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Information on patterns of clinical care for elderly breast cancer patients is lacking. The aims of this study are two-fold, firstly, to clarify daily practice treatments for elderly breast cancer patients in Japan, and secondly, to plan a prospective clinical trial to address unresolved clinical questions. We investigated practice care of elderly breast cancer patients in 38 institutions of the Japan Clinical Oncology Group (JCOG). Questionnaires asked: (1) definition of "elderly" for each treatment, (2) clinical standard anti-HER2 therapy in each age-group, (3) recommended docetaxel dose in each age-group, (4) considerations for future clinical trials, and (5) other information about geriatric oncology concerning breast cancer. The upper age-limit for surgery and irradiation therapy was generally 80 years, while many physicians considered anti-cytotoxic adjuvant therapy unsuitable for patients70-75 years. For HER2-positive metastatic breast cancer, 82% of physicians recommended docetaxel (DTX) plus trastuzumab plus pertuzumab (DTP) as standard care for patients aged 65-70, although 54% of physicians avoided DTP for those aged 71-75 as first-line standard preference. Most physicians recommended 75 mg/m

Background No standard second-line chemotherapy has been yet established for gemcitabine-refractory biliary tract cancer (BTC). Patients and methods We conducted multivariable Cox regression analysis to examine the prognostic factors for overall survival (OS) in patients who had received gemcitabine-based treatment. Results Forty-six patients received second-line chemotherapy. The median serum carbohydrate antigen 19-9 (CA 19-9) value was 487 U/ml. The modified Glasgow prognostic score (mGPS) was: 0 (n=24), 1 (n=10), or 2 (n=10). The second-line chemotherapy included: S-1 in 20 patients, gemcitabine-based in 20, and tyrosine kinase inhibitors in five. The median OS was 8.3 months, and the median progression-free survival was 3.0 months. Multivariate analysis identified serum CA 19-9 ≥500 U/ml, mGPS ≥1, and presence of liver metastasis as significant prognostic factors for OS. Conclusion Second-line chemotherapy for gemcitabine-refractory BTC remains inadequate. Randomized trials with appropriate stratification criteria are required.

Most elderly patients poorly tolerate the standard treatment for esophageal cancer; however, little information is available regarding the appropriateness of non-standard esophageal cancer treatments for those patients. This study aims to analyze the treatment costs and completion rates of patients undergoing a real-world treatment for esophageal cancer to elucidate the treatment selection and its quality. We analyzed treatment costs and completion rates for patients with esophageal cancer and analyzed these data relative to patient age and center volumes. Patients with esophageal cancer [UICC, TMN, Clinical stage II/III (excluding T4)] who were diagnosed in 2013 were analyzed. Patients were classified into five groups defined as follows: surgical therapy, chemotherapy, concurrent chemoradiotherapy (CCRT), modified concurrent chemoradiotherapy (mCRT), and radiotherapy (RT). Mean and median age of patients who received surgery and CCRT were comparable; however, patients who underwent mCRT and RT tended to be older. Medical costs associated with surgery were higher than costs associated with other non-surgical treatments. Cost and completion rate of chemoradiotherapy did not differ between CCRT and mCRT; however, both had higher completion rates compared to that of RT. Surgical expenses tended to be the highest in low-volume centers and the lowest in high-volume centers. Treatment of esophageal cancer at high-volume centers seems well balanced compared with medium- to low-volume centers. mCRT was widely performed and comparable in medical cost to CCRT, although additional clinical impacts were unclear.

Background Trametinib is an inhibitor of MEK1/MEK2 activation and kinase activity. In order to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of single-agent trametinib (part 1) and trametinib in combination with gemcitabine (part 2), we undertook the first clinical study of this combination in Japanese patients with cancer and herein report our results. Methods In part 1, 13 patients with advanced solid tumors were enrolled into 3 dose cohorts, receiving trametinib once daily at a dose of 1.0, 2.0, or 3.0 mg. In part 2, 5 patients with pancreatic cancer received trametinib (2.0 mg once daily) in combination with gemcitabine (1000 mg/m2). Results In part 1, a dose-limiting toxicity was observed in a patient in the 2.0-mg dose cohort, but the maximum tolerated dose was not reached at doses up to 3.0 mg daily. The best overall response was a PR in 1 patient, and 6 patients had SD. In part 2, the combination of trametinib and gemcitabine was tolerated for a short period of time. However, serious interstitial lung disease (ILD) was observed in 3 of 5 patients 4 weeks or more after the start of the treatment, including 1 fatal case. Three patients achieved a PR, and 2 patients had SD. The most common adverse event was rash (85 % in part 1 and 100 % in part 2). Conclusions Trametinib monotherapy was tolerable in Japanese patients with cancer. However, the combination of trametinib plus gemcitabine carried a higher risk as compared with monotherapy, during which no ILD was observed. (ClinicalTrials.gov number, NCT01324258.)

Background/aim Vascular endothelial growth factor receptor (VEGFR) has been identified as a treatment target for biliary tract cancer (BTC) and axitinib is a selective inhibitor of vascular endothelial growth factor receptor (VEGFR)-1/2/3. This study was conducted as a preliminary evaluation of the safety and efficacy of axitinib for patients with advanced BTC. Patients and methods Patients refractory to gemcitabine-based regimens were administered axitinib at the dose of 5 mg twice daily. Results Five patients (3 male and 2 female) with a median age of 68 years were enrolled. Although 3 patients developed treatment-related grade 3/4 adverse events (AEs), none of these patients required discontinuation of the protocol treatment due to the AEs. Partial response (PR) was achieved in 1 patient, with a 67% reduction. The response was classified as stable disease (SD) in 3 patients and as progressive disease (PD) in 1 patient. Overall survival (OS) and progression-free survival (PFS) ranged from 2.0 to 19.9 months and 1.5 to 7.4 months, respectively. Conclusion This preliminary study suggested that axitinib is well-tolerated and might exert promising activity in patients with BTC.

