Publications by authors named "Fumihiro Oshita"

65 Publications

Phase II study of bevacizumab, cisplatin, and pemetrexed in advanced non-squamous non-small cell lung cancer (NS-NSCLC) with EGFR wild-type.

J Exp Ther Oncol 2019 Dec;13(2):131-138

Department of Thoracic Oncology, Kanagawa Cancer Center, Yokohama, Japan.

Background: Continuation maintenance therapy with pemetrexed (PEM) and bevacizumab (BEV) following induction therapy with cisplatin (CDDP), PEM, and BEV is beneficial in advanced non-squamous non-small-cell lung cancer (NS-NSCLC), but the survival benefit of addition of BEV to CDDP/PEM as induction therapy is still unclear. The aim of this phase II study was to evaluate the feasibility and safety of a CDDP/PEM/BEV regimen in Japanese patients with EGFR wild-type NS-NSCLC.

Patients And Methods: This study included 25 patients who receive intravenous CDDP, PEM, and BEV (15 mg/kg) from August 2010 to February 2013. The primary endpoint of this study was the response rate (RR) and the secondary endpoint was progression free survival (PFS), overall survival (OS), and safety.

Results: The median cycles of induction chemotherapy were four (range 1-6). RR was 64%. Most patients (64%) transitioned to maintenance therapy. The median PFS was 9.7 months. Median OS was 21.6 months. Haematological adverse events reaching grade 3 to 4 were neutropenia (8%) without febrile neutropenia, thrombocytopenia (4%), and anemia (4%). BEV-related non-haematological toxicities of grade 3/4 were hypertension (16%), thrombosis (4%), and gastrointestinal perforation (4%). Each adverse events was controllable, and there were no treatment-related deaths.

Conclusions: CDDP/PEM/BEV regimen is effective and tolerable in patients with EGFR wild-type advanced NS-NSCLC, but should be paid attention to some BEV-related toxicities.
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December 2019

Cancer treatment and management for elderly patients 80 years of age or older with malignant solid tumors.

J Exp Ther Oncol 2017 Nov;12(2):143-149

Department of General Medicine, Kanagawa Prefectural Ashigarakami Hospital, Matsuda-soryo 866-1, Matsuda, Kanagawa 258-0003, Japan.

Objective: We retrospectively analyzed the backgrounds, treatment and nursing care for 96 patients aged 80 years or more with malignant tumors. Twenty of them were hospitalized on an emergency basis. Sixty patients were male and 36 were female, with a median age of 83 years (range: 80-94 years). Twenty-seven had a PS of 3 or 4, and 41 were rated as not independent based on analysis of autonomy at hospitalization. Forty-seven patients had clinical stage III or IV malignancies. The proportions of patients with disease complications were 33.3% for neurological disease, 21.9% for respiratory disease, 70.8% for cardiovascular disease including hypertension, and 36.5% for metabolic disease. Thirty-nine patients underwent surgical or endoscopic resection of their tumors. Twenty-three patients received chemotherapy: hormonal treatment in 14, local injection of cytotoxic agent(s) in 6 and systemic anti-cancer therapy in 3. Thirty-nine patients received supportive care only. Forty-three patients newly required nursing care or an increased level of care at discharge. The median survival time was 10.9 and 15.3 months for stage III/IV and 0/I/II patients, respectively. In conclusion, most elderly patients with malignant tumors require full supportive care, including social nursing care, from the time of cancer diagnosis.
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November 2017

Phase II study of nedaplatin and irinotecan as adjuvant chemotherapy for completely resected non-small cell lung cancer.

Cancer Chemother Pharmacol 2018 01 7;81(1):81-87. Epub 2017 Nov 7.

Department of Thoracic Oncology, Kanagawa Cancer Center, Nakao 2-3-2, Asahi-ku, Yokohama, 241-8515, Japan.

Introduction: Cisplatin-based chemotherapy is the standard adjuvant therapy for patients with completely resected stage II or III non-small cell lung cancer (NSCLC). However, the completion rate of four cycles of cisplatin-based chemotherapy is about 50%. This phase II study was conducted to evaluate the tolerability and efficacy of nedaplatin and irinotecan as adjuvant chemotherapy.

Methods: Patients with pathological stage II or III NSCLC who underwent complete resection were enrolled. Treatment consisted of four cycles of nedaplatin (50 mg/m) and irinotecan (50 mg/m) on days 1 and 8 every 4 weeks. The primary end-point was the completion rate of four cycles of nedaplatin and irinotecan.

Results: Between January 2009 and March 2012, 39 patients (23 males and 16 females; median age 68 years) were registered. Overall, 36/39 (92.3%) patients completed four cycles. The median clinical follow-up time was 56 months (range 11-88 months). There were no differences in adverse events between patients with UGT1A1 polymorphisms and patients with wild-type UGT1A1. The median disease-free survival (DFS) was 49.4 months (95% confidence interval 14.2-84.5 months). Median overall survival (OS) was not reached. There were no treatment-related deaths, and adverse events were acceptable. The 5-year DFS and OS rates were 43.1 and 69.8%, respectively.

Conclusion: Nedaplatin and irinotecan is a tolerable regimen for adjuvant chemotherapy, and was associated with adequate 5-year DFS and OS rates.
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http://dx.doi.org/10.1007/s00280-017-3460-0DOI Listing
January 2018

Phase III, Randomized, Placebo-Controlled, Double-Blind Trial of Motesanib (AMG-706) in Combination With Paclitaxel and Carboplatin in East Asian Patients With Advanced Nonsquamous Non-Small-Cell Lung Cancer.

J Clin Oncol 2017 Nov 13;35(32):3662-3670. Epub 2017 Sep 13.

Kaoru Kubota, Nippon Medical School; Kaori Hara and Takayuki Asato, Takeda Pharmaceutical, Tokyo; Hiroshige Yoshioka, Kurashiki Central Hospital, Kurashiki; Fumihiro Oshita, Kanagawa Prefectural Ashigarakami Hospital, Matsuda; Toyoaki Hida, Aichi Cancer Center Hospital, Nagoya; Kiyotaka Yoh, National Cancer Center Hospital East, Chiba; Hidetoshi Hayashi, Hiroyasu Kaneda, and Kazuhiko Nakagawa, Kindai University Faculty of Medicine; Hidetoshi Hayashi, Kishiwada Municipal Hospital, Osaka; Terufumi Kato, Kanagawa Cardiovascular and Respiratory Center, Yokohama; Kazuhiko Yamada, Kurume University School of Medicine; Yukito Ichinose, National Kyushu Cancer Center, Fukuoka; Hiroshi Tanaka, Niigata Cancer Center Hospital, Niigata, Japan; Keunchil Park, Samsung Biomedical Research Institute, Seoul; Eun Kyung Cho, Gachon University; Kyung-Hee Lee, Inha University Hospital, Incheon, South Korea; Chih-Bin Lin, Buddhist Tzu-Chi General Hospital, Hualien; James Chih-Hsin Yang, National Taiwan University Hospital; National Taiwan University Cancer Center, Taipei City, Peoples Republic of China.

