研究者詳細 - 長島　健悟

論文 - 長島　健悟

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Safety and efficacy of thalidomide in patients with POEMS syndrome: a multicentre, randomised, double-blind, placebo-controlled trial

Misawa S, Sato Y, Katayama K, Nagashima K, Aoyagi R, Sekiguchi Y, Sobue G, Koike H, Yabe I, Sasaki H, Watanabe O, Takashima H, Nishizawa M, Kawachi I, Kusunoki S, Mitsui Y, Kikuchi S, Nakashima I, Ikeda S-i, Kohara N, Kanda T, Kira J-i, Hanaoka H, Kuwabara S, for the Japanese POEMS Syndrome for Thalidomide (J-POST) Trial Study Group

The Lancet Neurology 15 （ 11 ） 1129 - 1137 2016年10月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 14744422

Background Polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS) syndrome is a rare cause of demyelinating neuropathy, with multi-organ involvement characterised by plasma cell dyscrasia and VEGF overproduction. No treatments have been established for patients with POEMS syndrome who are not eligible for stem-cell transplantation. Thalidomide suppresses VEGF and plasma cell proliferation. We aimed to assess the safety and efficacy of thalidomide for the treatment of POEMS syndrome. Methods We did a randomised, double-blind, placebo-controlled, phase 2/3 trial at 12 hospitals in Japan. Adults (age ≥20 years) with POEMS syndrome who were ineligible for autotransplantation were randomly assigned (1:1) by a minimisation method to treatment with oral dexamethasone (12 mg/m per day on the first 4 days of every 28-day cycle) plus either oral thalidomide (200 mg daily) or placebo for six cycles. All study personnel and patients were masked to treatment allocation. The primary endpoint was the reduction rate of serum VEGF concentrations at 24 weeks. Analysis was by intention to treat. This study is registered with the UMIN Clinical Trials Registry, UMIN000004179. Findings Between Nov 11, 2010, and July 3, 2014, we randomly assigned 25 patients to receive either thalidomide (n=13) or placebo (n=12); one patient in the placebo group was excluded from analyses because of a protocol violation. The adjusted mean VEGF concentration reduction rate at 24 weeks was 0·39 (SD 0·34) in the thalidomide group compared with −0·02 (0·54) in the placebo group (adjusted mean difference 0·41, 95% CI 0·02–0·80; p=0·04). Mild sinus bradycardia was more frequent in the thalidomide group than in the placebo group (seven [54%] vs zero; p=0·006). Five patients had serious adverse events: three in the thalidomide group (transient cardiac arrest, heart failure, and dehydration) and two in the placebo group (ileus and fever). No deaths occurred during the randomised study. In the 48-week open-label study period (n=22), newly developed adverse events were sinus bradycardia (n=4), constipation (n=5), and mild sensory neuropathy (n=5). Two patients died in the open-label study; both patients were initially in the placebo group, and the cause of death was progression of the disease. Interpretation Thalidomide reduces serum VEGF concentrations and represents a new treatment for patients with POEMS syndrome who are not eligible for stem-cell transplantation. Thalidomide treatment poses a risk of bradycardia; however, the benefits are likely to exceed the risk. Funding Japanese Ministry of Health, Labour, and Welfare, and Fujimoto Pharmaceuticals. 2

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Comparison of panitumumab plus irinotecan and cetuximab plus irinotecan for KRAS wild-type metastatic colorectal cancer

Yamaguchi T, Iwasa S, Nagashima K, Ikezawa N, Hamaguchi T, Shoji H, Honma Y, Takashima A, Okita N, Kato K, Yamada Y, Shimada Y

Anticancer Research 36 （ 7 ） 3531 - 3536 2016年07月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 02507005

Background/Aim: Panitumumab and cetuximab are known to be effective treatments for KRAS wild-type metastatic colorectal cancer (mCRC). However, it remains unclear which of these two biologic agents confers the greatest benefit when combined with irinotecan in patients with KRAS wild-type mCRC previously treated with fluoropyrimidine, oxaliplatin and irinotecan. Patients and Methods: Data, from 139 patients who received panitumumab or cetuximab, in combination with irinotecan, for KRAS wild-type mCRC previously treated with fluoropyrimidine, oxaliplatin and irinotecan were analyzed. The efficacy and safety of panitumumab plus irinotecan was compared to that of cetuximab plus irinotecan. Results: Baseline characteristics of the panitumumab plus irinotecan (n=42) and cetuximab plus irinotecan (n=97) groups were similar. Among patients with measurable lesions, the response rate was 34% in the panitumumab plus irinotecan group and 20% in the cetuximab plus irinotecan group. Median progression-free survival (PFS) was 4.3 and 5.7 months in the panitumumab and cetuximab groups, respectively. Median overall survival was 13.6 months with panitumumab and 11.2 months with cetuximab. Conclusion: Panitumumab plus irinotecan was well-tolerated and displayed a similar level of efficacy to that of cetuximab plus irinotecan.