The number of older adults in Japan is rising, and healthcare for older patients differs from those of younger patients.We have limited available data regarding the outcomes of cancer treatment in this population.In addition, we have few guidelines to address the evaluation and treatment of older cancer patients in Japan.The Japan Agency for Medical Research and Development(AMED)has funded clinical research focusing on elderly cancer patients.We organized the Geriatric Study Committee in Japan Clinical Oncology Group(JCOG)to develop geriatric research policy in this area.This policy includes the (1)definition of a selection policy for the subjects of geriatric research,(2)establishment of standard endpoints and methodological schemes for geriatric research, and(3)recommendations for standard tools of geriatric assessment.We are also developing a curriculum in geriatric oncology for medical doctors and oncology nurses to improve the evidence-based evaluation and treatment of elderly cancer patients.Japanese society is progressing to address the increasing number of elderly patients using a team approach in a broad sense, which consists of cancer professionals, healthcare providers, and government.

A phase 1 study of pazopanib alone or in combination with lapatinib was conducted to assess the safety, tolerability, and pharmacokinetics of these oral tyrosine kinase inhibitors in Japanese patients with solid tumors.In part A (monotherapy), 7 patients initially received pazopanib 800 mg/day, the recommended dose for non-Japanese patients. Then, 3 patients received pazopanib 400 mg/day on day 1 followed by 800 mg/day from day 2 onward. Three other patients received pazopanib 1,000 mg/day. In part B (combination therapy), 17 patients received pazopanib plus lapatinib (pazopanib/lapatinib) at once-daily doses of 400/1,000 mg (4 patients), 800/1,000 mg (3 patients), 400/1,500 mg (3 patients), and then 600/1,250 mg (7 patients).There was no dose-limiting toxicity during the study. In part A, most drug-related adverse events were grade 2 or lower, including neutropenia/neutrophil count decreased, thrombocytopenia/platelet count decreased, diarrhea, hypertension, aspartate aminotransferase increased, and lipase increased. In part B, rash, decreased appetite, and serum thyroid-stimulating hormone increased also occurred. In all dose groups, the plasma concentrations after multiple doses of pazopanib exceeded the target trough concentration for inhibition of vascular endothelial growth factor receptor-2 activity (20 μg/mL).The pharmacokinetic profiles of pazopanib and lapatinib in Japanese patients were not apparently different from those reported in non-Japanese patients. There were no consistent trends in pharmacokinetic drug interactions between pazopanib and lapatinib. Pazopanib monotherapy at 800 and 1,000 mg once daily and pazopanib plus lapatinib once daily at any doses studied were well tolerated in Japanese patients.

Background Gemcitabine (GEM) plus cisplatin (CDDP) chemotherapy has been used worldwide as the standard first-line treatment for advanced biliary tract cancer (BTC). A phase II trial has also suggested promising activity of GEM plus S-1 chemotherapy against advanced BTC. The aim of this study was to evaluate the efficacy and safety of GEM plus S-1 chemotherapy in patients with advanced BTC. Patients and methods The eligibility criteria were as follows: histologically-proven BTC, unresectable or recurrent disease, ECOG performance status (PS) 0-1 regardless of previous treatment. Gemcitabine was administered intravenously at the dose of 1,000 mg/m2 over 30 min on days 1 and 8, and S-1 was administered orally at doses of 60/80/100 mg/day based on the BSA, from day 1 to day 14, every 3 weeks. The primary endpoint was the response rate according to RECIST, ver. 1.1, and the secondary endpoints were the frequency/severity of toxicities, progression-free survival (PFS) and overall survival (OS). Results A total of 38 patients were enrolled between August 2008 and November 2011. There were 19 men and 19 women, with a median age of 66 years (range=44-81 years). Seven patients had a previous history of first-line or adjuvant chemotherapy after surgery. The PS was 0 and 1 in 30 and 7 patients, respectively. The treatment response was classified as partial response in 6 patients (15.8%) and as stable disease in 18 patients (47.4%). The median PFS and OS were 5.8 and 15.9 months, respectively. The toxicity was generally mild, and the most common grade 3/4 toxicities were leukopenia (31.6%), neutropenia (36.8%), nausea/vomiting (2.6%), and diarrhea (2.6%). There was one treatment-related death due to interstitial pneumonia. Conclusion Our study revealed that gemcitabine plus S-1 chemotherapy was well-tolerated and exhibited favorable antitumor activity in patients with advanced BTC.

TPS1100 Background: Systemic chemotherapy with anti-HER2 therapy is the standard of care for HER2-positive advanced breast cancer. Patient outcomes have improved remarkably with the use of novel anti-HER2 drugs, including trastuzumab (H), pertuzumab (P), and trastuzumab emtansine (T-DM1). The combination treatment comprising H, P, and docetaxel (D) (HPD) is highly recommended as the 1st-line treatment for patients with HER2-positive advanced breast cancer. In contrast, for elderly patients over 65 years of age, this regimen seems to be intolerable mentally and physically, and impairs their quality of life. A new standard treatment with less toxicity and non-inferior efficacy for elderly patients is needed. Methods: We have planned a randomized, multicenter, open-label, phase III trial to confirm the non-inferiority of T-DM1 compared to HPD in terms of overall survival (OS) in elderly patients with HER2-positive advanced breast cancer. The eligibility criteria are as follows: 1) histologically proven metastatic breast cancer, 2) age 65-74 years with a performance status (PS) score 0-2, or 75-79 years with a PS score 0-1, 3) HER2 overexpression or amplification confirmed in primary or metastatic tissues, and 4) no anti-HER2 therapy with chemotherapy for breast cancer, excluding (neo) adjuvant therapy. Patients are randomized to receive either HPD (H 6 mg/kg, P 420 mg/body, and D 60 mg/m2) or T-DM1 3.6 mg/kg every 3 weeks. The dose up of D (75 mg/m2) after the second cycle is defined based on the data regarding safety during the first cycle. The primary endpoint is OS. The secondary endpoints are progression-free survival, response rate, adverse events, breast cancer-related death, and deterioration of activities of daily living. The trial is designed to achieve 70% power to confirm non-inferiority of T-DM1 to HPD at a one-sided alpha of 5% with a non-inferiority margin of 1.3 in terms of hazard ratio. With a median OS of 30 months in both arms, 6 years of accrual, and 5 years of follow up, the planned sample size is 330. The trial began in January 2018 and nineteen patients have been enrolled as of January 2019. Clinical trial information: UMIN000030783.

