Kanagawa Cancer Center Hospital

Kawasaki, Japan

Kanagawa Cancer Center Hospital

Kawasaki, Japan
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Kindler H.L.,University of Chicago | Ioka T.,Japan National Cardiovascular Center Research Institute | Richel D.J.,University of Amsterdam | Bennouna J.,Center Rene Gauducheau | And 13 more authors.
The Lancet Oncology | Year: 2011

Background: Axitinib is a potent, selective inhibitor of vascular endothelial growth factor (VEGF) receptors 1, 2, and 3. A randomised phase 2 trial of gemcitabine with or without axitinib in advanced pancreatic cancer suggested increased overall survival in axitinib-treated patients. On the basis of these results, we aimed to assess the effect of treatment with gemcitabine plus axitinib on overall survival in a phase 3 trial. Methods: In this double-blind, placebo-controlled, phase 3 study, eligible patients had metastatic or locally advanced pancreatic adenocarcinoma, no uncontrolled hypertension or venous thrombosis, and Eastern Cooperative Oncology Group performance status 0 or 1. Patients, stratified by disease extent (metastatic vs locally advanced), were randomly assigned (1:1) to receive gemcitabine 1000 mg/m2 intravenously on days 1, 8, and 15 every 28 days plus either axitinib or placebo. Axitinib or placebo were administered orally with food at a starting dose of 5 mg twice a day, which could be dose-titrated up to 10 mg twice daily if well tolerated. A centralised randomisation procedure was used to assign patients to each treatment group, with randomised permuted blocks within strata. Patients, investigators, and the trial sponsor were masked to treatment assignments. The primary endpoint was overall survival. All efficacy analyses were done in all patients assigned to treatment groups for whom data were available; safety and treatment administration and compliance assessments were based on treatment received. This study is registered at ClinicalTrials.gov, number NCT00471146. Findings: Between July 27, 2007, and Oct 31, 2008, 632 patients were enrolled and assigned to treatment groups (316 axitinib, 316 placebo). At an interim analysis in January, 2009, the independent data monitoring committee concluded that the futility boundary had been crossed. Median overall survival was 8·5 months (95% CI 6·9-9·5) for gemcitabine plus axitinib (n=314, data missing for two patients) and 8·3 months (6·9-10·3) for gemcitabine plus placebo (n=316; hazard ratio 1·014, 95% CI 0·786-1·309; one-sided p=0·5436). The most common grade 3 or higher adverse events for gemcitabine plus axitinib and gemcitabine plus placebo were hypertension (20 [7%] and 5 [2%] events, respectively), abdominal pain (20 [7%] and 17 [6%]), fatigue (27 [9%] and 21 [7%]), and anorexia (19 [6%] and 11 [4%]). Interpretation: The addition of axitinib to gemcitabine does not improve overall survival in advanced pancreatic cancer. These results add to increasing evidence that targeting of VEGF signalling is an ineffective strategy in this disease. Funding: Pfizer. © 2011 Elsevier Ltd.

Sakuma Y.,Kanagawa Cancer Center Research Institute | Takeuchi T.,Kanagawa Cancer Center Research Institute | Takeuchi T.,University of Tsukuba | Nakamura Y.,Kanagawa Cancer Center Research Institute | And 8 more authors.
Journal of Pathology | Year: 2010

