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Standard first-line chemotherapy results in disease progression and death within one year in most patients with human epidermal growth factor receptor 2 (HER2)-negative gastro-oesophageal adenocarcinoma1–4. Nivolumab plus chemotherapy demonstrated superior overall survival versus chemotherapy at 12-month follow-up in gastric, gastro-oesophageal junction or oesophageal adenocarcinoma in the randomized, global CheckMate 649 phase 3 trial5(programmed death ligand-1 (PD-L1) combined positive score ≥5 and all randomized patients). On the basis of these results, nivolumab plus chemotherapy is now approved as a first-line treatment for these patients in many countries6. Nivolumab and the cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibitor ipilimumab have distinct but complementary mechanisms of action that contribute to the restoration of anti-tumour T-cell function and induction of de novo anti-tumour T-cell responses, respectively7–11. Treatment combining 1 mg kg−1nivolumab with 3 mg kg−1ipilimumab demonstrated clinically meaningful anti-tumour activity with a manageable safety profile in heavily pre-treated patients with advanced gastro-oesophageal cancer12. Here we report both long-term follow-up results comparing nivolumab plus chemotherapy versus chemotherapy alone and the first results comparing nivolumab plus ipilimumab versus chemotherapy alone from CheckMate 649. After the 24.0-month minimum follow-up, nivolumab plus chemotherapy continued to demonstrate improvement in overall survival versus chemotherapy alone in patients with PD-L1 combined positive score ≥5 (hazard ratio 0.70; 95% confidence interval 0.61, 0.81) and all randomized patients (hazard ratio 0.79; 95% confidence interval 0.71, 0.88). Overall survival in patients with PD-L1 combined positive score ≥ 5 for nivolumab plus ipilimumab versus chemotherapy alone did not meet the prespecified boundary for significance. No new safety signals were identified. Our results support the continued use of nivolumab plus chemotherapy as standard first-line treatment for advanced gastro-oesophageal adenocarcinoma.

Background A questionnaire related to patients’ physical condition is required to assess their quality of life and improve their self-management skills. Methods It was a descriptive, cross-sectional, multicenter study that aimed to assess the life-satisfaction and self-efficacy questionnaires verified in Japan, which were related to physical parameters in patients undergoing hemodialysis. A total of 196 outpatients receiving hemodialysis at four dialysis centers were included in the study. Responses to life-satisfaction and self-efficacy questionnaires were collected. Demographic and clinical characteristics of patients were obtained, including life circumstances, in addition to nutritional indices such as normalized protein catabolic rate, creatinine generation rate, and geriatric nutritional risk index. Results Life-satisfaction scores were related to prognostic physical parameters, such as normalized protein catabolic rate and creatinine generation rate. Female sex, non-diabetic status, and working patients were more satisfied with their lives undergoing hemodialysis. Elderly patients had higher self-efficacy scores, which were related to their life-satisfaction. However, the self-efficacy scores were not associated with physical parameters. Conclusions This life-satisfaction questionnaire is simple and related to the patient’s condition.

What is this summary about? This is a summary of the 1-year results of a clinical research study known as CheckMate 649 published in The Lancet in June 2021. The 2-year results on the participants' health and overall quality of life from the same study are in a second publication in Nature in March 2022. Until recently, chemotherapy was the only first treatment option for people with advanced or metastatic gastroesophageal adenocarcinoma who had not been treated before. Patients receiving chemotherapy lived on average for less than 1 year. Nivolumab is an immunotherapy that works by activating a person's immune system to fight back against cancer cells. The goal of CheckMate 649 was to find out if the combination of nivolumab and chemotherapy would help patients with advanced or metastatic gastroesophageal adenocarcinoma live longer and without their cancer getting worse. What were the results? Results from the final analysis are reported here. Of 1581 people who took part in the study, 789 received nivolumab and chemotherapy and 792 received chemotherapy. Researchers found that, on average, participants who received nivolumab and chemotherapy lived longer overall than those who received chemotherapy alone. The length of time participants lived without their cancer getting worse was also longer on average with nivolumab and chemotherapy than chemotherapy treatment alone. However, more participants in the nivolumab and chemotherapy group had side effects than those in the chemotherapy group. The three most common side effects in both types of treatment were nausea (urge to vomit), diarrhea and peripheral neuropathy. Participants who received nivolumab and chemotherapy had a lower risk of their cancer symptoms worsening and reported that they were ‘less bothered’ from side effects of treatment than those receiving chemotherapy alone. What do the results mean? The nivolumab and chemotherapy combination is considered a new standard treatment option and is approved in several countries as a treatment for adults who have not been treated before for their advanced or metastatic gastroesophageal cancer based on results from CheckMate 649. Clinical Trial Registration: NCT02872116 ( ClinicalTrials.gov )

Background Bronchial atresia is a congenital obstruction of the segmental or lobar bronchus that often leads to hyperinflation of the affected area. It can cause intractable infections and abnormal nodules in these regions and surgical resection needs to be considered. The precise resection of the abnormal pulmonary segment is crucial for diagnosis and treatment. Case presentation A 24-year-old male patient was incidentally diagnosed with an abnormal lung shadow, which was confirmed to be bronchial atresia with computerized tomography imaging and bronchofiberscopy. Segmentectomy using fluorescence navigation with indocyanine green dye was performed. The patient had no trouble in his clinical course, indicating that this procedure may be useful in the resection of congenital bronchial atresia regions. Conclusion Segmentectomy using indocyanine green is an appropriate technique for minimal resection without respiratory impairment and diagnostic therapy of bronchial atresia.