e15106 Background: Tumor mismatch repair (MMR) predicts benefit of immune checkpoint inhibitors (ICIs) in metastatic colorectal cancer (mCRC). We conducted a large-scale prospective observational trial on microsatellite instability (MSI) status in mCRC: SCRUM-Japan GI-SCREEN CRC-MSI. Methods: mCRC patients (pts) appropriate for systemic chemotherapy were eligible. Paired tumor and normal DNA extracted from FFPE samples were analyzed by the MSI Analysis System, which includes 5 mononucleotide markers. Tumors exhibiting ≥2 unstable markers were defined as MSI-H, while those with ≤1 were labelled MSI-L/MSS. Results: From 2/2016 to 3/2018, 1,711 pts were enrolled, and 1,696 samples were submitted. MSI status was determined in 1,676 pts (98.8%); 51 pts (3.0%) were MSI-H. For MSI-H vs. MSI-L/MSS pts: Median age (years) 64/64; male gender (%) 51.0 vs. 43.8, p=0.31; right-sided primary (%) 70.6 vs. 25.0, p20 mt/Mb, was observed in 27/29 (93.1%) MSI-H pts. The frequency of representative gene mutations (%) for MSI-H vs. MSI-L/MSS pts were: TP53 17.2 vs. 66.1, p

The safety, pharmacokinetics, and antitumor activity of the multikinase inhibitor regorafenib in Japanese patients was assessed in this multicenter, single-arm, phase I trial. Fifteen patients with treatment-refractory advanced solid tumors received regorafenib 160 mg once daily for the first 3 weeks of each 4-week cycle until disease progression, unacceptable toxicity, or investigator or patient decision to stop. The median duration of treatment was 2.1 months (range, 0.9–20.1 months). At data cutoff, one patient was still receiving regorafenib in cycle 21. Reasons for treatment discontinuation were disease progression (n = 12) and adverse events (liver enzyme elevation n = 1; anemia n = 1). Adverse events necessitated dose reduction in six patients, interruption of daily treatment in seven patients, and cycle delay in four patients. All patients experienced at least one drug-related adverse event, particularly gastrointestinal (87 %), dermatologic (73 %), or hematologic (67 %) events. There was no significant change in time to maximum concentration or terminal half-life of regorafenib and its active metabolites M2 and M5 between single dosing and 21-day continuous dosing. The area under the concentration–time curve was 2.1-fold higher for regorafenib, 5.2-fold higher for M2, and 37.3-fold higher for M5, and the maximum concentration was 2.0-fold, 4.8-fold, and 36.0-fold higher, respectively, after continuous dosing than after single dosing. One patient had a partial response (duration 10.5 months) and seven patients had stable disease. This study indicates that regorafenib 160 mg orally once daily (21 days on/7 days off treatment) can be given to Japanese patients who have solid tumors, without undue toxicity.

Reversible posterior leukoencephalopathy syndrome (RPLS) is a serious neurologic disease characterized by visual disturbance, seizures, headache, and altered mental status associated with white matter changes, particularly in the occipital lobes. RPLS has been attributed to chemotherapy, including modified FOLFOX6 regimens consisting of 5-fluorouracil, oxaliplatin, and leucovorin. Although the mechanism of development of RPLS remains unclear, impaired cerebral blood flow autoregulation and endothelial dysfunction seem to be involved. In particular, endothelial dysfunction has been implicated in the pathophysiology of RPLS associated with platinum agents. Platinum-based chemotherapy is thought to have a direct toxic effect on the vascular endothelium, leading to capillary leakage, disruption of the blood–brain barrier, and axonal swelling, triggering vasogenic edema. Much progress has been made in chemotherapy for colorectal cancer, and the increasing use of molecular-targeted agents is expected to further improve the outcome of therapy. RPLS has recently been associated with such molecular-targeted therapy, particularly in patients concurrently receiving platinum agents. This finding is consistent with previous reports suggesting that RPLS occurs more often in patients receiving platinum-based therapy than in those receiving molecular-targeted agents. Because platinum agents are the most widely used in cancer chemotherapy, clinicians should strongly suspect RPLS in patients receiving treatment with this class of drug.

The purpose of chemotherapy in patients with advanced solid cancers, including biliary tract cancer, is generally to improve the survival and quality of life of the patients. Also, adjuvant chemotherapy is expected to increase the curability of surgery in patients scheduled to undergo surgery. Most patients with unresectable biliary tract cancer develop obstructive jaundice, and biliary drainage is needed before any of the aforementioned treatments. Once jaundice is resolved by stenting of the bile duct or bilio-intestinal bypass, cholangitis often develops, leading to rapid deterioration of the patient's general condition. Therefore, the beneficial effect of chemotherapy in such patients remains controversial. A few randomized controlled trials have demonstrated the survival benefit of chemotherapy as compared with supportive care. In one of these trials, improvement of the quality of life was also confirmed. Recently, since the survival benefit of combined gemcitabine plus cisplatin therapy over gemcitabine alone has been demonstrated in randomized controlled clinical trials, this combined regimen has been recognized as a standard therapy for unresectable biliary tract cancer. A second-line regimen is now expected to be established for patients with gemcitabine-refractory biliary tract cancer, although the significance of second-line therapy remains unclear. One of the next issues in relation to chemotherapy for biliary tract cancer is the development of molecular-targeted agents; however, few large clinical trials of such agents have been conducted for biliary tract cancer. Various issues in chemotherapy for biliary tract cancer remain to be investigated, and global cooperation is necessary to conduct large clinical trials.

Objective: To evaluate the safety and efficacy of combination chemotherapy with 5-fluorouracil (5-FU), leucovorin, irinotecan and oxaliplatin (FOLFOXIRI) in Japanese patients with advanced colorectal cancer. Methods: This phase I dose-finding study was designed to determine the maximum tolerated dose (MTD), recommended dose (RD) or both of FOLFOXIRI. Patients with UDP-glucuronosyltransferase (UGT) 1A1*6/*6, *28/*28 and *6/*28 genotypes were excluded, because these UGT1A1 genotypes are linked to severe neutropenia in Japanese. Results: A total of 10 Japanese patients with advanced colorectal cancer were studied. The MTD of FOLFOXIRI in these Japanese patients was 165 mg/m2 irinotecan, 85 mg/m2 oxaliplatin and 2,400 mg/m2 5-FU. Accordingly, the RD of FOLFOXIRI was determined to be 150 mg/m2 irinotecan, 85 mg/m2 oxaliplatin and 2,400 mg/m2 5-FU. Toxic effects, evaluated until the completion of 4 cycles, were manageable. Grade 3–4 neutropenia occurred in 27% of cycles, but there was no febrile neutropenia. Among the 9 assessable patients, the objective response rate was 89%. Conclusions: We thus determined the RD of FOLFOXIRI in Japanese patients with advanced colorectal cancer who do not have UGT1A1*28/*28, *6/*6 or *6/*28 genotypes. Our results indicate that FOLFOXIRI is a well-tolerated regimen for these Japanese patients.

