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Purpose Alectinib is an anaplastic lymphoma kinase (ALK) –specific kinase inhibitor that seems to be effective against non–small-cell lung cancer (NSCLC) with a variety of ALK mutations. The primary analysis of AF-001JP reported a promising overall response rate. To assess progression-free survival (PFS) and overall survival (OS), patients from the phase II part of AF-001JP were followed up for approximately 3 years. Patients and Methods Oral alectinib 300 mg was administered twice per day to patients with ALK inhibitor–naïve, ALK-positive NSCLC who had progressed after one or more regimens of previous chemotherapy. In this long-term follow-up, efficacy (PFS, OS), correlation between tumor shrinkage and PFS, safety of alectinib, and relief of cancer symptoms were evaluated. Results At the updated data cutoff (September 10, 2015; first patient in August 30, 2011, last patient in April 18, 2012), 25 of 46 phase II patients were still receiving alectinib. Disease progression was confirmed in 18 patients (39%); median PFS was not reached (3-year PFS rate, 62%; 95% CI, 45 to 75). Fourteen patients had brain metastases at baseline; of these, 6 remained in the study without CNS and systemic progression. Tumor shrinkage and PFS showed no correlation. The 3-year OS rate was 78% (13 events). The most common treatment-related adverse event (all grades) was increased blood bilirubin (36.2%). Most cancer symptoms were relieved early, and medication for symptoms was dramatically decreased during alectinib therapy. Conclusion Alectinib was effective in this 3-year follow-up with a favorable safety profile over a long administration period in ALK-positive NSCLC without previous ALK inhibitor treatment.

Summary We report pharmacokinetics, efficacy, and safety data for a new 150 mg alectinib capsule in ALK+ non-small-cell lung cancer in a multicenter, open-label pharmacologic study (JP28927). Eligible patients (≥20 years, locally advanced/metastatic ALK+ disease, ALK inhibitor-naive and -pretreated [including crizotinib refractory]) were randomized 1:1 to receive one of two sequences of alectinib 300 mg twice daily (comprising different schedules of 20/40 mg and 150 mg capsules) until investigator-determined lack of clinical benefit. Co-primary endpoints were: bioequivalence of alectinib 20/40 mg versus 150 mg; food effect with 150 mg; and safety. Thirty-five patients were enrolled; median treatment duration was 13.1 months (range 1.1−15.0). Under fasting conditions, exposure of the two formulations was similar; mean AUClast ± standard deviation 3230 ± 914 h•ng/mL versus 3710 ± 1040 h•ng/mL, respectively, for 150 mg versus 20/40 mg capsules. Food effect with 150 mg alectinib was negligible. Treatment-related adverse events in >20% of patients were constipation (31.4%), dysgeusia (25.7%), and decreased white blood cell and neutrophil count (22.9% each). No treatment-related grade 4/5 events occurred. Median time to response was 1.2 months (95% CI 1.1−2.1). For the full analysis set (n = 35) and crizotinib-failure subpopulations (n = 23), overall response rate was 70.0% (95% CI 50.6−85.3) and 65.0% (95% CI 40.8−84.6), and median progression-free survival was 13.9 months (95% CI 11.1−not reached) and 12.9 months (95% CI 3.9−not reached), respectively. The 150 mg capsule had a similar exposure profile to 20/40 mg capsules. Alectinib demonstrated promising efficacy and was well tolerated. This article is protected by copyright. All rights reserved.

