Yasunari Sakamoto

C-Reactive Protein Level Is an Indicator of the Aggressiveness of Advanced Pancreatic Cancer.

Objectives This study investigated the ability of serum levels of C-reactive protein (CRP) to stratify the aggressiveness of advanced pancreatic cancer (PCa), including poor outcomes, systemic weakness, and extent of the disease in patients receiving first-line chemotherapy. Methods The prognostic CRP classification was constructed in the retrospective cohort, consisting of advanced PCa patients with first-line gemcitabine monotherapy (GEM). Stratification using the prognostic CRP classification was validated for relationships with the aggressiveness of advanced PCa in the prospective cohort, consisting of treatment-naive patients without obvious infections who received first-line GEM or GEM-based regimens. Results C-reactive protein low (<0.5 mg/dL), intermediate (≥0.5 and <2.0 mg/dL), and high (≥2.0 mg/dL) related good, moderate, and poor survival, respectively, and were independent predictors of survival in multivariate analyses among the 280 patients in the retrospective cohort and the 141 patients in the prospective cohort. Low Karnofsky Performance Status, hypoalbuminemia, anemia, and large tumor burden were more common in the high CRP group than in the low CRP group. The intermediate CRP group showed a larger burden of tumor than the low CRP group. Conclusions C-reactive protein stratified the outcomes, systemic weakness, and tumor burden. C-reactive protein is an indicator of the aggressiveness of advanced PCa.

Utility of Assessing the Number of Mutated kras , cdkn2a , tp53 , and smad4 Genes Using a Targeted Deep Sequencing Assay as a Prognostic Biomarker for Pancreatic Cancer

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

Pancreatic neuroendocrine tumors: a single-center 20-year experience with 100 patients

BACKGROUND/OBJECTIVESnPancreatic neuroendocrine neoplasms (NENs) are rare tumors, exhibiting several morphological, functional, and behavioral characteristics. However, only few reports have evaluated large case series of pancreatic NEN.nnnMETHODSnWe conducted a retrospective review of 100 consecutive patients with pancreatic NEN diagnosed pathologically and treated at the National Cancer Center Hospital between 1991 and 2010.nnnRESULTSnThe study included 48 males and 52 females (median age: 55 years). Fourteen patients had clinical symptoms caused by excess hormone secretion at diagnosis. Twelve patients were diagnosed with neuroendocrine tumor (NET) G1, 54 with NET G2, and 32 with neuroendocrine carcinoma (NEC) as per the 2010 World Health Organization classification. Distant metastases were observed in 25%, 43%, and 84% of the patients with NET G1, NET G2, and NEC, respectively. Serum levels of neuron-specific enolase and lactate dehydrogenase significantly increased in patients with NEC compared with those in patients with NET G1/G2. The 5-year survival rates of patients with NET G1, NET G2, and NEC were 91%, 69%, and 10%, respectively. Good performance status (PS), lower stage, and histopathological grade were identified as independent favorable prognostic factors.nnnCONCLUSIONSnPatients with NET G1/G2 treated with surgical resection had a good prognosis. Most patients with NEC exhibited distant metastases and had a poor prognosis. Staging classification and the WHO 2010 grading are important factors for selecting the appropriate treatment strategy and predicting prognosis for patients with pancreatic NEN.

Cytotoxic chemotherapy for pancreatic neuroendocrine tumors.

Advanced neuroendocrine tumors are incurable, and most patients will succumb to the disease. Chemotherapies with cytotoxic agents such as streptozocin, 5‐fluorouracil, or temozolomide have been frequently used as drug therapies for neuroendocrine tumors. Streptozocin, which is the only approved cytotoxic agent available for the treatment of this disease in many countries, has been considered a key agent for the treatment of advanced neuroendocrine tumors based on the results of phase III studies. However, the widespread acceptance of streptozocin‐based chemotherapy for this indication has been limited by concerns regarding toxicity. Recent prospective and retrospective studies showed the promising activity of a temozolomide‐based regimen, although an adequate prospective controlled study defining the role of temozolomide in the treatment of neuroendocrine tumors is lacking. The promising activity of cytotoxic agents awaits confirmation; solid evidence‐based recommendations and treatment decisions are needed for the optimal use of chemotherapy against this disease.

Phase I study on the safety, pharmacokinetic profile, and efficacy of the combination of TSU-68, an oral antiangiogenic agent, and S-1 in patients with advanced hepatocellular carcinoma.