The ability to resist anoikis is critical for carcinoma cells to metastasize. Although several lung adenocarcinoma cell lines were shown to repress anoikis through the activation of Src, it remains unknown whether Src actually plays a crucial role in anoikis resistance in lung adenocarcinoma tissues. We examined 20 human lung adenocarcinoma tissues with lymphatic permeation and nine cell lines to investigate whether intralymphatic floating carcinoma cells in the tissues, used as an in vivo model of anoikis resistance, actually suppressed anoikis and whether cell lines in suspension culture, an in vitro model of anoikis resistance, survived through Src activation. We observed that the intralymphatic carcinoma cells aggregated tightly to form nests expressing E-cadherin and phosphorylated Src (p-Src). The apoptotic indices of these cells were comparable to those of extracellular matrix adhesive cells in all tissues, indicating that the intralymphatic cells actually evaded anoikis. Next, we found that the nine cell lines in suspension aggregated loosely (five cell lines) or tightly (four cell lines), and all cells resisted anoikis. Upon detachment, four cell lines (LC-KJ, HCC827, H1650, and H1975) formed compact spheroids that expressed E-cadherin and p-Src. The spheroids were similar to intralymphatic tumour nests and were thus considered to be a suitable model of the nests. The spheroids of the four cell lines underwent apoptosis after treatment with the Src/Abl/Kit inhibitor PP1 or Src/Abl inhibitor bosutinib. On the other hand, the Abl/Kit inhibitor imatinib did not affect cell growth or apoptosis in the four types of spheroids. These results indicate that Src, but not Abl or Kit, plays an essential role in the development of anoikis resistance in lung adenocarcinomas. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Wada H.,Kanagawa Cancer Center Hospital | Shiozawa M.,Kanagawa Cancer Center Hospital | Katayama K.,Kanagawa Cancer Center | Okamoto N.,Kanagawa Cancer Center | And 4 more authors.
Journal of Gastroenterology | Year: 2015

Background: In this study we examined whether histopathological findings, specifically lymphatic vessel invasion identified by an anti-human podoplanin antibody, and several other factors are associated with lymph node metastasis in T1 colorectal cancer. Methods: We searched PubMed and Cochrane Library, and also handsearched relevant journals, for reports written in English and published between 1998 and 2012, utilizing combination headings, such as ‘colorectal cancer,’ ‘lymph node metastasis,’ and ‘risk factors.’ For the report to be included in our study, the following criteria had to be met: (1) data on the frequency of lymph node metastasis in T1 colorectal cancer in relation to histopathological factors were reported; (2) patients had undergone bowel resection and had histologically diagnosed T1 colorectal cancer; (3) lymphatic vessel invasion was identified by immunohistochemistry with an anti-human podoplanin antibody rather than by hematoxylin and eosin staining; (4) univariate and multivariate analyses were conducted. Studies investigating molecular markers were excluded. The independent predictive factors were confirmed in at least one study included in the meta-analysis in the present systematic review. Microsoft Excel 2013 for Windows was used for the statistical analysis. Results: Initially, 369 publications were identified in the database searches and handsearches, of which five ultimately met all of the inclusion criteria and selected for this systematic review. The meta-analysis revealed that only two factors were significantly associated with T1 colorectal cancer lymph node metastasis: (1) lymphatic vessel invasion identified by an anti-human podoplanin antibody [Mantel–Haenszel odds ratio (OR) 5.19; (95 % confidence interval (CI) 3.31–8.15; P = 0.01]; (2) tumor budding (OR 7.45; 95 % CI 4.27–13.02; P = 0.0077). Conclusion: Our meta-analysis revealed that lymphatic vessel invasion identified by an anti-human podoplanin antibody and tumor budding were significantly associated with T1 colorectal cancer lymph node metastasis. © 2015, Springer Japan.

Sakuma Y.,Kanagawa Cancer Center Research Institute | Yamazaki Y.,Kanagawa Cancer Center Research Institute | Nakamura Y.,Kanagawa Cancer Center Research Institute | Yoshihara M.,Kanagawa Cancer Center Research Institute | And 6 more authors.
Laboratory Investigation | Year: 2012