Purpose This phase III, randomized, placebo-controlled, double-blind study determined whether motesanib improved progression-free survival (PFS) compared with placebo in combination with paclitaxel and carboplatin (P/C) in East Asian patients with stage IV/recurrent nonsquamous non-small-cell lung cancer. Patients and Methods Patients were randomly assigned (1:1) to receive oral motesanib 125 mg or placebo once daily plus paclitaxel 200 mg/m IV and carboplatin area under the concentration-time curve 6 mg/mL ⋅ min IV for up to six 3-week cycles. Random assignment was stratified by epidermal growth factor receptor status, region, and weight loss in the 6 months before assignment. The primary end point was PFS, the key secondary end point was overall survival, and other secondary end points were objective response rate, time to tumor response, duration of response, and adverse events (AEs). Results Four hundred one patients were assigned to receive motesanib plus P/C (n = 197) or placebo plus P/C (n = 204). Median PFS was 6.1 v 5.6 months for motesanib versus placebo (stratified log-rank test P = .0825; stratified hazard ratio, 0.81; 95% CI, 0.64 to 1.03; P = .0820); median overall survival was not reached versus 21.6 months ( P = .5514). In secondary analyses, the objective response rate was 60.1% v 41.6% ( P < .001); median time to tumor response, 1.4 v 1.6 months, and median duration of response, 5.3 v 4.1 months. Incidence of grade ≥ 3 AEs (86.7% v 67.6%) and AEs that led to drug discontinuation (32.7% v 14.2%) were higher with motesanib than with placebo. AEs reported more frequently with motesanib were GI disorders, hypertension, and gallbladder related. Conclusion Motesanib plus P/C did not significantly improve PFS versus placebo plus P/C in East Asian patients with stage IV/recurrent nonsquamous non-small-cell lung cancer.
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http://dx.doi.org/10.1200/JCO.2017.72.7297DOI Listing
November 2017

Randomized phase II trial of weekly dose-intensive chemotherapy or amrubicin plus cisplatin chemotherapy following induction chemoradiotherapy for limited-disease small cell lung cancer (JCOG1011).

Lung Cancer 2017 06 4;108:232-237. Epub 2017 Apr 4.

Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan.

Objectives: The objective of this study was to select, for a phase III trial, the more promising of weekly-dose intensive chemotherapy or amrubicin+cisplatin chemotherapy as subsequent therapy after induction chemoradiotherapy for previously untreated limited-disease small cell lung cancer (LD-SCLC).

Materials And Methods: Patients aged 20-70 years with untreated clinical stage II/III LD-SCLC were eligible. After one cycle of accelerated hyperfractionation thoracic radiotherapy with etoposide plus cisplatin, patients without progression were randomized to either 3 cycles of cisplatin 25mg/m2 (days 1, 8), doxorubicin 40mg/m2 (day 1), etoposide 80mg/m2 (days 1-3), and vincristine 1mg/m2 (day 8) every 2 weeks (CODE) or amrubicin 40mg/m2 (days 1-3) and cisplatin 60mg/m2 (day 1) every 3 weeks (AP). The primary endpoint was the one-year progression-free survival (PFS). The sample size was 72 to select the arm yielding a better one-year PFS (55% vs. 65%) with a probability of 80%.

Results: From March 2011 to February 2014, 85 patients were registered. After the induction chemoradiotherapy, 75 patients were randomized to CODE (n=39) or AP (n=36). The one-year PFS (95% confidence interval) was 41.0% (25.7-55.8) in the CODE group and 54.3% (36.6-69.0) in the AP group. Grade 4 neutropenia/grade 3 febrile neutropenia occurred in 47%/16% in the CODE group and 78%/42% in the AP group.

Conclusion: The one-year PFS was better in the AP group, but it did not reach the expected 55%. Therefore, neither regimen is suitable for a phase III trial.
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http://dx.doi.org/10.1016/j.lungcan.2017.04.002DOI Listing
June 2017

Severe human parechovirus type 3 infection in adults associated with gastroenteritis in their children.

Infect Dis (Lond) 2017 Oct 12;49(10):772-774. Epub 2017 May 12.

a Department of Internal Medicine , Kanagawa Prefectural Ashigarakami Hospital , Matsuda-machi , Kanagawa , Japan.

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http://dx.doi.org/10.1080/23744235.2017.1323347DOI Listing
October 2017

Nedaplatin and irinotecan with concurrent thoracic radiotherapy followed by docetaxel consolidation in patients with locally advanced non-small cell lung cancer.

J Exp Ther Oncol 2017 May;12(1):17-23

Department of Radiotherapy, Kanagawa Cancer Center, Nakao 2-3-2, Asahi-ku, Yokohama 241-0815.

Objective: We conducted a phase II study of nedaplatin (NP) and irinotecan (CPT) with concurrent thoracic radiotherapy (TRT) followed by docetaxel for locally advanced non-small cell lung cancer (NSCLC) to determine the safety and efficacy of the treatment. Patients with stage IIIA or IIIB NSCLC were treated with 3 cycles of chemotherapy comprising NP at 50 mg/m and CPT at 50 mg/m on days 1 and 8 every 4 weeks with concurrent TRT (2 Gy/day, total 66 Gy) followed by 3 cycles of docetaxel at 60 mg/m on day 1 every 3 weeks.

Conclusion: Fifteen patients were registered, and 8 were able to receive the entire treatment regimen. Grade 4 neutropenia and thrombocytopenia occurred in 6 and 1 patient, respectively, receiving NP and CPT with concurrent TRT. Major non-hematological toxicities were nausea, vomiting and fatigue. Grade 3 pneumonitis and esophagitis occurred in one patient each, and 4 patients developed febrile neutropenia. Docetaxel consolidation was associated with mild toxicities. Two patients died of late pulmonary failure 3 to 4 months after treatment completion, and the study was terminated. Twelve patients responded, and the median survival time, and the 1-year and 3-year survival rates were 39.3 months, 86.7% and 60.0%, respectively. In conclusion, NP and CPT with concurrent TRT is effective for patients with locally advanced NSCLC, but frequently induces pulmonary damage.
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May 2017

Multiplex genomic test of mutation and fusion genes in small biopsy specimen of lung cancer.

J Exp Ther Oncol 2016 Jul;11(3):189-194

Pathology and Laboratory for Molecular Diagnostics, Kanagawa Cancer Center, Nakao 2-3-2, Asahi-ku, Yokohama 241-0815, Japan.