SummaryPurpose We aimed to investigate the recommended dose for the combination of TSU-68, a multiple-receptor tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor-2 and platelet-derived growth factor receptor-β, and S-1, an oral fluoropyrimidine, in patients with advanced hepatocellular carcinoma (HCC) based on its associated dose-limiting toxicity (DLT) frequency. We also determined the safety, tolerability, pharmacokinetics (PK), and efficacy of the combination treatment. Patients and methods Patients without any prior systemic therapy received 400xa0mg/day TSU-68 orally and 80xa0mg/day (level 1) or 100xa0mg/day (level 2) S-1 for 4 or 2xa0weeks followed by a 2- or 1-week rest period (groups A and B, respectively). According to the treatment, patients progressed from level 1B to level 2A, then level 2B. Safety and response rates were assessed. Results Eighteen patients were enrolled. Two patients at levels 1B and 2A but none at level 2B showed DLTs. The common adverse drug reactions were a decrease in hemoglobin levels, hypoalbuminemia, and anorexia, which were mild in severity (grades 1–2). PK data from levels 1B and 2A indicated that the area under the curve for TSU-68 and 5-fluorouracil was unlikely to be affected by the combination treatment. Response rate, disease control rate, median time to progression, and median overall survival were 27.8xa0%, 61.1xa0%, 5.3xa0months, and 12.8xa0months, respectively. Conclusion The recommended dose for advanced HCC should be 400xa0mg/day TSU-68 and 100xa0mg/dayxa0S-1 for 4xa0weeks followed by 2-week rest.

An Oncogenic ALK Fusion and an RRAS Mutation in KRAS Mutation‐Negative Pancreatic Ductal Adenocarcinoma

PURPOSEnOncogenic mutations in the KRAS gene are a well-known driver event, occurring in >95% of pancreatic cancers. The objective of this study was to identify driver oncogene aberrations in pancreatic cancers without the KRAS mutation.nnnMETHODSnWhole-exome and transcriptome sequencing was performed on four cases of KRAS mutation-negative pancreatic ductal adenocarcinoma, which were identified in a cohort of 100 cases.nnnRESULTSnOne case harbored an oncogenic DCTN1-ALK fusion. The fusion gene enabled interleukin-3-independent growth of Ba/F3 cells and rendered them susceptible to the anaplastic lymphoma kinase tyrosine kinase inhibitors crizotinib and alectinib. The structure of the breakpoint junction indicated that the fusion was generated by nonhomologous end joining between a segment of DCTN1 exon DNA and a segment of ALK intron DNA, resulting in the generation of a cryptic splicing site. Another case harbored an oncogenic RRAS mutation that activated the GTPase of the RRAS protein.nnnCONCLUSIONnRare oncogenic aberrations, such as the ALK fusion and RRAS mutation, may drive pancreatic carcinogenesis independent of the KRAS mutation. The Oncologist 2017;22:158-164Implications for Practice: The oncogenic DCTN1-ALK fusion and the RRAS mutation were associated with the development of pancreatic ductal adenocarcinoma (PDAC) in the absence of the KRAS mutation. Constitutional activation of DCTN1-ALK fusion protein was suppressed by the anaplastic lymphoma kinase tyrosine kinase inhibitors crizotinib and alectinib. Thus, a small subset of PDAC patients might benefit from therapy using these inhibitors.

Phase I clinical trial of oral administration of S-1 in combination with intravenous gemcitabine and cisplatin in patients with advanced biliary tract cancer

OBJECTIVEnThis study aimed to determine the maximum tolerated dose and the recommended dose of combining S-1 with gemcitabine and cisplatin for advanced biliary tract adenocarcinoma first-line therapy.nnnMETHODSnChemotherapy-naive patients with histologically or cytologically proven unresectable or metastatic biliary tract adenocarcinoma were enrolled. Patients with advanced biliary tract adenocarcinoma received gemcitabine and cisplatin intravenously on Days 1 and 8 and S-1 orally twice daily from Days 1 to 14. Cycles were repeated every 21 days until disease progression. Patients were scheduled to receive gemcitabine (mg/m(2)/week), cisplatin (mg/m(2)/week) and S-1 (mg/m(2)/day) at four dose levels: 800/25/40 (level 0), 1000/25/40 (level 1), 1000/25/60 (level 2) and 1000/25/80 (level 3). Level 1 was chosen as the starting dose. For cases where recommended dose could not be determined within the triweekly schedule, we prepared a biweekly schedule to find recommended dose.nnnRESULTSnSeventeen patients with advanced biliary tract adenocarcinoma were treated across three dose levels. Maximum tolerated dose and recommended dose were defined as level 0. Dose-limiting toxicities included a Grade 3 maculopapular rash, Grade 4 thrombocytopenia and consecutive administration skips of gemcitabine and cisplatin on Day 8. Five partial responses were observed.nnnCONCLUSIONSnThis triweekly triplet regimen was well tolerated and showed promising antitumor activity in patients with advanced biliary tract adenocarcinoma. We recommend level 0, gemcitabine at 800 mg/m(2)/week, cisplatin at 25 mg/m(2)/week and S-1 at 40 mg/m(2)/day during a 21-day cycle, in further studies with this schedule.

