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Gemcitabine is one of the standard treatments for locally advanced pancreatic cancer. Recent studies on metastatic pancreatic cancer have shown that combination chemotherapy with oxaliplatin, irinotecan, fluorouracil, and leucovorin (FOLFIRINOX) and gemcitabine plus nab-paclitaxel (GnP) prolonged the overall survival compared with gemcitabine alone. To select the most promising chemotherapy, a randomized phase II selection design trial was started in July 2016 to compare between modified FOLFIRINOX and GnP for patients with locally advanced pancreatic cancer. A total of 124 patients will be enrolled from 36 Japanese institutions within 2.5 years. The primary endpoint is the proportion of 1-year overall survival, and secondary endpoints are progression-free survival, distant metastasis-free survival, response rate in patients with target lesions, CA19-9 response, adverse events, treatment-related death, early death, grade 4 non-hematological toxicity, and dose intensity. This trial has been registered with the UMIN Clinical Trials Registry [http://www.umin.ac.jp/ctr/index.htm], and the registration number is UMIN000023143., (Copyright © 2018. Published by Elsevier B.V.)

Objectives: The objectives of this study were to assess the feasibility of preoperative gemcitabine/nab-paclitaxel-based chemoradiation therapy (CRT) for patients with borderline resectable pancreatic cancer (BRPC), which consists of induction chemotherapy and subsequent CRT, and to determine the recommended dose (RD) of gemcitabine/nab-paclitaxel with concurrent radiation therapy in a phase I trial., Methods: Patients with BRPC received gemcitabine (1000 mg/m(2))/nab-paclitaxel (125 mg/m(2)) on days 1, 8, and 15 during each 4-week cycle, which was repeated for 2 cycles as induction chemotherapy. After induction chemotherapy, the patients received gemcitabine/nab-paclitaxel with concurrent radiation therapy. During CRT, the patients were scheduled to receive gemcitabine/nab-paclitaxel at 7 dose levels using a standard 3 + 3 dose escalation scheme. Radiation therapy was concurrently delivered at a total dose of 60 Gy., Results: Thirty-eight patients initiated induction gemcitabine/nab-paclitaxel. Among these patients, 30 received subsequent gemcitabine/nab-paclitaxel-based CRT. The RD was determined to be level 5 (gemcitabine, 800 mg/m(2); nab-paclitaxel, 100 mg/m(2)). The dose-limiting toxicities included hematologic toxicity, infection, febrile neutropenia, and peripheral neuropathy. Twenty-four of 30 patients underwent pancreatectomy, and the R0 resection rate was 96%., Conclusions: The RD of gemcitabine/nab-paclitaxel-based CRT after induction gemcitabine/nab-paclitaxel for patients with BRPC was 800 and 100 mg/m(2), respectively.

We examined whether fingolimod (FTY720), an S1PR (sphingosine-1-phosphate receptor) modulator, has beneficial or harmful effects on mineralocorticoid/salt-induced renal injury. Uninephrectomized rats on 0.9% NaCl/0.3% KCl drinking solution were randomly divided into control, control+FTY720, deoxycorticosterone acetate (DOCA), and DOCA+FTY720 groups and administered vehicle, vehicle+FTY720, DOCA+vehicle, and DOCA+FTY720 for 4 weeks, respectively. Only the DOCA+FTY720 group had reduced survival rates and showed hemolysis because of intravascular mechanical fragmentation of erythrocytes and thrombocytopenia. Both the DOCA+FTY720 and DOCA groups developed malignant hypertension, which was more severe in the DOCA+FTY720 group. In the DOCA+FTY720 group only, thrombotic microangiopathy involving severe renal arteriole endothelial cell injury was observed and was characterized by fibrinoid necrosis and onion-skin lesions in arterioles. There were fewer circulating endothelial progenitor cells in the DOCA+FTY720 group but more in the DOCA group compared with the control group. Expression levels of VEGF (vascular endothelial growth factor), S1PR1, and S1PR3 in renal arteriole endothelial cells were significantly greater in the DOCA+FTY720 and DOCA groups compared with the control group, with levels being similar between the 2 groups. Expression levels of endothelial nitric oxide synthase in renal arteriole endothelial cells were significantly lower in the DOCA+FTY720 group only. The control+FTY720 group showed reduced circulating endothelial progenitor cells but no significant functional or pathological changes in kidneys or changes in blood pressure. Exposure of uninephrectomized rats to DOCA/salt+FTY720 for 4 weeks induced renal arteriolar endothelial cell injury, resulting in the development of thrombotic microangiopathy. Consideration of this possibility is recommended when prescribing FTY720.

Bubble-seeded histotripsy (BSH) is a newly developed ultrasound-based mechanical fractionation technique using locally injected phase change nanodroplets (PCNDs) as sensitizers. The PCNDs are a kind of microbubble precursor compressed into submicron-size in droplets form, which were designed for local administration and will expand into microbubbles under ultrasound exposure. Previously, we reported that a combination of PCNDs injection and pulsed high-intensity focused ultrasound (pHIFU) with an acoustic intensity as low as about 3 kW/cm 2 at 1.1 MHz, which is similar to the acoustic intensity of currently available HIFU coagulation therapy, was enough to induce tissue fractionation after significant antitumor effects in an in vivo study. Toward therapeutic application of BSH to deep-seated tissues such as the pancreas, the transluminal approach, using endoscopic ultrasound was thought to be ideal. Therefore, for a preliminary examination, we developed a new transducer with a small aperture (20- × 20-mm square) and long focal length (35 mm), operating at 2.1 MHz that could be attached to an EUS-mimicking probe. With the newly developed transducer and locally injected PCNDs, predictable tissue mechanical fractionation was observed in both ex vivo and in vivo studies at acoustic intensities that were too low to induce any significant bioeffects (around 4 kW/cm 2 ) without using PCNDs. For in situ monitoring of the treatment site during a procedure, the degree of attenuation of microbubble motions after exposing the microbubbles to pHIFU was monitored, using ultrafast echographic imaging. Microbubble movements were observed to be largest at 25-30 s after pHIFU exposure. On the contrary, after 40 s, the movement of microbubbles decreased to the same level as at the start of the procedure, suggesting that an overdose of pHIFU exposure causes coagulation attributable to the thermal effect caused by absorption of the energy. Those results were promising for expanding the application of BSH for a transluminal approach, using a small transducer under real-time monitoring., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: The aim of this study was to evaluate the effects of single-nucleotide polymorphisms (SNPs) on advanced pancreatic cancer risk and overall survival (OS) in a candidate-gene approach., Methods: Overall, 5438 SNPs in 219 candidate genes encoding several drug-metabolizing enzymes or transporters were analyzed. In the screening study, 3 SNPs were found associated with OS (P ≤ 0.0005). We validated these SNPs as part of the randomized phase 3 study (GEST study). The associations between OS and SNPs were investigated using log-rank test and Cox proportional hazards model., Results: From the GEST study, the SNP rs4149086 in the 3' UTR of the solute carrier organic anion transporter family member 1B1 (SLCO1B1) gene showed significant interaction with treatment (P = 0.02). In the gemcitabine group, the SNP was associated with short OS (hazard ratio [HR], 3.75; 95% confidence interval [CI], 1.30-10.8; P = 0.008) even after multiple-comparisons adjustment. In contrast, the SNP was not associated with OS in S-1 (HR, 0.77; 95% CI, 0.33-1.81; P = 0.55) or gemcitabine plus S-1 groups (HR, 1.18; 95% CI, 0.46-3.00; P = 0.72)., Conclusions: Patients with advanced pancreatic cancer with the rs4149086 AG or GG genotype may obtain good clinical results when treated with S-1-containing regimens.