We evaluated multiple oncogenic mutations and fusion genes in small specimen obtained by bronchoscopy. Eight patients with lung cancer were recruited, 3 small cell lung cancer, 3 non-small cell lung cancer, 1 adenocarcinoma and 1 squamous cell carcinoma. A median value of extracted RNA and DNA amounts from specimen was 1573 ng (range 367.5 to 8900) and 6700 ng (range 550 to 68000 ng), respectively. We applied amplicon sequencing panels that cover exon regions of 41 genes related to lung tumorigenesis as well as total 61 major variants of ALK, ROS, RET or NTRK1 fusion transcripts. Nineteen of 41 gene mutations were detected in our isolated DNAs of 8 patients. We could detect four to eleven mutations in each specimen; however the mutation combination in each 8 patients were different. The most common genetic alterations were TP53, KMT2D, MET, NOTCH2 and SETD2, which were detected in 4 to 6 patients. We did not detect fusion transcripts of ALK, ROS, RET and NTRK1 in every specimen. In conclusion, multiplex genomic test was performed on small amounts specimen of bronchoscopy biopsy with a 100% success rate. Such testing is considered to be able to assist physicians in matching patients with approved or experimental targeted treatments.
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July 2016

Prognostic value of EGFR mutations in surgically resected pathological stage I lung adenocarcinoma.

Asia Pac J Clin Oncol 2017 Oct 28;13(5):e204-e211. Epub 2016 Jun 28.

Department of Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan.

Aim: With the advent of the molecular-targeted therapy, rapid progress has been made in the treatment of advanced or recurrent non-small-cell lung cancer (NSCLC). Although surgical complete resection remains the standard and most promising treatment, the clinical significance of epidermal growth factor receptor (EGFR) gene mutations in early-stage NSCLC remains uncertain.

Methods: We investigated the prognostic value of EGFR mutations in surgically resected pathological stage I NSCLC. A total of 388 consecutive patients with NSCLC who underwent complete tumor resection in our hospital from 2006 through 2008 were studied retrospectively. Formalin-fixed, paraffin-embedded tissue sections were used to isolate DNA from carcinoma lesions. Mutational analyses of EGFR gene were performed by loop-hybrid mobility shift assay, a highly sensitive polymerase chain reaction-based method.

Results: Mutations of EGFR were detected in 185 of the 388 patients (47.7%). EGFR mutations were more frequently found in women (110 of 185, 59.5%), adenocarcinoma (183 of 185, 98.9%), patients with no vascular invasion (139 of 185, 75.1%) and nonsmokers (106 of 185, 57.3%). In patients with pathological stage I adenocarcinoma, both overall survival (OS) and disease-free survival (DFS) were significantly higher in patients with EGFR mutation than in those with wild-type EGFR. Furthermore, patients with exon 21 mutation have better DFS than those with exon 19 mutation in stage IB adenocarcinoma. Cox's proportional hazard model indicated that EGFR status was an independent variable for predicting the OS and DFS in patients with pathological stage IB adenocarcinoma.

Conclusion: Our results suggest that EGFR mutations might be a prognostic factor in patients with pathological stage I lung adenocarcinoma.
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http://dx.doi.org/10.1111/ajco.12512DOI Listing
October 2017

Relationship between phosphorylation of sperm-specific antigen and prognosis of lung adenocarcinoma.

J Proteomics 2016 Apr 3;139:60-6. Epub 2016 Mar 3.

Yokohama City University, Graduate School of Medical Life Science and Advanced Medical Research Center, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa 236-0004, Japan. Electronic address:

Unlabelled: Lung cancer is generally considered as a highly malignant cancer. A major challenge for the management of lung adenocarcinoma patients is to predict the clinical course of the disease after resection. We analyzed the different levels of phosphorylation of proteins in lung adenocarcinoma tissues between a poor prognosis (PP) group, in which six patients exhibited recurrence within five years after surgery, and a good prognosis (GP) group, in which seven patients did not exhibit recurrence within five years after surgery. We found that phosphorylation at Ser92 of the sperm-specific antigen 2 (SSFA2) [phospho-SSFA2(pS92)] was stimulated in the PP group. Using samples from a total of 46 patients, we investigated the utility of phospho-SSFA2(pS92) to discriminate patients of GP and PP groups, with multiple reaction monitoring (MRM) mass spectrometry. Consequently, we confirmed that the PP group had significantly elevated phospho-SSFA2(pS92) levels. Additionally, no expression of SSFA2 recognized in the normal lung tissues. From these results, we demonstrate that phospho-SSFA2 (pS92) is related to the prognosis of early resected lung adenocarcinomas. Therefore, we suggest that phosphorylation of this protein indicates its role as a potential biomarker and new therapeutic target.

Biological Significance: Lung adenocarcinoma patients often experience a high rate of recurrence after surgery. It is important to discover biomarkers for prognostic prediction and therapeutic targets for treatment of early-stage lung adenocarcinoma. In this study, using tissue samples obtained from patients with lung adenocarcinoma that had been stored for five years at -80°C, we identified 13 unique phosphorylated peptides, which were differentially expressed between poor and good prognosis groups. We confirmed that phosphorylation at Ser92 of the sperm-specific antigen 2 (SSFA2)[phospho-SSFA2 (pS92)], was related to poor prognosis. Our study demonstrates that prognostic prediction of early-stage lung adenocarcinoma is possible, and suggests new therapeutic targets for its treatment.
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http://dx.doi.org/10.1016/j.jprot.2016.03.005DOI Listing
April 2016

Multicenter Phase II Study of Nedaplatin and Irinotecan for Patients with Squamous Cell Carcinoma of the Lung: Thoracic Oncology Research Group 0910.

Anticancer Res 2015 Dec;35(12):6705-11

Thoracic Oncology Research Group, Kanagawa, Japan.

Squamous cell carcinoma (SCC) of the lung is moderately responsive to anticancer drugs, but no specific chemotherapy regimens have yet been established. We conducted a multicenter phase II study of nedaplatin (NP) and irinotecan (CPT) for SCC of the lung. Fifty patients underwent 4 to 6 cycles of chemotherapy comprising of NP at 100 mg/m(2) on day 1 and CPT at 60 mg/m(2) on days 1 and 8 every 4 weeks. Twenty-seven patients received 4 to 6 cycles of chemotherapy (median=4 cycles). Major toxicities included neutropenia (46.0%), grade 3 or 4 anorexia (22.0%), febrile neutropenia (16.0%), diarrhea (12.0%), hyponatremia (12.0%), grade 4 anemia (10.0%), thrombocytopenia (10.0%) and infection (10.0%). There were no treatment-related deaths. One patient achieved a complete response and 16 a partial response, with an overall response rate of 34.0%. The median survival time was 11.8 months (95% CI=8.3-15.8 months) and the 2-year survival rate was 22.0%. In conclusion, the NP and CPT regimen is not recommend for further evaluation for patients with advanced SCC of the lung.
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December 2015

Feasibility study of docetaxel plus bevacizumab as first line therapy for elderly patients with advanced non-small-cell lung cancer: Thoracic Oncology Research Group (TORG) 1014.

BMC Cancer 2015 Oct 19;15:740. Epub 2015 Oct 19.

Yokohama Municipal Citizen's Hospital, 56 Kazawa-cho, Hodogaya-ku, Yokohama, 240-8555, Japan.