Prognostic and predictive value of extended RAS mutation and mismatch repair status in stage III colorectal cancer

Sasaki Y, Akasu T, Saito N, Kojima H, Matsuda K, Nakamori S, Komori K, Amagai K, Yamaguchi T, Ohue M, Nagashima K, Yamada Y

Cancer Science 107 （ 7 ） 1006 - 1012 2016年07月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 13479032

The prognostic and predictive value of KRAS gene mutations in stage III colorectal cancer is controversial because many recent clinical trials have not involved a surgery-alone arm. Additionally, data on the significance of extended RAS (KRAS/NRAS) mutations in stage III cancer are not available. Hence, we undertook a combined analysis of two phase III randomized trials, in which the usefulness of adjuvant chemotherapy with tegafur–uracil (UFT) was evaluated, as compared with surgery alone. We determined the association of extended RAS and mismatch repair (MMR) status with the effectiveness of adjuvant chemotherapy. Mutations in KRAS exons 2, 3, and 4 and NRAS exons 2 and 3 were detected by direct DNA sequencing. Tumor MMR status was determined by immunohistochemistry. Total RAS mutations were detected in 134/304 (44%) patients. In patients with RAS mutations, a significant benefit was associated with adjuvant UFT in relapse-free survival (RFS) (hazard ratio = 0.49; P = 0.02) and overall survival (hazard ratio = 0.51; P = 0.03). In contrast, among patients without RAS mutations, there was no difference in RFS or overall survival between the adjuvant UFT group and surgery-alone group. We detected deficient DNA MMR in 23/304 (8%) patients. The MMR status was neither prognostic nor predictive for adjuvant chemotherapy. An interaction analysis showed that there was better RFS among patients treated with UFT with RAS mutations, but not for those without RAS mutations. Extended RAS (KRAS/NRAS) mutations are proposed as predictive indicators with respect to the efficacy of adjuvant UFT chemotherapy in patients with resected stage III colorectal cancer.

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Pretreatment immune status correlates with progression-free survival in chemotherapy-treated metastatic colorectal cancer patients

Tada K, Kitano S, Shoji H, Nishimura T, Shimada Y, Nagashima K, Aoki K, Hiraoka N, Honma Y, Iwasa S, Okita N, Takashima A, Kato K, Yamada Y, Katayama N, Boku N, Heike Y, Hamaguchi T

Cancer Immunology Research 4 （ 7 ） 592 - 599 2016年07月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 23266066

It remains unclear whether the immunologic status of cells in peripheral blood can be used as a prognostic indicator of response to treatment for patients with unresectable metastatic colorectal cancer (MCRC). We therefore investigated the relationship between the pretreatment immunologic status of 40 patients with MCRC who planned to receive the first-line chemotherapy and their progression-free survival. Twenty-five immune cell subsets, including monocytic myeloid-derived suppressor cells (M-MDSC) and effector memory T cells (TEM), were measured by multicolor-flow cytometry.Wedivided patients into high and low (above and below the median, respectively) groups based on the median value for each immune cell subset and compared progression-free survival of the two groups. Patients with high M-MDSC, low CD4 TEM, or low CD8 TEM quantities had significantly shorter progression-free survival (P = 0.004, 0.005, and 0.002, respectively). Patients were classified into two prognostic groups based on numbers of adverse factors; having two or three adverse factors (n =21, 52.5%) was correlated with significantly shorter progression-free survival compared with none or one (n = 19, 47.5%; P < 0.001). The presence of two or three adverse factors was an independent poor prognostic factor for progression-free survival (HR, 9.2; 95% confidence interval, 2.5-34.2; P < 0.001). These results provide evidence that pretreatment peripheral immune status can inform the outcome of patients with MCRC treated with first-line chemotherapy.

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Utility of prediction scores for hepatocellular carcinoma in patients with chronic hepatitis B treated with nucleos(t)ide analogues

Tawada A, Chiba T, Saito T, Ogasawara S, Suzuki E, Ooka Y, Arai M, Kanda T, Shinozaki M, Goto N, Nagashima K, Yokosuka O

Oncology 90 （ 4 ） 199 - 208 2016年04月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 00302414

Objective: The utility of risk scores to predict the development of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients treated with nucleos(t)ide analogue (NA) remains to be elucidated. Methods: CU-HCC (The Chinese University of Hong Kong-HCC) and GAG-HCC (Guide with Age, Gender, HBV DNA, Core promoter mutations and Cirrhosis) scores of 225 Japanese patients treated with NAs for at least 2 years were calculated before and 2 years after the NA treatment. According to the cutoff values, the patients were categorized into high-score or low-score groups. Results: Sixteen of 225 patients developed HCC. Patients with a high score before the NA treatment showed a significantly higher HCC incidence than those with a low score using both score models (p < 0.001). Time-dependent receiver operating characteristic analyses based on scores before and 2 years after the NA treatment showed that both models exhibited moderate accuracy in predicting HCC development. The HCC incidence was significantly lower in the patients whose scores decreased below the cutoff values in response to the NA treatment than in those whose scores remained high using both models (p < 0.01). Conclusions: The predictive performance of the CU-HCC and GAG-HCC scores in the CHB patients treated with NAs is comparable to that in the NA-naive patients. The patients with sustained high scores after the NA treatment showed a higher incidence of HCC development.

