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We conducted a multicenter retrospective analysis to evaluate the efficacy of systemic chemotherapy for unresectable combined hepatocellular and cholangiocarcinoma. We enrolled 36 patients with pathologically proven, unresectable combined hepatocellular and cholangiocarcinoma treated with systemic chemotherapy. The log‐rank test determined the significance of each prognostic factor. Elevated alpha‐fetoprotein, carcinoembryonic antigen and carbohydrate antigen 19‐9 levels were observed in 58.3%, 16.7% and 38.9% of patients, respectively. First‐line chemotherapy included platinum‐containing regimens consisting of gemcitabine/cisplatin (n = 12) and fluorouracil/cisplatin (n = 11), sorafenib (n = 5) and others (n = 8). The median overall and progression‐free survival times were 8.9 and 2.8 months, respectively, with an overall response rate of 5.6%. Prognostic factors associated with negative outcomes included poor performance status, no prior primary tumor resection, a Child‐Pugh class of B, and elevated carcinoembryonic antigen levels with a hazard ratio of 2.25, 2.48, 3.25 and 2.84 by univariate analysis, respectively. The median overall survival times of the gemcitabine/cisplatin, fluorouracil/cisplatin, sorafenib and other groups were 11.9, 10.2, 3.5 and 8.1 months, respectively. Multivariate analysis revealed that the overall survival of patients within the sorafenib monotherapy group was poor compared with platinum‐containing regimens (HR: 15.83 [95% CI: 2.25‐111.43], P = .006). All 7 patients in the sorafenib group had progressive disease, including 2 patients with second‐line therapy. In conclusion, the platinum‐containing regimens such as gemcitabine/cisplatin were associated with more favorable outcomes than sorafenib monotherapy for unresectable combined hepatocellular and cholangiocarcinoma. We conducted multicenter retrospective analysis of systemic chemotherapy for unresectable combined hepatocellular and cholangiocarcinoma, because it is a rare type of cancer and only few case series were reported about systemic chemotherapy for the disease. Our results showed platinum‐containing regimen would be favor compared to sorafenib monotherapy and it supported the use of gemcitabine plus cisplatin which is a standard of care for unresectable cholangiocarcinoma.

FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, oxaliplatin) and gemcitabine plus nab-paclitaxel therapy have recently been introduced for the treatment of metastatic pancreatic cancer. Herein, overall treatment outcomes of metastatic pancreatic cancer after introduction of FOLFIRINOX and gemcitabine plus nab-paclitaxel therapy were evaluated, in daily practice. Metastatic pancreatic cancer patients (n=321) who started systemic chemotherapy between January 2011 and December 2016 were included and were divided into two groups: group A (2011-2013) and group B (2014-2016). Treatment outcomes were evaluated retrospectively. Patient characteristics were similar between the two groups except for the rates of distant lymph node metastasis and peritoneal metastasis. The preferred regimens in groups A and B were gemcitabine monotherapy and gemcitabine plus nab-paclitaxel therapy, respectively. The response rates, median progression-free survival, and median overall survival of groups A and B were 7.8% and 28.4% (p<0.01), 3.1 months and 5.4 months (p<0.01), and 6.7 months and 10.2 months (p<0.01), respectively. Overall treatment outcomes for metastatic pancreatic cancer were significantly improved after introduction of FOLFIRINOX and gemcitabine plus nab-paclitaxel combination therapy in daily practice.

BackgroundUGT1A1 *28 and *6 polymorphism is associated with reduced enzyme activity and severe toxicities of irinotecan, especially in patients with homozygous or heterozygous for UGT1A1*28 or *6 polymorphism for both UGT1A1*28 and *6 (double-variant-type of UGT1A1 polymorphism, UGT1A1-DV). FOLFIRINOX is one of the standard treatments for metastatic pancreatic cancer (PC). The optimal dose of irinotecan as a component of the FOLFIRINOX has not been established yet for patients with UGT1A1-DV.Patients and methodsAdvanced PC patients with UGT1A1-DV who had received at least one cycle of FOLFIRINOX from December 2013 to March 2016 were collected retrospectively conducted at multicenter in Japan. We evaluated the patient characteristics, efficacy and safety of FOLFIRINOX and investigate the optimal initial dose of irinotecan in Japanese advanced PC patients with UGT1A1-DV.ResultsA total of 31 patients were enrolled. Grade 4 neutropenia was seen more frequently (67%; 4/6) in patients who had received irinotecan at an initial dose of  ≥ 150 mg/m2 than in those who had received the drug at an initial dose of  ≤ 120 mg/m2 (20%; 5/24). The response rate (RR) and progression-free survival (PFS) in patients given irinotecan of  ≤ 120 mg/m2 were 21.4% and 8.1 months, respectively, which were consistent with previous report for patients without UGT1A1-DV.ConclusionBased on our findings, we recommend that in Japanese advanced PC patients with UGT1A1- DV treated with FOLFIRINOX, irinotecan be administered at an initial dose of  ≤ 120 mg/m2.