Background: Docetaxel monotherapy is one of the standard treatments for non-small-cell lung cancer in elderly patients. The addition of bevacizumab to docetaxel seems promising; however, the feasibility of this combination has not been investigated in such patients.

Methods: Patients with advanced non-squamous non-small-cell lung cancer aged 70 years or older who had not previously received cytotoxic chemotherapy were enrolled. Patients in the Level 0 cohort received docetaxel 60 mg/m(2) and bevacizumab 15 mg/kg, whereas those in the Level-1 cohort received docetaxel 50 mg/m(2) and bevacizumab 15 mg/kg. Chemotherapy was repeated 3 weekly for six cycles. The primary endpoint was toxicity and the secondary endpoints were response rate, progression-free survival, overall survival, and proportion of patients who underwent three or more cycles of chemotherapy.

Results: Twenty-one patients were enrolled from December 2010 to September 2012 at six institutes. Of the nine patients enrolled in Level 0, two experienced dose-limiting toxicity (febrile neutropenia and prolonged Grade 4 neutropenia in one patient, and Grade 3 infection in another patient) during the first cycle. Enrollment to the Level 0 cohort was terminated because two patients developed Grade 4 sepsis during later cycles. The remaining 12 patients were enrolled in the Level-1 cohort, in which two dose-limiting toxicities (prolonged Grade 4 neutropenia and Grade 3 increased aminotransferase level) were observed. No patient in the Level-1 cohort experienced Grade 4 nonhematologic toxicity. Grade 4 neutropenia occurred in 89 % of Level 0 patients and 50 % of Level-1 patients. The proportion of patients who experienced Grade 3/4 infection, febrile neutropenia or sepsis was 44 % in the Level 0 cohort, and 8 % in the Level-1 cohort. The overall response rate to chemotherapy and progression-free survival were 29 % (95 % CI, 11-52 %) and 5.9 months (95 % CI, 3.6-9.1 months), respectively. Efficacy outcomes did not differ significantly between the cohorts.

Conclusions: Toxicities were tolerable in level-1 cohort. The recommended dose of combination chemotherapy with docetaxel and bevacizumab for elderly patients was determined as 50 mg/m(2) of docetaxel and 15 mg/kg of bevacizumab and toxicities were tolerable. Further studies are warranted.

Trial Registration: UMIN Clinical Trial Registry; UMIN000004240 .
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http://dx.doi.org/10.1186/s12885-015-1756-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4612532PMC
October 2015

Identification of Tyrosine-Phosphorylated Proteins Upregulated during Epithelial-Mesenchymal Transition Induced with TGF-β.

J Proteome Res 2015 Oct 28;14(10):4127-36. Epub 2015 Aug 28.

Yokohama City University , Advanced Medical Research Center, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa 236-0004, Japan.

The epithelial-to-mesenchymal transition (EMT) is a unique process for the phenotypic changes of tumor cells characterized by a transition from polarized rigid epithelial cells to migrant mesenchymal cells, thus conferring the ability of tumor invasion and metastasis. A major challenge in the treatment of lung adenocarcinoma is to identify early stage patients at a high risk of recurrence or metastasis, thereby permitting the best therapeutic strategy and prognosis. In this study, we used a transforming growth factor-β (TGF-β)-induced EMT model to quantitatively identify protein tyrosine phosphorylation during the course of EMT in relation to malignant characteristics of lung adenocarcinoma cells. We performed relative quantitation analysis of tyrosine-phosphorylated peptides in TGF-β-treated and -untreated lung adenocarcinoma cells and identified tyrosine-phosphorylated proteins that were upregulated in TGF-β-treated cells. These include tensin-1 (TNS1) phosphorylated on Y1404, hepatocyte growth factor receptor (c-Met) phosphorylated on Y1234, and NT-3 growth factor receptor (TrkC) phosphorylated on Y516. We also found that these protein phosphorylation profiles were specifically observed in tissue samples of patients with poor prognostic lung adenocarcinoma. Tyrosine phosphorylations of these proteins represent possible candidates of prognostic prediction markers for lung adenocarcinoma.
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http://dx.doi.org/10.1021/acs.jproteome.5b00082DOI Listing
October 2015

Relation between thin-section computed tomography and clinical findings of mucinous adenocarcinoma.

Ann Thorac Surg 2015 Mar 24;99(3):975-81. Epub 2015 Jan 24.

Division of Thoracic Surgery, Department of Surgery, Tokai University School of Medicine, Isehara, Japan.

Background: Detailed reports on mucinous adenocarcinoma (formerly "mucinous bronchioloalveolar carcinoma") have not been published. We evaluated the correlation between thin-section computed tomography findings and the clinicopathologic characteristics and prognosis of mucinous adenocarcinoma.

Methods: From April 1997 to March 2008, 45 resected lung carcinomas were diagnosed as mucinous adenocarcinoma. Five cases of multiple lung cancers or ambiguous mucinous adenocarcinoma were excluded. Tumors were classified as "solitary-type" or "pneumonic-type" tumors according to the thin-section computed tomography findings. We evaluated the clinicopathologic characteristics and the epidermal growth factor receptor and KRAS gene mutation statuses and correlated the thin-section computed tomography findings with patient prognoses.

Results: Thirty patients had solitary-type and 10 had pneumonic-type tumors. The lesions in 23, 14, and 3 patients were classified as pathologic stage I, stage II, and stage III, respectively. Five patients had adenocarcinoma in situ, 9 had minimally invasive adenocarcinoma, and 26 had invasive mucinous adenocarcinoma. Thirteen patients showed recurrences, which were classified as intrapulmonary metastases in all patients. The 5-year overall and relapse-free survival rates were 83.3% and 88.8%, respectively, in patients with solitary-type tumors and 20.0% and 0%, respectively, in patients with pneumonic-type tumors (p < 0.001). The median follow-up time for surviving patients was 81 months. KRAS mutations were detected in 30 patients, but epidermal growth factor receptor mutations were absent in all patients.

Conclusions: Our results indicated that thin-section computed tomography findings for mucinous adenocarcinoma were useful in predicting prognosis before surgical resection. Further studies are required to improve the treatment strategy for mucinous adenocarcinoma.
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http://dx.doi.org/10.1016/j.athoracsur.2014.10.065DOI Listing
March 2015

Clinicopathological features and EGFR gene mutation status in elderly patients with resected non-small-cell lung cancer.

BMC Cancer 2014 Aug 25;14:610. Epub 2014 Aug 25.

Department of Thoracic Oncology, Kanagawa Cancer Center Hospital, 2-3-2 Nakao, Asahi-ku, Yokohama 2418515, Japan.