Src has a role in the anoikis resistance in lung adenocarcinomas. We focused on two epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma cell lines, HCC827 (E746-A750 deletion) and H1975 (L858RT790M), in suspension to elucidate whether suspended lung adenocarcinoma cells are eradicated by long-term treatment with Src tyrosine kinase inhibitors (TKIs). We also examined metastasis-positive lymph nodes from 16 EGFR-mutant lung adenocarcinoma patients for immunohistochemical expression of mutant-specific EGFR. Almost all suspended HCC827 cells underwent apoptosis after 144 h of combination treatment with AZD0530, trichostatin A (TSA), and ABT-263, whereas many suspended H1975 cells survived the treatment. AZD0530 is a Src TKI, TSA is a histone deacetylase inhibitor, and ABT-263 is a Bcl-2 inhibitor. During the therapy, the phosphorylation of EGFR decreased in HCC827 cells and remained stable in H1975 cells. The phosphorylated EGFR of Src TKI-resistant H1975 cells, as well as HCC827 cells, was completely suppressed by the third generation EGFR TKI, WZ4002. Consequently, both the suspended cell lines were almost completely eradicated within 144 h, with the combined therapy of WZ4002, ABT-263, and TSA. Interestingly, treated suspended cells underwent apoptosis to a greater extent than did adherent cells. Intrasinus floating lung adenocarcinoma cells in the lymph nodes expressed a mutant-specific EGFR. These findings suggest that suspended EGFR-mutant lung adenocarcinoma cells depend significantly more on EGFR activation for survival than attached cells do. The tumor cells circulating in vessels, which express mutant-specific EGFR, would be highly susceptible to the combination therapy of WZ4002, ABT-263, and TSA. © 2012 USCAP, Inc All rights reserved.

Miyagi Y.,Kanagawa Cancer Center Research Institute | Sasaki T.,Yokohama City University | Fujinami K.,Chigasaki Municipal Hospital | Sano J.,Chigasaki Municipal Hospital | And 7 more authors.
Modern Pathology | Year: 2010

The incidence and clinical significance of the TMPRSS2:ERG gene fusion in prostate cancer has been investigated with contradictory results. It is now common knowledge that significant variability in gene alterations exists according to ethnic background in various kinds of cancer. In this study, we evaluated gene fusions involving the ETS gene family in Japanese prostate cancer. Total RNA from 194 formalin-fixed and paraffin-embedded prostate cancer samples obtained by radical prostatectomy was subjected to reverse-transcriptase polymerase chain reaction to detect the common TMPRSS2:ERG T1-E4 and T1-E5 fusion transcripts and five other non-TMPRSS2:ERG fusion transcripts. We identified 54 TMPRSS2:ERG-positive cases (54/194, 28%) and two HNRPA2B1:ETV1-positive cases (2/194, 1%). The SLC45A3-ELK4 transcript, a fusion transcript without structural gene rearrangement, was detectable in five cases (5/194, 3%). The frequencies of both TMPRSS2:ERG- and non-TMPRSS2:ERG-positive cases were lower than those reported for European, North American or Brazilian patients. Internodular heterogeneity of TMPRSS2:ERG was observed in 5 out of 11 multifocal cases (45%); a frequency similar to that found in European and North American cases. We found a positive correlation between the TMPRSS2:ERG fusion and a Gleason score of 7 and patient age, but found no relationship with pT stage or plasma prostate-specific antigen concentration. To exclude the possibility that Japanese prostate cancer displays novel TMPRSS2:ERG transcript variants or has unique 5′ fusion partners for the ETS genes, we performed 5′ RACE using fresh-frozen prostate cancer samples. We identified only the normal 5′ cDNA ends for ERG, ETV1 and ETV5 in fusion-negative cases. Because we identified a relatively low frequency of TMPRSS2:ERG and other fusions, further evaluation is required before this promising molecular marker should be introduced into the management of Japanese prostate cancer patients. © 2010 USCAP, Inc. All rights reserved.

PubMed | Yokohama City University, Kanagawa Cancer Center Research Institute and Kanagawa Cancer Center Hospital
Type: Journal Article | Journal: Cancer science | Year: 2016