Objective: A questionnaire suggestive of patients’ health status is needed to assess their quality of life and improve their self-management skills. It is a descriptive, cross-sectional and multicenter study. The aim of this study was to assess the life-satisfaction and self-efficacy questionnaires verified in Japan which was more related to the biochemical and nutritional markers in patients receiving hemodialysis. A total of 196 outpatients receiving hemodialysis in four dialysis centers were included. The responses to the life-satisfaction and self-efficacy questionnaires were collected. Demographic and clinical characteristics of patients were obtained including life circumstances, in addition to nutritional indices such as normalized protein catabolism rate, creatinine generation rate and geriatric nutritional risk index. Results: Life-satisfaction scores were related to prognostic nutritional markers such as normalized protein catabolism rate and creatinine generation rate. Female sex and non-diabetic patients were more satisfied with the life undergoing hemodialysis. Elderly patients had higher self-efficacy scores, which was related to their life-satisfaction scores. However, self-efficacy scores were not associated with the biochemical and nutritional markers. This life-satisfaction questionnaire was simple and useful to assess the patient’s condition.

First-line chemotherapy for advanced or metastatic human epidermal growth factor receptor 2 (HER2)-negative gastric or gastro-oesophageal junction adenocarcinoma has a median overall survival (OS) of less than 1 year. We aimed to evaluate first-line programmed cell death (PD)-1 inhibitor-based therapies in gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma. We report the first results for nivolumab plus chemotherapy versus chemotherapy alone.In this multicentre, randomised, open-label, phase 3 trial (CheckMate 649), we enrolled adults (≥18 years) with previously untreated, unresectable, non-HER2-positive gastric, gastro-oesophageal junction, or oesophageal adenocarcinoma, regardless of PD-ligand 1 (PD-L1) expression from 175 hospitals and cancer centres in 29 countries. Patients were randomly assigned (1:1:1 while all three groups were open) via interactive web response technology (block sizes of six) to nivolumab (360 mg every 3 weeks or 240 mg every 2 weeks) plus chemotherapy (capecitabine and oxaliplatin every 3 weeks or leucovorin, fluorouracil, and oxaliplatin every 2 weeks), nivolumab plus ipilimumab, or chemotherapy alone. Primary endpoints for nivolumab plus chemotherapy versus chemotherapy alone were OS or progression-free survival (PFS) by blinded independent central review, in patients whose tumours had a PD-L1 combined positive score (CPS) of five or more. Safety was assessed in all patients who received at least one dose of the assigned treatment. This study is registered with ClinicalTrials.gov, NCT02872116.From March 27, 2017, to April 24, 2019, of 2687 patients assessed for eligibility, we concurrently randomly assigned 1581 patients to treatment (nivolumab plus chemotherapy [n=789, 50%] or chemotherapy alone [n=792, 50%]). The median follow-up for OS was 13·1 months (IQR 6·7-19·1) for nivolumab plus chemotherapy and 11·1 months (5·8-16·1) for chemotherapy alone. Nivolumab plus chemotherapy resulted in significant improvements in OS (hazard ratio [HR] 0·71 [98·4% CI 0·59-0·86]; p0·0001) and PFS (HR 0·68 [98 % CI 0·56-0·81]; p0·0001) versus chemotherapy alone in patients with a PD-L1 CPS of five or more (minimum follow-up 12·1 months). Additional results showed significant improvement in OS, along with PFS benefit, in patients with a PD-L1 CPS of one or more and all randomly assigned patients. Among all treated patients, 462 (59%) of 782 patients in the nivolumab plus chemotherapy group and 341 (44%) of 767 patients in the chemotherapy alone group had grade 3-4 treatment-related adverse events. The most common any-grade treatment-related adverse events (≥25%) were nausea, diarrhoea, and peripheral neuropathy across both groups. 16 (2%) deaths in the nivolumab plus chemotherapy group and four (1%) deaths in the chemotherapy alone group were considered to be treatment-related. No new safety signals were identified.Nivolumab is the first PD-1 inhibitor to show superior OS, along with PFS benefit and an acceptable safety profile, in combination with chemotherapy versus chemotherapy alone in previously untreated patients with advanced gastric, gastro-oesophageal junction, or oesophageal adenocarcinoma. Nivolumab plus chemotherapy represents a new standard first-line treatment for these patients.Bristol Myers Squibb, in collaboration with Ono Pharmaceutical.

BACKGROUND: First-line chemotherapy for advanced esophageal squamous-cell carcinoma results in poor outcomes. The monoclonal antibody nivolumab has shown an overall survival benefit over chemotherapy in previously treated patients with advanced esophageal squamous-cell carcinoma. METHODS: In this open-label, phase 3 trial, we randomly assigned adults with previously untreated, unresectable advanced, recurrent, or metastatic esophageal squamous-cell carcinoma in a 1:1:1 ratio to receive nivolumab plus chemotherapy, nivolumab plus the monoclonal antibody ipilimumab, or chemotherapy. The primary end points were overall survival and progression-free survival, as determined by blinded independent central review. Hierarchical testing was performed first in patients with tumor-cell programmed death ligand 1 (PD-L1) expression of 1% or greater and then in the overall population (all randomly assigned patients). RESULTS: A total of 970 patients underwent randomization. At a 13-month minimum follow-up, overall survival was significantly longer with nivolumab plus chemotherapy than with chemotherapy alone, both among patients with tumor-cell PD-L1 expression of 1% or greater (median, 15.4 vs. 9.1 months; hazard ratio, 0.54; 99.5% confidence interval [CI], 0.37 to 0.80; P