Background: The rapid aging of the population in Japan has been accompanied by an increased rate of surgery for lung cancer among elderly patients. It is thus an urgent priority to map out a treatment strategy for elderly patients with primary lung cancer. Although surgical resection remains standard treatment for early stage non-small-cell lung cancer (NSCLC), it is now essential to confirm the status of epidermal growth factor receptor (EGFR) gene mutations when planning treatment strategies. Furthermore, several studies have reported that EGFR mutations are an independent prognostic marker in NSCLC. However, the relations between age group and the molecular and pathological characteristics of NSCLC remain unclear. We studied the status of EGFR mutations in elderly patients with NSCLC and examined the relations of EGFR mutations to clinicopathological factors and outcomes according to age group.

Methods: A total of 388 consecutive patients with NSCLC who underwent complete tumor resection in our hospital from 2006 through 2008 were studied retrospectively. Formalin-fixed, paraffin-embedded tissue sections were used to isolate DNA from carcinoma lesions. Mutational analyses of EGFR gene exons 19, 20, and 21 and KRAS gene exons 12 and 13 were performed by loop-hybrid mobility shift assay, a highly sensitive polymerase chain reaction-based method.

Results: EGFR mutations were detected in 185 (47.7%) and KRAS mutations were detected in 33 (8.5%) of the 388 patients. EGFR mutations were found in a significantly higher proportion of patients younger than 80 years (younger group; 178/359, 49.6%) than in patients 80 years or older (older group; 7/29, 24.1%) (P = 0.008). In contrast, KRAS mutations were more common in the older group (6/29, 20.7%) than in the younger group (27/359, 7.5%) (P = 0.014). The older group showed a trend toward a higher rate of 5-year overall survival among elderly patients with EGFR mutations (100%) than among those with wild-type EGFR (66.2%), but the difference was not significant.

Conclusions: Our results suggest that the EGFR status of patients with NSCLC differs between patients 80 years or older and those younger than 80 years. EGFR mutation status might be a prognostic marker in elderly patients with completely resected NSCLC.
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http://dx.doi.org/10.1186/1471-2407-14-610DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4161910PMC
August 2014

Clinical usefulness of testing for UDP glucuronosyltransferase 1 family, polypeptide A1 polymorphism prior to the inititation of irinotecan-based chemotherapy.

Mol Clin Oncol 2014 Sep 6;2(5):737-743. Epub 2014 Jun 6.

Department of Thoracic Oncology, Kanagawa Cancer Center, Yokohama, Kanagawa 241-0815, Japan.

An association between UDP glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1) polymorphisms and irinotecan-induced neutropenia has been previously reported. In this study, we assessed the clinical usefulness of testing for UGT1A1 polymorphisms prior to the initiation of irinotecan-based chemotherapy, as this remains a controversial subject. A total of 136 lung cancer patients who were treated with a combination of nedaplatin and irinotecan as initial chemotherapy were assessed. Following exclusion of patients exhibiting low UGT1A1 enzyme activity, 70 patients were treated after UGT1A1 polymorphism testing (test group) and 66 patients were treated without UGT1A1 polymorphism testing (non-test group). We retrospectively analyzed and compared the adverse events between the test and the non-test groups and observed no reduction in hematological or non-hematological toxicities in the test group compared to that in the non-test group. Of the 9 patients with grade 4 or 5 non-hematological toxicity, 6 patients had febrile neutropenia (FN). All the patients with FN were aged >70 years. The incidence of adverse events was significantly higher among patients aged >70 years compared to that among younger patients. In conclusion, in patients treated with nedaplatin and irinotecan combination chemotherapy, UGT1A1 polymorphism testing prior to the initiation of chemotherapy did not reduce the incidence of adverse events. Therefore, UGT1A1 polymorphism testing alone may not be sufficient to predict the occurrence of severe adverse events and it may be more important to effectively manage adverse events, particularly in elderly patients.
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http://dx.doi.org/10.3892/mco.2014.308DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4106749PMC
September 2014

Proteomic analysis of proteins related to prognosis of lung adenocarcinoma.

J Proteome Res 2014 Nov 8;13(11):4686-94. Epub 2014 Jul 8.

Graduate School of Medical Life Science and Advanced Medical Research Center, Yokohama City University , 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa 236-0004, Japan.

We attempted to identify prognosis-related proteins expressed in early resection lung adenocarcinomas that had higher metastatic potential. Early resection of lung adenocarcinoma tissues were collected from patients who experienced recurrence within 5 years after surgery; these patients are defined here as the poor prognosis group. From these samples, we prepared frozen tissue sections and then isolated cancerous areas by laser capture microdissection to allow extraction of cancer tissue-derived soluble proteins. Shotgun LC-MS/MS analysis detected and identified a total of 875 proteins in these cancer tissues. Relative quantitative analysis revealed that 17 proteins were preferentially expressed in the poor prognosis group relative to the good prognosis group, which consisted of patients who did not exhibit recurrence. Among them, 14-3-3 beta/alpha and calnexin were reported to be potentially involved in tumor recurrence and the malignant properties of lung cancer. Here immunological analyses confirmed disease-associated expression of these proteins. In a cell-culture model using A549, targeted depletion of either 14-3-3 beta/alpha or calnexin reduced proliferation, invasion, and migration, suggesting that both proteins are involved in determining the malignant properties of lung cancer that contribute to poor prognosis.
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http://dx.doi.org/10.1021/pr4012969DOI Listing
November 2014

A pilot study of adjuvant chemotherapy with irinotecan and cisplatin for completely resected high-grade pulmonary neuroendocrine carcinoma (large cell neuroendocrine carcinoma and small cell lung cancer).

Lung Cancer 2014 Jun 13;84(3):254-8. Epub 2014 Mar 13.

Division of Thoracic Surgery, National Cancer Center Hospital East, Chiba, Japan.

Background: Large cell neuroendocrine carcinoma (LCNEC) and small cell lung cancer (SCLC) are recognized as high-grade neuroendocrine carcinomas (HGNEC) of the lung. In patients with completely resected HGNEC, platinum-based adjuvant chemotherapy may be considered. However, the optimum chemotherapy regimen has not been determined. We conducted a multicenter single-arm phase II trial to evaluate irinotecan and cisplatin in postoperative adjuvant chemotherapy for HGNEC patients.

Patients And Methods: Patients with completely resected stage I-IIIA HGNEC received four cycles of irinotecan (60 mg/m(2), day 1, 8, 15) plus cisplatin (60 mg/m(2), day 1). This regimen was repeated every 4 weeks. The primary endpoint was the rate of completion of chemotherapy (defined as having undergone three or four cycles), and secondary endpoints were the rate of 3-year relapse-free survival (RFS), rate of 3-year survival and toxicities.

Results: Forty patients were enrolled between September 2007 and April 2010. Patients' characteristics were: median age (range) 65 [45-73] years; male 85%; ECOG-PS 1 60%; LCNEC 57% and SCLC 43%; stage IA/IB/IIB/IIIA 32/35/8/5%; 95% received lobectomy. The rate of completion of chemotherapy was 83% (90%C.I.; 71-90%). The rate of overall survival at 3 years was estimated at 81%, and that of RFS at 3 years was 74%. The rates of overall survival and RFS at 3 years were 86 and 74% among 23 LCNEC patients, and 74 and 76% among 17 SCLC patients, respectively. Nineteen patients (48%) experienced grade 3 or 4 neutropenia, but only five patients (13%) developed febrile neutropenia. Two patients (5%) developed grade 3 diarrhea, and four patients (10%) had grade 3 nausea. No treatment-related deaths were observed in this study. All 40 specimens were also diagnosed as HGNEC by central pathological review.