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Fujita M, Sato Y, Nagashima K, Takahashi S, Hata A

PLoS ONE 11 （ 3 ） e0151690 2016年03月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1932-6203

The purpose of this retrospective cohort study was to analyze the association between income level and health care access in Japan. Data from a total of 222,259 subjects (age range, 0-74 years) who submitted National Health Insurance claims in Chiba City from April 2012 to March 2014 and who declared income for the tax period from January 1 to December 31,2012 were integrated and analyzed. The generalized estimating equation, in which household was defined as a cluster, was used to evaluate the association between equivalent income and utilization and duration of hospitalization and outpatient care services. A significant positive linear association was observed between income level and outpatient visit rates among all age groups of both sexes; however, a significantly higher rate and longer period of hospitalization, and longer outpatient care, were observed among certain lower income subgroups. To control for decreased income due to hospitalization, subjects hospitalized during the previous year were excluded, and the data was then reanalyzed. Significant inverse associations remained in the hospitalization rate among 40-59-year-old men and 60-69-year-old women, and in duration of hospitalization among 40-59 and 60-69-year-olds of both sexes and 70-74-year-old women. These results suggest that low-income individuals in Japan have poorer access to outpatient care and more serious health conditions than their higher income counterparts.

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The impact of heptavalent pneumococcal conjugate vaccine on the incidence of childhood community-acquired pneumonia and bacteriologically confirmed pneumococcal pneumonia in Japan

Naito S, Tanaka J, Nagashima K, Chang B, Hishiki H, Takahashi Y, Oikawa J, Nagasawa K, Shimojo N, Ishiwada N

Epidemiology & Infection 144 （ 3 ） 494 - 506 2016年02月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 09502688

Heptavalent pneumococcal conjugate vaccine (PCV7) was introduced to Japan in 2010. We investigated the impact of PCV7 on childhood community-acquired pneumonia (CAP) and pneumococcal pneumonia (PP). Children aged <5 years living in Chiba city, Japan, who were admitted to hospitals were enrolled to estimate the incidence of CAP based on the mid-year population. PP was determined by the presence of Streptococcus pneumoniae in cultured blood and/or sputum samples of CAP patients. The incidence of CAP and S. pneumoniae isolated from PP patients was compared before (April 2008-March 2009) and after (April 2012-March 2013) the introduction of PCV7 immunization. The annual incidence of CAP was reduced [incidence rate ratio 0·81, 95% confidence interval (CI) 0·73-0·90]. When comparing post-vaccine with pre-vaccine periods, the odds ratio for PP incidence was 0·60 (95% CI 0·39-0·93, P = 0·024). PCV7-covered serotypes markedly decreased (66·6% in pre-vaccine vs. 15·6% in post-vaccine, P < 0·01), and serotypes 6C, 15A, 15C and 19A increased. Multidrug-resistant international clones in the pre-vaccine period (Spain -2/ST90, Taiwan -14/ST236) decreased, while Sweden -25/ST63 was the dominant clone in the post-vaccine period. A significant reduction in the incidence of both CAP hospitalizations and culture-confirmed PP of vaccine serotypes was observed at 2 years after PCV7 vaccination. 6B 19F 15A

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Quantitative ultrasound elastography with an acoustic coupler for Achilles tendon elasticity: measurement repeatability and normative values

Yamamoto Y, Yamaguchi S, Sasho T, Fukawa T, Akatsu Y, Nagashima K, Takahashi K

Journal of Ultrasound in Medicine 35 （ 1 ） 159 - 166 2016年01月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 02784297