Summary Background Currently, crizotinib is the only drug that has been approved for treatment of ALK -rearranged non-small-cell lung cancer (NSCLC). We aimed to study the activity and safety of CH5424802, a potent, selective, and orally available ALK inhibitor. Methods In this multicentre, single-arm, open-label, phase 1–2 study of CH5424802, we recruited ALK inhibitor-naive patients with ALK -rearranged advanced NSCLC from 13 hospitals in Japan. In the phase 1 portion of the study, patients received CH5424802 orally twice daily by dose escalation. The primary endpoints of the phase 1 were dose limiting toxicity (DLT), maximum tolerated dose (MTD), and pharmacokinetic parameters. In the phase 2 portion of the study, patients received CH5424802 at the recommended dose identified in the phase 1 portion of the study orally twice a day. The primary endpoint of the phase 2 was the proportion of patients who had an objective response. Treatment was continued in 21-day cycles until disease progression, intolerable adverse events, or withdrawal of consent. The analysis was done by intent to treat. This study is registered with the Japan Pharmaceutical Information Center, number JapicCTI-101264. Findings Patients were enrolled between Sept 10, 2010, and April 18, 2012. The data cutoff date was July 31, 2012. In the phase 1 portion, 24 patients were treated at doses of 20–300 mg twice daily. No DLTs or adverse events of grade 4 were noted up to the highest dose; thus 300 mg twice daily was the recommended phase 2 dose. In the phase 2 portion of the study, 46 patients were treated with the recommended dose, of whom 43 achieved an objective response (93·5%, 95% CI 82·1–98·6) including two complete responses (4·3%, 0·5–14·8) and 41 partial responses (89·1%, 76·4–96·4). Treatment-related adverse events of grade 3 were recorded in 12 (26%) of 46 patients, including two patients each experiencing decreased neutrophil count and increased blood creatine phosphokinase. Serious adverse events occurred in five patients (11%). No grade 4 adverse events or deaths were reported. The study is still ongoing, since 40 of the 46 patients in the phase 2 portion remain on treatment. Interpretation CH5424802 is well tolerated and highly active in patients with advanced ALK -rearranged NSCLC. Funding Chugai Pharmaceutical Co, Ltd.

イソシアナートと反応させてポリウレタンを生成するポリ (プロピレンオキシド) 系ポリオールの末端基の解析法として, 直接1Hおよび13C NMRを用いない方法を総合的に研究した. 末端基としては, ヒドロキシル基と少量の不飽和基の2種が存在しており, ヒドロキシル基の定量 (ヒドロキシル基価) には, ピリジン溶液でのフタル酸エステル化法 (JIS法) に替わる近赤外法を開発した. また定性では, トリフルオロ酢酸付加物の19F NMRによる解析法を示した. 水酸末端基数の違いによる高速液体クロマトグラフィー (HPLC) による分離法を確立した. 不飽和基の定量法として酢酸第二水銀法に替わる一塩化ヨウ素付加による方法を, また不飽和基のアリル基・cis-プロペニル基の識別法としてラマン法を示した.

Aluminium titanate was strengthened by alloying with 3 mol% yttria stabilized zirconia to attain a small expansion coefficient of 2 × 10 −6 and a high strength of 100 MPa, simultaneously. Long milling and optimization of the composition of the alloy to an equal weight of the component oxides and also of the firing temperature at 1400 °C were important for the purpose. In the optimal conditions, aluminum titanate grains of 3 μm was surrounded by zirconia matrix of ca. 0.3 μm grains containing zirconium titanate where would be a balance between the tension in the matrix and the expansion force of aluminum titanate grains. Formation of zirconium titanate was important for the strengthening to decrease the lowering of the strength brought about by the unstabilization of PSZ.

A case of adenoid cystic carcinoma of the breast is reported. A 70-year-old woman was referred to our clinic with the chief complaint of right breast pain. The impression of the mass was chronic mastopathy, but a possible malignancy was suspected ultrasonographycally. Excisional biopsy and pathological examination revealed an adenoid cystic carcinoma. Patey operation was performed, no metastasis to axillary lymph node being found. Histologically, the tumor was characterized by “cysts” with a cribriform pattern. Histochemically, hyaline material inside “cysts” were alcian blue-positive and PAS-negative or weakly positive, and contents of the duct structures gave a positive reaction with PAS but negative with alcian blue. Immunohistochemically, CEA (carcinoembryonic antigen) and secretory component were disclosed in the duct structures, but none in the “cysts”.

A 52-year-old man visited our hospital, complaining of epigastric pain. ERCP, which was performed under a suspicion of acute pancreatitis due to his alcoholophilia, and gastrcendoscopy led to a preoperative diagnosis of synchronous early double carcinoma of the stomach and papilla of Vater. Pancreaticoduodenectomy was carried out. Carcinoma of the papilla of Vater was measured 1.1×1.0cm in size and histopathologically diagnosed as a moderatelly differentiated tubullar adenocarcinoma which slightly invaded the Oddi's muscle. Gastric cancer located on the gastric angle was 0.3×0.2cm in size. It was a well differentiated tubullar adenocarcinoma of type IIc limited to the mucosal layer. Any regional lymphnode metastasis was not found.