Conclusions: The combination of irinotecan and cisplatin as postoperative adjuvant chemotherapy was feasible and possibly efficacious for resected HGNEC.
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http://dx.doi.org/10.1016/j.lungcan.2014.03.007DOI Listing
June 2014

Prospective study of paclitaxel and irinotecan for elderly patients with unresectable non-small cell lung cancer.

J Exp Ther Oncol 2013 ;10(3):203-8

Department of Thoracic Oncology, Kanagawa Cancer Center, Nakao 1-1-2, Asahi-ku, Yokohama 241-0815, Japan.

We conducted a phase II study of combination chemotherapy with paclitaxel (Pac) and irinotecan (CPT) to determine the effects and toxicities in patients 70 years or older with unresectable non-small cell lung cancer (NSCLC). Eligible patients were entered to receive three courses of Pac at 160 mg/m2 and CPT at 60 mg/m2 every 2-3 weeks. Twenty-one patients were registered. Thirteen patients were male and 8 were female, with a median age of 72 years (range: 70-82 years). Eight patients had a performance status (PS) of 0 and the other 13 patients had a PS of 1. Six and 15 patients were stage IIIB and stage IV, respectively. Ten patients received 3 to 6 cycles of the chemotherapy. Of the hematological toxicities, grade 4 neutropenia was observed in 23.8% of the patients. Of the non-hematological toxicities, grade 3 or 4 fatigue, anorexia and nausea were observed in 5, 3 and 4 patients, respectively. Three of 6 patients with infection developed grade 3 pneumonia. Grade 3 allergy with rash occurred in a patient. Cerebral infarction occurred in two patients and grade 3 peripheral neuropathy in one. The outcome of the Pac and CPT regimen in 21 patients was 8 PR, 10 SD and three PD, and the response rate was 38.1% The median survival time was 9.1 months. The one- and 2-year survival rates were 38.1% and 19.0%, respectively. The Pac plus CPT regimen is feasible and active with moderate toxicity for elderly patients with NSCLC.
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July 2014

¹⁸F-fluorodeoxyglucose uptake on positron emission tomography in mucinous adenocarcinoma.

Eur J Radiol 2013 Nov 12;82(11):e721-5. Epub 2013 Aug 12.

Department of Thoracic Oncology, Kanagawa Cancer Center Hospital, Japan. Electronic address:

Background: The prognostic value of maximum standardized uptake value (maxSUV) on (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) is known for localized pulmonary adenocarcinoma, which is most commonly non-mucinous adenocarcinoma. We examined the validity of thin-section computed tomography (TS-CT) and FDG-PET findings in mucinous adenocarcinoma.

Materials And Methods: TS-CT and FDG-PET were performed on 25 patients with mucinous lung adenocarcinoma that was subsequently resected between January 2009 and March 2013. Based on the percentage reduction of maximum tumor diameter on the mediastinal window image compared with the diameter on the lung window image on TS-CT, tumors were classified as air-type (≥50%) or solid-type (<50%). All resected specimens were pathologically diagnosed according to the International Association for the Study of Lung Cancer (IASLC) classification, and the diameter of the pathological invasive area was assessed.

Results: Most mucinous adenocarcinomas were located in the lower lobe. All except two were classified as solid-type tumor on TS-CT. Multiple regression analysis revealed the correlation of maxSUV with pathological tumor size and diameter of pathological invasive area; these two parameters showed no significant correlation with each other (r=0.354, p=0.083). maxSUV was significantly lower for tumors with invasive area ≤5 mm than for tumors with invasive area >5mm (1.62 vs. 3.77, p=0.01), but no statistically significant difference was found in terms of other pathological invasive findings such as the presence of lymphatic or vascular invasion, pleural involvement, or predominant histological subtype.

Conclusions: Most mucinous adenocarcinomas had appearances of solid-type tumor on TS-CT. maxSUV on FDG-PET indicates the pathological invasive area in mucinous adenocarcinoma as well as non-mucinous adenocarcinoma.
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http://dx.doi.org/10.1016/j.ejrad.2013.07.028DOI Listing
November 2013

Combination chemotherapy with irinotecan and cisplatin for large-cell neuroendocrine carcinoma of the lung: a multicenter phase II study.

J Thorac Oncol 2013 Jul;8(7):980-4

Division of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan.

Introduction: We conducted a phase II study of combination chemotherapy with irinotecan (CPT) and cisplatin (CDDP) in patients with advanced large-cell neuroendocrine carcinoma (LCNEC) of the lung.

Methods: Patients received irinotecan (60 mg/m², days 1, 8, and 15) and cisplatin (60 mg/m², day 1) every 4 weeks for up to four cycles. The primary endpoint was the response rate. Expected and threshold values for the primary endpoint were 50% and 30%.

Results: Forty-four patients were enrolled between January 2005 and November 2011. The response rate (RR) was 54.5% (95% confidence interval [CI], 38.8-69.6%). The median progression-free survival time was 5.9 months (95% CI, 5.5-6.3), and the median survival time was 15.1 months (95% CI, 11.2-19.0). A central pathological review of specimens from 41 patients demonstrated that 30 patients had LCNEC but that 10 patients had small-cell lung cancer (SCLC) and one had non-small-cell lung cancer with a neuroendocrine structure. The RR was 46.7% (95% CI, 28.3-65.7%) in the LCNEC group and 80% (95% CI, 44.4-97.5%) in the SCLC group (p = 0.0823). The median survival time was 12.6 months (95% CI, 9.3-16.0) in the LCNEC group and 17.3 months (95% CI, 11.2-23.3) in the SCLC group (p = 0.047).

Conclusions: Combination chemotherapy with irinotecan and cisplatin was active in patients with LCNEC, but the RR and the overall survival period among the patients with LCNEC seemed to be inferior to those among the patients with SCLC. Small numbers of patients were a major limitation in this study.
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http://dx.doi.org/10.1097/JTO.0b013e31828f6989DOI Listing
July 2013

Periaortitis associated with anti-neutrophil cytoplasmic antibodies induced by bevacizumab combination therapy.

Intern Med 2013 1;52(5):589-91. Epub 2013 Mar 1.

Department of Thoracic Oncology, Kanagawa Cancer Center Hospital, Japan.

