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Major hepatectomy (MH) may produce the impaired liver function and affect the feasibility of adjuvant chemotherapy in terms of early period after the surgery, but there have not been detailed investigations. JCOG1202 (UMIN000011688) is a randomized phase III trial demonstrating the superiority of adjuvant S-1 chemotherapy for biliary tract cancer (BTC). The aim of this study is to examine the influence of MH for BTC on adjuvant S-1. Of the total 424 patients, 207 received S-1 (S-1 arm) while the remaining 217 were not. We compared MH with non-major hepatectomy (NMH) for BTC. In the S-1 arm, 42 had undergone MH, and 165 had undergone NMH. MH had similar pretreatment features to NMH, including the proportion of biliary reconstruction, to NMH, except for a lower platelet count (17.7 vs. 23.4 × 104/mm3, p < 0.0001) and lower serum albumin level (3.5 vs. 3.8 g/dL, p < 0.0001). The treatment completion proportion tended to be lower for MH than for NMH (59.5 % vs. 75.8 %; risk ratio, 0.786 [95 % confidence interval, 0.603–1.023], p = 0.0733), and the median dose intensity was lower as well (88.7 % vs. 99.6 %, p = 0.0358). The major reasons for discontinuation were biliary tract infections and gastrointestinal disorders after MH. The frequency of grade 3–4 biliary tract infection was 19.0 % in MH vs. 4.2 % in NMH. The treatment completion proportion and dose intensity were lower in MH than in NMH. Caution should be exercised against biliary tract infections and gastrointestinal disorders during adjuvant S-1 after MH for BTC. Major hepatectomy for biliary tract cancer may be associated with an impaired postoperative liver function, which can influence the feasibility of adjuvant chemotherapy. Our exploratory subset analysis using the data set of JCOG1202, which clarified the efficacy of S-1 adjuvant chemotherapy, showed higher discontinuation and/or dose reduction after major hepatectomy. [ABSTRACT FROM AUTHOR]

Background/purpose: Complications from biliary drainage in biliary tract cancer (BTC) may influence the relative dose intensity of chemotherapy or increase adverse events during chemotherapy. BT22 was a randomized phase II trial, the results of which were consistent with those of a phase III trial in non-Japanese that demonstrated the effectiveness of gemcitabine plus cisplatin combination therapy (GC) in BTC. The purpose of this exploratory analysis of the BT22 study was to identify the possible effects of biliary drainage on the efficacy and safety of GC or gemcitabine monotherapy (G). Patients and Methods: The 83 BTC patients who received GC or G in BT22 were retrospectively analysed in two subgroups dependent upon whether biliary drainage was performed before study entry. Efficacy and safety of treatment (GC vs. G) were compared in these two groups. Results: The GC arm had a higher 1-year survival rate and longer median survival time (MST) than the G arm independent of prior biliary drainage. Patients in the drainage subgroup developed cholangitis more frequently, however, the frequency of grade 3/4 adverse events did not differ between the treatment regimens with/without drainage. Conclusions: Biliary drainage before chemotherapy did not affect the therapeutic efficacy or tolerability of chemotherapy using G or GC. [ABSTRACT FROM AUTHOR]

Abstract: There had been no standard chemotherapy established for advanced biliary tract cancer (BTC) until 2009, when the combination of cisplatin and gemcitabine (GC) was adopted as a first line standard chemotherapy option based on the results from two randomized studies: ABC-02, a UK investigator-initiated trial and the largest randomized phase III study in this tumor type with 410 patients; and BT22, a Japanese, industry-sponsored, randomized phase II study with 83 patients. In this review, investigators from both studies collaborated to compare protocols, patient characteristics, and outcomes of both studies including sub-analyses of study results. Although both studies showed GC combination therapy to be more effective than monotherapy, a detailed comparison revealed disparities between efficacy and safety end-points between the studies, which did not necessarily arise from different populations but from differences in protocol design. This review provides clinicians with insights for advanced BTC clinical study design and interpretation of historical studies. [Copyright &y& Elsevier]