Efficacy markers for cisplatin and S-1 in biliary tract carcinoma.

334 Background: Gemcitabine (GEM) + cisplatin (CDDP) combination chemotherapy is the first choice for advanced biliary tract carcinoma (BTC). In Japan, the GEM + S-1 therapy has shown promise for the treatment of BTC. Our aim was to investigate the cytotoxic effects of GEM, CDDP and S-1 on BTC cell lines and find an immunohistochemical marker for predicting the efficacy of chemotherapy. Methods: We evaluated the efficacy of GEM, CDDP, and S-1 by means of the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay of 17 BTC cell lines. Furthermore, we subdivided the cell lines into sensitive and insensitive groups on the basis of the sensitivity of each drug. Moreover, pairwise studies were conducted using the MTT assay, Bliss additivism model, and Combination Index for analysis. Immunohistochemical expression analysis of excision repair cross-complementation group 1 (ERCC1), thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), orotate phosphoribosyltransferase (OPRT), and thy...

689PGENE MUTATION PROFILE OF PANCREATIC CANCER OBTAINED USING TARGETED DEEP SEQUENCING AND ITS ASSOCIATION WITH PROGNOSIS

ABSTRACT Aim: Activating KRAS mutations are the major driver gene aberrations of pancreatic cancer and are present in over 90% of patients with pancreatic cancer. On the other hand, aberrations of the CDKN2A, TP53, and SMAD4 genes are also frequent events in pancreatic carcinogenesis. We constructed a mutation profile of pancreatic cancer-associated genes. Additionally, we analyzed the relationship between gene mutations and clinicopathological factors. Methods: Genomic DNA samples were extracted from fresh frozen surgical specimens obtained from 100 patients (98 with pancreatic ductal adenocarcinoma, 2 with adenosquamous carcinoma) who underwent radical operations for pancreatic cancer at the National Cancer Center Hospital between March 2005 and June 2012. Next-generation sequencer-based targeted deep sequencing was performed using a Cancer Panel reagent that covers representative cancer-related genes (50 genes, 190 hot spots). Results: Mutations were detected in 97% of the cases, and the average number of mutations per tumor sample was 1.6. The most frequently mutated genes were KRAS (96%), TP53 (42%), SMAD4 (13%), and CDKN2A (7%). The most common mutation types of KRAS were G12D (48%), G12V (32%), and G12R (10%) in our cohort. The known druggable mutations that were detected were GNAS (1%), PIK3CA (1%), and KIT (1%). Among the patients who underwent radical operations followed by adjuvant chemotherapy (71 patients), the survival of patients who had 0 to 2 mutations in the 4 major driver genes (KRAS, TP53, SMAD4, and CDKN2A) was significantly longer than that of patients who had 3 or more mutations (median overall survival, 40.0 months vs. 12.6 months, P = 0.0020). A multivariate Cox proportional hazard model analysis showed that a low number of mutations among these 4 genes was significantly associated with a better prognosis. Conclusions: KRAS, TP53, SMAD4, and CDKN2A were the most frequently mutated genes in Japanese patients with pancreatic cancer. The number of mutations among these 4 genes as detected using targeted deep sequencing may be a useful biomarker for the prediction of postoperative outcomes. Disclosure: All authors have declared no conflicts of interest.

A phase I and pharmacokinetic clinical trial of oral administration of the acyclic retinoid NIK-333

3108 Background: NIK-333 is an acyclic retinoid, polyprenoic acid, that prevents recurrence of hepatocellular carcinoma (HCC) after curative treatment (New Eng J Med 334:1561). We are conducting cl...