240 Background: CheckMate 649 is a randomized, global phase 3 study of 1L programmed death-1 (PD-1) inhibitor–based therapies in advanced non-HER2-positive GC/GEJC/EAC that demonstrated superior overall survival (OS) with NIVO + chemo vs chemo, leading to approvals in the US and other countries. Clinically meaningful long-term survival benefit with NIVO + chemo vs chemo was observed with 24 months (mo) of minimum follow-up in all randomized patients (pts) for both OS (HR 0.79 [95% CI 0.71–0.88]) and progression-free survival (PFS; HR 0.79 [95% CI 0.70–0.89]; Janjigian YY et al; ESMO 2021). We present expanded analyses of NIVO + chemo vs chemo with minimum follow-up of 24 mo. Methods: Adults with previously untreated, unresectable advanced or metastatic GC/GEJC/EAC were enrolled regardless of PD-ligand (L)1 expression. Pts with known HER2-positive status were excluded. Pts were randomized to NIVO (360 mg Q3W or 240 mg Q2W) + chemo (XELOX Q3W or FOLFOX Q2W), NIVO 1 mg/kg + IPI 3 mg/kg Q3W (4 doses, then NIVO 240 mg Q2W), or chemo. Dual primary endpoints were OS and PFS (per blinded independent central review) in pts with PD-L1 combined positive score (CPS) ≥ 5 for NIVO + chemo vs chemo. Hierarchically tested secondary endpoints included OS in NIVO + chemo vs chemo (PD-L1 CPS ≥ 1, then all randomized). Results: Of 2031 pts, 1581 were randomized to NIVO + chemo or chemo. In all randomized pts, 41% of pts (NIVO + chemo) and 44% of pts (chemo) received subsequent therapy. Median PFS2 (time from randomization to progression after subsequent systemic therapy, initiation of second subsequent systemic therapy, or death, whichever is earlier) was 12.2 (95% CI 11.3–13.5) mo with NIVO + chemo and 10.4 (95% CI 9.7–11.2) mo with chemo (HR 0.75 [95% CI 0.67–0.84]). 51% of pts (NIVO + chemo) and 43% of pts (chemo) had > 50% reduction from baseline in tumor burden, while 24% and 17% had > 80% reduction, respectively. The HR (95% CI) for OS was 0.66 (0.56–0.77) among pts with a PD-L1 CPS ≥ 10 (median OS for NIVO + chemo vs chemo: 15.0 [95% CI 13.7–16.7] vs 10.9 [95% CI 9.8–11.9] mo). OS benefit was observed with NIVO + chemo vs chemo across multiple additional subgroups, and these data will be presented. No new safety signals were identified. The majority of the treatment-related adverse events with potential immunologic etiology were grade 1 or 2 and grade 3 or 4 events were reported in ≤ 5% of pts in both treatment arms. Conclusions: NIVO + chemo continued to demonstrate clinically meaningful efficacy and an acceptable safety profile with longer follow-up, further supporting the use of NIVO + chemo as a standard 1L therapy in previously untreated pts with advanced GC/GEJC/EAC. Clinical trial information: NCT02872116.

167 Background: CheckMate 649 (NCT02872116) is a randomized, open label phase 3 study in first line (1L) treatment of pts with advanced GC/GEJC/EAC. Primary analysis results showed statistically significant improvement in overall survival (OS) for NIVO+chemo vs. chemo in all randomized pts. We present HRQOL results for these pts, included as an exploratory study objective. Methods: HRQOL was assessed using EQ-5D-3L (EQ-5D) and Functional Assessment of Cancer Therapy–Gastric Cancer (FACT-Ga). Assessments were performed at baseline (BL), every 6 weeks during treatment and during follow-up. Change from BL EQ-5D Visual Analog Scale (VAS), Utility Index (UI) and FACT-Ga scores were analyzed using mixed models. Time to first symptom deterioration (TTSD), time until definitive deterioration (TuDD), and time to improvement (TTI) were estimated with Kaplan-Meier estimators and stratified Cox models; deterioration/improvement was based on prespecified meaningful change thresholds. Results: 1581 pts were randomized to NIVO+chemo (n = 789) or chemo (n = 792). Among 1359 pts with BL and post-BL patient-reported outcomes (NIVO+chemo, n = 693; chemo, n = 666), BL scores for FACT-Ga total were similar between treatment groups. Least squares mean differences from BL favored NIVO+chemo at most visits for EQ-5D, FACT-Ga total, and Gastric Cancer Subscale (GaCS), and were comparable for other subscales (not shown). TTI generally favored NIVO+chemo (most HR > 1) but was not significantly different between arms. TTSD was longer in NIVO+chemo arm compared with chemo alone (all HRs < 1), except for Emotional Well-Being (WB); only GaCS and FACT-Ga total were significantly different between arms. TuDD showed statistically significant delays in deterioration (HR with CI < 1) for all scores expect Social WB. Conclusions: Compared with chemo alone, the addition of NIVO to chemo maintained HRQoL with a decreased risk of symptom deterioration in patients with previously untreated advanced or metastatic GC/GEJC/EAC. Together with improved OS, these data support NIVO+chemo as a new 1L standard treatment for GC/GEJC/EAC. Clinical trial information: NCT02872116. [Table: see text]