Budding or the presence poorly differentiated clusters at the boundary of cancer tissue is a pathologically important finding and serves as a prognostic factor in colorectal cancer. However, few studies have examined the cancer tissue boundary in clinical samples. The purpose of the present study was to examine gene expression at the tumor front of colon cancer in surgically resected samples. Cancer tissues were obtained by laser microdissection of 20 surgically resected specimens. Genes with significantly different microarray signals between the tumor front and the tumor center were identified. Among genes showing significant up-regulation at the tumor front were six chemokines [chemokine c-c motif ligand (CCL)2 and -18, chemokine (C-X-C motif) ligand (CXCL)9-11, and interleukin 8 (IL8)], and two apoptosis-related molecules [ubiquitin D (UBD) and baculoviral iap repeat-containing 3 (BIRC3)]. Expression of laminin gamma 2 (LAMC2), matrix metallopeptidase 7 (MMP7) and epithelial-mesenchymal transition (EMT)-related molecules were elevated in the tumor front, but their fold changes were smaller than those of the aforementioned genes. These results suggest that chemokines, in addition to EMT-related molecules, may play important roles in invasion of colon cancer.

Older patients are considered to have increased risk for complications after major surgery, but age alone is not a reliable predictor of postoperative complications. However, no universal screening test adequately predicts postoperative complications in older patients. This prospective study recorded pertinent baseline geriatric assessment variables to identify risk factors for postoperative complications in hepatocellular carcinoma (HCC) for patients aged ≥70 years who undergo hepatectomy. We retrospectively analyzed 71 consecutive patients ≥70 years of age. Patients had geriatric assessments of baseline and later cognition, nutritional and functional status, and burden of comorbidities, completed preoperatively and at 1, 3, and 6 months postoperatively. Postoperative morbidities were recorded. Postoperative morbidities developed in 18 patients (25 %). Univariate analysis identified serum albumin, operating time and blood loss, cirrhosis, geriatric 8 (G8), and Mini Nutritional Assessment as possible risk factors for postoperative complications, but only G8

We propose continuous-time system identification using discrete data and continuous curves of the data obtained by curve fitting. We describe a method for fitting a finite Fourier series to discrete data and show that the fitted curve can be created as the output from a bilinear neural network system. By using this method for fitting, we propose a method for determining the optimal values for coefficients in the differential equation which expresses a continuous-time system.

The use of FOLFIRINOX and gemcitabine plus nab-paclitaxel for unresectable pancreatic cancer is currently approved in Japan. Although the efficacies of these regimens were investigated only in patients with metastatic pancreatic cancer, they are also expected to be effective for locally advanced pancreatic cancer. Meanwhile, chemoradiotherapy is recognized as a treatment option for locally advanced pancreatic cancer. S-1 or capecitabine-based chemoradiotherapy is being developed in Japan or in Western countries, respectively. Recently, the concept of induction chemotherapy followed by chemoradiotherapy has been accepted and applied in clinical trials. In the JCOG1106 trial, induction gemcitabine followed by S-1 and concurrent radiotherapy demonstrated promising results. This regimen has been recognized as a very promising one for chemoradiotherapy in Japan. However, the optimal therapy for locally advanced pancreatic cancer remains controversial, especially in terms of which between chemotherapy and chemoradiotherapy is superior.

Objective: This phase I/II study determined the recommended dose of FOLFIRI (irinotecan, infusional 5-fluorouracil and leucovorin) for Japanese patients with advanced colorectal cancer, and evaluated safety at the recommended dose in patients without the UDP-glucuronosyltransferase 1A1*28 allele which caused reduced enzyme expression. Methods: The phase I part assessed the maximum tolerated dose of FOLFIRI to determine the recommended doses of irinotecan and infusional 5-fluorouracil. The doses were escalated from 150 to 180 mg/m 2 (irinotecan) and 2000 to 2400 mg/m 2 (5-fluorouracil). UDPglucuronosyltransferase 1A1*6 and *28, and pharmacokinetics of irinotecan were observationally examined. In the phase II part, patients without the UDP-glucuronosyltransferase 1A1*28 allele received FOLFIRI at the recommended dose to evaluate safety. Results: Among 15 patients in the phase I part, dose-limiting toxicity (diarrhea) occurred in one patient who received 150 mg/m 2 irinotecan and 2400 mg/m 2 infusional 5-fluorouracil. The respective recommended doses were 180 and 2400 mg/m 2 for irinotecan and infusional 5-fluorouracil, without reaching the maximum tolerated dose. Twenty-five patients received FOLFIRI at the recommended doses. Grade 3 or 4 neutropenia occurred in 44%, and Grade 3 diarrhea in 4%. Conclusions: This phase I/II study demonstrates that the recommended doses of irinotecan and infusional 5-fluorouracil in FOLFIRI for Japanese patients with advanced colorectal cancer who do not possess the UDP-glucuronosyltransferase 1A1*28 allele are 180 and 2400 mg/m 2 , respectively. Toxicities occurring at the recommended doses are manageable in

Differences in efficacy and toxicity between UDP-glucuronosyltransferase (UGT) 1A1*1/*1 and *1/*6 or *1/*28 genotypes remain unclear in Japanese patients. Patients with advanced colorectal cancer who received irinotecan combined with 5-fluorouracil plus l-leucovorin (FOLFIRI) as first-line therapy were divided into two groups: those with UGT1A1*1/*1 genotype and those with UGT1A1*1/*6 or *1/*28 genotype. Efficacy and toxicity were compared between these groups retrospectively. Forty-two patients (24 *1/*1 and 18 *1/*6 or *1/*28) were evaluated. The response rate was 48% in *1/*1 group and 56% in *1/*6 or *1/*28 group (P = 0.847). Median progression-free survival was 8.6 months in *1/*1 group and 8.5 months in *1/*6 or *1/*28 group (P = 0.888). No hematologic or non-hematologic toxic effects were clearly related to UGT1A1*1/*6 or *1/*28 during the first cycle or throughout the entire course of chemotherapy. There were no significant differences in the efficacy or toxicity of FOLFIRI between patients with UGT1A1*1/*1 genotype and those with UGT1A1*1/*6 or *1/*28 genotype. Our results suggest that patients with the latter genotypes can receive FOLFIRI at the same dose of irinotecan as those with the UGT1A1*1/*1 genotype receive.