Abstract: Despite various effective local treatments for hepatocellular carcinoma (HCC), some patients do not meet the treatment criteria because of extrahepatic metastases or macroscopic vascular invasion at the time of their diagnosis. Furthermore, many patients treated with successful local treatments develop recurrences after treatment. Although these patients receive systemic treatment including chemotherapy, HCC is generally recognized as a chemo-resistant tumor. Recently, new molecular targets have been confirmed and various targeted agents are now being investigated for the treatment of HCC. Epidermal growth factor receptor (EGFR) is frequently expressed in human hepatoma cells, and EGF may be one of the mitogens that are needed for the growth of hepatoma cells. HCC is generally hypervascular, and vascular endothelial growth factor (VEGF) promotes HCC development and metastasis. Various inhibitors targeting EGFR and/or VEGF, VEGF receptor (VEGFR) have been developed as treatments of HCC. In phase-II studies of these growth factor inhibitors, the response rates are relatively low; however, high rates of disease control, enabling a good time to progression, have been achieved. Recently, a randomized phase III trial of sorafenib versus placebo conducted in patients with advanced HCC demonstrated the beneficial effects of this drug on the time-to-progression and overall survival of the patients, and the drug could become established as the standard chemotherapeutic agent for advanced HCC. Further clinical trials using biologic agents are warranted to prolong the survival in HCC patients. [Copyright &y& Elsevier]

A 70-year-old male was admitted to hospital for a liver tumor. We diagnosed that hepatocellular carcinoma (HCC), 1.5 cm in diameter, by several examinations. We performed ultrasonically guided radio-frequency ablation (RFA). Ultrasonography (US) 9 days post-therapy revealed a cystic lesion 1.5 cm in diameter. Color Doppler US revealed color imaging throughout the lesion and dynamic computed tomography (CT) demonstrated an area of hyperattenuation. Intrahepatic pseudoaneurysm was diagnosed. On 14 days post-therapy, no color signals on color Doppler US or enhanced areas on CT were seen. We submit that pseudoaneurysm should be recognized as a complication of radio-frequency ablation. [Copyright &y& Elsevier]

This phase 1b trial evaluated the toxicity and efficacy of S-1, irinotecan, and oxaliplatin combination therapy (S-IROX) as first-line chemotherapy in patients with advanced pancreatic cancer (APC). Patients aged 20–75 years with APC and an Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible to receive escalating doses of S-1 (60 or 80 mg m2·day) on days 1–7, fixed doses of oxaliplatin (85 mg/m2) biweekly, and escalating doses of irinotecan (150, 165, or 180 mg/m2) once every 2 weeks. In the dose-escalation cohort, a 3 + 3 design was used to determine the maximum-tolerated dose (MTD) and explore the recommended dose (RD). A dose-expansion cohort was added to further evaluate the safety and efficacy of the combination. This trial was registered at UMIN-CTR (UMIN000012054). Approximately 47 patients were enrolled, of whom 45 were eligible for the analysis. The MTD was not determined, but the RD was determined to be dose level 1 based on a review of data from each level. Among the 45 patients, the ORR was 51.1% [95% confidence interval (CI), 35.8–66.3%]. The median progression-free survival and median overall survival was 6.9 months (95% CI, 5.1–8.8 months) and 15.8 months (95% CI, 9.8–20.8 months), respectively. Common adverse events included neutropenia, elevated liver enzyme levels, diarrhoea, and nausea. The S-IROX regimen showed promising efficacy with manageable toxicities in Japanese patients with APC. A randomised phase 2/3 trial comparing S-IROX, mFOLFIRINOX, and gemcitabine plus nab-paclitaxel is currently ongoing (jRCTs031190009). • Phase 1b trial of S-1, irinotecan, and oxaliplatin in pancreatic cancer. • The RD was S-1 80 mg/m2, irinotecan 150 mg/m2, and oxaliplatin 85 mg/m2. • The ORR was 51.1%, and PFS and OS were better than those of the historical FOLFIRINOX. [ABSTRACT FROM AUTHOR]