8061 Background: Alectinib, a CNS-penetrant, selective ALK inhibitor with a novel scaffold, was granted approval in Japan 2014, since it showed good efficacy and tolerability in ALK+ NSCLC pts with...

Aim: Alectinib is a CNS-penentrant, highly selective ALK inhibitor with a novel scaffold. JP28927 is a clinical pharmacological study to evaluate the bioequivalence of alectinib 300 mg b.i.d. with 20 and 40 mg capsules (caps) vs. 150 mg caps and food effect with 150mg caps in ALK-rearranged NSCLC patients (pts), regardless of history of previous ALK inhibitor treatment. Results for bioequivalence, food effect, efficacy and safety were reported at ASCO2014. ALK-rearranged NSCLC pts had to discontinue treatment from crizotinib, a first generation ALK inhibitor, because of drug resistance or intolerance. Methods: 35 ALK-rearranged NSCLC pts were enrolled into JP28927 study. Pts continued alectinib 300 mg b.i.d. with 150 mg caps until the investigator determined lack of clinical benefit. This report describes the updated efficacy and safety data for alectinib in 28 crizotinib pre-treated NSCLC pts included in JP28927. Results: As of Jan 11, 2014, median follow-up duration was 141 days (range: 35-166) and 21 pts continued treatment with alectinib without progressive disease (PD). Among 24 pts with target lesions, tumor shrinkage of more than 30 % was observed in 18 pts. Confirmed response rate was 58.3% (95%CI: 36.6-77.9) and disease control rate was 83.3 % (95%CI: 62.6-95.3) by investigator assessment. 19 of 28 pts had brain metastases at baseline, and 6 pts had no prior brain irradiation. 13 pts with brain metastases, including 4 pts without prior brain irradiation, were still on study treatment without PD. The safety profile was favorable, and continued the same trend previously reported. No pts discontinued study treatment for a safety reason. Gastrointestinal and visual disorders, characteristic of crizotinib treatment, were mild and not so frequent with alectinib. Conclusions: Alectinib showed promising response, including in brain metastases, and good tolerability in crizotinib pre-treated pts. These findings suggest that alectinib is a novel therapeutic option for crizotinib pre-treated ALK-rearranged NSCLC. Disclosure: T. Seto: Other substantive relationships: Honoraria (Chugai Pharmaceutical Co., Ltd., Pfizer Japan Inc., Novartis Pharma K.K.), Research funding(Chugai Pharmaceutical Co., Ltd., Pfizer Japan Inc., Novartis Pharma K.K., Astellas Pharma Inc.); T. Hida: Corporate sponsored research: Chugai, Pfizer, Novartis; K. Nakagawa: Advisory board: Abbott Japan Co., Ltd. Astellas Pharma Inc. Chugai Pharmaceutical Co.,Ltd. Pfizer Japan Inc.Novartis Pharma K.K. Corporate sponsored research:Chugai Pharmaceutical Co.,Ltd.Pfizer Japan Inc.Novartis Pharma K.K.; M. Satouchi: Corporate sponsored research:Chugai, Pfizer, Novartis Other substantive relationships:Honoraria; Chugai, Pfizer, Novartis; M. Nishio: Corporate sponsored research:Chugai, Novartis, Pfizer Other substantive relationships:Honoraria; Chugai, Novartis, Pfizer; K. Hotta: Corporate sponsored research: Chugai Other substantive relationships:Honoraria; Chugai, Pfizer; H. Murakami: Corporate sponsored research:Chugai, Novartis, Astellas; Y. Ohe: Corporate sponsored research: Chugai, Pfizer Other substantive relationships: Honoraria; Chugai, Pfizer; K. Takeda: Other substantive relationships: Chugai, Pfizer, Novartis; M. Tatsuno: Chugai employee; T. Shimada: Chugai employee; T. Tanaka: Chugai employee; T. Tamura: Corporate sponsored research: Chugai, Astellas, AbbVie (Abbott) Other substantive relationships: Honoraria; Chugai, Astellas, Novartis.

