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The purpose of this study was to evaluate whether N(ε)-hexanoyl lysine (N(ε)-HEL) and acrolein reflect the severity of cisplatin-induced nephrotoxicity. Immunoexpression of N(ε)-HEL and acrolein in kidneys and their urinary concentration were examined up to day 4 post-cisplatin injection in rats. Cisplatin-induced tubular injury was observed histopathologically on days 2-4 after injection and became more severe time-dependently. On days 2-4, N(ε)-HEL and acrolein were immunostained in the cytoplasm of damaged tubular cells. Their immunostaining intensity and urinary levels increased as tubular injury became more severe. These results suggest that expressions of N(ε)-HEL and acrolein were associated with the pathogenesis of cisplatin-induced nephrotoxicity.

9005Background: Although EGFR-TKI alone has been a standard first-line treatment for pts with advanced NSCLC with EGFR mutations, our phase II study (NEJ005) showed promising efficacy of GCP. NEJ00...

Purpose We investigated the efficacy of gefitinib re-challenge for the patients who responded to initial treatment with gefitinib and acquired resistance to gefitinib thereafter. Experimental design Medical records were retrospectively reviewed in the hospitals of National Hospital Organization from August 2002 to August 2008. Patients histologically or cytologically confirmed NSCLC were eligible if they once responded to initial treatment with gefitinib (CR, PR or SD) and then re-treated with gefitinib following subsequent chemotherapy. Result Twenty patients (16 PR, 4 SD) were enrolled in this study. After re-treatment with gefitinib, 5 cases showed PR and 8 cases SD. Overall response rate was 25% (5/20) and disease control rate was 65% (13/20) in the gefitinib re-treated patients. Median survival time from the start of the initial gefitinib and from the start of the re-administration of gefitinib were 34.0 and 10.0 months, respectively. Conclusion Re-administration of gefitinib was effective and therefore should be considered as one of the treatment option for the patients with NCLCL who once responded and acquired resistant to gefitinib following subsequent chemotherapy.

Background The North-East Japan Study Group (NEJ) 005/Tokyo Cooperative Oncology Group (TCOG) 0902 study has reported that first-line concurrent and sequential alternating combination therapies of an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (gefitinib) plus platinum-based doublet chemotherapy (carboplatin/pemetrexed) offer promising efficacy with predictable toxicities for patients with EGFR -mutant non-small cell lung cancer. However, overall survival (OS) data were insufficient in the primary report because of the lack of death events. Patients and methods Progression-free survival (PFS) and OS were re-evaluated at the final data cut-off point (March 2017) for the entire population (n=80). Results At the median follow-up time of 35.6 months, 88.8% of patients had progressive disease and 77.5% of patients had died. Median PFS was 17.5 months for the concurrent regimen and 15.3 months for the sequential alternating regimen (P=0.13). Median OS was 41.9 and 30.7 months, respectively (P=0.036). Updated response rates were similar in both groups (90.2% and 82.1%, respectively; P=0.34). Patients with Del19 tumours displayed relatively better OS (median: 45.3 vs 33.3 months, respectively) than those with L858R (31.4 vs 28.9 months, respectively). No severe adverse events, including interstitial lung disease, occurred in the period since the primary report. Conclusions This updated analysis confirms that PFS is improved with first-line combination therapy compared with gefitinib monotherapy and that the concurrent regimen, in particular, offers an OS benefit of 42 months in the EGFR -mutated setting. Our ongoing NEJ009 study will clarify whether this combination strategy can be incorporated into routine clinical practice. Trial registration number UMIN C000002789, Post-results.

To elucidate the role of Abf2p, a major mitochondrial DNA-binding protein in the yeast Saccharomyces cerevisiae, we examined the morphology of the mitochondrial nucleoids (mt-nucleoids) in an ABF2-deficient mutant (Δabf2) in vivo and in vitro by 4',6-diamidino-2-phenylindole (DAPI) staining. The mt-nucleoids appeared as diffuse structures with irregular-size in Δabf2 cells that were grown to log phase in YPG medium containing glycerol, in contrast to the strings-of-beads appearance of mt-nucleoids in wild-type cells. In addition, DAPI-fluorescence intensity of the mt-nucleoids transmitted to the bud was significantly lower in Δabf2 cells than in wild-type cells at log phase. However, the lack of Abf2p did not affect the morphology or segregation of mitochondria. The protein composition of the mt-nucleoids isolated from Δabf2 cells grown to stationary phase in YPG medium was very similar to that of the mt-nucleoids isolated from wild-type cells cultured under the same conditions, except for the lack of Abf2p. These results together suggested that in log-phase cells, the lack of Abf2p influences not only the morphology of mt-nucleoids but also their transmission into the bud. On the other hand, our result suggested that in stationary-phase cells, the lack of Abf2p does not significantly alter the protein composition of the mt-nucleoids.

A fluorescence endoscopic system, PDS-2000, enabled observation of color auto-fluorescence from the human body. We performed a clinical study to determine whether color auto-fluorescence bronchoscopy using PDS-2000 improved the accuracy of central type lung cancer diagnosis, as compared to white light bronchoscopy. White light bronchoscopy followed by auto-fluorescence bronchoscopy was performed in 71 subjects with either bronchogenic cancer, previous lung cancer, bloody sputum or who were at a high risk of developing lung cancer. Findings of white light bronchoscopy and auto-fluorescence bronchoscopy were classified into three categories. Two hundred eighty-eight biopsy specimens were taken from all sites which were considered to be abnormal by white light bronchoscopy as well as by auto-fluorescence bronchoscopy. The pathological findings were classified into nine categories. The sensitivity of only white light bronchoscopy (WLB) regarding the detection of severe dysplasia and cancer was compared with that of only auto-fluorescence bronchoscopy (AFB) and that of WLB+AFB. We quantified color endoscopic fluorescence images and compared the red/green signal intensity ratio (R/G ratio) according to the pathological diagnosis. The pathological diagnosis was normal in 123, inflammation, hyperplasia or metaplasia in 120, mild or moderate dysplasia in 8, severe dysplasia in 14 and cancer in 23. The sensitivity of WLB, AFB and WLB+AFB regarding the detection of severe dysplasia or cancer was 54.1%, 81.1% and 89.2%, respectively. The R/G ratio was significantly increased in the areas with severe dysplasia and cancer.