Purpose: To determine the recommended dose (RD) of gemcitabine (GEM) plus S-1 (GS) in curatively resected biliary tract cancer (BTC) patients without major hepatectomy., Methods: A standard 3 + 3 dose-escalation design was used with planned dose levels (mg/m 2 ) of GEM (administered intravenously on days 1 and 8) and S-1 (administered orally twice daily on days 1-14, with a 1-week rest, every 3 weeks for up to 24 weeks) of 1000/80 (Level 2), 1000/65 (Level 1), 800/65 (Level - 1), and 800/50 (Level - 2)., Results: Thirty-one patients (17 men and 14 women; median age, 70 years) were enrolled. Level 1 was chosen as the starting dose. Three of seven patients developed dose-limiting toxicities at Level 1 and the dose was de-escalated to Level - 1. Five of 12 patients developed Grade 4 neutropenia at Level - 1 and the dose was de-escalated to Level - 2. One patient developed Grade 4 neutropenia at Level - 2. Another patient was unable to receive the day 8 dose due to Grade 3 neutropenia at Level - 2. Level - 1 was confirmed as the maximum tolerated dose and Level - 2 the RD for this regimen. The 1- and 2-year recurrence-free survival rates were 77.0 and 54.0%, respectively. The recurrence-free survival rate of patients in the GS completion group was significantly higher than that of the GS discontinuation group., Conclusions: Level - 2 was confirmed as the RD (GEM 800 mg/m 2 and S-1 50 mg/m 2 ) for GS adjuvant chemotherapy in curatively resected BTC patients without major hepatectomy.

Gemcitabine-based therapy remains the mainstay of treatment for patients with biliary tract cancers (BTCs) with no second-line treatment(s) established yet. Aberrant activation of the MAPK pathway in patients with BTC indicates its importance in BTC. Trametinib is a potent, highly selective, allosteric non-competitive inhibitor of MEK1/MEK2. In this phase IIa open-label, single-arm study, we investigated the efficacy and safety of trametinib in Japanese patients with advanced BTC refractory to gemcitabine-based therapy. All patients received oral trametinib 2 mg once daily until progressive disease (PD), death, or unacceptable toxicity. The primary objective was to determine the 12-week non-PD rate. Secondary assessments included safety, progression-free survival (PFS), overall survival, and overall response rate. Targeted exome sequencing was used to identify biomarkers for sensitivity or resistance to trametinib monotherapy. Twenty patients (median age, 61.5 years) with carcinoma of gall bladder (40%), intrahepatic (25%) or extrahepatic (30%) bile duct, and ampulla of Vater (5%) were enrolled. The non-PD rate at week 12 was 10% (95% confidence interval, 1.2-31.7); it did not reach the threshold rate of 25%. Median PFS was 10.6 weeks (95% confidence interval, 4.6-12.1) and 1-year overall survival was 20.0%. Stable disease and PD were observed in 13 (65%) and seven (35%) patients, respectively. No new safety signals were reported. Although the primary end-point was not met, prolonged PFS was observed in one patient having six somatic variants including synonymous NF1 exon 12 splice variant and a loss-of-function variant in ARID1A. Efforts to understand responsive mutations and sensitivity to targeted therapies are warranted. This trial was registered with ClinicalTrials.gov: NCT01943864., (© 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: We investigated the efficacy and safety of 60, 120, or 240 mg of Z-360, which is a highly potent cholecystokinin2-receptor-selective antagonist, combined with gemcitabine in patients with metastatic pancreatic cancer., Methods: Patients were randomly assigned in a 1:1:1:1 ratio to one of four treatment groups. Patients received 1000 mg/m 2 gemcitabine for each cycle and Z-360 tablets of 60 mg (GZ 60 mg group), 120, 240 mg or placebo tablets (Gem group) orally twice daily. The primary endpoint was overall survival (OS)., Results: The median OS was 1.3 months longer in the GZ 60 mg group compared with the Gem group (8.5 vs. 7.2 months) and the risk of death was reduced by 19% compared with the Gem group, although there were no statistically significant differences. The study treatments were well tolerated., Conclusions: In this Phase II study, no statistically significant differences between the GZ groups and Gem group were detected in any analysis. However, Z-360 in dose of 60 mg tends to improve OS in patients with metastatic pancreatic cancer with low toxic effect. Further exploratory trials with other agents such as gemcitabine plus nab-paclitaxel might be beneficial.

Purpose: The ability to detect pancreatic cysts was compared between special ultrasonography (US) examination focusing on the pancreas (special pancreatic US) and routine upper abdominal ultrasonography to objectively assess the ability of the former to detect cysts., Subjects and Methods: Of 3704 patients who underwent special pancreatic US at our hospital, 186 underwent routine upper abdominal US within six months, had pancreatic cysts, and underwent magnetic resonance imaging (MRI). In these patients, 447 cysts measuring ≥5mm were detected via MRI, which was used as the gold standard. The ability and sensitivity of the US modalities to detect each cyst was determined., Results: The sensitivity of special pancreatic US was 92.2% (95% confidence interval [CI], 89.7%-94.7%) and that of routine upper abdominal US was 70.2% (95% CI, 66.0%-74.5%). McNemar test (Stata Version 13.1) revealed a significant difference in the cyst (≥5mm) detection sensitivity between the two modalities (p<0.001). An analysis stratified by patients similarly revealed a significant difference between the two modalities (p<0.001). The cyst detection sensitivity was also analyzed in various parts of the pancreas. The sensitivity of special pancreatic US was 88.7% for the uncinate process and inferior head, 97.5% for the head, 97.1% for the body, 89.0% for the body-tail, and 66.7% for the tail, whereas that of routine upper abdominal US was 74.2% for the uncinate process, 69.5% for the head, 81.0% for the body, 67.0% for the body-tail, and 26.7% for the tail. The McNemar test revealed significant differences in the sensitivity of the two modalities for all pancreatic parts (p<0.001-0.016)., Conclusion: Compared with routine upper abdominal US, special pancreatic US had higher sensitivity in detecting pancreatic cysts., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: To improve prognosis of pancreatic cancer (PC) patients, the discovery of more reliable biomarkers for the early detection is desired., Methods: Blood samples were collected by 2 independent groups. The 1st set was included 55 early PC and 58 healthy volunteers (HV), and the 2nd set was included 16 PC and 16HV. The 16 targeted metabolites were quantitatively analyzed by gas chromatography/tandem mass spectrometry together with their corresponding stable isotopes. In the 1st set, the levels of these metabolites were evaluated, and diagnostic models were constructed via multivariate logistic regression analysis, leading to validation using the 2nd set., Results: In the 1st set, model X consisting of 4 candidates based on our previous report possessed higher sensitivity (74.1%) than carbohydrate antigen 19-9 (CA19-9). Model Y, consisting of 2 metabolites newly selected from 16 metabolites via stepwise method possessed higher sensitivity (70.4%) than CA19-9. Furthermore, combining model Y with CA19-9 increased its sensitivity (90.7%) and specificity (89.5%). In the 2nd set, combining model Y with CA19-9 displayed high sensitivity (81.3%) and specificity (93.8%). In particular, it displayed very high sensitivity (100%) for resectable PC., Conclusions: Quantitative analysis confirmed that metabolomics-based diagnostic methods are useful for detecting PC early., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objective: This study was performed to compare health-related quality of life (HRQOL) of gemcitabine plus S-1 (GS), S-1 alone and gemcitabine alone as first-line chemotherapy for locally advanced or metastatic pancreatic cancer in the GEST (Gemcitabine and TS-1 Trial) study and to assess the impacts of adverse events and tumour response on HRQOL., Methods: Patients were randomly assigned to receive gemcitabine alone (1000 mg/m 2 weekly for 3 of 4 weeks), S-1 alone (80, 100 or 120 mg/day twice daily for 4 of 6 weeks) or GS (gemcitabine at 1000 mg/m 2 weekly plus S-1 at 60, 80 or 100 mg/day twice daily for 2 of 3 weeks). HRQOL was assessed using the EuroQoL-5D (EQ-5D) questionnaire at baseline and weeks 6, 12, 24, 48 and 72. EQ-5D scores, quality-adjusted life months (QALMs), quality-adjusted progression-free months (QAPFMs) and time until definitive HRQOL deterioration (TUDD) were compared among the three groups. The impacts of adverse events and tumour response on EQ-5D scores were analysed., Results: Including EQ-5D scores after death as 0, the mean profile was significantly better in the GS than gemcitabine group (difference, 0.069; p=0.003), but not the S-1 group (difference, -0.011; p=0.613). The mean profiles until death were similar in the three groups. QALMs, QAPFMs and TUDD were significantly longer in the GS than gemcitabine group (p<0.001, p<0.001 and p=0.004, respectively), but not the S-1 group (p=0.563, p=0.741 and p=0.701, respectively). Fatigue, anorexia and tumour response were significantly associated with changes in EQ-5D scores., Conclusions: GS achieved better HRQOL than gemcitabine alone, resulting a good balance between overall survival and HRQOL benefits. S-1 alone provides HRQOL similar to that provided by gemcitabine alone. Preventing fatigue and anorexia and maintaining better response would improve HRQOL., Competing Interests: Competing interests: YH is contractually employed by J-CRSU. YO has a leadership position at Statcom and J-CRSU; has stock in Statcom; received honoraria from Sanofi, Shionogi, Taiho, Kowa, Chugai and Eisai; and received research funding from Eisai. TO received honoraria from Chugai, Pfizer Japan, Novartis, Taiho, Merck Serono, Eli Lilly Japan, Sumitomo Dainippon, Eisai, Bayer, Yakult, Nobelpharma, Nippon Kayaku, Baxter and Astellas; received rewards for an advisory role from Eli Lilly Japan, Sumitomo Dainippon, Taiho, Ono, Nippon Boehringer Ingelheim, Nano Carrier and Zeria; and received research funding from Chugai, Eli Lilly Japan, Eisai, Novartis, Shizuoka Industry, Takeda Bio Development Center, Yakult, Onco Therapy Science, Otsuka, Taiho, Sceti Medical Labo, Nippon Boehringer Ingelheim, Kowa, Kyowa Hakko Kirin, Merck Serono, Ono, Bayer, Pfizer Japan, AstraZeneca, Sumitomo Dainippon, Nobelpharma, Zeria and Glaxo Smith Kline. HU received honoraria from Taiho and Chugai and received research funding from Taiho, NanoCarrier and Baxalta Japan. TI received rewards for an advisory role from Taiho, Yakult, Baxalta and JCRO; served on the speakers’ bureau of Taiho, Yakult, Daiichi Sankyo, Eisai, Mochida and Fujifilm; and received research funding from Taiho, AstraZeneca, Glaxo Smith Kline, Nihon Zouki, Zeria and Merck Sereno. NB received honoraria from Taiho and Eli Lilly. JF received honoraria from Taiho, Yakult, Eli Lilly Japan, Chugai, Eisai, Ono, Daiichi Sankyo, Merck Serono, Bayer, Novartis, Sumitomo Dainippon, Mitsubishi Tanabe, MSD, AstraZeneca, Sawai, Mochida, Takeda, Pfizer and Astellas; received rewards for an advisory role from Taiho, Yakult, Fujifilm, Chugai, Kyowa Hakko Kirin, Otsuka, Zeria and J-Pharma; served on the speakers’ bureau of Taiho and Yakult; and received research funding from J-Pharma, Taiho, Sumitomo Dainippon, Janssen, Daiichi Sankyo, MSD, Yakult, Takeda, Chugai, Ono, Astellas, Zeria, Novartis, Nanocarrier, Shionogi, Onco Therapy Science, Eli Lilly Japan, Bayer, Bristol-Myers Squibb, Merck Serono, Kyowa Hakko Kirin, Eisai and Mochida. SO received honoraria from Eli Lilly, Taiho, Yakult, Otsuka and Sandoz; received rewards for an advisory role from Boehringer Ingelheim; and received research funding from AstraZeneca. ALC received rewards for an advisory role from Bayer, Eisai, Novartis and Merck KGaA. AS received honoraria from Taiho and received rewards for an advisory role from Taiho. MT received honoraria from Taiho and Eli Lilly and received research funding from Eli Lilly. All remaining authors have declared no conflict of interest.