8033 Background: Anaplastic lymphoma kinase (ALK) is a constitutively activated tyrosine kinase in a subset of NSCLC with ALK fusion gene derived from chromosomal rearrangement. Previously, CH5424802, a highly selective, second-generation ALK inhibitor, has demonstrated clinically meaningful antitumor activity and a favorable toxicity profile (ESMO 2012). Here we report the updated results of this study. Methods: Patients (Pts) with ALK-positive NSCLC and no prior ALK inhibitor therapy were treated with CH5424802 at 300 mg bid until progressive disease or intolerable toxicity to investigate the efficacy and safety. Results: As of the cut-off date of Dec. 14, 2012, 58 pts have been treated with CH5424802: median age 49.5 years, M/F 25/33, ECOG PS 0/1 26/32, never-smoker 60.3%, ≥2 prior chemotherapy regimens 62%. Among the 46 pts in phase II part of this study, the overall response rate was 93.5% (95% CI: 82.1%, 98.6%) with 2 CRs and 41 PRs. Tumor shrinkage by 30% (PR) was achieved quickly with 65% occurring within 3 weeks of treatment and 87% within 6 weeks. With a median follow-up period of 12.6 months, 47/58 pts (40/46 pts in phase II part) were still on study treatment, and the median treatment duration has passed 10.3 months. The major treatment-related AEs were dysgeusia (21/58, 36%), rash, AST increased, blood bilirubin increased (19/58, 33% each), constipation and blood creatinine increased (17/58, 29% each), mostly grade 1-2. The major treatment-related grade 3 AEs were neutrophil count decreased (4/58, 7%). No grade 4 or fatal AEs were observed. Treatment-related visual disorders, vomiting and nausea were rare and mild. Conclusions: In patients with ALK-positive NSCLC but naïve to any ALK inhibitor therapy, treatment with CH5424802 demonstrated generally mild toxicity and lead to high response rate of 93.5% and durable treatment beyond 10 months, expecting that treatment duration can be longer than that of crizotinib. CH5424802 is therefore a promising new ALK inhibitor for NSCLC. Clinical trial information: JapicCTI-101264.

Background Single-agent chemotherapy (i.e. doxetaxel, gemcitabine or vinorelbine) is one of the standard treatments for elderly patients with advanced NSCLC. Pemetrexed has clinically equivalent efficacy, but with less toxicity compared with doxetaxel in the second-line setting of patients with advanced NSCLC. We conducted a phase II trial to evaluate the efficacy and safety of frontline pemetrexed in elderly patients with advanced non-squamous (non-Sq) NSCLC. Methods In this multicenter phase II trial, we recruited elderly patients with non-Sq NSCLC. Eligibility criteria were as follows: chemonaive; locally advanced or metastatic non-Sq NSCLC; age 75 or older; ECOG performance status 0-1; adequate organ function. Patients received pemetrexed (500 mg/m2) intravenously on day 1 every 3 weeks until disease progression had been confirmed. The primary end point was response rate (RR). The secondary end points included progression free survival (PFS), overall survival (OS), disease control rate (DCR) and safety. The planned sample size was 45 patients. Results Between August 2009 and July 2011, 47 patients were enrolled. Median age was 79 years (range: 75–91), 57% (20 of 47) were male, 36% (17 of 47) had never smoked, 85% (40 of 47) had adenocarcinoma, 72% (34 of 47) had stage IV and 41% (16 of 39) had EGFR tyrosine kinase activating mutation. Median number of cycles was 4 (1 to 15). RR was 13.3% (95% CI: 5.1, 26.8), DCR was 66.7% (95% CI: 51.0, 80.0), PFS was 4.9 months (95% CI: 3.0, 6.2 months), median OS was not reached. The most frequent treatment-related AEs were anemia, fatigue, hypocalcemia, mostly grade 1/2. Treatment-related grade 3/4 AEs were reported in 17.8% of patients (mostly neutropenia and fatigue). No treatment-related death occurred. Conclusions The efficacy and limited side-effects of pemetrexed are promising in elderly patients with non-Sq NSCLC.