Background: Single-agent nivolumab showed durable responses, manageable safety, and promising survival in patients with advanced hepatocellular carcinoma in the phase 1-2 CheckMate 040 study. We aimed to investigate nivolumab monotherapy compared with sorafenib monotherapy in the first-line setting for patients with advanced hepatocellular carcinoma.Methods: In this randomised, open-label, phase 3 trial done at medical centres across 22 countries and territories in Asia, Australasia, Europe, and North America, patients at least 18 years old with histologically confirmed advanced hepatocellular carcinoma not eligible for, or whose disease had progressed after, surgery or locoregional treatment; with no previous systemic therapy for hepatocellular carcinoma, with Child-Pugh class A and Eastern Cooperative Oncology Group performance status score of 0 or 1, and regardless of viral hepatitis status were randomly assigned (1:1) via an interactive voice response system to receive nivolumab (240 mg intravenously every 2 weeks) or sorafenib (400 mg orally twice daily) until disease progression or unacceptable toxicity. The primary endpoint was overall survival assessed in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study drug. This completed trial is registered with ClinicalTrials.gov, NCT02576509.Findings: Between Jan 11, 2016, and May 24, 2017, 743 patients were randomly assigned to treatment (nivolumab, n=371; sorafenib, n=372). At the primary analysis, the median follow-up for overall survival was 15·2 months (IQR 5·7-28·0) for the nivolumab group and 13·4 months (5·7-25·9) in the sorafenib group. Median overall survival was 16·4 months (95% CI 13·9-18·4) with nivolumab and 14·7 months (11·9-17·2) with sorafenib (hazard ratio 0·85 [95% CI 0·72-1·02]; p=0·075; minimum follow-up 22·8 months); the protocol-defined significance level of p=0·0419 was not reached. The most common grade 3 or worse treatment-related adverse events were palmar-plantar erythrodysaesthesia (1 [<1%] of 367 patients in the nivolumab group vs 52 [14%] of patients in the sorafenib group), aspartate aminotransferase increase (22 [6%] vs 13 [4%]), and hypertension (0 vs 26 [7%]). Serious treatment-related adverse events were reported in 43 (12%) patients receiving nivolumab and 39 (11%) patients receiving sorafenib. Four deaths in the nivolumab group and one death in the sorafenib group were assessed as treatment related.Interpretation: First-line nivolumab treatment did not significantly improve overall survival compared with sorafenib, but clinical activity and a favourable safety profile were observed in patients with advanced hepatocellular carcinoma. Thus, nivolumab might be considered a therapeutic option for patients in whom tyrosine kinase inhibitors and antiangiogenic drugs are contraindicated or have substantial risks.Funding: Bristol Myers Squibb in collaboration with Ono Pharmaceutical. [ABSTRACT FROM AUTHOR]

Nivolumab, a programmed death (PD)-1 (PD-1) inhibitor, led to durable responses, manageable safety, and increased survival in patients with advanced hepatocellular carcinoma (HCC). In our retrospective analysis, we studied the immunobiology and potential associations between biomarkers and outcomes with nivolumab in HCC. Fresh and archival tumour samples from dose-escalation and dose-expansion phases of the CheckMate 040 trial were analysed by immunohistochemistry and RNA sequencing to assess several inflammatory gene expression signatures, including CD274 (PD-ligand 1 [PD-L1]), CD8A , LAG3 , and STAT1. Biomarkers were assessed for association with clinical outcomes (best overall response by blinded independent central review per RECIST v1.1 and overall survival [OS]). Complete or partial tumour responses were observed in PD-L1–positive and PD-L1–negative patients treated with nivolumab monotherapy. Median OS was 28.1 (95% CI 18.2–n.a.) vs. 16.6 months (95% CI 14.2–20.2) for patients with tumour PD-L1 ≥1% vs. <1% (p = 0.03). Increased CD3 and CD8 showed a non-significant trend towards improved OS (both p = 0.08), and macrophage markers were not associated with OS. Tumour PD-1 and PD-L1 expression were associated with improved OS (p = 0.05 and p = 0.03, respectively). An inflammatory gene signature consisting of 4 genes was associated with improved objective response rate (p = 0.05) and OS (p = 0.01). PD-1 and PD-L1 expression, biomarkers of inflammation, and inflammatory gene signatures trended with improved survival and response. While further confirmation within a larger phase III trial is needed to evaluate predictive value of these biomarkers, these exploratory analyses suggest that anti-tumour immune response may play a role in the treatment benefit of nivolumab in HCC. Certain tests may be used to provide a picture of how a tumour is escaping the immune system, allowing it to continue to grow and create more tumours. Therapies such as nivolumab are designed to help the immune system fight the tumour. These tests may be used to determine how effective such therapies will be in the treatment of advanced liver cancer. NCT01658878. • Many inflammation-related markers are associated with response to nivolumab in HCC. • Many inflammatory signature scores within tumour samples are associated with survival. • Lower ratios of systemic inflammation markers are associated with clinical benefit. • Patients with HCC demonstrated positive responses regardless of AFP and viral dynamics. [ABSTRACT FROM AUTHOR]