Background: Intermediate-stage [Barcelona Clinic Liver Cancer stage-B (BCLC-B)] hepatocellular carcinoma (HCC) comprises of a heterogeneous population of patients with a wide range of tumor burdens. We therefore formulated a subclassification of BCLC-B HCC using the up-to-seven criteria and tumor markers according to the results of a retrospective analysis of these patients., Methods: This study included 125 patients newly diagnosed with BCLC-B HCC who underwent transarterial chemoembolization. Among them, 39 and 86 were within or beyond the up-to-seven criteria, respectively. Multivariate Cox proportional hazards analysis was performed to investigate factors that contributed to better prognosis associated with the criteria., Results: Cumulative overall survival (OS) and disease-free survival rates were significantly higher for patients within the up-to-seven criteria compared with those beyond (p = 0.034 and p = 0.001, respectively). Multivariate analysis revealed that low concentrations of des-γ-carboxy prothrombin (DCP) (<150 mAU/ml) and α-fetoprotein (AFP) (<100 ng/ml) were independent contributors to better OS of patients within or beyond the up-to-seven criteria, respectively. Accordingly, the patients were classified as follows: group A (patients within the up-to-seven criteria with DCP <150 mAU/ml), group C (patients beyond the up-to-seven criteria with AFP ≥100 ng/ml), and group B (other patients). OS differed significantly among groups (p < 0.001), and the median survival times of group A, B, and C were 4.2, 2.7, and 1.5 years, respectively., Conclusion: The subclassification system incorporating the up-to-seven criteria combined with DCP and AFP levels may serve as better predictors of prognosis that may guide efforts to improve treatment strategies.

A 68-year-old woman was referred to our hospital with increased levels of biliary enzymes. On imaging, the patient was diagnosed with unresectable intrahepatic biliary tract cancer (BTC) with invasion of the portal vein and para-aortic lymph node metastasis (cT3N1M1, cStage IVb) and underwent endoscopic biliary drainage for the biliary stricture prior to therapy. The patient was subsequently enrolled in a phase III randomized trial (UMIN000014371/NCT02182778) and randomly assigned to receive gemcitabine/cisplatin/S-1 (GCS) combination therapy intravenously at doses of 1,000 or 25 mg/m 2 on day 1 and orally twice daily at a dose of 80 mg/m 2 on days 1-7 every 2 weeks. After 12 cycles of scheduled therapy without uncontrollable adverse effects, the patient achieved a good partial response with chemotherapy. Computed tomography (CT) revealed a marked reduction of the primary and metastatic lesions. In addition, 18 F-fluorodeoxyglucose-positron emission tomography/CT revealed diminishing abnormal uptake and no macroscopic evidence of factors adversely affecting tumor resectability. Therefore, the patient underwent extended right hepatic lobectomy, lymph node dissection and left hepaticojejunostomy. Finally, histological examination of the resected tissues revealed no residual cancer cells, suggesting a pathologically complete response. We herein present the case of a patient with intrahepatic BTC who achieved a pathologically complete response following combination chemotherapy with GCS.

Purpose: The aim of this pilot study is to confirm the safety and efficacy of neoadjuvant therapy and also treatment duration efficacy using modified FOLFIRINOX for patients with borderline resectable pancreatic cancer (BRPC)., Methods: The study is a prospective multicenter pilot trial conducted on patients with BRPC. Intervention for clinical trials: Modified FOLFIRINOX (without bolus 5-FU and LV, also decreased the dose of irinotecan; FIRINOX) was given to the first five patients in the 4-cycle group of the regimen and next five patients in the 8-cycle group. The primary end point was the toxicity of the therapy and one of the secondary end points were the optimal duration., Results: The overall rate of grade 3 and 4 events was 80 %: 3 patients (60 %) in the four-cycle group and five patients (100 %) in the eight-cycle group had grade 3 or 4 adverse events. There was no incidence of serious adverse effect such as febrile neutropenia, sepsis, liver abscess or uncontrollable diarrhea. There was no clinically relevant morbidity presented in patients who underwent surgery. R0 rates by intention to treat were 60.0 % in the four-cycle group and 40 % in the eight-cycle group (P = 0.999). The histopathologic treatment effect based on the Evans grade revealed grade I (n = 1), IIa (n = 3) in the four-cycle group and grade I (n = 2), IIa (n = 1) in the eight-cycle group., Conclusions: FIRINOX therapy was feasible and safe for strictly selected patients with BRPC. Four cycles of FIRINOX would be sufficient for patients with BRPC as neoadjuvant therapy.

