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Aikawa N.,Keio University | Shimazaki S.,Kyorin University | Yamamoto Y.,Tokyo Rinkai Hospital | Saito H.,Nagoya Central Hospital | And 5 more authors.
Shock | Year: 2011

To investigate treatment effects of thrombomodulin alfa (TM-α) in patients with disseminated intravascular coagulation (DIC) having infection as the underlying disease, retrospective subanalysis of a double-blind, randomized controlled phase 3 trial was conducted. In the phase 3 trial, 227 DIC patients (full-analysis set) having infection and/or hematologic malignancy as the underlying disease received either TM-α (0.06 mg·kg-1 for 30 min once daily) or heparin (8 U·kg-1·h -1 for 24 h) for 6 days using the double-dummy method. Among these patients, 147 patients with noninfectious comorbidity leading to severe thrombocytopenia (e.g., hematologic malignancy, or aplastic anemia) were excluded from the present analysis, and 80 patients with infectious disease and DIC were extracted and subjected to the present retrospective subanalysis. Disseminated intravascular coagulation resolution rates were determined using the DIC diagnostic criteria for critically ill patients at 7 days, and mortality rates were evaluated at 28 days. In the TM-α and heparin groups, DIC resolution rates were 67.5% (27/40) and 55.6% (20/36), and 28-day mortality rates were 21.4% (9/42) and 31.6% (12/38), respectively. Mortality rates of patients who recovered from DIC were 3.7% (1/27) in the TM-α group and 15% (3/20) in the heparin group. These results suggest TM-α may be valuable in the treatment of DIC associated with infection. Copyright © 2011 by the Shock Society. Source


Kato K.,National Cancer Center Hospital | Chin K.,Cancer Institute Hospital Tokyo | Yoshikawa T.,Kanagawa Cancer Center | Yamaguchi K.,Saitama Cancer Center | And 8 more authors.
Investigational New Drugs | Year: 2012

Purpose NK105 is a new drug delivery system formulation for paclitaxel (PTX) whose recommended dose (RD) is 150 mg PTX equivalent/m 2 administered every 3 weeks, as determined in a phase I trial. This study aimed to evaluate the efficacy and safety of NK105 in patients with advanced gastric cancer after failure of first-line chemotherapy. Experimental design Eligible patients had measurable disease and one chemotherapeutic regimen except taxane. NK105 (150 mg PTX equivalent/m 2) was administered by a 30-minute intravenous infusion every 3 weeks without antiallergic premedication until disease progression, unacceptable toxicity or patient refusal. The primary efficacy endpoint was best overall response rate (ORR) post baseline. The secondary endpoints were progression-free survival (PFS), time to treatment failure (TTF) and overall survival (OS). All adverse events were reported using CTCAE v3.0. Results Between November 2007 and July 2009, 57 patients were enrolled and 56 were evaluable for efficacy. Two complete responses and 12 partial responses were observed for an ORR of 25%. The median PFS was 3.0 months, the median TTF was 2.8 months, and the median OS was 14.4 months. Drug related toxicity was mainly mild (grades 1-2) to severe (grades 3-4); other data: neutropenia (64.9%); leukopenia (17.5%); lymphopenia (8.8%); neuropathysensory (1.8%); fatigue (3.5%); and stomatitis (1.8%). There were no treatment-related deaths. Conclusions This study of NK105 (150 mg PTX equivalent/m 2) proves the concept for the modest activity and tolerability of a new drug delivery system formulation for PTX. A phase III trial will be evaluated to clarify survival benefit. © Springer Science+Business Media, LLC 2011. Source


Hirakawa M.,Sapporo Medical University | Sato Y.,Sapporo Medical University | Ohnuma H.,Sapporo Medical University | Takayama T.,Tokushima University | And 19 more authors.
Cancer Chemotherapy and Pharmacology | Year: 2013