In the FUGA-BT trial (JCOG1113), gemcitabine plus S-1 (GS) showed non-inferiority to gemcitabine plus cisplatin (GC) in overall survival (OS) with good tolerance for patients with advanced biliary tract cancer (BTC). We performed a subgroup analysis focused on the elderly cohort of this trial. All 354 enrolled patients in JCOG1113 were classify into two groups; < 75 (non-elderly) and ≥ 75 years (elderly) group. We investigated the influence of age on the safety analysis, including the incidence of chemotherapeutic adverse events and the efficacy analysis, including OS. There were no remarkable differences in OS between the elderly ( n  = 60) and the non-elderly groups ( n  = 294). In the elderly group, median OS was 12.7 and 17.7 months for those who received GC ( n  = 20) and GS ( n  = 40), respectively. The prevalence of all-grade adverse events was similar between the elderly and the non-elderly groups. However, among the elderly group, Grade ≥ 3 hematological adverse events were more frequently observed in the GC arm than in the GS arm. The clinical outcomes of combination chemotherapy in elderly patients with advanced BTC were comparable to non-elderly patients. GS may be the more favorable treatment for elderly patients with advanced BTC.

Introduction A viral breakthrough occurs when a patient achieves a response while on interferon (IFN) therapy and then loses the response despite continued IFN therapy. The cause of viral breakthroughs is not well understood. We encountered three cases with viral breakthrough during treatment with pegylated interferon (PEG-IFN) and ribavirin (RBV). Case presentation The three cases were all late virological responders. They did not express anti-IFN alpha-2b antibodies after PEG-IFN and RBV therapy. We analyzed amino acid substitutions of core 70, core 91, and interferon sensitivity-determining region (ISDR), which significantly influence sustained virological response (SVR). Their amino acid substitutions of core 91 were mutant in two cases. Amino acid substitutions of ISDR were wild pattern in two cases. PEG-IFN adherence was above 80% in three cases, and RBV adherence was below 80% in two cases. Conclusion During PEG-IFN and RBV therapy, we should watch for viral breakthrough in late virological responders with mutant type of amino acid substitutions of core 91, wild pattern of amino acid substitution of ISDR, and decrease of RBV adherence. Viral breakthrough is an important problem in PEG-IFN and RBV therapy for chronic hepatitis C. Therefore, it should be investigated more thoroughly in more cases.

Introduction: A viral breakthrough occurs when a patient achieves a response while on interferon (IFN) therapy and then loses the response despite continued IFN therapy. The cause of viral breakthroughs is not well understood. We encountered three cases with viral breakthrough during treatment with pegylated interferon (PEG-IFN) and ribavirin (RBV). Case presentation: The three cases were all late virological responders. They did not express anti-IFN alpha-2b antibodies after PEG-IFN and RBV therapy. We analyzed amino acid substitutions of core 70, core 91, and interferon sensitivity-determining region (ISDR), which significantly influence sustained virological response (SVR). Their amino acid substitutions of core 91 were mutant in two cases. Amino acid substitutions of ISDR were wild pattern in two cases. PEG-IFN adherence was above 80% in three cases, and RBV adherence was below 80% in two cases. Conclusion: During PEG-IFN and RBV therapy, we should watch for viral breakthrough in late virological responders with mutant type of amino acid substitutions of core 91, wild pattern of amino acid substitution of ISDR, and decrease of RBV adherence. Viral breakthrough is an important problem in PEG-IFN and RBV therapy for chronic hepatitis C. Therefore, it should be investigated more thoroughly in more cases.

Knee osteoarthritis (Knee OA) is an irreversible condition that causes bone deformity and degeneration of the articular cartilage that comprises the joints, resulting in chronic pain and movement disorders. The administration of cultured adipose-derived stem cells (ADSCs) into the knee joint cavity improves the clinical symptoms of Knee OA; however, the effect of synovial fluid (SF) filling the joint cavity on the injected ADSCs remains unclear. In this study, we investigated the effect of adding SF from Knee OA patients to cultured ADSCs prepared for therapeutic use in an environment that mimics the joint cavity. An increase in the viability of ADSCs was observed following the addition of SF. Gene expression profiling of SF-treated ADSCs using DNA microarrays revealed changes in several genes involved in cell survival. Of these genes, we focused on FOSL1, which is involved in the therapeutic effect of ADSCs and the survival and proliferation of cancer stem cells. We confirmed the upregulation of FOSL1 mRNA and protein expression using RT-PCR and western blot analysis, respectively. Next, we knocked down FOSL1 in ADSCs using siRNA and observed a decrease in cell viability, indicating the involvement of FOSL1 in the survival of ADSCs. Interestingly, in the knockdown cells, ADSC viability was also decreased by SF exposure. These results suggest that SF enhances cell viability by upregulating FOSL1 expression in ADSCs. For therapy using cultured ADSCs, the therapeutic effect of ADSCs may be further enhanced if an environment more conducive to the upregulation of FOSL1 expression in ADSCs can be established.