Pancreatic cancer is one of the most lethal tumors, and reliable detection of early-stage pancreatic cancer and risk diseases for pancreatic cancer is essential to improve the prognosis. As 260 genes were previously reported to be upregulated in invasive ductal adenocarcinoma of pancreas (IDACP) cells, quantification of the corresponding proteins in plasma might be useful for IDACP diagnosis. Therefore, the purpose of the present study was to identify plasma biomarkers for early detection of IDACP by using two proteomics strategies: antibody-based proteomics and liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based proteomics. Among the 260 genes, we focused on 130 encoded proteins with known function for which antibodies were available. Twenty-three proteins showed values of the area under the curve (AUC) of more than 0.8 in receiver operating characteristic (ROC) analysis of reverse-phase protein array (RPPA) data of IDACP patients compared with healthy controls, and these proteins were selected as biomarker candidates. We then used our high-throughput selected reaction monitoring or multiple reaction monitoring (SRM/MRM) methodology, together with an automated sample preparation system, micro LC and auto analysis system, to quantify these candidate proteins in plasma from healthy controls and IDACP patients on a large scale. The results revealed that insulin-like growth factor-binding protein (IGFBP)2 and IGFBP3 have the ability to discriminate IDACP patients at an early stage from healthy controls, and IGFBP2 appeared to be increased in risk diseases of pancreatic malignancy, such as intraductal papillary mucinous neoplasms (IPMNs). Furthermore, diagnosis of IDACP using the combination of carbohydrate antigen 19-9 (CA19-9), IGFBP2 and IGFBP3 is significantly more effective than CA19-9 alone. This suggests that IGFBP2 and IGFBP3 may serve as compensatory biomarkers for CA19-9. Early diagnosis with this marker combination may improve the prognosis of IDACP patients., Competing Interests: The authors declare no competing financial interest. One of our authors, W.H., is a CEO of Abnova and receives salary from Abnova. He also owns stock in Abnova. This does not alter the authors’ adherence to PLOS ONE policies on sharing data and materials.

Purpose: Efficacy and safety of nab-paclitaxel plus gemcitabine have not been clarified in Japanese patients with metastatic pancreatic cancer. No pharmacokinetic profile of co-administration of nab-paclitaxel and gemcitabine has been reported. We conducted a phase I/II study of the efficacy, safety, and pharmacokinetics in Japanese patients with metastatic pancreatic cancer., Methods: The patients were administered 125 mg/m(2) nab-paclitaxel followed by 1000 mg/m(2) gemcitabine on day 1, 8, and 15 every 4 weeks. Treatment was continued until disease progression, unacceptable adverse events, or withdrawal of consent, whichever occurred first. The primary endpoints were tolerability in phase I and overall response rate according to RECIST in phase II., Results: A total of 34 patients were enrolled. At the time of 1-year follow-up analysis since the last patient enrollment, the objective response rate by independent review committee was 58.8% (20 of 34 patients; 95% confidence interval [CI], 40.7-75.4%). The median progression-free survival and median overall survival were 6.5 months (95% CI, 5.1-8.3) and 13.5 months (95% CI, 10.6--not reached), respectively. Main adverse drug reactions of grade 3 or higher were neutropenia (70.6%), leukopenia (55.9%), anemia (14.7%), lymphocytopenia (14.7%), thrombocytopenia (14.7%), and peripheral sensory neuropathy (11.8%). There were no treatment-related deaths and no marked differences in pharmacokinetics of combined paclitaxel and gemcitabine in historical comparison between co-administration and monotherapies., Conclusions: Nab-paclitaxel plus gemcitabine regimen showed highly promising efficacy with manageable safety profile under careful observation and with appropriate supportive care in Japanese patients with metastatic pancreatic cancer., Clinical Trial Number: JapicCTI-121987.

The aortic arch and major branch arteries are formed from the three pairs of pharyngeal arch arteries (PAAs) during embryonic development. Their morphological defects are clinically observed as isolated diseases, as a part of complicated cardiovascular anomalies or as a manifestation of multi-organ syndromes such as 22q11.2 deletion syndrome. Although numerous genes have been implicated in PAA formation and remodeling, detailed mechanisms remain poorly understood. Here we report that the mice null for Hrt1/Hey1, a gene encoding a downstream transcription factor of Notch and ALK1 signaling pathways, show perinatal lethality on the C57BL/6N, C57BL/6N × C57BL/6J or C57BL/6N × 129X1/SvJ background. Hrt1/Hey1 null embryos display abnormal development of the fourth PAA (PAA4), which results in congenital vascular defects including right-sided aortic arch, interruption of the aortic arch and aberrant origin of the right subclavian artery. Impaired vessel formation occurs randomly in PAA4 of Hrt1/Hey1 null embryos, which likely causes the variability of congenital malformations. Endothelial cells in PAA4 of null embryos differentiate normally but are structurally disorganized at embryonic day 10.5 and 11.5. Vascular smooth muscle cells are nearly absent in the structurally-defective PAA4, despite the appropriate migration of cardiac neural crest cells into the fourth pharyngeal arches. Endothelial expression of Jag1 is down-regulated in the structurally-defective PAA4 of null embryos, which may be one of the mechanisms underlying the suppression of vascular smooth muscle cell differentiation. While the direct downstream phenomena of the Hrt1/Hey1 deficiency remain to be clarified, we suggest that Hrt1/Hey1-dependent transcriptional regulation has an important role in PAA formation during embryonic development., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: Biliary tract cancer (BTC) patients who have undergone surgical resection with major hepatectomy cannot tolerate the standard gemcitabine regimen (1,000 mg/m2 on days 1, 8, and 15 every 4 weeks) due to severe toxicities such as myelosuppression. Our dose-finding study of adjuvant gemcitabine therapy for biliary tract cancer following major hepatectomy determined that the recommended dose is 1,000 mg/m2 on days 1 and 15 every 4 weeks. Here, we evaluate the pharmacokinetics and pharmacodynamics of gemcitabine in these subjects., Methods: We evaluated BTC patients scheduled to undergo surgical resection with major hepatectomy followed by gemcitabine therapy. A pharmacokinetic evaluation of gemcitabine and its main metabolite, 2',2'-difluorodeoxyuridine (dFdU), was conducted at the initial administration of gemcitabine, which was given by intravenous infusion over 30 min at a dose of 800-1,000 mg/m2. Physical examination and adverse events were monitored for 12 weeks., Results: Thirteen patients were enrolled from August 2011 to January 2013, with 12 ultimately completing the pharmacokinetic study. Eight patients had hilar cholangiocarcinoma, three had intrahepatic cholangiocarcinoma, and one had superficial spreading type cholangiocarcinoma. The median interval from surgery to first administration of gemcitabine was 65.5 days (range, 43-83 days). We observed the following toxicities: neutropenia (n = 11, 91.7%), leukopenia (n = 10, 83.3%), thrombocytopenia (n = 6, 50.0%), and infection (n = 5, 41.7%). Grade 3 or 4 neutropenia was observed in 25% (n = 3) of patients. There were differences in clearance of gemcitabine and dFdU between our subjects and the subjects who had not undergone hepatectomy., Conclusion: Major hepatectomy did not affect the pharmacokinetics of gemcitabine or dFdU., Trial Registration: UMIN-CTR in (JPRN) UMIN000005109.