Drug-induced vessel vasculitis is a rare complication of chemotherapy. In particular, few reports have investigated drug-induced large vessel vasculitis. We herein report the case of a 57-year-old woman with advanced lung adenocarcinoma who developed perinuclear anti-neutrophil cytoplastic antibodies (p-ANCA)-positive periaortitis induced by bevacizumab combination chemotherapy. With the increasing use of combination therapy with bevacizumab, the incidence of vascular complications will potentially increase. A noninfectious fever occurring during chemotherapy might be a sign of vasculitis; therefore, we must ensure that possible periaortitis is not overlooked.
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http://dx.doi.org/10.2169/internalmedicine.52.6632DOI Listing
December 2013

Phase I/II study of amrubicin in combination with S-1 as second-line chemotherapy for non-small-cell lung cancer without EGFR mutation.

Cancer Chemother Pharmacol 2013 Mar 18;71(3):705-11. Epub 2013 Jan 18.

Department of Thoracic Oncology, Kanagawa Cancer Center, Nakao 1-1-2, Asahi-ku, Yokohama 241-0815, Japan.

Introduction: Both amrubicin (Am) and S-1 are effective against non-small-cell lung cancer (NSCLC), and preclinical studies have demonstrated that the effect of tegafur/uracil, the original compound of S-1, in combination with Am significantly inhibits tumor growth.

Methods: We conducted a phase I/II study of Am and S-1 against pretreated NSCLC without EGFR mutation. We fixed the dose of S-1 at 40 mg/m(2) on days 1-14 and escalated the Am dose in increments of 5 mg/m(2) from a starting dose of 30 mg/m(2)/day on days 1-3 and repeated the cycle every 4 weeks.

Results: Twenty-six patients were registered. In phase I, at an Am dose of 35 mg/m(2)/day, three patients experienced grade 2 leukopenia during S-1 administration, and S-1 was withdrawn. Another patient developed grade 2 serum bilirubin in the first cycle. DLTs were observed in four of six patients at this dose level, and therefore, 30 mg/m(2)/day was set as the recommended dose for Am. Twenty patients received this recommended Am dose. Febrile neutropenia was observed in two patients, and one patient developed a grade 4 increase in serum creatinine. Grade 3 vomiting, infection, hypotension, and urinary retention were observed in one patient each, respectively. Other toxicities were mild, and there were no treatment-related deaths. Two patients showed a CR, three showed a PR, and the overall response rate was 25.0%. The median progression-free and the median survival times were 3.8 and 15.6 months, respectively, and the 1-year survival rate was 60%.

Conclusion: Am and S-1 every 4 weeks is an effective combination for pretreated NSCLC without EGFR mutation.
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http://dx.doi.org/10.1007/s00280-012-2061-1DOI Listing
March 2013

Phase II study of nedaplatin and irinotecan in patients with extensive small-cell lung cancer.

Cancer Chemother Pharmacol 2013 Feb 3;71(2):345-50. Epub 2012 Nov 3.

Department of Thoracic Oncology Kanagawa Cancer Center, Nakao 1-1-2, Asahi-ku, Yokohama 241-0815, Japan.

Background: The standard chemotherapy for Japanese patients with extensive disease of small-cell lung cancer (ED-SCLC) is cisplatin and irinotecan.

Methods: Patients with untreated ED-SCLC were treated with nedaplatin (NP) at 50 mg/m(2) and irinotecan (CPT) at 50 mg/m(2) on days 1 and 8 every 4 weeks for four cycles.

Results: Twenty-five patients were registered. Nineteen patients were male and six female, with a median age of 64 years (50-79 years). Two patients had a performance status of 2. Nineteen of them were able to receive 4 courses of NP and CPT chemotherapy. Grade 3 or 4 anemia, neutropenia, and thrombocytopenia occurred in 8.0, 68.0, and 36.0 % of patients, respectively. Other grade 3 toxicities were SGOT, hyponatremia, fatigue, vomiting, diarrhea, hypotension, febrile neutropenia, oral hemorrhage, and pneumonia. Grade 4 fatigue occurred in one patient. There was no treatment-related death. The overall response rate was 100 %. The median progression-free and overall survivals were 6.6 and 16.0 months, respectively, and the 2-year survival rate was 28 %.

Conclusion: NP with CPT is effective and safe for patients with ED-SCLC.
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http://dx.doi.org/10.1007/s00280-012-2011-yDOI Listing
February 2013

Nedaplatin and irinotecan for patients with recurrent small cell lung cancer.

J Exp Ther Oncol 2012 ;10(1):65-9

Department of Thoracic Oncology, Kanagawa Cancer Center, Nakao 1-1-2, Asahi-ku, Yokohama 241-0815, Japan.

Background: No standard second-line combination chemotherapy has yet been established for patients with recurrent small cell lung cancer (RSCLC).

Methods: Patients with RSCLC were treated with nedaplatin (NP) at 50 mg/m2 and irinotecan (CPT) at 50 mg/m2 on days 1 and 8 every 4 weeks for four cycles.

Results: The clinical outcomes of 12 patients (9 male and 3 female; age range 48-76 years, median 62 years) were retrospectively analyzed. Seven of the patients showed sensitive relapse. Two patients had a performance status of 2. Nine of the patients were able to receive 4 to 6 courses of NP and CPT chemotherapy. Grade 3 or 4 anemia, neutropenia and thrombocytopenia occurred in 25.0%, 50.0% and 41.7% of patients, respectively. There were no grade 3 or 4 non-hematologic toxicities except for febrile neutropenia in 1 patient. There was no treatment-related death. Nine patients achieved PR, and the objective response rate was 75.0%. The median survival time was 11.1 months (range 4.8 to 31.3+ months) and the 1-year survival rate was 50.0%.

Conclusion: NP and CPT in combination are effective and safe for patients with RSCLC.
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September 2012

Nedaplatin and irinotecan in patients with large-cell neuroendocrine carcinoma of the lung.

Anticancer Res 2012 Apr;32(4):1453-6

Department of Thoracic Oncology, Kanagawa Cancer Center, Asahi-ku, Yokohama, Japan.

Background: No standard chemotherapy has been established for patients with large-cell neuroendocrine carcinoma (LCNEC).

Patients And Methods: Patients with LCNEC of the lung were treated with nedaplatin (NP) at 50 mg/m(2) and irinotecan at 50 mg/m(2) on days 1 and 8 every four weeks for four cycles.

Results: Data for 18 of the LCNEC patients were retrospectively analyzed. All patients were male, with a performance status 0 or 1, and the median age was 68 (range 58-80) years. Nine patients received adjuvant chemotherapy after undergoing complete surgical resection. Fourteen patients were able to receive four cycles of nedaplatin and irinotecan. Grade 4 leukopenia and neutropenia occurred in 5.6% and 16.7%, respectively. Four patients experienced grade 3 non-hematologic toxicities, such as diarrhea, enterocolitis, duodenal perforation and myocardial infarction. There were no treatment-related deaths. Two patients achieved complete response and four achieved partial response, and the median survival time was 12.3 months for the nine patients with advanced disease.

Conclusion: Nedaplatin plus irinotecan is effective and safe for patients with LCNEC of the lung.
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April 2012

Effectiveness of erlotinib in advanced non-small cell lung cancer in cases of gefitinib resistance after treatment of more than 6 months.

