The combination chemotherapy consisting of cisplatin and etoposide, one of the standard regimens for small cell lung cancer, has been widely used to treat extrapulmonary poorly differentiated neuroendocrine carcinomas. However, there were no prior reports limited to the hepatobiliary tract and pancreas as the primary sites. We reviewed the cases in our database from October 1995 to January 2009 and retrospectively examined the clinical data of patients, with unresectable or recurrent poorly differentiated neuroendocrine carcinoma arising from the hepatobiliary tract and pancreas, who received combination chemotherapy with cisplatin and etoposide as the first-line treatment. The chemotherapy regimen consisted of cisplatin 80 mg/m² given intravenously on day 1 and etoposide 100 mg/m² intravenously on days 1–3, repeated every 3–4 weeks. Twenty-one patients were treated with the above regimen of cisplatin and etoposide combination chemotherapy. The primary tumor site was the liver in 2 patients, gallbladder in 8 patients, pancreas in 10 patients and ampulla of Vater in 1 patient. Although no complete responses were obtained, three patients had partial responses, resulting in an overall response rate of 14%. Median progression-free survival was 1.8 months, and median overall survival was 5.8 months. The major adverse events were myelosuppression and gastrointestinal toxicities, with Grade 3 or 4 neutropenia (90%), nausea (33%) and anorexia (24%). Cisplatin and etoposide combination as the first-line chemotherapy for hepatobiliary or pancreatic poorly differentiated neuroendocrine carcinoma had only marginal antitumor activity and relatively severe toxicity compared with previous studies on extrapulmonary poorly differentiated neuroendocrine carcinoma treated with the same regimen.

An open-labeled, dose-escalation phase 1 trial of Wilms tumor 1 (WT1) vaccine and gemcitabine (GEM) combination therapy for patients with advanced pancreatic cancer or biliary tract cancer was performed. The primary end point was evaluation of toxicity, safety, and optimal immunologic dose of vaccine. Human leukocyte antigen (HLA)-A 0201, HLA-A 0206, and/or HLA-A 2402-positive patients with inoperable advanced pancreatic or biliary tract cancer who had not previously been treated with GEM were eligible for this study. Six doses of GEM and 4 doses of WT1 peptide (1 or 3 mg) emulsified in Montanide adjuvant were administered over 2 months. Twenty-five patients (13 male and 12 female) were enrolled. Nine patients had inoperable advanced pancreatic cancer, 8 had gallbladder cancer, 4 had intrahepatic, and 4 had extrahepatic bile duct cancer. The adverse events were comparable to those with GEM alone. Delayed-type hypersensitivity test was positive after vaccination in 2 patients, and WT1-specific T cells in peptide-stimulated culture were detected by tetramer assay in 59% (13 of 22) of patients. The disease control rate at 2 months was 89% for pancreatic cancer and 50% for biliary tract cancer. With a median follow-up time of 259 days, the median survival time for biliary tract cancer was 288 days, and that for pancreatic cancer was 259 days. Although objective clinical efficacy was not apparent, the safety of WT1 vaccine and GEM combination therapy was confirmed in this study.

Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer deaths worldwide. The high mortality rate in HCC is largely due to the difficulty of early detection. In this study, to improve patient outcomes, serum samples from 345 patients with HCC, 46 patients with chronic hepatitis (CH), 93 patients with liver cirrhosis (LC), and 1,033 healthy individuals were analyzed with microRNA (miRNA) microarrays. We investigated the diagnostic potential of circulating miRNAs in serum and developed a detection model of HCC, including early stage. A diagnostic model was constructed based on the expression levels of a combination of miRNAs in a discovery set. We selected 52 miRNAs that had altered expressions according to disease progression status, established the diagnostic model with a combination of eight miRNAs in the discovery set, and tested the model in a validation set. The diagnostic values for discriminating cancer from HCC at‐risk control samples were as follows: area under the curve, 0.99; sensitivity, 97.7%; specificity, 94.7%. With this model, 98% of stage I HCC cases were detected; these results were much better than those observed from conventional methods. Conclusion: Circulating miRNAs could serve as biomarkers for the accurate detection of HCC. Because the diagnostic accuracy was maintained even in stage I, this may represent an accurate detection method even for early stage HCC.

KRAS, CDKN2A, TP53, and SMAD4 have been recognized as major driver genes in pancreatic carcinogenesis. We examined somatic mutations in 50 cancer-related genes, including the four above-mentioned driver genes, to identify genomic biomarkers for predicting the outcome of patients with pancreatic cancer. Genomic DNA was extracted from fresh-frozen specimens obtained from 100 patients with pancreatic cancer who had undergone a pancreatectomy with curative intent. The mutation profile was obtained using a single targeted deep sequencing assay performed with a next-generation sequencer, and the associations with clinicopathological factors were analyzed. Mutations in the KRAS, CDKN2A, TP53, and SMAD4 genes were detected in 96% (96/100), 42% (42/100), 13% (13/100), and 7% (7/100) of all patients, respectively. Among the 71 patients who underwent a radical operation followed by adjuvant chemotherapy, patients with fewer mutations among the four driver genes tended to have a better outcome. A multivariate analysis using the Cox proportional hazard model showed that the presence of 0 to 2 mutated driver genes was an independent predictor of a better overall survival (hazard ratio for death, 0.20; P = 0.0040). The number of mutated driver genes assessed using a targeted deep sequencing assay was a promising prognostic biomarker for pancreatic cancer.