We recently reported that circulating apolipoprotein AII (apoAII) isoforms apoAII-ATQ/AT (C-terminal truncations of the apoAII homo-dimer) decline significantly in pancreatic cancer and thus might serve as plasma biomarkers for the early detection of this disease. We report here the development of novel enzyme-linked immunosorbent assays (ELISAs) for measurement of apoAII-ATQ/AT and their clinical applicability for early detection of pancreatic cancer. Plasma and serum concentrations of apoAII-ATQ/AT were measured in three independent cohorts, which comprised healthy control subjects and patients with pancreatic cancer and gastroenterologic diseases (n = 1156). These cohorts included 151 cases of stage I/II pancreatic cancer. ApoAII-ATQ/AT not only distinguished the early stages of pancreatic cancer from healthy controls but also identified patients at high risk for pancreatic malignancy. AUC values of apoAII-ATQ/AT to detect early stage pancreatic cancer were higher than those of CA19-9 in all independent cohorts. ApoAII-ATQ/AT is a potential biomarker for screening patients for the early stage of pancreatic cancer and identifying patients at risk for pancreatic malignancy (161 words).

Purpose: The aim of this study was to investigate the combination effects of pulsed HIFU (pHIFU) and phase-change nanodroplets (PCND) as a sensitizer on efficient induction of mechanical effects of pHIFU and chemically enhanced tumor growth inhibition for local anti-tumor therapy., Method: Changes in growth of colon 26 tumor tissue inoculated onto CDF1 mice were evaluated by the following treatments. (1) pHIFU exposure (1.1 MHz, 3.2 kW/cm(2), 300 cycles, and 50 ms interval) for 60 s, (2) PCND (1 %) injection, (3) adriamycin (4 mg/kg) injection, (4) pHIFU exposure after PCND injection, and (5) pHIFU exposure after PCND + adriamycin injection simultaneously., Results: Significant changes in tumor growth were observed in the group with combination of pHIFU and PCND, although single therapy did not show any significant difference. PCND enhanced mechanical tissue fractionation by pHIFU, which was detectable by Real-time tissue elastography. Moreover, the combination of pHIFU and PCND + Adriamycin suppressed the tumor growth for 2 weeks, and 3 of 4 mice did not show any sign of regrowth during the 30-day observation., Conclusion: The combination of pHIFU and PCND exerted a significant anti-tumor effect and may be a new candidate for treatment of locally advanced cancer.

Objectives: Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is accurate in cytological diagnosis of pancreatic lesions. Our aim was to determine optimal number of needle passes in EUS-FNA for pancreatic lesions without onsite cytopathologist, who is not routinely available to participate in the procedure., Methods: Results of all needle passes in EUS-FNAs for 117 pancreatic neoplasms in 115 patients were reviewed retrospectively. Factors that required 2 or more needle passes for correct diagnosis were identified by multivariate logistic regression analysis. In each lesion group defined by the factors that required 2 or more passes and were known at the time of EUS-FNA, number of needle passes was regarded as optimal when an increase in diagnostic sensitivity by an additional needle pass did not reach 10%., Results: Size of 15 mm or less (OR 4.58, 95% CI 1.70-12.3, P < 0.01), location of head (OR 5.02, 95% CI 1.82-13.9, P < 0.01), and neuroendocrine tumor (NET) (OR 5.04, 95% CI 1.38-18.4, P = 0.01) independently required 2 or more needle passes. Optimal numbers of needle passes for lesions of 15 mm or less in the head, those of more than 15 mm in the head, those of 15 mm or less in the body or tail, and those of more than 15 mm in the body or tail were 3, 2, 2, and 1, respectively. When these numbers of needle passes were performed, 93% of pancreatic lesions were correctly diagnosed., Conclusions: Optimal numbers of needle passes in EUS-FNA for pancreatic lesions without onsite cytopathologist were between 1 and 3., (Copyright © 2015 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Purpose: Gemcitabine/cisplatin combination therapy has been the standard palliative chemotherapy for patients with advanced biliary tract cancer (BTC). We aimed to evaluate the efficacy and safety of adding S-1 to gemcitabine/cisplatin combination therapy for patients with advanced BTC., Methods: Patients with histologically or cytologically confirmed unresectable or recurrent BTC were eligible for inclusion. The primary end point was overall survival. Based on the results of our preceding phase I study, gemcitabine and cisplatin were administered intravenously at doses of 1,000 or 25 mg/m(2), respectively, on day 1, and oral S-1 was administered daily at a dose of 80 mg/m(2) on days 1-7 every 2 weeks. This study was registered with ClinicalTrials.gov (NCT01284413) and the UMIN Clinical Trials Registry (ID 000004468)., Results: Fifty patients enrolled between October 2011 and August 2012 were evaluated. After a median follow-up of 15.1 months (range 2.4-24.4 months), the median overall survival time was 16.2 months [95% confidence interval (CI) 10.2-22.2 months], and the one-year overall survival rate was 59.9% (95% CI 46.2-73.5%). The grade 3-4 hematological toxicities were as follows: neutropenia (32%), anemia (32%), thrombocytopenia (10%), and febrile neutropenia (4%). The common grade 3-4 non-hematological toxicities were biliary tract infection (14%), anorexia/nausea (10%), and fatigue (8%)., Conclusions: Gemcitabine/cisplatin/S-1 combination chemotherapy offered a promising survival benefit with manageable toxicity in patients with advanced BTC. A randomized phase III trial to investigate the efficacy of this regimen compared to gemcitabine/cisplatin combination therapy in patients with advanced BTC is now underway (UMIN000014371/NCT02182778).

This study was undertaken to evaluate the differences in chronotherapeutic effects of angiotensin-II receptor blockers, valsartan and olmesartan in hypertensive patients with non-dipper blood pressure (BP) pattern during valsartan at morning. Ninety four patients were enrolled, and 40 patients were judged to be non-dippers. In these patients, same dose of valsartan was changed to evening (Val-E, n = 12), or olmesartan (equivalent dose of valsartan) was given at morning (Olm-M, n = 13) or evening (Olm-E, n = 15) for 4 months. BP decreased during sleep and increased during waking hours in Val-E group. In Olm-M and Olm-E groups, BP decreased during sleep and waking hours. Percent reduction in BP at night-time compared to BP at waking hours significantly increased after changing the dose regimen in each group. Serum creatinine decreased and estimated glomerular filtration rate (eGFR) elevated in Olm-M and Olm-E, but not Val-E groups. Positive correlation between systolic BP (SBP) during sleep and serum creatinine, and negative correlation between SBP during sleep and eGFR were detected. These data suggest that dipper BP pattern could be obtained by chronotherapeutic approach using valsartan and olmesartan in non-dipper patients with valsartan at morning. Morning and evening olmesartan, but not evening valsartan improved renal function in these patients., (Copyright © 2014 Japanese Pharmacological Society. Production and hosting by Elsevier B.V. All rights reserved.)

Background: Endothelial-mesenchymal transformation (EndMT) is essential for endocardial cushion formation during cardiac morphogenesis. We recently identified Tmem100 as an endothelial gene indispensable for vascular development. In this study, we further investigated its roles for EndMT during atrioventricular canal (AVC) cushion formation., Results: Tmem100 was expressed in AVC endocardial cells, and Tmem100 null embryos showed severe EndMT defect in the AVC cushions. While calcineurin-dependent suppression of vascular endothelial growth factor (VEGF) expression in the AVC myocardium is important for EndMT, significant up-regulation of Vegfa expression was observed in Tmem100 null heart. EndMT impaired in Tmem100 null AVC explants was partially but significantly restored by the expression of constitutively-active calcineurin A, suggesting dysregulation of myocardial calcineurin-VEGF signaling in Tmem100 null heart. Moreover, Tmem100 null endocardial cells in explant culture did not show EndMT in response to the treatment with myocardium-derived growth factors, transforming growth factor β2 and bone morphogenetic protein 2, indicating involvement of an additional endocardial-specific abnormality in the mechanism of EndMT defect. The lack of NFATc1 nuclear translocation in endocardial cells of Tmem100 null embryos suggests impairment of endocardial calcium signaling., Conclusions: The Tmem100 deficiency causes EndMT defect during AVC cushion formation possibly via disturbance of multiple calcium-related signaling events., (© 2014 Wiley Periodicals, Inc.)