Objectives-The purposes of this study were to measure intraobserver and interobserver repeatability of quantitative elastography using an acoustic coupler for the Achilles tendon, to compare elastographic values among different age groups, and to assess the correlation between quantitative and conventional qualitative measurements. Methods-One hundred asymptomatic Achilles tendons of 50 volunteers were examined. For quantitative elastography, the strain value of the tendon was divided by that of the acoustic coupler with a known Young modulus, and the strain ratio was calculated. B-mode image assessment and qualitative elastography were also performed. Intraobserver repeatability and interobserver repeatability of strain ratio measurements were calculated. The strain ratios were compared among age groups by the Kruskal-Wallis test. Additionally, strain ratios for each B-mode grade and qualitative elastographic grade were compared by the Wilcoxon signed rank test. Results-Intraobserver repeatability intraclass correlation coefficient (1, 3) values were 0.87 and 0.93, respectively. The correlation coefficient between the observers' measurements was 0.61. The strain ratio for the 30s age group was 0.27, which was significantly lower than the values for the other age groups (P < .001). Although 97 of 100 tendons were normal on B-mode evaluations, 36 of the 97 tendons were degenerated on qualitative elastography and also had higher strain ratio values than normal tendons. Conclusions-Quantitative elastography using an acoustic coupler is a reproducible technique for measuring the elasticity of the Achilles tendon. It may detect early tendon degeneration that is not depicted on B-mode imaging.

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Study protocol for a phase III multicentre, randomised, open-label, blinded-end point trial to evaluate the efficacy and safety of immunoglobulin plus cyclosporin A in patients with severe Kawasaki disease (KAICA Trial)

Aoyagi R, Hamada H, Sato Y, Suzuki H, Onouchi Y, Ebata R, Nagashima K, Terauchi M, Terai M, Hanaoka H, Hata A, on behalf of the KAICA Trial investigators

BMJ Open 5 （ 12 ） e009562 2015年12月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 2044-6055

Introduction: Kawasaki disease (KD) is an acute, selflimited vasculitis of unknown aetiology that predominantly affects infants and young children. We hypothesise that cyclosporin A (CsA) may be effective in treating KD by regulating the Ca2+/NFAT signalling pathway. This trial compares the current standard therapy of intravenous immunoglobulin (IVIG) and the combined IVIG+CsA therapy in paediatric patients with severe KD. Methods and analysis: This trial is a phase III, multicentre, randomised, open-label, blinded-end point trial that evaluates the efficacy and safety of IVIG+CsA therapy. Patients with severe KD who satisfy the eligibility criteria are randomised (1:1) to receive either CsA (5 mg/kg/day for 5 days; Neoral) plus high-dose IVIG (2 g/kg for 24 h and aspirin 30 mg/kg/day), or high-dose IVIG alone (2 g/kg for 24 h and aspirin 30 mg/kg/day). The primary end point is the frequency of occurrence of coronary artery abnormalities during the trial period. An independent end point review committee will be in charge of the trial assessment. Ethics and dissemination: The protocol was approved by the Institutional Review Board of each institution. The trial was notified and registered at the Pharmaceutical and Medical Devices Agency, in Japan. The trial is currently on-going and is scheduled to finish in April 2017. The findings will be disseminated through peer-reviewed publications and conference presentations. Trial registration number: JMA-IIA00174; Preresults.

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Validity assessment of self-reported medication use by comparing to pharmacy insurance claims

Fujita M, Sato Y, Nagashima K, Takahashi S, Hata A

BMJ Open 5 （ 11 ） e009490 2015年11月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 2044-6055

Objectives: In Japan, an annual health check-up and health promotion guidance programme was established in 2008 in accordance with the Act on Assurance of Medical Care for the Elderly. A self-reported questionnaire on medication use is a required item in this programme and has been used widely, but its validity has not been assessed. The aim of this study was to evaluate the validity of this questionnaire by comparing self-reported usage to pharmacy insurance claims. Setting: This is a population-based validation study. Self-reported medication use for hypertension, diabetes and dyslipidaemia is the evaluated measurement. Data on pharmacy insurance claims are used as a reference standard. Participants: Participants were 54 712 beneficiaries of the National Health Insurance of Chiba City. Primary and secondary outcome measures: Sensitivity, specificity and κ statistics of the self-reported medication-use questionnaire for predicting actual prescriptions during 1 month (that of the checkup) and 3 months (that of the check-up and the previous 2 months) were calculated. Results: Sensitivity and specificity scores of questionnaire data for predicting insurance claims covering 3 months were, respectively, 92.4% (95% CI 91.9 to 92.8) and 86.4% (95% CI 86.0 to 86.7) for hypertension, 82.6% (95% CI 81.1 to 84.0) and 98.5% (95% CI 98.4 to 98.6) for diabetes, and 86.2% (95% CI 85.5 to 86.8) and 91.0% (95% CI 90.8 to 91.3) for dyslipidaemia. Corresponding κ statistics were 70.9% (95% CI 70.1 to 71.7), 77.1% (95% CI 76.2 to 77.9) and 69.8% (95% CI 68.9 to 70.6). The specificity was significantly higher for questionnaire data covering 3 months compared with data covering 1 month for all 3 conditions. Conclusions: Self-reported questionnaire data on medication use had sufficiently high validity for further analyses. Item responses showed close agreement with actual prescriptions, particularly those covering 3 months.