Abstract Background In our previous randomised phase 2 study for patients with gemcitabine-refractory advanced pancreatic cancer, S-1 plus leucovorin improved progression-free survival compared with S-1 alone. Here, we evaluated the efficacy of TAS-118 (S-1 plus leucovorin) versus S-1 in overall survival (OS). Patients and methods This randomised, open-label, phase 3 study was conducted at 58 centres in Japan and Korea. Patients with metastatic pancreatic cancer that progressed during first-line gemcitabine-based chemotherapy or recurred during or after post-operative gemcitabine-based adjuvant treatment were randomly assigned (1:1) to receive either S-1 (40–60 mg, twice daily for 4 weeks in a 6-week cycle) or TAS-118 (S-1 40–60 mg plus leucovorin 25 mg, twice daily for 1 week in a 2-week cycle). The primary end-point was OS. Results A total of 603 patients were randomised, and 300 and 301 patients received TAS-118 and S-1, respectively. There was no difference in OS between groups (median OS for TAS-118 versus S-1, 7.6 months versus 7.9 months; hazard ratio [HR], 0.98 [95% confidence interval (CI), 0.82–1.16]; P = 0.756). Progression-free survival was significantly longer with TAS-118 than S-1 (median, 3.9 months versus 2.8 months; HR, 0.80 [95% CI, 0.67–0.95]; P = 0.009). There were interactions between Japan and Korea (P = 0.004) and between unresectable and recurrent disease (P = 0.025) in OS. Incidence, profile and severity of adverse events were similar between groups. Conclusion TAS-118 did not improve OS in patients with gemcitabine-refractory advanced pancreatic cancer compared to S-1. Further studies are needed to find patients who have benefit from adding leucovorin to S-1. Highlights • TAS-118 did not improve overall survival for gemcitabine-refractory advanced pancreatic cancer. • TAS-118 improved progression-free survival compared with S-1 monotherapy. • TAS-118 might be more effective than S-1 in some populations of patients. [ABSTRACT FROM AUTHOR]

Background & Aims GIDEON (Global Investigation of therapeutic DEcisions in hepatocellular carcinoma and Of its treatment with sorafeNib) is a prospective, observational registry study evaluating the safety of sorafenib and treatment practices in hepatocellular carcinoma patients. This large global database allowed for assessment of the use and tolerability of sorafenib in patients with liver dysfunction. Methods Baseline characteristics and medical/treatment history were collected in patients for whom a decision to treat with sorafenib had been made. Adverse event, dosing, and outcomes data were collected during follow-up. Results In the overall safety population (n = 3202), 1968 patients (61%) had Child-Pugh A status and 666 (21%) had Child-Pugh B. The majority of Child-Pugh A (72%) and Child-Pugh B (70%) patients received an initial sorafenib dose of 800 mg, consistent with the label, and dose reduction rates were 40% and 29%, respectively. The type and incidence of adverse events were generally consistent across Child-Pugh subgroups. The incidence of drug-related adverse events leading to discontinuation was similar between Child-Pugh A and Child-Pugh B patients (17% and 21%). In the intent-to-treat population (n = 3213), median overall survival (months [95% confidence interval]) was longer in Child-Pugh A patients (13.6 [12.8–14.7]) compared with Child-Pugh B patients (5.2 [4.6–6.3]). Conclusions In clinical practice, the safety profile of sorafenib appeared to be consistent across Child-Pugh A and Child-Pugh B patients. Findings suggest sorafenib may be safely used in some Child-Pugh B patients and indicate the importance of careful patient evaluation when making treatment decisions. Lay summary The GIDEON (Global Investigation of therapeutic DEcisions in hepatocellular carcinoma and Of its treatment with sorafeNib) study is a large prospective registry of patients with liver cancer who were treated with sorafenib. The aims were to evaluate the safety and tolerability of sorafenib among those in which the liver was not functioning properly. The study showed that the safety profile of sorafenib was consistent across patients with preserved liver function and those in which the liver was not functioning properly, and therefore, suggesting that sorafenib may be a valid treatment for some patients with liver impairment. [ABSTRACT FROM AUTHOR]