Purpose: The combination of docetaxel, cisplatin, and S-1 (DCS) chemotherapy is expected to be a promising regimen for advanced gastric cancer. This study was performed to evaluate the efficacy and safety of neoadjuvant DCS chemotherapy for locally advanced resectable gastric cancer. Methods: Patients with locally advanced gastric cancer received 2 courses of preoperative chemotherapy with S-1 (40 mg/m2 b.i.d.) on days 1-14 and docetaxel (60 mg/m2) plus cisplatin (60 mg/m2) on day 8 every 3 weeks, followed by standard curative surgery within 4-8 weeks. The primary endpoint was R0 resectability. Expression of damage DNA binding protein complex subunit 2 (DDB2)/excision repair cross-complementing 1 (ERCC1) in the pretreated tumor tissues was examined by immunohistochemistry. Results: A total of 43 patients received neoadjuvant chemotherapy. The response rate was 74.4 %, and disease control ratio was 100 %. Grade 4 neutropenia developed in 53.5 % of patients and febrile neutropenia in 16.3 %. Non-hematological grade 3/4 adverse events were anorexia (23.3 %), nausea (14.0 %), and diarrhea (23.3 %), but these were generally transient and manageable. The proportion of R0 resections in the 43 eligible patients was 90.7 %, and a pathological response was found in 65.9 % of patients. There were no treatment-related deaths and no major surgical complications. The accuracy of the combination of DDB2 and ERCC1 expression for predicting chemoresistance was 82.5 %. Conclusions: Preoperative treatment with DCS combination for locally advanced gastric cancer demonstrated a sufficient R0 resection rate and a good pathological response with manageable toxicities. The DDB2/ERCC1-high phenotype, as determined by immunohistochemistry, may be useful predictor of resistance to DCS chemotherapy. © 2013 Springer-Verlag Berlin Heidelberg. Source


Oyamada M.,Fuji Womens University | Takebe K.,Fuji Womens University | Oyamada Y.,Tonan Hospital
Biochimica et Biophysica Acta - Biomembranes | Year: 2013

Gap junctions are specialized cell-cell junctions that directly link the cytoplasm of neighboring cells. They mediate the direct transfer of metabolites and ions from one cell to another. Discoveries of human genetic disorders due to mutations in gap junction protein (connexin [Cx]) genes and experimental data on connexin knockout mice provide direct evidence that gap junctional intercellular communication is essential for tissue functions and organ development, and that its dysfunction causes diseases. Connexin-related signaling also involves extracellular signaling (hemichannels) and non-channel intracellular signaling. Thus far, 21 human genes and 20 mouse genes for connexins have been identified. Each connexin shows tissue- or cell-type-specific expression, and most organs and many cell types express more than one connexin. Connexin expression can be regulated at many of the steps in the pathway from DNA to RNA to protein. In recent years, it has become clear that epigenetic processes are also essentially involved in connexin gene expression. In this review, we summarize recent knowledge on regulation of connexin expression by transcription factors and epigenetic mechanisms including histone modifications, DNA methylation, and microRNA. This article is part of a Special Issue entitled: The communicating junctions, roles and dysfunctions. © 2011 Elsevier B.V. Source


Yamada Y.,National Cancer Center Hospital | Boku N.,St. Marianna University School of Medicine | Nishina T.,Shikoku Cancer Center | Yamaguchi K.,Saitama Cancer Center | And 14 more authors.
Annals of Oncology | Year: 2013

Background: Since the best chemotherapy regimen for each patient with advanced gastric cancer is uncertain, we aimed to identify molecular prognostic or predictive biomarkers from biopsy specimens in JCOG9912, a randomized phase III trial for advanced gastric cancer. Patients and methods: Endoscopic biopsy specimens from primary lesions were collected in 445 of 704 randomized patients in JCOG9912. We measured the mRNA expression of excision repair cross-complementing group 1 (ERCC1), thymidylate synthase, dihydropyrimidine dehydrogenase, and five other genes, then, categorized them into low and high groups relative to the median, and examined whether gene expression was associated with efficacy end point. Results: Multivariate analyses showed that high ERCC1 expression [HR 1.37; 95% confidence interval (CI) 1.08-1.75; P = 0.010], performance status =1 (HR 1.45; 95% CI 1.13-1.86; P = 0.004), and number of metastatic sites =2 (HR 1.66; 95% CI 1.28-1.86; P < 0.001) were associated with a poor prognosis, and recurrent disease (versus unresectable; HR 0.75; 95% CI 0.56-1.00; P = 0.049) was associated with a favorable prognosis. None of these molecular factors were a predictive marker for choosing irinotecan plus cisplatin or 5-fluorouracil rather than S-1. Conclusion: These correlative analyses suggest that ERCC1 is an independent prognostic factor for overall survival in the first-line treatment of gastric cancer. © The Author 2013. Source

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