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S-1 and irinotecan with or without bevacizumab versus 5-fluorouracil and leucovorin plus oxaliplatin with or without bevacizumab in metastatic colorectal cancer: A pooled analysis of four phase II studies

Iwasa S., Nagashima K., Yamaguchi T., Matsumoto H., Ichikawa Y., Goto A., Yasui H., Kato K., Okita N.T., Shimada Y., Yamada Y.

Cancer Chemotherapy and Pharmacology （Cancer Chemotherapy and Pharmacology） 76 （ 3 ） 605 - 614 2015年09月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 03445704

Purpose: S-1, a novel oral prodrug of 5-fluorouracil (5-FU), and irinotecan with or without bevacizumab is known to be effective in metastatic colorectal cancer (mCRC). However, it is not clear whether S-1 and irinotecan confers benefits compared to 5-FU and leucovorin plus oxaliplatin (FOLFOX) in patients with mCRC. Our aim was to compare the efficacy and safety of these regimens. Methods: We analyzed 187 patients with previously untreated mCRC who were enrolled in four phase II studies: SIR (S-1 and irinotecan, n = 40), SIRB (S-1 and irinotecan with bevacizumab, n = 51), FOLFOX (5-FU and leucovorin plus oxaliplatin, n = 46), and STOX (stop-and-go strategy of modified FOLFOX-6 with bevacizumab, n = 50). We evaluated efficacy and safety between SIR/SIRB and FOLFOX/STOX. Results: Baseline characteristics were similar in the two groups composed of SIR/SIRB (n = 91) and FOLFOX/STOX (n = 96). The overall response rates were not significantly different between the two groups (65 % in SIR/SIRB vs. 52 % in FOLFOX/STOX, p = 0.125). The median progression-free survival was 10.9 months in SIR/SIRB versus 12.1 months in FOLFOX/STOX (p = 0.59). The median overall survival was 27.3 months in SIR/SIRB versus 26.8 months in FOLFOX/STOX (p = 0.97). Gastrointestinal adverse events were the most common toxicities in SIR/SIRB, while neutropenia and sensory neuropathy were the most common toxicities in FOLFOX/STOX. Conclusions: S-1 and irinotecan with or without bevacizumab was well tolerated and showed similar response rates and survival compared to the FOLFOX regimen. This combination should be considered as an experimental first-line treatment for mCRC.

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Predictive power of a body shape index for development of diabetes, hypertension, and dyslipidemia in Japanese adults: a retrospective cohort study

Fujita M, Sato Y, Nagashima K, Takahashi S, Hata A

PLoS One 10 （ 6 ） e0128972 2015年06月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1932-6203

Background/Objectives Recently, a body shape index (ABSI) was reported to predict all-cause mortality independently of body mass index (BMI) in Americans. This study aimed to evaluate whether ABSI is applicable to Japanese adults as a predictor for development of diabetes, hypertension, and dyslipidemia. Subjects/Methods We evaluated the predictive power of ABSI in a retrospective cohort study using annual health examination data from Chiba City Hall in Japan, for the period 2008 to 2012. Subjects included 37,581 without diabetes, 23,090 without hypertension, and 20,776 without dyslipidemia at baseline who were monitored for disease incidence for 4 years. We examined the associations of standardized ABSI, BMI, and waist circumference (WC) at baseline with disease incidence by logistic regression analyses. Furthermore, we conducted a casematched study using the propensity score matching method. Results Elevated BMI, WC, and ABSI increased the risks of diabetes and dyslipidemia [BMI-diabetes: odds ratio (OR) = 1.26, 95% confidence interval (95%CI) = 1.20-1.32; BMI-dyslipidemia: OR = 1.15, 95%CI = 1.12-1.19; WC-diabetes: OR = 1.24, 95%CI = 1.18-1.31; WC-dyslipidemia: OR = 1.15, 95%CI = 1.11-1.19; ABSI-diabetes: OR = 1.06, 95%CI = 1.01 -1.11; ABSI-dyslipidemia: OR = 1.04, 95%CI = 1.01-1.07]. Elevated BMI and WC, but not higher ABSI, also increased the risk of hypertension [BMI: OR = 1.32, 95%CI = 1.27-1.37; WC: OR = 1.22, 95%CI = 1.18-1.26; ABSI: OR = 1.00, 95%CI = 0.97-1.02]. Areas under the curve (AUCs) in regression models with ABSI were significantly smaller than in models with BMI or WC for all three diseases. In case-matched subgroups, the power of ABSI was weaker than that of BMI and WC for predicting the incidence of diabetes, hypertension, and dyslipidemia. Conclusions Compared with BMI or WC, ABSI was not a better predictor of diabetes, hypertension, and dyslipidemia in Japanese adults.