The authors studied the possibility of adverse effects of chlorhexidine digluconate as applied to the oral area and the possible development of resistant Streptococcus mutans as a result of prolonged application.Different groups of experimental rats were respectively treated with 0.2% and 2.0% aquous solutions of chlorhexidine digluconate for 35 days. However, there were not observed any abnormal findings on the dental surfaces, gingivae and oral mucosa.In another series of tests with mice to which chlorhexidine digluconate was orally administerea in 5 different dosages of 12mg/Kg, 120mg/Kg, 180mg/Kg, 240mg/Kg, and 300mg/Kg, the 12mg/Kg group was found to show a normal healthy growth without abnormal findings.Five Streptococcus mutans strains were subjected to the dilution method in an effort to study the possibility of the development of resistant strains as a result of prolonged use of chlorhexidine digluconate. The result indicated that it would be difficult for resistant strains to develop.An experiment with primary school pupils, in which 3rd grade pupils were either treated with 2.0% solution or rinse of chlorhexidine digluconate in conjunction with instruction in the proper use of the toothbrush for a year, showed no abnormalcy on the dental surfaces, gingivae and oral mucosa. An application of chlorhexidine digluconate on a weekly basis proved successful in inhibiting the formation of dental plaques, and findings of this part of our studies will be given in a later report.

In 16 cases of abdominal aortic aneurysm (AAA) which we have treated surgically during the past two and half years, coincidental malignancy was encountered in four, i.e., three of gasric cancer and one of pulmonary cancer. The diagnosis of AAA and gastric or lung cancer was made simultaneously and preoperatively in cases 1, 2. AAA was diagnosed after 1.7 years and four years respectively, following the treatment of gastric cancer in cases 3 and 4. In case 1, gastric cancer with hemorrhagic complications was resected first, and aneurysmectomy was carried out on the 38th postoperative day. In case 2, a large AAA 6cm in size was wrapped first and a left upper lobectomy was done on the 19th postoperative day. In the other two patients, who were free of acertainable recurrence, aneurysmectomy was carried out in the early stage of gastric cancer in case 3, and wrapping was done in advanced gastric cancer in case.4. Case 2 died of myocardial infarction in third postoperative month. The other three patients are alive. In a patient with two life-threatening and separate diseases, surgical indications, method of the operation and priority of treatments should be carefully considered.

Transient receptor potential vanilloid 1 (TRPV1) is activated by elevated temperature (>42 °C), and it has been reported that cold temperature decreases capsaicin-induced TRPV1 activity. In contrast, transient receptor potential melastatin 8 (TRPM8) is activated by low temperatures and menthol, and heat stimulation suppresses menthol-evoked TRPM8 currents. These findings suggest that the effects of specific agents on TRPV1 and TRPM8 channels are intricately interrelated. We examined the effects of menthol on human (h)TRPV1 and of capsaicin on hTRPM8. hTRPV1 currents activated by heat and capsaicin were inhibited by menthol, whereas hTRPM8 currents activated by cold and menthol were similarly inhibited by capsaicin. An in vivo sensory irritation test showed that menthol conferred an analgesic effect on the sensory irritation evoked by a capsaicin analogue. These results indicate that in our study the agonists of TRPV1 and TRPM8 interacted with both of these channels and suggest that the anti-nociceptive effects of menthol can be partially explained by this phenomenon. Electronic supplementary material The online version of this article (doi:10.1007/s12576-015-0427-y) contains supplementary material, which is available to authorized users.

The present study was conducted for the purpose of elucidating the correlation of three items: i) the frequency of toothbrushing, ii) the degree of dental cleanliness, and iii) the PMA index for a three-year period till the graduation of the subjects from lower secondary school. The subjects were instructed to brush their teeth thoroughly in the inital examination of each year, and their oral conditions were examined for a total of 13 times, on an average of 3 to 5 times per year.When the correlative coefficient (r) was calculated based on the study, there was observed a weak minus correlation between the frequency of toothbrushing and the degree of dental cleanliness but there was no statistical difference between the frequency of toothbrushing and the PMA index, the statistical difference being about 1% risk level between the frequency of toothbrushing and the PMA index.When the 1975 data were analyzed concerning the above items, the correlation between the degree of dental cleanliness and the frequency of thoothbrushing and the PMA index was given the main attention. As a result, it was found that the correlation between the degree of dental cleanliness and the PMA index was +0.320-+0.578, with a fair degree of positive correlation.The correlation, on the other hand, between the degree of dental cleanliness and frequency of toothbrushing was slight, with a value of -0.084- -0.198.As stated above, a total of 314 children were subjected to the study for a consecutive period of three years. But some of the subjects were for a period of two years.