The FOLFIRINOX combination of chemotherapy drugs had not been fully evaluated for Japanese pancreatic cancer patients. Therefore, we carried out a phase II study to examine the efficacy and safety of FOLFIRINOX in chemotherapy-naïve Japanese patients with metastatic pancreatic cancer. FOLFIRINOX (i.v. infusion of 85 mg/m(2) oxaliplatin, 180 mg/m(2) irinotecan, and 200 mg/m(2) l-leucovorin, followed by a bolus of 400 mg/m(2) fluorouracil and a 46-h continuous infusion of 2400 mg/m(2) fluorouracil) was given every 2 weeks. The primary endpoint was the response rate. The 36 enrolled patients received a median of eight (range, 1-25) treatment cycles. The response rate was 38.9% (95% confidence interval [CI], 23.1-56.5); median overall survival, 10.7 months (95% CI, 6.9-13.2); and median progression-free survival, 5.6 months (95% CI, 3.0-7.8). Major grade 3 or 4 toxicities included neutropenia (77.8%), febrile neutropenia (22.2%), thrombocytopenia (11.1%), anemia (11.1%), anorexia (11.1%), diarrhea (8.3%), nausea (8.3%), elevated alanine aminotransferase levels (8.3%), and peripheral sensory neuropathy (5.6%). Febrile neutropenia occurred only during the first cycle. There were no treatment-related deaths. FOLFIRINOX can be a standard regimen showing favorable efficacy and acceptable toxicity profile in chemotherapy-naïve Japanese patients with metastatic pancreatic cancer., (© 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.)

Background: Standardized adjuvant therapy is not performed after major hepatectomy for biliary tract cancer (BTC) because of frequent adverse events, which may be caused by insufficient liver function. Therefore, the aim of this multicenter study (KHBO1003) was to determine the safety protocol for adjuvant chemotherapy after major hepatectomy., Methods: Within 12 weeks of R0 or R1 major hepatectomy (hemihepatectomy or trisectionectomy) for BTC, the following adjuvant chemotherapy was performed for 6 months: 800-1,000 mg/m(2) gemcitabine on days 1, 8, and 15 and then every 3-4 weeks or 40-80 mg/m(2)/day S-1 on days 1-28 and every 3-6 weeks. Major dose-limited toxicity (DLT) was defined as grade 4 hematotoxicity, grade 3/4 febrile neutropenia, grade 3/4 non-hematotoxicity, skipped gemcitabine on days 8 and 15, or halting the course at or after 14 days. Dose-escalation and de-escalation decisions were based on the continual reassessment method. Every three patients were alternately assigned to each arm., Results: Thirty-three patients (14 intrahepatic bile duct, 1 gall bladder, 18 extrahepatic bile duct) were enrolled in this study from February 2011 to July 2012 (n = 18 gemcitabine, n = 15 S-1). At 10% of DLT, the recommended dose was 1,000 mg/m(2) gemcitabine biweekly and 80 mg/m(2)/day S-1 on days 1-28 and every 6 weeks. Major DLT and adverse drug reactions were neutropenia. No grade 3 or 4 non-hematological adverse events were noted., Conclusion: We determined RDs for gemcitabine and S-1 adjuvant chemotherapy after major hepatectomy with a DLT that does not exceed 10%.

Background: The long-term prognosis for localized pancreatic cancer (PC) remains poor. Three randomized trials (GEST phase III, JACCRO PC-01 phase II and GEMSAP phase II) evaluated gemcitabine (Gem) with or without S-1 for patients with metastatic and locally advanced PC. A pooled analysis based on published data examined whether Gem with S-1 (GS) is superior to Gem alone in overall survival (OS) in patients with locally advanced PC., Methods: Data were extracted on 193 patients: 31 (JACCRO), 28 (GEMSAP), and 134 (GEST). OS was used for primary endpoint and progression-free survival (PFS) was used for secondary endpoint. A general variance-based method was used to estimate the pooled HR and 95% CI between GS (n = 96) and Gem (n = 97)., Results: Meta-analysis demonstrated that the overall risk of death was significantly different between the two chemotherapies (hazard ratio = 0.673, 95% confidence interval: 0.488-0.929, P = 0.016). The median PFSs for GS and GEM in the JACCRO, GEMSAP, and GEST studies were 12.0, 12.6, and 10.7 months, and 4.1, 8.1, and 6.2 months, respectively (P = 0.001). The random-effect pooled estimate for 165 patients showed the objective response rate (ORR) in the GS group (28.4%) was better in the Gem group (8.3%, P = 0.001)., Conclusions: GS improved ORR, PFS and OS in patients with locally advanced PC over Gem alone. GS could become one of the front-line chemotherapeutic agents., (© 2014 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Purpose: We conducted a phase I study to determine the maximum tolerated dose and recommended dose (RD) of this gemcitabine plus cisplatin (GC) combination in the adjuvant setting for biliary tract cancer (BTC). GC has become a standard chemotherapy regimen for patients with locally advanced or metastatic BTC; however, the benefit of adjuvant therapy for BTC is unclear., Methods: Patients with BTC were eligible if they met the following criteria: Stage IB or higher; and undergoing resection without major hepatectomy. The starting dose matched the standard dose of gemcitabine (1,000 mg/m(2)) and cisplatin (25 mg/m(2)) on days 1 and 8, every 3 weeks for up to 24 weeks. The dose limiting toxicities (DLTs) were determined during the first 6 weeks, and a 3+3 dose finding design with cohorts of 3-6 patients was used. Further cohort expansion took place., Results: One DLT, namely grade 4 neutropenia, was observed among six patients at the starting dosages. Then, we expanded the cohort with a total of eighteen patients to evaluate RD and no further DLTs were observed. During the entire study, the most common grade 3/4 adverse events were neutropenia (94 %) and leucopenia (56 %). Non-hematological toxicities were manageable., Conclusions: We defined the standard dose of GC as the RD for adjuvant chemotherapy for BTC treated by curative resection without major hepatectomy. Further study is warranted to clarify the safety and efficacy of this regimen for all patients.

Background and Aim: Few studies have reported the efficacy and safety of palliative chemotherapy in elderly patients with advanced biliary tract cancer. We aimed to investigate the clinical outcomes of palliative chemotherapy for advanced biliary tract cancer in elderly patients., Methods: We retrospectively evaluated 403 consecutive patients who received palliative chemotherapy between April 2006 and March 2009 for pathologically confirmed unresectable or recurrent biliary tract cancer. Clinical outcomes of the elderly group (≥ 75 years old; n = 94) were compared with those of the non-elderly group (< 75 years old; n = 309)., Results: Except for the extent of disease, patient baseline characteristics were well balanced between both groups. The median overall survival was 10.4 months in the elderly group and 11.5 months in the non-elderly group (hazard ratio, 1.14; 95% confidence interval, 0.89-1.45; P = 0.31). Although the frequency of adverse events between both groups was similar, interstitial pneumonitis was significantly more frequent in the elderly group than in the non-elderly group (4.3% vs 0%, P < 0.01)., Conclusions: In advanced biliary tract cancer, overall survival of elderly patients receiving palliative chemotherapy is comparable with that of non-elderly patients. To our knowledge, this is one of the largest studies that have reported the clinical outcomes of elderly patients following palliative chemotherapy., (© 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.)