Background & Aims The purpose of this study was to determine whether biomarkers from baseline plasma and archival tissue specimens collected from patients enrolled in the EVOLVE-1 trial – a randomized phase 3 study of everolimus in hepatocellular carcinoma (HCC) – were associated with prognosis, etiology or ethnicity. Methods Circulating plasma levels of bFGF, PLGF, VEGF, VEGF-D, c-Kit, collagen IV, sVEGFR1 and VEGFR2 were measured by ELISA (N = 503). Protein levels of IGF-1R, c-Met, mTOR, Tsc2 were assayed by immunohistochemistry (N = 125). Genomic DNA sequencing was conducted on a panel of 287 cancer-related genes (N = 69). Results Patients with baseline plasma concentrations of VEGF or sVEGFR1 above the cohort median had significantly shorter overall survival. These plasma biomarkers retained prognostic significance in a multivariate Cox regression model with geographic region, macroscopic vascular invasion and alpha fetoprotein AFP levels. Membranous c-Met protein levels were significantly lower for Asian patients, as well as for hepatitis B viral etiology. The prevalence of genetic changes were similar to previous reports, along with a trend towards higher PTEN and TSC2 mutations among Asians. Conclusions The angiogenesis biomarkers VEGF and sVEGFR1 were independent prognostic predictors of survival in patients with advanced HCC. Potential differences in c-Met and mTOR pathway activation between Asian and non-Asian patients should be considered in future clinical trials. Lay summary Our study demonstrates that circulating angiogenesis biomarkers can predict the survival outcome in patients with advanced hepatocellular carcinoma independent of the clinical variables. There is etiology and ethnicity variation in molecular pathway activation in hepatocellular carcinoma, which should be considered for future clinical trial design of targeted therapy. Clinical trial registration number: NCT01035229. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this trial was to evaluate the efficacy and toxicity of S-1 and concurrent radiation therapy for locally advanced pancreatic cancer (PC). Methods and Materials: Locally advanced PC patients with histologically or cytologically confirmed adenocarcinoma or adenosquamous carcinoma, who had no previous therapy were enrolled. Radiation therapy was delivered through 3 or more fields at a total dose of 50.4 Gy in 28 fractions over 5.5 weeks. S-1 was administered orally at a dose of 80 mg/m2 twice daily on the day of irradiation during radiation therapy. After a 2- to 8-week break, patients received a maintenance dose of S-1 (80 mg/m2/day for 28 consecutive days, followed by a 14-day rest period) was then administered until the appearance of disease progression or unacceptable toxicity. The primary efficacy endpoint was survival, and the secondary efficacy endpoints were progression-free survival, response rate, and serum carbohydrate antigen 19-9 (CA19-9) response; the safety endpoint was toxicity. Results: Of the 60 evaluable patients, 16 patients achieved a partial response (27%; 95% confidence interval [CI], 16%-40%). The median progression-free survival period, overall survival period, and 1-year survival rate of the evaluable patients were 9.7 months (95% CI, 6.9-11.6 months), 16.2 months (95% CI, 13.5-21.3 months), and 72% (95%CI, 59%-82%), respectively. Of the 42 patients with a pretreatment serum CA19-9 level of ≥100 U/ml, 34 (81%) patients showed a decrease of greater than 50%. Leukopenia (6 patients, 10%) and anorexia (4 patients, 7%) were the major grade 3-4 toxicities with chemoradiation therapy. Conclusions: The effect of S-1 with concurrent radiation therapy in patients with locally advanced PC was found to be very favorable, with only mild toxicity. [ABSTRACT FROM AUTHOR]