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Association between serum ligands and the skin toxicity of anti-epidermal growth factor receptor antibody in metastatic colorectal cancer

Takahashi N., Yamada Y., Furuta K., Nagashima K., Kubo A., Sasaki Y., Shoji H., Honma Y., Iwasa S., Okita N., Takashima A., Kato K., Hamaguchi T., Shimada Y.

Cancer Science （Cancer Science） 106 （ 5 ） 604 - 610 2015年05月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 13479032

Skin toxicity is a known clinical signature used to predict the prognosis of anti-epidermal growth factor receptor (EGFR) antibody treatment in metastatic colorectal cancer (mCRC). There are no biological markers to predict skin toxicity before anti-EGFR antibody treatment in mCRC patients. Between August 2008 and August 2011, pretreatment serum samples were obtained from KRAS wild-type (WT) patients who received anti-EGFR antibody treatment. Serum levels of ligands were measured by ELISA. A total of 103 KRAS WT patients were enrolled in the study. Progression-free survival and overall survival of patients with a high grade (grade 2-3) of skin toxicity were significantly longer than those with a low grade (grade 0-1) of skin toxicity (median progression-free survival, 6.4 months vs 2.4 months, P < 0.001; median overall survival, 14.6 months vs 7.1 months, P = 0.006). There were significant differences in distribution of serum levels of epiregulin (EREG), amphiregulin (AREG), and hepatocyte growth factor (HGF) between groups of low/high grade of skin toxicity (P < 0.048, P < 0.012, P < 0.012, respectively). In addition, serum levels of HGF, EREG, and AREG were inversely proportional to grades of skin toxicity as determined by the Cochran-Armitage test (P = 0.019, P = 0.047, P = 0.021, respectively). Our study indicated that serum levels such as HGF, EREG, and AREG may be significant markers to predict the grade of skin toxicity and the prognosis of anti-EGFR antibody treatment, which contribute to improvement of the management of skin toxicity and survival time in mCRC patients.

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Bevacizumab and postoperative wound complications in patients with liver metastases of colorectal cancer

Utsumi H, Honma Y, Nagashima K, Iwasa S, Takashima A, Kato K, Hamaguchi T, Yamada Y, Shimada Y, Kishi Y, Nara S, Esaki M, Shimada K

Anticancer Research 35 （ 4 ） 2255 - 2261 2015年04月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 02507005

Aim: The present study investigated whether bevacizumab (BV) is associated with postoperative wound complications (PWCs). Patients and Methods: We retrospectively analyzed patients undergoing surgery for liver metastases of colorectal cancer at our Institution. Patients were divided into 3 groups according to the preoperative treatment: chemotherapy with BV (group A), chemotherapy without BV (group B) and no chemotherapy (group C). Results: Between February 2003 and September 2012, 297 patients underwent 373 surgeries. Groups A, B and C consisted of 23, 62 and 288 patients, respectively. PWCs occurred in 29 patients (7.8%). In multivariate analysis, there were no differences in PWCs among the groups (C vs. B:P=0.739; C vs. A: P=0.110). Conversely, lower serum albumin levels (<3.5g/dl vs. ≥3.5g/dl: p=0.030) and synchronous colorectal resection (no vs. yes; p<0.001) remained significant risk factors of developing PWCs. Conclusion: Chemotherapy with or without BV did not influence the risk of PWCs.

A double-blind randomized Phase II study of olanzapine 10 mg versus 5 mg for emesis induced by highly emetogenic chemotherapy

Nagashima K, Yanai T, Iwasa S, Ohyanagi F, Kasai T, Minato K, Sakai H, Sakamoto C, Takeda K, Harada D, Goto K, Yamamoto N

Japanese Journal of Clinical Oncology 45 （ 2 ） 229 - 231 2015年02月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 03682811

A randomized Phase II dose-finding trial comparing olanzapine 10 mg with olanzapine 5 mg for patients receiving highly emetogenic chemotherapy with cisplatin was started in June 2014. The purpose of the trial is to evaluate the efficacy and safety of the two olanzapine doses and to determine which is more promising as a test arm for comparison with the current standard antiemetic care (a combination of aprepitant, a 5-HT3 receptor antagonist and dexamethasone) in a subsequent Phase III trial. Patients receiving cisplatin-containing regimens will be randomized to the olanzapine 10 or 5 mg arm. A total of 150 patients will be accumulated from nine institutions over 2 years. The primary endpoint is complete response defined as no emetic episodes and no use of rescue medications in the delayed (24-120 h) phase. This trial has been registered at the UMIN Clinical Trials Registry as UMIN000014214.

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A retrospective study of docetaxel or paclitaxel in patients with advanced or recurrent esophageal squamous cell carcinoma who previously received fluoropyrimidine- and platinum-based chemotherapy

Shirakawa T., Kato K., Nagashima K., Nishikawa A., Sawada R., Takahashi N., Shoji H., Sasaki Y., Honma Y., Iwasa S., Takashima A., Okita N., Hamaguchi T., Yamada Y., Shimada Y.