LBA4001 Background: NIVO demonstrated superior overall survival (OS) vs chemo in previously treated patients (pts) with ESCC (ATTRACTION-3). We report OS and progression-free survival (PFS) from CheckMate 648, the first global phase III study to evaluate both an immuno-oncology (I-O)/chemo combination and an I-O/I-O combination in advanced ESCC. Methods: Adults with previously untreated, unresectable advanced, recurrent or metastatic ESCC were enrolled regardless of tumor cell PD-L1 expression. Pts were randomized to NIVO (240 mg Q2W) + chemo (fluorouracil + cisplatin Q4W), NIVO (3 mg/kg Q2W) + IPI (1 mg/kg Q6W), or chemo alone. Primary endpoints for both comparisons were OS and PFS per blinded independent central review (BICR) in pts with tumor cell PD-L1 ≥ 1%. Hierarchically tested secondary endpoints included OS and PFS in all randomized pts. Results: 970 pts were randomized to NIVO + chemo, NIVO + IPI, and chemo arms (49% with tumor cell PD-L1 ≥ 1%). With 13 months (mo) minimum follow-up, NIVO + chemo and NIVO + IPI led to statistically significant improvement in OS vs chemo in pts with tumor cell PD-L1 ≥ 1% and all randomized pts (Table). Statistically significant PFS benefit was also observed for NIVO + chemo vs chemo (HR 0.65 [98.5% CI 0.46–0.92]; P = 0.0023) in pts with tumor cell PD-L1 ≥ 1%. PFS in NIVO + IPI vs chemo in pts with tumor cell PD-L1 ≥ 1% did not meet the prespecified boundary for significance. The objective response rate (per BICR) was 53% (NIVO + chemo), 35% (NIVO + IPI), and 20% (chemo) in pts with tumor cell PD-L1 ≥ 1% and in all randomized pts was 47%, 28%, and 27%, respectively; longer median (95% CI) duration of response was observed vs chemo for pts with tumor cell PD-L1 ≥ 1%: 8.4 (6.9–12.4), 11.8 (7.1–27.4), and 5.7 (4.4–8.7) mo and for all randomized pts: 8.2 (6.9–9.7), 11.1 (8.3–14.0), and 7.1 (5.7–8.2) mo, respectively. No new safety signals were identified (Table). Conclusions: NIVO plus chemo and NIVO plus IPI both demonstrated superior OS vs chemo, along with durable objective responses and acceptable safety, in pts with advanced ESCC, and each represents a potential new 1L treatment option. Clinical trial information: NCT03143153. [Table: see text]

4066 Background: CheckMate 649 (NCT02872116) is a randomized, open label phase 3 study in first line (1L) GC/GEJC/EAC. Prespecified interim results showed statistically significant improvement in overall survival (OS) and progression-free survival (PFS) for N+C vs C in all randomized pts and pts whose tumors expressed programmed death-ligand 1 combined positive score (CPS) ≥ 5. We present interim HRQOL results for CPS ≥ 5 pts, included as exploratory in the study. Methods: HRQOL was assessed using EQ-5D-3L (EQ-5D) and Functional Assessment of Cancer Therapy–Gastric Cancer (FACT-Ga). Assessments were performed at baseline (BL), every 6 weeks during treatment, and during follow-up. Change from BL EQ-5D Visual Analog Scale (VAS), Utility Index (UI) and FACT-Ga scores were analyzed using mixed models. Time to first symptom deterioration (TTSD), time until definitive deterioration (TuDD), and time to improvement (TTI) were estimated with Kaplan-Meier estimators and stratified Cox models; deterioration/improvement was based on prespecified meaningful change thresholds. Results: 1,581 pts were randomized to N+C (n = 789) and C (n = 792); of those, 955 pts had CPS ≥ 5 (N+C [n = 473] and C [n = 482]). Among 821 pts with BL and post BL PROs (N+C [n = 421] and C [n = 400]), BL scores for FACT-Ga total were similar for N+C and C. Least-squares mean differences from BL favored N+C at most visits for EQ-5D and FACT-Ga total and GaCS, and were comparable for other FACT subscales (data not shown). TTI largely favored N+C (most hazard ratios (HR) > 1) but was not significantly different between treatments. For TTSD, pts treated with N+C had decreased risk of deterioration (HR < 1) in EQ-5D UI, FACT-Ga total, and GaCS. TuDD showed statistically significant delays in deterioration (HR with confidence intervals [CI] < 1) for all scores. Conclusions: Pts with 1L GC/GEJC/EAC experienced better HRQOL with N+C compared with C alone. Change from BL in EQ-5D and FACT-Ga total and GaCS favored N+C at most visits. N+C decreased deterioration risk compared to C with OS and PFS improvement, suggesting favorable benefits in 1L GC/GEJC/EAC pts with CPS ≥ 5. Clinical trial information: NCT02872116. [Table: see text]

The importance of the contamination particle control in state of the art electron device production, such as a semiconductor, is increasing more than ever. Particle counter has been widely used as the technique of measuring particles suspended in the liquid phase and the gaseous phase. ITRS has been showing concretely the number concentration of particles, which should be controlled, in air, gas and liquid in contact with wafers. First, the leading-edge technology of the liquid-borne particle counter is shown, since the request about particle control in liquid of ITRS is considered as the typical information on a market trend. Meanwhile, the level of the particle contamination in process, such as a vacuum process does not have the shared roadmap. However, since TFT-LCD and PV which industrial scale has expanded rapidly, needs a high speed film deposition at a large substrate, the particle contamination control in vacuum process has been attracting attention. So the technique of the particle measurement in PECVD reactor is shown as an example of the particle measurement in vacuum processes which are expected as new application of a particle counter technology. Finally, a subject common to the measurement technique which uses a light scattering phenomenon as a principle, and the directivity of its improvement is shown.