Abstract: Background: In Japan and South Korea, transarterial chemoembolisation (TACE) is an important locoregional treatment for patients with unresectable hepatocellular carcinoma (HCC). Sorafenib, a multikinase inhibitor, has been shown effective and safe in patients with advanced HCC. This phase III trial assessed the efficacy and safety of sorafenib in Japanese and Korean patients with unresectable HCC who responded to TACE. Methods: Patients (n =458) with unresectable HCC, Child-Pugh class A cirrhosis and ⩾25% tumour necrosis/shrinkage 1–3months after 1 or 2 TACE sessions were randomised 1:1 to sorafenib 400mg bid or placebo and treated until progression/recurrence or unacceptable toxicity. Primary end-point was time to progression/recurrence (TTP). Secondary end-point was overall survival (OS). Findings: Baseline characteristics in the two groups were similar; >50% of patients started sorafenib >9weeks after TACE. Median TTP in the sorafenib and placebo groups was 5.4 and 3.7months, respectively (hazard ratio (HR), 0.87; 95% confidence interval (CI), 0.70–1.09; P = 0.252). HR (sorafenib/placebo) for OS was 1.06 (95% CI, 0.69–1.64; P =0.790). Median daily dose of sorafenib was 386mg, with 73% of patients having dose reductions and 91% having dose interruptions. Median administration of sorafenib and placebo was 17.1 and 20.1weeks, respectively. No unexpected adverse events were observed. Interpretation: This trial, conducted prior to the reporting of registrational phase III trials, found that sorafenib did not significantly prolong TTP in patients who responded to TACE. This may have been due to delays in starting sorafenib after TACE and/or low daily sorafenib doses. [Copyright &y& Elsevier]

Summary: Background: Axitinib is a potent, selective inhibitor of vascular endothelial growth factor (VEGF) receptors 1, 2, and 3. A randomised phase 2 trial of gemcitabine with or without axitinib in advanced pancreatic cancer suggested increased overall survival in axitinib-treated patients. On the basis of these results, we aimed to assess the effect of treatment with gemcitabine plus axitinib on overall survival in a phase 3 trial. Methods: In this double-blind, placebo-controlled, phase 3 study, eligible patients had metastatic or locally advanced pancreatic adenocarcinoma, no uncontrolled hypertension or venous thrombosis, and Eastern Cooperative Oncology Group performance status 0 or 1. Patients, stratified by disease extent (metastatic vs locally advanced), were randomly assigned (1:1) to receive gemcitabine 1000 mg/m2 intravenously on days 1, 8, and 15 every 28 days plus either axitinib or placebo. Axitinib or placebo were administered orally with food at a starting dose of 5 mg twice a day, which could be dose-titrated up to 10 mg twice daily if well tolerated. A centralised randomisation procedure was used to assign patients to each treatment group, with randomised permuted blocks within strata. Patients, investigators, and the trial sponsor were masked to treatment assignments. The primary endpoint was overall survival. All efficacy analyses were done in all patients assigned to treatment groups for whom data were available; safety and treatment administration and compliance assessments were based on treatment received. This study is registered at ClinicalTrials.gov, number NCT00471146. Findings: Between July 27, 2007, and Oct 31, 2008, 632 patients were enrolled and assigned to treatment groups (316 axitinib, 316 placebo). At an interim analysis in January, 2009, the independent data monitoring committee concluded that the futility boundary had been crossed. Median overall survival was 8·5 months (95% CI 6·9–9·5) for gemcitabine plus axitinib (n=314, data missing for two patients) and 8·3 months (6·9–10·3) for gemcitabine plus placebo (n=316; hazard ratio 1·014, 95% CI 0·786–1·309; one-sided p=0·5436). The most common grade 3 or higher adverse events for gemcitabine plus axitinib and gemcitabine plus placebo were hypertension (20 [7%] and 5 [2%] events, respectively), abdominal pain (20 [7%] and 17 [6%]), fatigue (27 [9%] and 21 [7%]), and anorexia (19 [6%] and 11 [4%]). Interpretation: The addition of axitinib to gemcitabine does not improve overall survival in advanced pancreatic cancer. These results add to increasing evidence that targeting of VEGF signalling is an ineffective strategy in this disease. Funding: Pfizer. [Copyright &y& Elsevier]

Abstract: Background: Secondary depression is common in the clinical oncology setting after pancreatic cancer diagnosis, following which the patients have to face the fact that they have a cancer with an extremely poor prognosis. However, the specific pathophysiology remains unclear. The present study examined the regional cerebral glucose metabolism using F18-fluorodeoxyglucose (F18-FDG) positron emission tomography (PET) in antidepressant-naïve pancreatic cancer patients with a depressive episode after their cancer diagnosis and before their cancer treatment. Methods: Regional cerebral glucose metabolism in pancreatic cancer patients without any antidepressant medication after the cancer diagnosis was measured with F18-FDG PET. A depressive episode after the cancer diagnosis was defined as including major and minor depressive episodes, and was diagnosed using the Diagnostic and Statistical Manual, Fourth Edition (DSM-IV). The prefrontal and limbic regions were the primary regions-of-interest, and an uncorrected value of p <0.005 was used as significant. Results: Six of 21 pancreatic cancer patients were diagnosed as having a depressive episode. Significantly higher glucose metabolism in depressed patients was found in the subgenual anterior cingulate cortex (sACC) (uncorrected p =0.002). Limitations: There was a small number of subjects, and there were no healthy controls. Conclusions: The higher metabolism in the sACC may be associated with the pathophysiology of secondary depressive episodes in patients following pancreatic cancer diagnosis. [Copyright &y& Elsevier]