2519Background: The uptake of amino acids is essential for cancer growth. The L-type amino acid transporter 1 (LAT1) is overexpressed in various cancers, and the LAT1-mediated uptake of plasma-free...

419 Background: Uptake of amino acids is essential for cancer growth. L-type amino acid transporter-1 (LAT-1) is overexpressed in various cancers, and uptake of LAT-1 substrate amino acids is known to have a critical role in cancer growth. JPH203 is a novel, selective, LAT-1 inhibitor. A first-in-human phase I study of JPH203 was designed to determine the safety, maximum-tolerated dose (MTD) and recommended dose. This study included evaluation of the anti-tumor effect, pharmacokinetics, and pharmacodynamics of JPH203 and analyzed plasma free amino acids. Methods: JPH203 was administered intravenously for 7 days followed by 21 days’ rest at planned doses ranging from 12 to 110 mg/m2 in patients with advanced solid tumors refractory to standard therapy. Before starting this schedule, we confirmed safety of a single dose of JPH203. Dose-limiting toxicity was evaluated during the first cycle, using a 3+3 design. Results: 17 patients were enrolled from January 2015 to August 2016. One patient was discontinued after a single dose of JPH203 because of tumor progression. Dosage was escalated up to 85 mg/m2. Grade 3 liver dysfunction occurred in 1 of 6 patients at 60 mg/m2 and in the first patient at 85 mg/m2. Therefore, it was determined that MTD was 60 mg/m2. Common treatment-related adverse events were increased ALT/AST, malaise, nausea, hypertension and fever of Grade 1 or 2. Partial response was achieved in a patient with biliary tract cancer (BTC) who continued JPH203 for two years without progression. Disease control (PR+SD) was observed in 3 of 5 patients with BTC and 2 of 6 with colorectal cancer. LAT-1 substrate amino acids and branched chain amino acids including LAT-1 substrate amino acids were higher in patients with BTC than in those with other cancers. All patients with disease control had a body mass index more than the median of 20.5 kg/m2. In exploratory analysis, longer survival was achieved in patients with high inhibition of uptake of LAT-1 substrate amino acids, compared with patients with low inhibition of uptake. Conclusions: JPH203 was well tolerated, resulting in promise against BTC. This phase I study suggested that LAT-1 could be targeted in treatment for advanced BTC, because LAT-1 substrate amino acids in plasma tended to remain high. Clinical trial information: UMIN000016546.

道路上を立体交差する鋼鉄道橋では，道路を走行するクレーン車等に衝突される事故が報告されている．この事故が発生した場合，現場技術者は即座に列車を抑止させ，鋼鉄道橋の損傷状況を調査し，抑止継続あるいは運転再開を判断している．軌道や支承部，主桁等に著しい損傷が発生した場合，抑止継続の判断は容易であるが，主桁下フランジの局部的な変形や面外変形のみが残留した場合，明確な運転再開評価法がなく，現場技術者の判断に委ねられているため，この評価法の策定が課題となっている．本研究は，この課題解決を目的に，過去の損傷事例の調査結果および鋼材の材料特性，鋼桁の耐荷力特性を検討した．その結果，下フランジの局部変形および面外変形の限界量を明らかにし，運転再開評価法を策定した．

To investigate the effects of genetic polymorphisms on morphine-induced adverse events in cancer patients. We examined the relation of morphine-related adverse events to polymorphisms in UDP-glucuronosyltransferase (UGT) 2B7, ATP-binding cassette, sub-family B, number 1 (ABCB1), and μ-opioid receptor 1 genes in 32 Japanese cancer patients receiving oral controlled-release morphine sulfate tablets. The T/T genotype at 1236 or TT/TT diplotype at 2677 and 3435 in ABCB1 was associated with significantly lower frequency of fatigue (grades 1–3) (P = 0.012 or 0.011, Fisher’s exact test). The UGT2B7*2 genotype was associated with the frequency of nausea (grades 1–3) (P = 0.023). The frequency of nausea was higher in patients without UGT2B7*2 allele than others. The diplotype at 2677 and 3435 in ABCB1 was associated with the frequency of vomiting (grades 1–3) (P = 0.011). No patient whose diplotype was consisted of no GC allele at 2677 and 3435 suffered from vomiting. Our findings suggest that pharmacogenetics can be used to predict the risk of morphine-induced adverse events.

兵庫県南部地震（1995）での文化財被害の教訓から，博物館などの展示物の転倒安全性を高めるために二次元免震装置が急速に普及した．しかし，新潟県中越地震（2004）では，この免震台上に置かれていた国宝の火焔土器が転倒·破損する被害を受けた．以後，免震台と他の転倒防止具との併用をするなど転倒に対する対策がとられているが，複雑な形状をしている文化財の転倒防止対策を施す必要の有無の判断や, どのような対策をどの程度とるべきかなどの検討は地震工学の専門家にとっても難しい問題である．本研究は, 文化財の地震時転倒安全性評価を支援するシステムの開発を目的としており，専門知識を持たない学芸員や一般の人を対象にし，できるだけ操作が簡易なシステムを目指したものである．

Accidents resulting in obstruction to train services sometimes occur due to collisions involving construction vehicles that exceed the height limit passing under old railway bridges. In this study, we used multipurpose LS-DYNA FEM code to analytically investigate the effects of collision deformation patterns and levels of damage on the load carrying capacity of riveted steel girders. Through this investigation, it was concluded that in cases where the lower flange is locally warped, the load carrying capacity of girders does not decrease, and in cases where out-of-plane deformation is caused, performance decreases slightly in comparison to that of an undamaged girder.