Steroidal nuclear receptors (NRs) have been acknowledged as a target binding protein of so-called endocrine disruptors. It is therefore necessary to develop an efficient assay system for screening these endocrine-disrupting chemicals. We here describe the first exemplification of a direct measure of fluorescence intensity for a binding assay of NRs. We designed and synthesized a series of conjugates of 17alpha-ethinylcarboxyestradiol with carboxyfluorescein, both carboxyl groups of which were cross-linked with alpha,omega-diaminoalkanes. The resulting fluorescein-linked estradiol derivatives E2(n)cF (n=2, 4, 6, 8, 10 and 12) were evaluated for their fluorescence and receptor-binding characteristics. E2(4)cF and E2(8)cF exhibited the sufficient binding affinity to the recombinant estrogen receptor (ER) in the radiolabel binding assay using [(3)H]17beta-estradiol, and showed excellent fluorescent characteristics in the fluorescence measurements with and without ER. They exhibited sufficiently large specific binding characteristics with adequate K(d)- and B(max)-values. When these fluorescent ligands were used as a tracer for the binding assay against the ER, assay data of various compounds were shown to be compatible with those obtained from the ordinary binding assay using [(3)H]17beta-estradiol. The present study clearly shows that measurement of fluorescence intensity, instead of fluorescence polarization, affords an adequate receptor-binding assay system.

THE cDNAs for glyceraldehyde-3-phosphate dehydrogenase (GAPDH; EC 1.2.1.12) were cloned from cerebellar neurons undergoing age-induced apoptosis and/or healthy cells. COS-7 cells were transfected with the isolated GAPDH cDNAs using to the Lipofectamine method. Assessment of cell death in this paradigm was performed by monitoring the co-transfected luciferase activities and the characterization of cell death was examined by the DNA fragmentation assay and Hoechst dye nuclear staining. These observations show that over-expression of GAPDH occurring from both cDNAs robustly induces apoptotic death in the transfected COS-7 cell cultures. Confocal-immunocytochemical studies using this GAPDH-specific monoclonal antibody revealed that nuclear translocation of over-expressed GAPDH is a primary apoptotic event. Our results directly demonstrate that over-expressed GAPDH functions as a 'killing protein' in apoptosis.

Seventy-nine aralkyl- and aralkenylamides related to piperamides were synthesized and their nematocidal activity against second-stage larvae of dog roundworm, Toxocara canis, was examined. The activity was greatly dependent on the alkyl chain length and the nature of the amine moiety, but was scarcely affected by the presence or absence of double bond(s) in the chain. The alkyl chain lengths which showed the strongest activity in a series of homologues were m = 11 for the pyrrolidine amides and m = 13 for the N-methylpiperazine amides. Although piperamides (3,4-methylenedioxyphenyl homologues) showed the strongest activity among the homologues tested, methoxy substituent(s) on the aromatic ring did not have much effect on the activity. However, conversion of the methoxy group to a hydroxy group greatly decreased the activity and shortened the chain length giving the strongest activity. Calculated log P values of non-phenolic aryl-piperamides fell in the range from 3.5 to 4.5, whereas those of hydroxyphenyl-piperamides were smaller, suggesting that different mechanisms are involved in the nematocidal activity of phenolic and non-phenolic compounds.

自然気胸手術194症例231手術中両側気胸は51例 (26.3%) で, その内訳は両側同時気胸5例 (2.6%), 両側異時気胸46例 (23.7%) であった.低年齢層ほど両側気胸の可能性が高い傾向にあり10歳代症例は28例 (45.9%) と有意に高率であった.両側同時気胸は3例 (60%) に胸腔鏡下両側一期的手術を施行した.一方両側異時気胸において一側手術後に対側気胸が発症した症例は32例 (16.9%) であり10歳代症例は18例 (31.0%) であった5初回手術時に対側にも既往歴のある20症例のうち一側手術後に対側に気胸を再発した症例は6例 (30.0%) であり, その内10歳代症例は11例中4例 (36.4%) であった.対側手術が必要でなかった症例も多く両側異時気胸に対する対側の予防的手術は慎重に考える必要がある.術側術後再発は両側気胸症例が10側 (13.9%) で, 一側気胸症例が9側 (7.4%) であり両側気胸症例に多い傾向にあった.両側気胸や一側気胸でも10歳代症例の胸腔鏡下手術に際しては外科的胸膜癒着術を追加したほうがよい.

後縦隔発生の嚢胞性腫瘍に対して3cmミニ開胸併用胸腔鏡手術を施行し, その術野展開を工夫することにより良好な結果が得られた.対象は気管支嚢胞3例, 食道重複症1例, 心嚢憩室1例の計5例.年齢16～59歳.男女比3 : 2.5例中気管支嚢胞の1例は嚢胞壁が破損し摘出困難になったためミニ開胸部を開大したが残りの4例は摘出できた.この手術のポイントはミニ開胸をおく位置と術野を展開するための鉗子口の位置である.鉗子により肺を牽引し術野がうまく展開できれば3cmミニ開胸部より時間的にも通常開胸とほとんど変わらない手術操作が可能であり, 出血が少なく術後創痛もほとんど無い.また美容上からも優れている.同手術は, 自覚症状がほとんど無く良性であることが多い後縦隔の嚢胞性腫瘍に対して有用である.