The laminin 2 chain, a subunit of laminin-332 (332), is a molecular marker for invasive cancer cells, but its pathological roles in tumor progression remain to be clarified. It was recently found that the most N-terminal, domain V (dV) of 2 chain has activities to bind CD44 and stimulate tumor cell migration and vascular permeability. In the present study, we prepared a mAb recognizing 2 dV. Immunoblotting with this antibody, for the first time, showed that proteolytic fragments containing dV in a range of 15-80 kDa were highly produced in various human cancer cell lines and lung cancer tissues. In immunohistochemistry of adenocarcinomas and squamous cell carcinomas of the lung, this antibody immunostained the cytoplasm of invasive tumor cells and adjacent stroma much more strongly than a widely used antibody recognizing the C-terminal core part of the processed 2 chain. This suggests that the dV fragments are highly accumulated in tumor cells and stroma compared to the processed 2 protein. The strong tumor cell staining with the dV antibody correlated with the tumor malignancy grade. We also found that the laminin 3 and 3 chains were frequently overexpressed in tumor cells and tumor stroma, respectively. The cytoplasmic dV detection was especially prominent in tumor cells infiltrating stroma, but low in the cells surrounded by basement membranes, suggesting that the active tumor-stroma interaction is critical for the aberrant 2 expression. The present study suggests important roles of laminin 2 N-terminal fragments in tumor progression.

Kato Y.,University of Colorado at Denver | Kato Y.,Tokyo Medical University | Peled N.,University of Colorado at Denver | Wynes M.W.,University of Colorado at Denver | And 9 more authors.
Journal of Thoracic Oncology | Year: 2010

Background: Epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) predict better outcome to EGFR tyrosine kinase inhibitors. The most common mutations are exon 19 deletions (most frequently E746-A750) and L858R point mutation in exon 21. Here, we evaluated the accuracy of novel EGFR mutation-specific antibodies in a Japanese cohort with NSCLC and compared with direct DNA sequencing and clinical outcome. Materials and Methods: Immunohistochemistry (IHC) using antibodies specific for the E746-A750 and L858R mutations in EGFR was performed on tissue microarrays of tumors from 70 gefitinib treated NSCLC patients. Extracted DNA was sequenced for mutational analysis of EGFR exons 18 to 21. Results: DNA sequencing showed EGFR mutations in 41 patients (58.6%) and exon 19 deletions in 18 patients (25.7%), 11 of 18 (61%) had a deletion in the range of E746-A750 and 12 (17.1%) had exon 21 mutations (L858R). IHC showed, for the E746-A750 and L858R mutations, sensitivity (81.8 and 75%), specificity (100 and 96.6%), positive predictive value (100 and 81.8%), and negative predictive value (96.7 and 94.9%). Analysis for objective response rates and survival were not correlated to IHC staining, although the combined staining showed nonsignificant trends toward better overall survival for patients with EGFR mutations. Conclusions: The mutation-specific IHC antibodies have high sensitivity and specificity for predefined EFGR mutations and may be suitable for screening for these predefined mutations. However, negative IHC results require further mutation analyses before excluding EGFR-targeted therapy. Copyright © 2010 by the International Association for the Study of Lung Cancer.

Ikeda M.,National Cancer Center Hospital East | Ohkawa S.,Kanagawa Cancer Center Hospital | Okusaka T.,National Cancer Center Hospital | Mitsunaga S.,National Cancer Center Hospital East | And 5 more authors.
Cancer Science | Year: 2014

GC33 is a humanized mAb against human glypican-3 (GPC3). In the first-in-human study carried out in the USA, GC33 was well tolerated and showed preliminary antitumor activity in patients with advanced hepatocellular carcinoma. This study aimed to assess the safety, tolerability, and pharmacokinetic characteristics of GC33 in Japanese patients with advanced hepatocellular carcinoma. The study design was a conventional 3 + 3 dose-escalation design to determine the maximum tolerated dose of GC33 given i.v. at 5, 10, or 20 mg/kg weekly. Immunohistochemistry was carried out on tumor biopsies to evaluate GPC3 expression. Thirteen patients were enrolled across the three dose levels, and no patients observed any dose-limiting toxicity up to the highest planned dose of 20 mg/kg. The most common adverse events were decreased lymphocyte count, decreased natural killer cell count, increased C-reactive protein, and pyrexia. Grade 3 adverse events (increased blood pressure, decreased lymphocyte count, and decreased platelet count) were observed in two or more patients. The AUCinf showed a dose-proportional increase from the 5 mg/kg dose group to the 20 mg/kg dose group. The trough concentrations of GC33 appeared to reach a steady state after the fourth to the sixth dose. Seven of the 13 patients showed stable disease, the other six showed progressive disease. Furthermore, three patients showed long-term stable disease of more than 5 months. In conclusion, GC33 given at up to 20 mg/kg weekly was well tolerated in Japanese patients with advanced hepatocellular carcinoma. GC33 administered at up to 20 mg/kg weekly was well tolerated in Japanese patients with advanced hepatocellular carcinoma. Seven of the 13 patients showed stable disease, the other six showed progressive disease. Furthermore, three patients showed long stable disease of more than 5 months. © 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