近年，古レール造跨線橋の耐震診断として，非線形特性をH型断面の鋼部材と仮定し，計算した例があるが，あくまでH型断面の評価，非線形特性も完全弾塑性型としてモデル化したものであり，降伏点以降のモデル化が適切に評価されているかどうかわからない実状がある．本論文では，古レール造乗換え跨線橋の耐震診断を行うにあたり，未解明である古レール柱の復元力特性について明らかにすることを目的とした．具体的には，古レール単柱に一定軸力の下，交番載荷試験を行い，古レール柱の履歴曲線を本試験より求め，復元力特性を適切に評価した．本検討結果について報告する．

Purpose: Recently, an objective response rate of 12% was reported in a phase II study of cetuximab in patients with epidermal growth factor receptor (EGFR)-expressing metastatic colorectal cancer (mCRC) refractory to fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy (IMC-0144). In this large molecular correlates study, we tested whether K-ras mutation status and polymorphisms in genes involved in the EGFR-signaling pathway were associated with clinical outcome in IMC-0144.Experimental Design: We analyzed all available tissue samples from 130 of 346 mCRC patients enrolled in the IMC-0144 phase II clinical trial of cetuximab. Genomic DNA was extracted from formalin-fixed paraffin-embedded tumor tissues, and K-ras mutation status and the genotypes were analyzed using PCR-RFLP, direct DNA-sequencing, and 5′-end [γ-33P] ATP–labeled PCR-protocols.Results: The PFS of patients with cyclooxygenase-2 (COX-2) −765 G>C [C/C; risk ratio (RR), 0.31; 95% confidence interval (95% CI), 0.12-0.84; P = 0.032], COX-2 +8473 T>C (C/C; RR, 0.67; 95% CI, 0.40-1.13; P = 0.003), EGF +61 A>G (G/G; RR, 0.57; 95% CI, 0.34-0.95; P = 0.042), and EGFR +497 G>A (A/G; RR, 0.82; 95% CI, 0.56-1.20; P = 0.017) genotypes was significantly longer compared with those with other genotypes. In addition, patients whose tumors did not have K-ras mutations showed better RR, PFS, and overall survival than patients with K-ras mutations. In multivariable analysis, COX-2 +8473 T>C (adjusted P = 0.013) and EGFR +497 G>A (adjusted P = 0.010) remained significantly associated with progression-free survival, independent of skin rash toxicity, K-ras mutation status, and Eastern Cooperative Group performance status.Conclusions: Polymorphisms in COX-2 and EGFR may be useful independent molecular markers to predict clinical outcome in patients with mCRC treated with single-agent cetuximab, independent of skin rash toxicity, K-ras mutation, and Eastern Cooperative Oncology Group performance status.

ATP-binding cassette, sub-family C, number 2 (ABCC2) is involved in the biliary excretion of irinotecan and its metabolites, SN-38 and SN-38 glucuronide. Effects of the ABCC2 genotype on the pharmacokinetics (PK) of irinotecan and the metabolites were examined in Japanese patients with metastatic colorectal cancer receiving irinotecan plus infusional 5-fluorouracil/leucovorin (FOLFIRI). ABCC2 genotypes (-1549G>A, -1023G>A, -1019A>G, -24C>T, 1249G>A and 3972C>T) and haplotypes were analyzed for 67 patients with cancer. PK was also examined in a subset of 31 patients receiving FOLFIRI. Relationship between the ABCC2 genotypes or diplotypes and area under the time-concentration curve (AUC) of irinotecan and the metabolites normalized by irinotecan dose was analyzed. The lower AUC of irinotecan was seen in patients with A/A or G/A genotypes at 1249 of the ABCC2 gene than others (p=0.011, Mann-Whitney U teat). AUC of SN-38 in patients with A/A or G/A genotypes at -1023 was significantly lower than that in others (p=0.018). The haplotype I included -1023A (GAACGC) was the most frequent one with the allele frequency of 0.366. The AUC of SN-38 observed in patients with diplotypes harboring at least one haplotype I was lower than that observed in others (p=0.023). The haplotype IV consisted of 1249 (GGACAC) and was the fourth most frequent one with the allele frequency of 0.127. Patients with diplotypes carrying at least one haplotype IV showed lower AUC of irinotecan than others (p=0.011). Thus, ABCC2 genotype is one of the predictors of the variability of irinotecan PK in Japanese patients with metastatic colorectal cancer receiving FOLFIRI.

Background: We have reported that vascular endothelial growth factor (VEGF) expression in gastric cancers might be a selective marker between 5-fluorouracil (5-FU) and a combination of 5-FU plus cisplatin (CDDP). In this study, the relationship between VEGF expression and effects of S-1 with and without CDDP is investigated. Methods: The subjects were 44 patients treated with S-1 (40 mg/m 2 , twice daily, days 1‐28, repeated every 6 weeks) and 24 patients treated with S-1 plus CDDP (S-1 40 mg/m 2 ,t wice daily, days 1‐21, CDDP, 60 or 70 mg/m 2 , day 8, repeated every 5 weeks). VEGF expression in pretreatment endoscopic biopsy samples was assessed immunohistochemically. Results: Median survival times (MST) of the patients treated with S-1 and S-1 plus CDDP were 344 and 388 days. Among evaluable patients, the response rates of patients with VEGF (þ )a nd (2) tumors to S-1 were 40% (6/15) and 54% (13/24), and to S-1 plus CDDP, 79% (15/19) and 80% (4/5). While the survival of patients with VEGF (2) tumors was slightly longer than those with VEGF (þ) tumors in the S-1 group (MST, 425 versus 308 days, P ¼ 0.42), patients with VEGF (þ) tumors survived remarkably longer than those with VEGF (2) tumors in the S-1 plus CDDP group (MST, 570 versus 333 days, P ¼ 0.19). Conclusion: Similarly to our previous study, it is suggested that the effects of adding CDDP to S-1 might be more remarkable in gastric cancer patients with VEGF (þ) tumors than in those with VEGF (2) tumors. These results should be confirmed in a large phase III study.