左外傷性横隔膜ヘルニアに対する胸腔鏡併用手術を経験した.症例は, 21歳男性.交通外傷にて来院.左外傷性気胸, 第5・9肋骨骨折の診断で保存的治療したが, 入院時より上腹部鈍痛があり, 第10病日に胃内視鏡を施行した.その後の胸部X線上, 左横隔膜直上に入院時にはみられなかった異常透亮像を認め, 左外傷性横隔膜ヘルニアと診断し, 第13病日胸腔鏡併用修復術を施行した.胸腔内は, 少量の血性胸水と, 結腸の一部, 大網, 胃及び脾臓の脱出が見られたが, 臓器損傷はなかった.横隔膜外側前後方向に約9cm大の破裂部があり, 脾門部まで及んでいた.結腸・大網・胃の還納は容易であったが, 脾臓の還納に難渋した.このため5cmミニ開胸とした.ヘルニア門は二層に縫合し修復した.術後経過は良好で10日目に退院した.外傷性横隔膜ヘルニアに対する胸腔鏡下手術は, 臓器損傷や癒着の少ない症例においては良い適応と考えられた.

Conventional automatic transmissions, which have fixed shift patterns, sometimes show inconvenient shifting patterns, especially in uphill and downhill driving. In order to improve the driveability for these road conditions, Mitsubishi developed an adaptive shift logic called “Fuzzy shift” in 1992. Since then, further evolutional shift scheduling strategies has been developed to cover more extensive road conditions. This paper introduces neural network, learning and continuous variable shift patterns control incorporating this strategy.

Summary Interleukin-8 (IL-8) has been shown to be a chemotactic factor for neutrophils, T-lymphocytes and eosinophils, but it is unknown whether the IL-8-induced inflammatory cell accumulation into the airways can cause the bronchial hyperresponsiveness (BHR) characteristic of asthma. IL-8 at a dose of 0.5 or 5μg/kg was administered intranasally to guinea-pigs twice a week for 3 weeks. One day after the last administration, animals were anesthetized and artificially ventilated through tracheal cannula and lateral pressure at the cannula (Pao) was measured as an overall index of airway responses to increasing concentrations of inhaled histamine (25, 50, 100, and 200 μg/ml). The IL-8 treatment significantly enhanced bronchial responsiveness to histamine in a dose-dependent manner (ANOVA P < 0.01). The provocative concentration of histamine causing a 100% increase in Pao (PC100) at a dose of 0.5 and 5μg/kg of IL-8 was 68.1 (Gsem 1.12) and 35.6 (Gsem 1.25) μg/ml, respectively. The latter was significantly (P < 0.01) lower than that in control animals treated with PBS (93.3 [Gsem, 1.14] μg/ml)- The IL-8 treatment also induced a significant influx of neutrophils, but not eosinophils, in bronchoalveolar lavage (BAL) fluid (18.3 ± 8.8 and 30.6 ± 8.3% in animals treated with 0.5 and 5 μg/kg, respectively, of IL-8 vs 3.6 ± 0.7% in phosphate buffered saline-(PBS)-treated animals). Furthermore, we examined the effect of the thromboxane receptor antagonist S-1452 (0.01 or 0.1 mg/kg, i.p. 24 and 1 h before anesthesia) on this IL-8 induced BHR. S-1452 significantly inhibited the BHR dose-dependently (ANOVA P < 0.001). PC100 was 94.0 (Gsem 1.19), 137.4 (Gsem 1.17) and 43.0 (Gsem 1.24) μg/ml with S-1452 at doses of 0.01 and 0.1mg/ml and saline, respectively. We conclude that IL-8 causes BHR and airway neutrophil inflammation, and that thromboxane A2 is important in the development of BHR induced by IL-8.

The in vitro effect of asarone, the nematocidal principle of the rhizome of Acorus calamus, on second-stage larvae of Toxocara canis is composed of two independent actions : one is a fast acting inhibition of the larval mobility and the other is a slow acting larvicidal action. Mobility of the larvae was rapidly inhibited when they were incubated with asarone. Dye exclusion assay revealed that larvae were alive at this stage, and their mobility was restored after the first inhibition, suggesting that this effect was temporary and reversible. However, when the mobility decreased again during prolonged incubation, the cellular viability of larvae disappeared, showing that they were killed by the compound. The above two-stage effect of asarone was almost identical in two geometrical isomers ((E)- and (Z)- asarone). Di- and tri-methoxypropenyl or propylbenzenes carrying two methoxy groups at a vicinal position on a benzene ring showed, more or less, a two-stage effect of this type. These two actions were suggested to be separable by an appropriate modification of the structure.

Eosinophilic bronchitis without asthma can cause a persistent non-productive cough which is resistant to bronchodilator therapy. To understand the mechanism of the cough in this disorder, an animal model of eosinophilic bronchitis was developed. Guinea-pigs were treated with transnasal administration of polymyxin B or saline twice a week for 3 weeks. The number of eosinophils in bronchoalveolar lavage fluid increased in polymyxin B-treated animals when compared with those treated with saline. In addition, histological examination showed that the number of eosinophils infiltrated into the tracheal epithelium increased; injury to the tracheal epithelium was greater in polymyxin B-treated animals. The numbers of coughs induced by saline and each concentration of capsaicin (10(-18), 10(-16), 10(-14) M) were greater in the polymyxin B-treated animals. FK-224 (a neurokinin receptor antagonist) decreased the heightened cough reflex in this animal model of eosinophilic bronchitis. These findings suggest that neuropeptides, and particularly neurokinins, are involved in the heightened cough receptor sensitivity in eosinophilic bronchitis without asthma. This has implications for better understanding of this disorder and its treatment.