Background: Prognostic factors for patients with advanced biliary tract cancer (BTC) who received palliative chemotherapy have not been fully established. Especially, the status of unresectable/recurrent disease has not been well studied because of a small number of patients with recurrent BTC in previous studies., Methods: This multicenter retrospective study was conducted in 18 institutions in Japan. We retrospectively reviewed data regarding 403 patients with pathologically proven BTC who received palliative chemotherapy between April 2006 and March 2009. One hundred and ninety-two patients with recurrent BTC were included. Univariate and multivariate analyses were performed to identify prognostic factors., Results: The median overall survival was significantly longer in the recurrent BTC patients than in the unresectable BTC patients (398 days vs. 323 days, P = 0.004). After adjustment using multivariate analysis, the status of recurrent/unresectable disease remained an independent prognostic factor (hazard ratio 1.33, 95% confidence interval 1.04-1.70, P = 0.022) in addition to performance status, extent of disease, carbohydrate antigen 19-9 levels, and carcinoembryonic antigen levels., Conclusions: The status of unresectable/recurrent disease was shown as an independent prognostic factor in the BTC patients. This result may help to predict life expectancy of BTC patients and design future clinical trials evaluating palliative chemotherapy in BTC., (© 2013 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Objective: To evaluate the outcome of preoperative gemcitabine-based chemoradiation therapy (CRT) for resectable and borderline resectable pancreatic cancer (PC), with a focus on the differences in surgical outcomes and patterns of recurrence between these 2 categories., Background: Various multimodal treatment strategies have been proposed to improve the surgical outcomes of PC. Preoperative CRT and subsequent surgery is one of the promising strategies for resectable (PC-R) and borderline resectable (PC-BR) PC., Methods: A total of 268 patients with PC-R and PC-BR received preoperative gemcitabine-based CRT. The numbers of PC-R and PC-BR cases were 188 and 80, respectively. We evaluated the following comparisons between patients with PC-R and those with PC-BR: (1) resection rate, (2) rate of margin-negative resection, (3) survival, and (4) pattern of the treatment failure, including local recurrence, peritoneal dissemination, and distant metastasis., Results: The resection rate of patients with PC-R (87%) was higher than that of patients with PC-BR (54%) (P < 0.001). Pathological margin-negative resection was achieved in 99% and 98% of the patients with PC-R and PC-BR, respectively. The 5-year survival rates of the PC-R and PC-BR cases were 57% and 34%, respectively (P = 0.029). Although the 5-year cumulative incidence of local recurrence was comparable in both groups (15% and 13%, respectively; P = 0.508), the 5-year cumulative incidence of peritoneal and distant recurrence was significantly higher in the patients with PC-BR (43 and 76%) than in the patients with PC-R (17% and 43%)., Conclusions: In the resected cases, the locoregional control was comparable between patients with PC-R and PC-BR after preoperative CRT. The survival rate for the patients with PC-BR was lower than the rate for those with PC-R due to a higher incidence of peritoneal and distant recurrence in the patients with PC-BR. (UMIN000001804).

Background: Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is an accurate method for cytological confirmation of pancreatic malignancy, but peritoneal dissemination caused by EUS-FNA could be a matter of concern because it may lead to poorer prognosis. Our aim was to estimate the risk of peritoneal carcinomatosis by EUS-FNA for pancreatic cancer., Methods: Two hundred and seventeen patients with cytopathologically proven pancreatic cancer in a tertiary referral center were retrospectively reviewed. They were divided into two groups: 161 patients who underwent endoscopic retrograde cholangiopancreatography (ERCP) alone (ERCP group), and 56 patients who had ever undergone EUS-FNA (EUS-FNA group). Peritoneal carcinomatosis was diagnosed by computed tomography and/or cytology during follow-up. Hazard ratios of factors including EUS-FNA for the development of peritoneal carcinomatosis were analyzed by the Cox proportional hazard model., Results: There was no significant difference in baseline characteristics between ERCP and EUS-FNA groups. Peritoneal carcinomatosis developed in 14.9 % (24/161) during an average follow-up period of 545 days, and 17.9 % (10/56) during 599 days among ERCP and EUS-FNA group, respectively. The EUS-FNA was not identified as a significant risk factor with hazard ratios (HR) of 1.07 [95 % confidence interval (CI) 0.51-2.25, p = 0.85] by univariate analysis and 1.35 (95 % CI 0.62-2.95, p = 0.45) by multivariate analysis. Nodal involvement (HR 2.19, 95 % CI 1.03-4.63, p = 0.04) and non-resection (HR 2.64, 95 % CI 1.11-6.25, p = 0.03) were shown to be statistically significant risk factors by multivariate analysis., Conclusions: EUS-FNA for pancreatic cancer did not significantly increase the risk of peritoneal carcinomatosis.

Purpose: The present phase III study was designed to investigate the noninferiority of S-1 alone and superiority of gemcitabine plus S-1 compared with gemcitabine alone with respect to overall survival., Patients and Methods: The participants were chemotherapy-naive patients with locally advanced or metastatic pancreatic cancer. Patients were randomly assigned to receive only gemcitabine (1,000 mg/m(2) on days 1, 8, and 15 of a 28-day cycle), only S-1 (80, 100, or 120 mg/d according to body-surface area on days 1 through 28 of a 42-day cycle), or gemcitabine plus S-1 (gemcitabine 1,000 mg/m(2) on days 1 and 8 plus S-1 60, 80, or 100 mg/d according to body-surface area on days 1 through 14 of a 21-day cycle)., Results: In the total of 834 enrolled patients, median overall survival was 8.8 months in the gemcitabine group, 9.7 months in the S-1 group, and 10.1 months in the gemcitabine plus S-1 group. The noninferiority of S-1 to gemcitabine was demonstrated (hazard ratio, 0.96; 97.5% CI, 0.78 to 1.18; P < .001 for noninferiority), whereas the superiority of gemcitabine plus S-1 was not (hazard ratio, 0.88; 97.5% CI, 0.71 to 1.08; P = .15). All treatments were generally well tolerated, although hematologic and GI toxicities were more severe in the gemcitabine plus S-1 group than in the gemcitabine group., Conclusion: Monotherapy with S-1 demonstrated noninferiority to gemcitabine in overall survival with good tolerability and presents a convenient oral alternative for locally advanced and metastatic pancreatic cancer.

Objective: When gemcitabine was approved as an anti-cancer drug, there were limited data for Japanese patients treated with gemcitabine. Generally, advanced or metastatic pancreatic cancer patients experience poor prognosis and suffer from debilitating disease-related symptoms. Reports and information on gemcitabine use within a large patient pool will be beneficial to aid physicians. Therefore, this post-marketing surveillance was conducted as a non-interventional, observational study on the use of gemcitabine in a clinical practice setting in Japan., Methods: Patients had no previous treatment with gemcitabine and were diagnosed with pancreatic cancer by an attending physician. Patients were registered between May 2001 and December 2003 in Japan. The patients were treated with gemcitabine. Data such as patient background, treatment details, adverse events, tumor response, serum CA19-9 levels and drug-related symptom improvement were assessed., Results: Of the 890 patients registered for the study, 855 were included in the analysis of gemcitabine for safety. Four hundred and forty-three (51.9%) patients reported drug-related adverse events, with 97 patients (11.4%) experiencing serious adverse events. The incidence of interstitial lung disease was 0.7% (six patients). Six hundred patients were evaluated for tumor response. The overall response rate was 6.0% and the disease control rate was 54.0%. CA19-9 decreased in 63.6% of the 335 evaluable patients, with a ≥75% decrease seen in 19.4% of the total group. Drug-related symptom improvement was observed in 27.0% of the 686 evaluable patients., Conclusions: This large-scale surveillance could confirm the safety of gemcitabine for Japanese pancreatic cancer patients as well as elucidate the efficacy profile, measured by drug-related symptom improvement, for Japanese pancreatic cancer patients.

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., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background/aims: Our aim was to investigate how 2cm or smaller pancreatic cancers were detected successfully in recent years., Methodology: Diagnostic clues and subsequent examinations that detected 15 histologically confirmed 2 cm or smaller pancreatic cancers were reviewed., Results: Diagnostic clues were imaging findings in 6 patients, symptoms in 5 and laboratory data in 4. Six of 8 patients who had risk factors of pancreatic cancer such as pancreatic cyst, dilated main pancreatic duct, pancreatitis, or diabetes had been followed-up by imaging and laboratory examinations. Five patients with extrapancreatic disease had been followed-up chiefly by laboratory examinations. The remaining 2 had neither of them. Detectabilities of pancreatic mass in US, CT and EUS were 89%, 67% and 100%, respectively; those of pancreatic mass and/or dilated main pancreatic duct were 100% in all three modalities. Cytological examination revealed adenocarcinoma preoperatively in 14 patients (93%)., Conclusions: Small pancreatic cancer of 2 cm or smaller were suggested by symptoms, laboratory data, or imaging examinations. They were confirmed by further examinations including cytology.