Objective There is little information about the patterns of care for elderly esophageal squamous cell carcinoma patients, and a standardized strategy has not been established. Therefore, we conducted a questionnaire survey about the patterns of care for these patients. Methods On September 2014, the questionnaires were sent to all 43 institutions of the Japan Esophageal Oncology Group, which comprised five parts: (i) definition of 'elderly' (age, method), (ii) basic treatment strategy according to stage and elderly status (fit/vulnerable/frail), (iii) patterns of care in each stage, (iv) considerations about conducting future clinical trials and (v) other information about geriatric oncology concerning esophageal squamous cell carcinoma. Results All answers were obtained by January 2015. Nearly half institutions (47%) considered the chronological definition of elderly to be over 80 years old. Among 43 institutions, 36 (84%) reported that the type of comorbidity and performance status were important factors for decision-making; no institution selected geriatric scale as an indicator. The most selected treatment strategy in fit healthy elderly patients was the same as the standard treatment of non-elderly patients. Radiation alone was considered the main treatment for vulnerable and frail esophageal squamous cell carcinoma patients. Most of the institutions answered that clinical trials for the elderly are warranted. Most institutions (70%) chose Stage II/III (non-T4) esophageal squamous cell carcinoma as an important investigational target. Conclusions Fit healthy elderly were considered the same as non-elderly patients, although there are no established treatment selection criteria. Radiation alone plays most important role in the treatment for vulnerable and frail esophageal squamous cell carcinoma patients. Stage II/III (non-T4) disease is attractive and warranted for future investigations.

Japan Clinical Oncology Group (JCOG) is a largest cooperative group in Japan, funded by the ministry of health, labor and welfare of Japanese government. We just established the Geriatric Study Committee in December 2013. The goal of this committee is to make a policy to promote clinical trials for older patients with 3 major tasks: (1) Create a clear and operational definition of vulnerability/frailty applicable to oncology,(2)Develop, test and disseminate geriatric assessments, (3) Improve research in the field of geriatric oncology, in collaboration with SIOG. JCOG1018 is a randomized phase III study of mFOLFOX7 or CAPOX plus bevacizumab versus 5-fluorouracil/Leucovorin or capecitabine plus bevacizumab as first-line treatment in elderly patients with metastatic colorectal cancer. This study includes geriatric assessments (VES-13) before chemotherapy.

Pharmacogenetic testing for UDP-glucuronosyltransferase (UGT) 1A1*28, a promoter variant of the UGT1A1 gene, is now carried out clinically to estimate the risk of irinotecan-associated toxicity. We studied the clinical significance of UGT1A1*6 and UGT1A1*27, two variants in exon 1 of the UGT1A1 gene that are found mainly in Asians. The study group comprised 46 Japanese patients who received various regimens of chemotherapy including irinotecan at doses from 50 to 180 mg/m(2). Pharmacogenetic relationships were explored between the UGT1A1 genotype and the ratio of the area under the plasma concentration-time curve (AUC) of the active metabolite of irinotecan (SN-38) to that of SN-38 glucuronide (SN-38G), used as a surrogate for UGT1A1 activity (AUC(SN-38)/AUC(SN-38G)). No patient was homozygous for UGT1A1*28, and none had UGT1A1*27. Two were heterozygous for UGT1A1*28. Two were homozygous and 15 heterozygous for UGT1A1*6, all of whom were wild type with respect to UGT1A1*28. Two patients were simultaneously heterozygous for UGT1A1*28 and UGT1A1*6, present on different chromosomes. The other 25 patients had none of the variants studied. The two patients simultaneously heterozygous for UGT1A1*28 and UGT1A1*6 and the two patients homozygous for UGT1A1*6 had significantly higher AUC(SN-38)/AUC(SN-38G) ratios than the others (P = 0.0039). Concurrence of UGT1A1*28 and UGT1A1*6, even when heterozygous, altered the disposition of irinotecan remarkably, potentially increasing susceptibility to toxicity. Patients homozygous for UGT1A1*6 should also be carefully monitored. UGT1A1 polymorphisms in the coding region of the UGT1A1 gene should be genotyped in addition to testing for UGT1A1*28 to more accurately predict irinotecan-related toxicity, at least in Asian patients.

The software system for the human friendly robot is important to realize a practical flexible robot. I propose the system based on a bilinear time delay neural network model for this purpose. The proposed model can describe both linear and non-linear models for robot software. And this model also can describe both algebraic and differential equation systems. I discuss how this model works for robot functions. I also show the example robot functions of motion, sensing and logic using proposed model.

A 60-year-old woman with non-small cell lung cancer was treated with gefitinib and developed acute pneumonitis on the third day. Pulmonary damage and/or interstitial lung disease (ILD) related to gefitinib was diagnosed clinically and radiographically. Despite the immediate withdrawal of gefitinib and the administration of high-dose steroid, the patient did not fully recover and finally died of respiratory failure on day 22 after gefitinib had commenced. This case cautions us that careful monitoring provides no guarantee of safeguarding patients against ILD caused by gefitinib. We should make the decision to treat patients with gefitinib very carefully until we can elucidate which patients are at high risk and which patients are likely to have a response to this drug.

A dose-escalation study of cisplatin (CDDP) combined with S-1, a new oral dihydropyrimidine dehydrogenase inhibitory fluoropyrimidine, was performed to determine the maximum-tolerated dose (MTD), recommended dose (RD), dose-limiting toxicities (DLTs), and objective response rate (RR) in advanced gastric cancer (AGC). S-1 was given orally at 40 mg m(-2) b.i.d. for 21 consecutive days following a 2-week rest. CDDP was planned to be given intravenously on day 8, at a dose of 60, 70, or 80 mg m(-2) depending on the DLT. Treatment was repeated every 5 weeks, unless disease progression was observed. In the phase I portion, the MTD of CDDP was presumed to be 70 mg m(-2), because 33.3% of patients (2/6) developed DLTs, mainly neutropenia. Therefore, the RD of CDDP was estimated as 60 mg m(-2). In the phase II portion, 19 patients including six patients of the RD phase I portion were evaluated. The median administered courses was four (range: 1-8). The incidences of severe (grades 3-4) haematological and nonhaematological toxicities were 15.8 and 26.3%, respectively, but all were manageable. The RR was 74% (14/19, 95% confidence interval: 54.9-90.6%), and the median survival day was 383. This regimen is considered to be active against AGC with acceptable toxicity.