びまん性悪性胸膜中皮腫は治療抵抗性で, 外科療法, 化学療法, 放射線療法のいずれもその効果は限定されたものとなっている. これまではこれらの治療が単独であるいは組み合わされて施行されてきたが, 一定の治療様式は未だ確立されていない. 今回われわれは, 温熱が胸膜表面に極めてよく伝導する性質に着目し, 外科療法に化学温熱療法を加えた治療を施行した. stage II, epithelial typeの3例に対し, 胸膜肺全摘後化学温熱療法を加えた. 2例は術後6カ月, 8カ月で腫瘍死したが, 1例は17カ月無再発生存中である. 3例の試験開胸例に化学温熱療法を施行したが, 1例はPD, 2例はNCであった. 胸膜肺全摘術に化学温熱療法を加えれば予後向上を図れる可能性があると思われた.

原発性肺癌切除610例中IIIA, IIIB, IV期146例 (23.9%) に対し拡大手術を施行し, 5生率24.3%, MST550日をえた.術死は9例 (6.2%) であった.5生率はT3 (32.2%) がT4 (13.5%) よりも (P

Second-stage larvae of Toxocara canis were maintained in vitro for one year. Susceptibility of the larvae to drugs was evaluated by means of minimal larvicidal concentration (MLC) and larval bursting percentage. MLCs of citral and decanoic acid were almost constant throughout all stages of incubation. However, bursting percentage markedly varied within the first 20 weeks of incubation. Therefore, while larvae are available for use in the MLC assay at any stage of incubation, those beyond the first 20 weeks after incubation should be used for the bursting assay to obtain reproducible results.

A new curcuminoid, cyclocurcumin (IV), was isolated from the nematocidally active fraction of turmeric, the rhizome of Curcuma longa, together with three known curcuminoids, curcumin (I), demethoxycurcumin (II) and bisdemethoxycurcumin (III). The structure of IV was elucidated on the basis of spectral data and confirmed by the partial synthesis from curcumin (I). Although the above curcuminoids were ineffective when they were applied independently, the nematocidal activity increased remarkably when they were mixed, suggesting a synergistic action between them.

For the development of new receptor molecules that can recognize sugar molecules, we synthesized diphenyl-3,3′-diboronic acid (2). The distance between the two boronic acids in 2 is designed so that it can selectively form cyclic 1:1 complexes with disaccharides. It was shown that 2 forms 1:1 complexes with several disaccharides and gives the characteristic exciton coupling in CD spectroscopy owing to immobilization of the two phenyl rings. Thus, the absolute configuration was successfully predicted from the sign of the exciton coupling.

Various (E)-hydroxystilbenes were synthesized from (E)/(Z) mixtures of methoxystilbenes through a new (Z)-(E) isomerization method followed dy demethylation. The nematocidal activity appears when methoxystilbenes are demethylated to hydroxystilbenes. For this activity, a hydroxy group at the C-2 or C-3 position is necessary. Thus, 2-hydroxy-, 3-hydroxy-, 2, 6-dihydroxy-, 3, 4-dihydroxy-, 3, 5-dihydroxy-, 2, 2'-dihydroxy-, 3, 3'-dihydroxy-, 3, 4'-dihydroxy-, 2-hydroxy-4-methoxy-, 5-hydroxy-2-methoxy-, 2-hydroxy-6-methoxy-, 6-allyloxy-2-hydroxy-, 3-hydroxy-5-methoxy-, and 5-allyloxy-3-hydroxystilbenes showed rather potent nematocidal activity. The activity of 5-allyloxy-3-hydroxystilbene was the strongest [minimal lethal concentration (MLC)=30 μM]. The activities of the (E) and (Z) isomers were comparable. The activities were also retained, though they were weaker, in the dihydro derivatives, hydroxybibenzyls.

For the development of new receptor molecules that can recognize sugar molecules, we synthesized diphenyl-3,3′-diboronic acid (2). The distance between the two boronic acids in 2 is designed so that it can selectively form cyclic 1:1 complexes with disaccharides. It was shown that 2 forms 1:1 complexes with several disaccharides and gives the characteristic exciton coupling in CD spectroscopy owing to immobilization of the two phenyl rings. Thus, the absolute configuration was successfully predicted from the sign of the exciton coupling.

A case of Hirschsprung's disease in an adult was treated in our hospital. A 23-year-old man had been suffering from severe constipation since the childhood, for which proctostomy was recommended but his family disliked it. His bowel function was preserved only with daily enemas or purgatives. After puberty, although constipation tendency continued, he had bowel movement in several days with no drugs until the age of 23. Recently constipation gradually became worse, and he admitted to our hospital complaining abdominal pain and distension. Bariun enema revealed atypical caliber change and dilatation in the oral side of it. Hirschsprung's disease was suspected. The definitive diagnosis was made by anorectal manometry and acetylcholine esterase staining after rectal biopsy. Rectosigmoidectomy according to Duhamel method was performed, and his postoperative course was uneventful.

The Mg-adenosinetriphosphatase (ATPase) in the thyroidal NaI-treated microsome fraction was activated by treatment with basic polyamino acids or trypsin, but not with acidic polyamino acids and basic proteins such as lysozyme and ribonuclease. The enzyme kinetics showed that the activation of trypsin or poly-L-lysine was due to an increase in the maximal velocity of the hydrolyzing reaction without a change in the affinity of the enzyme for its substrate. A break at about 25 degrees C was observed in the Arrhenius plots of Mg-ATPase in the trypsin- or poly-L-lysine treated preparations, but there was no break in the control preparation. These results suggest that the activating effect of trypsin or poly-L-lysine on Mg-ATPase activity in the thyroidal NaI-treated microsome fraction is related to the lipid environment surrounding the enzyme molecule in the thyroid cell membrane.