Members of the transforming growth factor-β superfamily play essential roles in various aspects of embryonic development and physiological organ function. Among them, bone morphogenetic protein (BMP) 9 and BMP10 regulate embryonic vascular development by activating their endothelial receptor ALK1 (activin receptor-like kinase 1, also called Acvrl1). ALK1-mediated intracellular signaling is implicated in the etiologies of human diseases, but their downstream functional proteins are largely unknown. In this study, we identified Tmem100, a gene encoding a previously uncharacterized intracellular transmembrane protein, to be an embryonic endothelium-enriched gene activated by BMP9 and BMP10 through the ALK1 receptor. Tmem100 null mice showed embryonic lethality due to impaired differentiation of arterial endothelium and defects of vascular morphogenesis, which phenocopied most of the vascular abnormalities observed with the Acvrl1/Alk1 deficiency. The activity of Notch- and Akt-mediated signaling, which is essential for vascular development, was down-regulated in Tmem100 null mice. Cre-mediated deletion of Tmem100 in endothelial cells was sufficient to recapitulate the null phenotypes. These data indicated that TMEM100 may play indispensable roles downstream of BMP9/BMP10-ALK1 signaling during endothelial differentiation and vascular morphogenesis.

Background: Among the more common human malignancies, invasive ductal carcinoma of the pancreas has the worst prognosis. The poor outcome seems to be attributable to difficulty in early detection., Methods: We compared the plasma protein profiles of 112 pancreatic cancer patients with those of 103 sex- and age-matched healthy controls (Cohort 1) using a newly developed matrix-assisted laser desorption/ionization (oMALDI) QqTOF (quadrupole time-of-flight) mass spectrometry (MS) system., Results: We found that hemi-truncated apolipoprotein AII dimer (ApoAII-2; 17252 m/z), unglycosylated apolipoprotein CIII (ApoCIII-0; 8766 m/z), and their summed value were significantly decreased in the pancreatic cancer patients [P = 1.36×10(-21), P = 4.35×10(-14), and P = 1.83×10(-24) (Mann-Whitney U-test); area-under-curve values of 0.877, 0.798, and 0.903, respectively]. The significance was further validated in a total of 1099 plasma/serum samples, consisting of 2 retrospective cohorts [Cohort 2 (n = 103) and Cohort 3 (n = 163)] and a prospective cohort [Cohort 4 (n = 833)] collected from 8 medical institutions in Japan and Germany., Conclusions: We have constructed a robust quantitative MS profiling system and used it to validate alterations of modified apolipoproteins in multiple cohorts of patients with pancreatic cancer.

Background: The aim of this study was to identify a new plasma biomarker for use in early detection of colorectal cancer., Methods: Using the combination of hollow fiber membrane (HFM)-based low-molecular weight protein enrichment and two-dimensional image converted analysis of liquid chromatography and mass spectrometry (2DICAL), we compared the plasma proteome of 22 colorectal cancer patients with those of 21 healthy controls. An identified biomarker candidate was then validated in two larger cohorts [validation-1 (n = 210) and validation-2 (n = 113)] using a high-density reverse-phase protein microarray., Results: From a total of 53,009 mass peaks, we identified 103 with an area under curve (AUC) value of 0.80 or higher that could distinguish cancer patients from healthy controls. A peak that increased in colorectal cancer patients, with an AUC of 0.81 and P value of 0.0004 (Mann-Whitney U test), was identified as a product of the PLIN2 gene [also known as perilipin-2, adipose differentiation-related protein (ADRP), or adipophilin]. An increase in plasma adipophilin was consistently observed in colorectal cancer patients, including those with stage I or stage II disease (P < 0.0001, Welch's t test). Immunohistochemical analysis revealed that adipophilin is expressed primarily in the basal sides of colorectal cancer cells forming polarized tubular structures, and that it is absent from adjacent normal intestinal mucosae., Conclusions: Adipophilin is a plasma biomarker potentially useful for the detection of early-stage colorectal cancer., Impact: The combination of HFM and 2DICAL enables the comprehensive analysis of plasma proteins and is ideal for use in all biomarker discovery studies., (©2011 AACR)

Recent studies have reported that pancreatic ductal carcinomas are frequently found during the follow-up of pancreatic cysts distinct from carcinoma; however, the majority of them are detected in advanced stages. Therefore, the early detection of metachronous ductal carcinomas is one of the issues in the management of pancreatic cysts. A 25-mm pancreatic cyst in the pancreatic head was found during an annual check-up in a 70-year-old woman. She was followed up every 6 months by abdominal ultrasound (US) and blood tests, and every 12 months by an additional magnetic resonance imaging scan. Twelve months later, abdominal US revealed a suspicious low-echoic area of 17 mm diameter in the pancreatic body. Eighteen months later, her serum carbohydrate antigen 19-9 level rose to 92 U/ml. Endoscopic retrograde pancreatography demonstrated a strictured main pancreatic duct (MPD) of 15 mm in length in the pancreatic body. A cytological examination of the brushed MPD revealed adenocarcinoma. The patient underwent distal pancreatectomy and splenectomy after chemoradiotherapy. An histological examination revealed a ductal carcinoma of 26 mm diameter in the pancreatic body, which was successfully resected. This case might help to establish an optimal surveillance method to detect metachronous ductal carcinomas arising from the pancreas harboring cystic lesions.

The development of a new plasma biomarker for early detection would be necessary to improve the overall outcome of colorectal cancer. Here we report the identification and validation of the ninth component of complement (C9) as a novel plasma biomarker for colorectal cancer by cutting-edge proteomic technologies. Plasma proteins were enzymatically digested into a large array of peptides, and the relative quantity of a total of 94,803 peptide peaks was compared between 31 colorectal cancer patients and 59 age/sex-matched healthy controls using 2D image-converted analysis of liquid chromatography and mass spectrometry. The selected biomarker candidates were validated in 345 subjects (115 colorectal cancer patients and 230 age/sex-matched healthy controls) using high-density reverse-phase protein microarrays. Plasma levels of Apo AI and C9 in colorectal cancer patients significantly differed from healthy controls with P values of 7.94×10(-4) and 1.43×10(-12) (Student's t-test), respectively. In particular, C9 was elevated in patients with colorectal cancer, including those with stage-I and -II diseases (P=3.01×10(-3) and P=1.13×10(-5) , respectively). Although the significance of the present study must be validated in an independent clinical study, the increment of plasma C9 may be applicable to the early detection of colorectal cancer., (© 2010 Japanese Cancer Association.)

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/m(2) 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 © 2011 Elsevier Ltd. All rights reserved.)

Erlotinib combined with gemcitabine has not been evaluated in Japanese patients with unresectable pancreatic cancer. This two-step phase II study assessed the safety and pharmacokinetics of erlotinib 100 mg/day (oral) plus gemcitabine 1000 mg/m(2) (i.v. days 1, 8, 15) in a 28-day cycle in the first step, and efficacy and safety in the second step. The primary end-point was safety. One hundred and seven patients were enrolled (first step, n = 6; second step, n = 101). The most common adverse event was RASH (compiled using the preferred terms rash, acne, exfoliative rash, dermatitis acneiform, erythema, eczema, dermatitis and pustular rash) in 93.4% of patients. One treatment-related death occurred. While interstitial lung disease-like events were reported in nine patients (8.5%; grade 1/2/3, 3.8/2.8/1.9%), all patients recovered or improved. The median overall survival, the 1-year survival rate and median progression-free survival were 9.23 months, 33.0% and 3.48 months, respectively. The overall response and disease control rates were 20.3% and 50.0%, respectively. In Japanese patients with unresectable pancreatic cancer, erlotinib plus gemcitabine had acceptable toxicity and efficacy that was not inferior to that seen in Western patients., (© 2010 Japanese Cancer Association.)