310 Background: LEN inhibits the activity of vascular endothelial growth factor receptor, fibroblast growth factor receptor, and platelet-derived growth factor receptor–α. These targets have been shown to be expressed in patients (pts) with BTC. The objective of this study is to evaluate LEN as a potential treatment option for these pts. Methods: This is an open-label, phase 2 study conducted in Japan. Pts aged ≥ 20 years with confirmed diagnosis of unresectable BTC, measureable disease per Response Evaluation Criteria in Solid Tumors v1.1, and 1 prior gemcitabine-based doublet chemotherapy, will receive LEN 24 mg/d. The primary endpoint is objective response rate. Secondary objectives include disease control rate (DCR), safety, and pharmacokinetics. Enrollment of 25 pts is planned. The study includes an interim evaluation for futility. If there is no objective response and disease control is achieved in < 5 pts of 15‒17 pts, the study will end. Results: An interim evaluation was performed with 17 pts enrolled (data cutoff: 25 July 2016). Ten (59%) pts were aged < 65 years, 10 (59%) were male, 2 (12%) had prior surgery, and 13 (76%) received prior gemcitabine + cisplatin therapy. Efficacy results appear in the table. One pt had a partial response (PR) and 13 had stable disease (SD). The DCR was 82%. All pts experienced treatment-emergent adverse events (TEAEs). Grade ≥ 3 TEAEs occurred in 11 (65%) and serious AEs (SAEs) occurred in 7 (41%) pts. There were no fatal SAEs. TEAEs leading to LEN discontinuation, dose reduction, and dose interruption occurred in 1 (6%), 12 (71%), and 9 (53%) pts, respectively. Analysis of trough plasma concentration in 13 pts from this study showed no difference versus that observed in a previous phase 3 study of LEN in differentiated thyroid cancer. Conclusions: Because results of this interim evaluation did not meet futility criteria, the study was continued, with findings suggesting possible activity of LEN in pts with unresectable BTC who failed gemcitabine-based doublet chemotherapy. Toxicities were generally manageable with dose modifications as only 1 pt required discontinuation from LEN. Clinical trial information: NCT02579616. [Table: see text]

Evaluation of: Bekaii-Saab T, Phelps MA, Li X et al. Multi-institutional Phase II study of selumetinib in patients with metastatic biliary cancers. J. Clin. Oncol. 29, 2357–2363 (2011).It is necessary to establish effective chemotherapy to improve the survival of patients with biliary tract cancer. Although the useful of some molecular-targeted agents as first-line therapies has been investigated, none have been found to exert satisfactory efficacy. In this article, we report the results of a Phase II study of selumetinib in patients with metastatic biliary cancer. Selumetinib is an inhibitor of MEK1/2 targeting the RAS/RAF/MEK/extracellular signal-related kinase pathway. Three out of 28 patients showed a confirmed partial response, representing a response rate of 12%. The median progression-free survival was 3.7 months and the median overall survival was 9.8 months. The most common toxicities were rash, xerostomia and nausea. Most toxicities were grade 1 or 2, and the most common grade 3/4 toxicities wer...

The purpose of this study was to assess the efficacy and safety of fixed dose rate infusion of gemcitabine and S-1 combination therapy (FGS) in patients with gemcitabine (GEM)-refractory pancreatic cancer (PC) and to explore independent variables associated with survival. We retrospectively reviewed consecutive patients with GEM-refractory PC who received FGS at our institution from March 2009 to December 2013. GEM was administered by fixed dose rate intravenous infusion of 1,200 mg/m2 as a 120-min infusion on day 1, and S-1 was administered orally twice a day at a dose of 40 mg/m2 on days 1–7. Cycles were repeated every 14 days. Sixty-one patients with GEM-refractory PC received FGS. Sixteen patients received FGS as third-line treatment. Twenty-nine patients (48 %) had a history of S-1 administration. The objective response rate was 13 %, and the disease control rate was 49 %. The median progression-free survival time was 2.7 months, and the median overall survival time was 6.0 months. Major Grade 3 or 4 adverse events included neutropenia (15 %), diarrhea (3 %), anorexia (2 %), and fatigue (2 %). A high inflammation-based prognostic score (modified Glasgow prognostic score (mGPS), which incorporates C-reactive protein and albumin), a performance status >0, and serum carbohydrate antigen 19–9 level >2,000 IU/ml were independently associated with a poor outcome. FGS might be effective and well tolerated as salvage chemotherapy in a practical setting. The inflammation-based prognostic score is a simple and reliable indicator of survival in the setting of salvage chemotherapy.

Background. Most gastric cancer patients with peritoneal dissemination have been excluded from clinical studies because they usually have no measurable lesions. They also have a high risk of toxicity because of complications such as intestinal obstruction and ascites. We conducted a retrospective analysis to evaluate the efficacy and feasibility of sequential methotrexate (MTX) and 5-flurorouracil (5FU) therapy for this population. Methods. This analysis was based on 56 consecutive chemotherapy-naive patients with confirmed peritoneal dissemination of gastric cancer who were being treated with sequential MTX/5FU. The therapy comprised a weekly schedule of MTX 100 mg/m2, given as a bolus infusion 3 h prior to a bolus infusion of 5FU 600 mg/m2. Leucovorin 10 mg/m2 was administered six times, every 6 h, starting 24 h after MTX administration. Results. Evidence of peritoneal dissemination was confirmed by laparotomy in 16 patients, by cytologic examination of ascites in 11 patients, and by clinical imaging in 29 patients (15 with ascites, 13 with intestinal obstruction; in 10 of the 29 patients, detection was by barium enema or computed tomography [CT] scan). Neutropenia of grade 3 or worse and anemia were observed in 8 (14%) and 10 (18%) of the 56 patients, respectively. There was one treatment-related death due to neutropenic sepsis. Of the 26 patients with measurable lesions, 9 showed a response (36%). The median survival time and median time to treatment failure were 259 days and 167 days, respectively. Objective improvement of ascites was seen in 13 of 26 patients (50%), including 5 with showed complete disappearance of ascites. Seven of the 15 patients (47%) with intestinal obstruction showed resolution, and 8 of the 21 patients (38%) who needed nutritional support before the treatment were free of that support for a median duration of 220 days after the completion of the treatment. Forty-seven of the 56 patients (84%) could be treated at outpatient clinics. Conclusions. This regimen may be of clinical benefit for patients with peritoneal dissemination of gastric cancer.