PubMed | Kanagawa Cancer Center Hospital
Type: Journal Article | Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2016

14043 Background: FDG-PET was performed on 32 consecutive patients with APC between July 2001 and April 2004. The patients fasted for at least 5 hr before the study. The plasma glucose level was controlled under 150 mg/dl by using oral antidiabetic or insulin therapy in advance. FDG-PET images were acquired 45 min after intravenous injection of FDG. We did not measure the plasma glucose level directly before imaging. The FDG uptake in the primary tumor was quantitated as the standardized uptake value (SUV), and the maximum SUV (SUVmax) was measured in the regions of interest. All of the 32 APC patients received chemotherapy (26: gemcitabine, 1: gemcitabine + UFT, 5: TS-1). We analyzed the correlation between SUVmax and the overall survival. Then, we excluded the diabetics (n = 8) and compared SUV in the non-diabetic patients (n = 24). The overall survival curve was plotted according to the method of Kaplan and Meier. The difference in the overall survival was calculated using the log-rank test, and a multivariate analysis was conducted.32 patients were examined. All cases showed FDG uptake in the pancreatic tumor (SUVmax ranged from 2.73 to 9.67). The overall survival ranged from 38 to 945 days with a median of 261 days.These patients were classified into two groups at a median SUVmax value of 4.81. There was no significant difference in the overall survival between these two groups (p > 0.05). The non-diabetic patients (n = 24) were classified into two groups at a median SUVmax value of 5.51. The high SUVmax group had shorter overall survival than the low SUVmax group (p = 0.039). The multivariate analysis using Cox hazard model also revealed that SUVmax was a significant, independent factor that influenced the survival (p = 0.043) in the non-diabetic patients.FDG-PET may be a useful modality in determining the prognosis of APC. No significant financial relationships to disclose.

PubMed | Kanagawa Cancer Center Hospital
Type: Journal Article | Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2016

377 Background: As there was no standard chemotherapy for advanced biliary tract cancer before ABC-02, we had treated our patients with gemcitabine alone. However, recently cisplatin plus gemcitabine became standard as first line chemotherapy. We assessed the benefits of chemotherapy with cisplatin plus gemcitabine after failure of gemcitabine alone before ABC-02 era.We retrospectively examined the patients with advanced biliary tract cancer, who were treated with chemotherapy using cisplatin plus gemcitabine after failure of gemcitabine alone. The eligible patients had unresectable or recurrent biliary tract cancer, objective tumor progression after gemcitabine alone chemotherapy, adequate organ function including renal function and ECOG performance status (PS) 0-1. The treatment consisted of cisplatin (25 mg per square meter of body-surface area) plus gemcitabine (1000 mg per square meter) on days 1 and 8, every 3 weeks.Between December 2010 and July 2011, 10 patients were enrolled. Their median age was 63 years, the male : female ratio was 8:2, intrahepatic bile ducts : gall bladder : extrahepatic bile duct 6:3:1, locally advanced : metastatic disease 1:9, PS0 : PS1 7:3. The objective response rate was 30%, and the tumor control rate was 60%. The median progression-free survival was 4.0 months (95% confidence interval (CI): 1.4-6.9 months) with median overall survival 6.4 months (95% CI: 3.7-7.6 months). Grade 3-4 toxicities were neutropenia (30%) and anemia (30%).Cisplatin plus gemcitabine can be an optional therapy for unresectable or recurrent biliary tract cancer after failure of gemcitabine alone.

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