Onkologie 2012 13;35(1-2):18-22. Epub 2012 Jan 13.

Department of Thoracic Oncology, Kanagawa Cancer Center, Yokohama, Kanagawa, Japan.

Background: There have been reports on the use of erlotinib in non-small cell lung cancer (NSCLC) patients after gefitinib resistance occurs, and it has been stated that erlotinib may be beneficial in patients with long stable disease (SD) previously treated with gefitinib.

Patients And Methods: We retrospectively studied gefitinib-resistant NSCLC patients with favorable clinical features, who received erlotinib following disease progression after gefitinib treatment of more than 6 months.

Results: A total of 21 patients with NSCLC were included. Partial response was seen in 2 cases (9%), SD in 6 cases (19%), and progressive disease (PD) in 13 cases (62%). Disease control (DC) was achieved with erlotinib in 8 cases (36%). The median survival time (MST) was 369 days in DC cases and 133 days in PD cases. There were no statistical differences between DC cases and PD cases in terms of MST relative to sex, smoking and skin rash.

Conclusion: Subsequent erlotinib therapy is one of the therapeutic options in the treatment of gefitinib-resistant NSCLC in which prior gefitinib has shown long-term SD of more than 6 months.
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http://dx.doi.org/10.1159/000335736DOI Listing
June 2012

Plasma free amino acid profiling of five types of cancer patients and its application for early detection.

PLoS One 2011 7;6(9):e24143. Epub 2011 Sep 7.

Molecular Pathology and Genetics Division, Kanagawa Cancer Center, Yokohama, Japan.

Background: Recently, rapid advances have been made in metabolomics-based, easy-to-use early cancer detection methods using blood samples. Among metabolites, profiling of plasma free amino acids (PFAAs) is a promising approach because PFAAs link all organ systems and have important roles in metabolism. Furthermore, PFAA profiles are known to be influenced by specific diseases, including cancers. Therefore, the purpose of the present study was to determine the characteristics of the PFAA profiles in cancer patients and the possibility of using this information for early detection.

Methods And Findings: Plasma samples were collected from approximately 200 patients from multiple institutes, each diagnosed with one of the following five types of cancer: lung, gastric, colorectal, breast, or prostate cancer. Patients were compared to gender- and age- matched controls also used in this study. The PFAA levels were measured using high-performance liquid chromatography (HPLC)-electrospray ionization (ESI)-mass spectrometry (MS). Univariate analysis revealed significant differences in the PFAA profiles between the controls and the patients with any of the five types of cancer listed above, even those with asymptomatic early-stage disease. Furthermore, multivariate analysis clearly discriminated the cancer patients from the controls in terms of the area under the receiver-operator characteristics curve (AUC of ROC >0.75 for each cancer), regardless of cancer stage. Because this study was designed as case-control study, further investigations, including model construction and validation using cohorts with larger sample sizes, are necessary to determine the usefulness of PFAA profiling.

Conclusions: These findings suggest that PFAA profiling has great potential for improving cancer screening and diagnosis and understanding disease pathogenesis. PFAA profiles can also be used to determine various disease diagnoses from a single blood sample, which involves a relatively simple plasma assay and imposes a lower physical burden on subjects when compared to existing screening methods.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0024143PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3168486PMC
February 2012

Growth rate of lung cancer recognized as small solid nodule on initial CT findings.

Eur J Radiol 2012 Apr 26;81(4):e548-53. Epub 2011 Jul 26.

Department of Thoracic Oncology, Kanagawa Cancer Center, 1-1-2 Nakao, Asahi-ku, Yokohama 241-0815, Japan.

Introduction: To study the characteristics of lung cancer, appearing as small solid nodules on initial computed tomography (CT) findings, and to determine an appropriate follow-up duration so as to differentiate between malignancy and benign tumor.

Methods: We analyzed the records of 34 patients who had undergone surgical resection of lung cancer, which appeared as small solid nodules on initial CT findings. We studied the CT findings, volume doubling times (VDT), follow-up durations, pathological and clinical findings.

Results: VDT is classified as follows: (1) slow growth group (SGG), with a VDT of more than 700 days and (2) rapid growth group (RGG), with a VDT of less than 700 days. The median VDT of the SGG was 1083 days, and the RGG was 256 days (p<0.01). The median duration for follow-up of the SGG was 1218 days, and 179 days for the RGG. A statistical difference was noted in the follow-up durations (p<0.01). There were no statistical differences in the preoperative thin-section CT (TSCT) findings, or in the pathological findings. The RGG included more patients with smoking histories. The CT findings of RGG tended to reveal changed in base lung field such as emphysema, and lung fibrosis.

Conclusions: Generally, lung cancer appearing as small solid nodules on initial CT findings grew rapidly, but there were some cases which displayed slow growth patterns. These cases required follow up for over two years, before diagnosis was possible. We concluded the appropriate maximum followup duration is three years.
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http://dx.doi.org/10.1016/j.ejrad.2011.06.032DOI Listing
April 2012

Prognostic value of preoperative FDG-PET in stage IA lung adenocarcinoma.

Eur J Radiol 2012 Aug 4;81(8):1891-5. Epub 2011 May 4.

Department of Thoracic Oncology, Kanagawa Cancer Center Hospital, Yokohama, Kanagawa, Japan.

Background: Maximum standardized uptake value (SUVmax) of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) has been found to have prognostic value. We previously reported the correlation between SUVmax and pathological invasive area, and determined an SUVmax cut-off value of 2.15 for predicting the recurrence potential of an invasive area of diameter 5mm. Here, we evaluate the validity of FDG-PET for prediction of recurrence in pathological stage IA lung adenocarcinoma.

Methods: From February 2006 to May 2008, 100 patients with pathological stage IA lung adenocarcinoma underwent complete resection at our hospital. Tumors were classified as air-type or solid-type based on thin-section computed tomography (TS-CT) findings and the influence of TS-CT classification, SUVmax, and clinicopathologic features were evaluated in terms of the incidence of recurrence.

Results: Unlike air-type adenocarcinomas, recurrent disease was detected in 8 of 62 solid-type adenocarcinomas. SUVmax and diameter of invasive area were significantly correlated with recurrence and a shorter time to recurrence. All 8 recurrent cases had pathological invasive area >5mm. All except one case of recurrence were solid-type adenocarcinomas with SUVmax≥2.15. Three-year disease-free survival rates were 100% in air-type adenocarcinomas, 97.1% in solid-type adenocarcinomas with SUVmax<2.15, and 74.1% in solid-type adenocarcinoma with SUVmax≥2.15.

Conclusion: Combined evaluation of TS-CT classification and SUVmax had significant value in predicting recurrence in stage IA lung adenocarcinoma, reflecting the aggressiveness of primary lung adenocarcinoma. Prediction of tumor aggressiveness could contribute to decision-making regarding the choice of surgical procedure and treatment after surgery.
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http://dx.doi.org/10.1016/j.ejrad.2011.04.007DOI Listing
August 2012