Cancer Chemotherapy and Pharmacology （Cancer Chemotherapy and Pharmacology） 74 （ 6 ） 1207 - 1215 2014年12月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 03445704

Introduction: Fluoropyrimidine plus platinum (FP)-based chemotherapy has been widely used as a first-line regimen for advanced or recurrent esophageal cancer, and taxanes have shown efficacy after FP-based chemotherapy, but there is no standard regimen for second-line chemotherapy (SLC). We retrospectively investigated the clinical features of taxane therapy in SLC for esophageal squamous cell carcinoma (ESCC). Methods: The selection criteria were pathologically proven ESCC; advanced or recurrent disease previously treated with FP at our hospital; performance status (PS) 0-2; and adequate organ function. Docetaxel (DTX) was administered 3-weekly at 70 mg/m<sup>2</sup>. Paclitaxel (PTX) was administered at 100 mg/m<sup>2</sup> weekly for 6 weeks, with 1 week's rest. Results: The analysis covered 163 patients from August 2006 to June 2012. Median age was 64 years (range 37-83: DTX group 132 patients and PTX group 31). Progression-free survival and median overall survival (OS) were 2.3 and 6.1 months, respectively, with PTX and 2.3 and 5.3 months with DTX. Response rates were 20.7 % for PTX and 5.9 % for DTX. The rate of grades 3-4 neutropenia was higher with DTX (32.6 %) than with PTX (16.1 %). Grade 3 febrile neutropenia was seen in 6.1 % of DTX recipients but in no PTX group. According to multivariate analyses of OS, PS 2, number of metastatic sites 2, and CRP 1 mg/dL were independent predictors of poor prognosis. Conclusions: PTX and DTX were both effective in SLC for ESCC, but their toxicity profiles differed. In terms of febrile neutropenia, PTX seems more appropriate.

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Clinical impact of c-MET expression and genetic mutational status in colorectal cancer patients after liver resection

Shoji H., Yamada Y., Taniguchi H., Nagashima K., Okita N., Takashima A., Honma Y., Iwasa S., Kato K., Hamaguchi T., Shimada Y.

Cancer Science （Cancer Science） 105 （ 8 ） 1002 - 1007 2014年08月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 13479032

c-MET is implicated in the pathogenesis and growth of a wide variety of human malignancies, including colorectal cancer (CRC). The aim of the present study was to clarify the association between c-MET expression and tumor recurrence in CRC patients after curative liver resection, and to evaluate concordance in c-MET expression and various mutations of KRAS, BRAF and PIK3CA between primary CRC and paired liver metastases. A cohort of patients was tested for c-MET immunoreactivity (i.e. immunohistochemistry [IHC]) and KRAS, BRAF and PIK3CA mutations. Analyses were performed both on primary tumors and paired liver metastases, and the association between IHC and mutations results were assessed. A total of 108 patients were eligible. A total of 53% of patients underwent simultaneous resection of primary tumors and metastases, and the others underwent metachronous resection. Levels of concordance between primary tumors and metastases were 65.7%, 87.7%, 100% and 95.2% for c-MET, KRAS, BRAF and PIK3CA, respectively. High levels of c-MET expression (c-MET-high) in the primary tumors were observed in 52% of patients. Relapse-free survival was significantly shorter for patients with c-MET-high primary tumors (9.7 months) than for those with c-MET-low primary tumors (21.1 months) (P = 0.013). These results suggest that a high level of genetic concordance in KRAS, BRAF and PIK3CA between primary tumors and liver metastases, and c-MET-high in the primary tumors were associated with shorter relapse-free survival after hepatic metastasectomy. A high expression of c-MET in primary tumors was associated with worse RFS for patients who had undergone curative hepatectomy. © 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

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Lack of association of proteinuria and clinical outcome in patients treated with bevacizumab for metastatic colorectal cancer

Iwasa S, Nakajima TE, Nagashima K, Honma Y, Kato K, Hamaguchi T, Yamada Y, Shimada Y

Anticancer Research 33 （ 1 ） 309 - 316 2013年01月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 02507005

Background: Although bevacizumab-related hypertension has been reported as a predictive marker of therapy efficacy, an association between proteinuria and efficacy has not been reported. Patients and Methods: Eighty-two consecutive patients with metastatic colorectal cancer treated with bevacizumab as first-line treatment between July 2007 and April 2009 were examined. Results: Seventy-one patients were included in the analysis set. Proteinuria occurred in 29 patients: Grade 1 in 15 patients and grade 2 in 14 patients; no grade 3 or higher proteinuria was observed. The response rate did not increase with the severity of proteinuria (p=0.307). The median progressionfree survival was 17.8 months in cases with grade 2 proteinuria, 16.0 months in those with grade 1 proteinuria, and 10.4 months in those with grade 0 proteinuria (p=0.030). In multivariate analysis with a time-dependent adjustment, there was no correlation between severity of proteinuria and survival. Conclusion: Bevacizumab-related proteinuria was not a predictive marker for patients with colorectal cancer treated with first-line bevacizumab.