This open-label study in Japan evaluated the safety and efficacy of an immune checkpoint inhibitor nivolumab (NIVO) alone or with gemcitabine-cisplatin (NIVO+GC) to treat biliary tract cancer (BTC). We present updated results for longer follow-up (minimum:493 days; median:679 days). Patients with unresectable/recurrent BTC refractory or intolerant to gemcitabine-based treatment received NIVO (240 mg, 2-week intervals, N = 30). Chemonaïve patients with unresectable/recurrent BTC received the same NIVO regimen + GC (N = 30). Primary objectives were tolerability and safety. Overall survival (OS) and centrally assessed progression-free survival (PFS) and objective response rate (ORR) were secondary efficacy endpoints. The most frequent drug-related adverse events with NIVO were decreased appetite (5/30, 17%), malaise (4/30, 13%), and pruritus (4/30, 13%), and with NIVO+GC w ere platelet count decreased (25/30, 83%) and neutrophil count decreased (25/30, 83%). In the NIVO cohort, median OS was 5.7 months (mo) (95% CI: 4.5, 8.7), median PFS was 1.4 mo (1.4, 1.4) and ORR was 10% (4, 23). Median OS was longer, and ORR higher, in the subgroup with programmed death-ligand 1 (PD-L1) ≥1% in tumor-associated immune cells (TAIC) (n = 19) than in those with PD-L1 <1% (n = 10) (OS:8.3 mo [4.8, 9.4] vs 4.3 mo [3.1, 6.4]; ORR:16% [7, 34] vs 0% [0, 21]). In the NIVO+GC cohort, median OS was 13.8 mo (95% CI:12.2, 15.9), median PFS was 4.3 mo (4.0, 7.9), and ORR was 37% (24, 52). Median OS was longer, and ORR higher, in patients with PD-L1 ≥1% (n = 18) than in those with PD-L1 <1% (n = 10) (OS:15.0 mo [12.2, 17.5] vs 13.0 mo [5.7, 15.4]; ORR:44% [27, 63] vs 20% [7, 46]). Median PFS was similar in the PD-L1 subgroups for both cohorts. Longer follow-up of patients with unresectable/recurrent BTC confirmed NIVO was well tolerated, with a manageable safety profile. Further data may show an association between PD-L1 expression in TAIC and longer OS with NIVO. [ABSTRACT FROM AUTHOR]

Background A family and personal history of breast (B), ovarian(O), and pancreatic(P) cancer was reported to be a predictive marker in patients with pancreatic adenocarcinoma (PA) treated with platinum-based chemotherapy. We planned a prospective phase II trial to evaluate the efficacy and safety of platinum-based chemotherapy in this population. Method Eligible patients had chemotherapy-naïve metastatic PA, had one or more of the followings: 1) at least one family history of P/B/O/prostate (PR) cancer in a first-degree relative, 2) at least two family members with history of P/B/O/PR cancer within third-degree relatives, and 3) at least one personal history of B/O/PR cancer.Patient suitable for FOLFIRINOX or gemcitabine plus nab-paclitaxel were ineligible unless patient refuse those regimens. Patients received gemcitabine 1000mg/m2and oxaliplatin 100 mg/m2 every two weeks (GEMOX). The primary endpoint was the one-year survival rate and 44% were desired. The sample size was calculated to be 43 pts, with a one-sided alpha of 5% and a power of 80%. Results A total of 45 pts were enrolled. First 43 pts were included in primary analysis. One-year survival rate was 27.9 [90%CI;17.0-41.3]% and didn't met pre-planned boundary. Response rate was 27.9%. Tendency of prolonged survival was observed in patients with two or more family histories of P/B/O/PR cancer (HR 0.65, 95%CI [0.34-1.23]). Family history or personal history with B/O/PR cancer tended to be associate with better response and prolonged survival. In this study, patient with family history of pancreatic cancer seemed to be associate with poor response. The most common adverse events of grade 3 or higher were neutropenia (36%), leukopenia (27%), thrombocytopenia (23%) and elevated level of ALT (20%). Treatment related death was not observed. Conclusion GEMOX did not show expected efficacy in patients with metastatic PA with family history or personal history of P/B/O/PR cancer. [ABSTRACT FROM AUTHOR]