The nematocidal activity of amides and amines having a long alkyl chain against the second-stage larva of dog roundworm, Toxocara canis, was examined. Long chain acyl amides with smaller substituents on the nitrogen showed stronger activity and the activity of cyclic amine amides was stronger than that of acyclic ones. In a series of homologous amides, the activity was dependent on the alkyl chain length: it reached a maximum at an optimal chain length and decreased in both shorter and longer homologues. The relationship between the activity and hydrophobicity of the homologues was analysed by the use of the bilinear model. The hydrophobicity of a compound, which gives a maximal activity, was similar for all neutral amides, but amides which have an additional amine group in the molecule had different values. Tertiary amines and their salts having a long alkyl chain also showed nematocidal activities comparable to those of the corresponding amides. The salts killed the larva at concentrations lower than their critical micell concentration, suggesting that they behave as a single molecule for the nematocidal action.

A 2-year-old girl living in southwestern Japan had a nodule of 2 months' duration on the left foot. A biopsy from the lesion showed transverse sections of a worm surrounded by granulomatous tissue. The worm was identified as an Onchocerca sp. from the morphological characteristics such as relatively thick cuticles, annular ridges on the cortical layer, and high somatic muscles. Positive serological tests using ELISA for Onchocerca gutturosa and Onchocerca volvulus supported the diagnosis. This was the first case of zoonotic Onchocerca infection detected in Japan. The clinicopathological aspects of zoonotic onchocerciasis of this case were discussed.

We investigated prostanoid-induced intracellular Ca2+ mobilization in Ca(2+)-sensitive dye fura-2-loaded cultured astrocytes. The thromboxane (TX) A2 analog STA2 (9,11-epithio-11,12-methano-TXA2) and/or prostaglandin (PG) F2 alpha (each used at 1 microM) stimulated intracellular Ca2+ mobilization in single cultured rat type 1 astrocytes. Three response patterns were observed: only STA2-sensitive, only PGF2 alpha-sensitive, and both prostanoids-sensitive cells. The Ca2+ response was prostanoid-dose-dependent (0.1 - 1 microM) and showed a rapid spike-like Ca2+ rise that peaked within 30 sec after the stimulation by the ligand. These observations suggest that type 1 astrocytes are heterogeneous with respect to the expression of receptors for TXA2 and PGF2 alpha, which are linked to Ca2+ mobilization.

From immunohistochemical and ligand-binding studies, it is known that the epidermal growth factor receptor (EGFR), a member of the erbB family of receptors, is expressed in tissues of epithelial, mesenchymal and neuronal origin and plays a major role in normal cellular processes such as proliferation, differentiation and development. EGFR is highly expressed in a number of solid tumours and its expression correlates with tumour progression, resistance to chemotherapy and a poor prognosis; it is consequently an attractive target for the rational design of novel anticancer agents. Knowledge of the role of EGFR in normal tissues will help the understanding of the adverse events associated with such agents. Studies in knockout mice and preclinical toxicology studies have shown that the major effects of inhibiting the EGFR are skin and gastrointestinal toxicities. Clinical studies with inhibitors of EGFR, such as gefitinib, cetuximab and erlotinib, have shown a favourable adverse-event profile, primarily consisting of skin and gastrointestinal toxicities, as predicted from the mechanism-based effects observed in preclinical studies.

Twenty diarylnonanones were synthesized and their nematocidal activity was examined. Among those, the p-hydroxy compound 16 exhibited the strongest activity comparable to the natural diarylnonanoids, malabaricones A and C. Diarylundecanoid 57 also showed appreciable activity.

A 40-year-old female was referred to our hospital for dysphagia. A hemangioma measuring 5 x 2.5 x 2.5 cm was revealed as a round defect by esophagography and was partially cystic on CT and MRI. Through a neck incision, the esophageal wall on the tumor side was initially opened. The tumor partially adhered to the esophageal wall, but was dissected from the esophageal wall and then resected easily. Microscopic examination of tumor revealed cavernous hemagioma. Thirty days after the initial surgery, the recurrent tumor was detected in the pharynx and increased rapidly. Then a second operation was performed. The tumor was completely resected by mucosectomy including normal esophageal mucosa. Recurrence was caused by residual cystic wall of the hemangioma adhering to the esophageal mucosa after the first procedure.

Three infants with congenital tracheal stenosis and three adults with various diseases of the central airway underwent esophageal tracheobronchoplasty to repair long-segment stenoses and defects. The primary operative goal was enlargement of the stenosis ( n = 4), repair of the defect ( n = 1), or both ( n = 1). Cardiopulmonary support was required in two cases. All three infants were operated on for generalized congenital tracheal stenoses. There was one postoperative death on the fifth day. Another infant died of pneumonia 3 months after operation. Tracheal patency was excellent in two infants. One infant is well without symptoms 6 years after the operation, although balloon dilation was required three times during the first postoperative year. In the three adult patients, the primary diseases were congenital tracheal stenosis, iatrogenic injury associated with relapsing polychondritis, and malignant mediastinal tumor involving the trachea. All lesions involved both the trachea and main stem bronchi. Postoperative airway patency was excellent in all three adults, although expandable metallic stents had to be inserted in one patient. Postoperative pulmonary function was improved, particularly forced expiratory volume in 1 second and peak expiratory flow rate. Although the postoperative mortality rate was still high, especially among the infants, and prolonged postoperative ventilatory support was required for five of the six patients, long-term patency and postoperative pulmonary functional improvement are encouraging. (J Thorac Cardiovasc Surg 1996;112:124-9)