Phase II clinical trial of second-line FOLFIRI plus bevacizumab for patients with metastatic colorectal cancer: AVASIRI trial

Horita Y, Yamada Y, Kato K, Hirashima Y, Akiyoshi K, Nagashima K, Nakajima TE, Hamaguchi T, Shimada Y

International Journal of Clinical Oncology 17 （ 6 ） 604 - 609 2012年12月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 13419625

Objective: FOLFIRI is a standard chemotherapy regimen for the treatment of metastatic colorectal cancer. Although some studies have shown its efficacy in combination with bevacizumab as first-line chemotherapy, there are no data to support FOLFIRI plus bevacizumab as second-line chemotherapy in patients with this form of cancer. The aim of this study was to evaluate the efficacy and safety of FOLFIRI and bevacizumab as second-line chemotherapy in patients with metastatic colorectal cancer. Methods: Eligible patients were ≥20 years old, previously treated (except with irinotecan [CPT-11] and bevacizumab), with an Eastern Cooperative Oncology Group performance status of 0, 1, or 2, and adequate organ function. Twenty-five eligible patients received FOLFIRI with bevacizumab at a dose of 10 mg/kg given intravenously on day 1. All therapy was administered every 2 weeks until disease progression. The primary endpoint was the response rate. Results: Twenty-five patients were enrolled between February 2008 and March 2009. The median age was 62 (range 38-73) years, the male/female distribution was 20/5, 16 patients had performance status 0 and 9 had performance status 1, and the proportion of patients who were oxaliplatin pretreated/untreated was 16/9. The overall response rate was 32% (90% confidence interval [CI]: 17.0-50.4%), with 8 patients showing partial responses, 15 with stable disease, and 2 with disease progression. Median progression-free survival was 11.6 months (95% CI: 6.9-16.4). Median overall survival was 21.4 months (95% CI: 12.0-30.8). The grade 3/4 adverse events with treatment were neutropenia (64%), leukopenia (16%), diarrhea (8%), anorexia (8%), and febrile neutropenia (8%). The bevacizumab-related grade 3/4 adverse event was hypertension, which was observed in 12% of patients. Conclusions: The FOLFIRI plus bevacizumab regimen is an active, well-tolerated second-line chemotherapy treatment for patients with metastatic colorectal cancer. © 2011 Japan Society of Clinical Oncology.

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A multicenter phase II study of the stop-and-go modified FOLFOX6 with bevacizumab for first-line treatment of patients with metastatic colorectal cancer

Okita NT, Esaki T, Baba E, Sakai D, Tokunaga S, Takiuchi H, Mizunuma N, Nagashima K, Kato K

Investigational New Drugs 30 （ 5 ） 2026 - 2031 2012年10月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 01676997

Summary: Currently, no prospective data exists to support a stop-and-go modified FOLFOX6 regimen with bevacizumab in metastatic colorectal cancer (mCRC) patients. This study aimed to evaluate the efficacy and safety of this regimen in first-line mCRC patients. Eligible patients (age ≥20 years) had previously untreated mCRC; Eastern Cooperative Oncology Group performance status of 0-2; and adequate hematologic, hepatic, and renal function. The modified FOLFOX6 regimen and bevacizumab (5 mg/kg) was administered intravenously every 2 weeks. After 8 cycles, patients received maintenance therapy with simplified LV5FU2 and bevacizumab until completion of 8 cycles or disease progression. After maintenance therapy, patients received another 8 cycles of modified FOLFOX6 with bevacizumab until completion of 8 cycles or disease progression. We recruited 50 patients between August 2007 and January 2009. The overall response rate was 48% (80% confidence interval [CI]; 38.2-58) with outcomes as follows: complete response, n=1; partial response, n=23; stable disease, n=21; progression, n=1; and not evaluated, n=4. Median time to treatment failure was 7.7 months (80% CI: 6.2-8.0), and median progression-free survival was 12.8 months (80% CI: 10.8-14). Grade 3/4 toxicities included neutropenia (40%), nausea (4%), diarrhea (14%), thrombosis (4%), and hypertension (4%) et al. Grade 1, 2, or 3 peripheral neuropathy was reported in 38%, 40%, and 10% of patients, respectively. The stop-and-go modified FOLFOX6 and bevacizumab regimen is effective and well tolerated as first-line chemotherapy for mCRC patients. © 2011 Springer Science+Business Media, LLC.

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