Background Nivolumab (NIVO), a programmed death-1 (PD-1) inhibitor, is approved in several countries for sorafenib-treated patients (pts) with advanced hepatocellular carcinoma (aHCC) based on CheckMate040. We report findings on exploratory biomarker analyses. Methods In CheckMate040, pts with aHCC received NIVO regardless of programmed death ligand 1 (PD-L1) status and HCC etiology. Baseline tumor samples were analyzed by IHC for expression of PD-L1, PD-1, T-cell markers (CD3, CD4, CD8, FOXP3), and macrophages (CD68, CD163), and (in a subset of pts) by RNA sequencing for inflammatory signatures (ISs). Results were correlated with clinical outcomes: response (complete response [CR]/partial response [PR]/stable disease [SD]/progressive disease [PD]) and overall survival (OS). Associations with etiology and geographical region (non-Asia vs Asia) were assessed. Data cutoff: June 2018. Results In 184 pts with evaluable data, increased tumor cell PD-L1 expression was associated with response (CR+PR vs SD [P = 0.00009]; CR+PR vs PD [P = 0.0007]) and OS (P = 0.03), as was increased PD-1 expression (CR+PR vs SD [P = 0.05]; CR+PR vs PD [P = 0.009]; OS [P = 0.05]). Of the T-cell markers assessed, CD3 was associated with response (n = 182, CR+PR vs SD; P = 0.05). In pts positive for CD3 or CD8, there was a trend toward improved OS (P = 0.08). There was no association between CD68 and CD163 expression and clinical outcomes. For 37 pts with RNA sequencing data available, median Bristol-Myers Squibb (BMS) IS score was higher in pts with PR vs SD (P = 0.05) and was correlated with improved OS (P = 0.01). For all inflammation markers assessed, there was no association with etiology or geographical region. Conclusions In pts with aHCC, improved OS and response to NIVO may be associated with higher PD-L1, PD-1, and CD3 expression, and higher BMS IS scores, supporting the role of PD-1 inhibition in HCC treatment. Further investigation of these biomarkers is required. Originally presented at the AACR 2019. [ABSTRACT FROM AUTHOR]

Nivolumab (anti-PD-1 mAb) is a promising drug that survival benefit has been proven in a phase III trial for advanced gastric cancer in third- or later line treatment. In Japan, nivolumab was approved for unresectable advanced gastric cancer in 2017, and its monotherapy is recommended as the standard treatment in the third or later line treatment in the Gastric Cancer Treatment Guidelines 2018. However, the response rate of the nivolumab monotherapy is only about 10%, and no therapeutic efficacy has been seen in about a half of the treated patients. In addition, pembrolizumab (also anti-PD-1 mAb) failed to show superiority to the weekly-paclitaxel in the Keynote-061 trial for PD-L1-positive (CPS > 1%) advanced gastric cancer. Thus, since the treatment efficacy of blocking PD-1 in gastric cancer is limited, it is urgently necessary for the treatment selection to establish more useful biomarkers. The WJOG10417GTR is a translational research using fresh and unfrozen specimens harvested from gastric cancer patients treated with nivolumab monotherapy. Peripheral blood, endoscopic biopsy samples are collected at 3 time points (before initiating treatment, about 1 month after treatment, and at disease progression), and systems oncoimmunology is being conducted by analyzing gene expression, pathological features of tumor tissues, soluble molecules in plasma, and phenotypes of immune cells by flow cytometry. Then, the relationship between these data and the clinicopathological characteristics including the response to nivolumab will be statistically evaluated. Eleven hospitals are collaborating in this study toward the goal of 100 patient's enrollment in July 2018. Thirty-three patients have been registered until May 2019. [ABSTRACT FROM AUTHOR]