancers, predicting prognosis, and guiding treatment decisions. For the new 8th edition, the AJCC Hepatobiliary Task Force, a multidisciplinary team of international experts, conducted two face-to-face meetings. At the first meeting, specialists in individual disease sites presented analysis of the literature and reviewed questions and issues from the 7th edition. Recommendations for revisions were proposed and discussed. At the second meeting, additional data to support the proposed revisions were reviewed, and revisions were approved by the full task force, including representatives from the Union for International Cancer Control (UICC) and the AJCC Editorial Board. Chapters were submitted to the Editorial Board for editing and final approval.The cornerstone of staging of hepatobiliary cancers is high-quality surgery, detailed pathologic analysis, and reliable follow-up, which are not available from large datasets and registries. Owing to the relative rarity of hepatobiliary cancers and the complex anatomy, often requiring technically demanding surgery, the AJCC staging system is largely based on single-institution series from centers of excellence in surgery and pathology. Much of the evidence that forms the basis for the revised 8th edition has been validated at other centers of excellence in hepatobiliary cancer. Importantly, the revisions also drew heavily on international expertise, particularly from Asia, where the incidence of hepatobiliary cancers is high.For the 8th edition, the N category has been harmonized for gallbladder, perihilar bile ducts, distal bile duct, ampulla, and pancreas. For these disease sites, N1 is defined as one to three metastatic lymph nodes, and N2 as four or more metastatic lymph nodes. A number-based categorization of metastatic lymph nodes results in better prognostic stratification.

BACKGROUNDThis phase 2 multi-institutional study was designed to determine whether gemcitabine (GEM) with fractionated stereotactic body radiotherapy (SBRT) results in acceptable late grade 2 to 4 gastrointestinal toxicity when compared with a prior trial of GEM with single-fraction SBRT in patients with locally advanced pancreatic cancer (LAPC).METHODSA total of 49 patients with LAPC received up to 3 doses of GEM (1000 mg/m2) followed by a 1-week break and SBRT (33.0 gray [Gy] in 5 fractions). After SBRT, patients continued to receive GEM until disease progression or toxicity. Toxicity was assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0] and the Radiation Therapy Oncology Group radiation morbidity scoring criteria. Patients completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30) and pancreatic cancer-specific QLQ-PAN26 module before SBRT and at 4 weeks and 4 months after SBRT.RESULTSThe median follow-up was 13.9 months (range, 3.9–45.2 months). The median age of the patients was 67 years and 84% had tumors of the pancreatic head. Rates of acute and late (primary endpoint) grade ≥2 gastritis, fistula, enteritis, or ulcer toxicities were 2% and 11%, respectively. QLQ-C30 global quality of life scores remained stable from baseline to after SBRT (67 at baseline, median change of 0 at both follow-ups; P>.05 for both). Patients reported a significant improvement in pancreatic pain (P =.001) 4 weeks after SBRT on the QLQ-PAN26 questionnaire. The median plasma carbohydrate antigen 19-9 (CA 19-9) level was reduced after SBRT (median time after SBRT, 4.2 weeks; 220 U/mL vs 62 U/mL [P<.001]). The median overall survival was 13.9 months (95% confidence interval, 10.2 months-16.7 months). Freedom from local disease progression at 1 year was 78%. Four patients (8%) underwent margin-negative and lymph node-negative surgical resections.CONCLUSIONSFractionated SBRT with GEM results in minimal acute and late gastrointestinal toxicity. Future studies should incorporate SBRT with more aggressive multiagent chemotherapy.

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