Objective: The aim of this study was to evaluate volume histogram analysis between usual interstitial pneumonia (UIP) and nonspecific interstitial pneumonia (NSIP). Methods: Sixty cases (UIP, n = 22; NSIP, n = 38) were evaluated retrospectively. Three parameters (contrast, variance, and entropy) were calculated in 3 types of regions of interest (ROIs): (a) whole lung, (b) right lower lobe, and (c) cubic ROIs. To evaluate the influence of extent of abnormal findings, the numbers of voxels with low or high density in whole lung were compared with the 3 parameters. Result: No significant differences were observed between the ROIs of whole lung and the right lower lobe. In all cubic ROIs, entropy in UIP was larger than that in NSIP (P < 0.001). The numbers of voxels with low-density areas significantly correlated with the values of contrast and entropy, whereas those with high-density areas significantly correlated with all 3 parameters. Conclusion: Volume histogram analysis for cubic ROIs may be feasible for differentiating between UIP and NSIP.

Several American and Japanese guidelines recommend surgery for patients with c-stage I small-cell lung cancer (SCLC), whereas the European Society of Medical Oncology (ESMO) guidelines recommend surgery for patients with not only c-stage I but also c-stage II (T2N1) SCLC. In addition, previous studies identified various factors other than clinical stage that are related to survival in these patients. Thus, further validation and examination of the association of clinical stage and other clinical variables with survival are required for establishing practical management of early-stage SCLC.We reviewed the clinical courses of 156 SCLC patients who had undergone surgery at 17 institutions between January 2003 and January 2013.Clinical stages (tumor-node-metastasis [TNM] version 7) of the 156 patients were 98 cases in IA, 14 in IB, 16 in IIA, 7 in IIB, 18 in IIIA, and 3 in IIIB. Median overall survival (OS) was 33.3 months (95% confidence interval: 20.9-45.8). Multivariate analysis revealed that OS was longer in patients either at c-stage II and under, with a maximum tumor diameter of20mm, with preoperative diagnosis, without a history or presence of other types of cancer, or who underwent prophylactic cranial irradiation (PCI).These results indicate that a history or presence of other types of cancer might be a major decisive factor for surgery. Patients with c-stages I and II (c-T2N1) can be considered for surgery, and PCI may be useful in patients undergoing surgery in a practical setting, partly supporting the ESMO guidelines.(1).

Introduction Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) treatment is the standard therapy for non-small cell lung cancer (NSCLC) harbouring EGFR-activating mutations. The NEJ002 phase 3 clinical trial demonstrated the efficacy of EGFR-TKI; gefitinib was significantly superior in both progression-free survival (PFS) and objective response rate (ORR) than carboplatin plus paclitaxel. However, several cases showed no response. In this study, we performed further analysis of the characteristics of these non-responders. Methods Available data from NEJ002 on maximum changes in tumour size were obtained from 103 cases (90.4%) and 110 cases (96.5%) in the carboplatin–paclitaxel and gefitinib groups, respectively. Waterfall plots of maximum tumour size changes were created for non-responders. Results Five (4.9%) and 9 (8.2%) cases in the carboplatin–paclitaxel and gefitinib groups were non-responders, respectively. The mean pack years of the non-responders in the carboplatin–paclitaxel and gefitinib groups were 0.33 and 31.7, respectively. The ORR of total smokers (61.5%) and heavy smokers (over 40 pack years, 52.6%) in the gefitinib group were significantly lower compared to people who have never smoked (80.0%) ( P =0.044 and P =0.020, respectively). Smoker cases also showed a tendency towards lower PFS and overall survival (OS). In addition, the EGFR common mutation types did not affect PFS and OS in gefitinib-treated cases in NEJ002. However, in this study, the ORR and waterfall plots showed that gefitinib-treated non-responders who had a deletion in exon 19 in the EGFR gene exhibited a tendency towards a higher response compared to those with a L858R mutation. Conclusions NSCLC patients with a smoking history or the EGFR L858R mutation may demonstrate a poorer response to gefitinib treatment.

To identify the disease-susceptibility genes of type 2 diabetes, we performed quantitative trait loci (QTL) analysis in F 2 populations generated from a BKS.Cg- m +/+ Lepr db and C3H/HeJ intercross, taking advantage of genetically determined obesity and diabetes traits associated with the db gene. A genome-wide scan in the F 2 populations divided by sex and db genotypes identified 14 QTLs in total and 3 major QTLs on chromosome (Chr) 3 (LOD 5.78) for fat pad weight, Chr 15 (LOD 6.64) for body weight, and Chr 16 (LOD 8.15) for blood glucose concentrations. A linear-model-based genome scan using interactive covariates allowed us to consider sex- or sex-by db -specific effects of each locus. For the most significant QTL on Chr 16, the high-resolution haplotype comparison between BKS and C3H strains reduced the critical QTL interval from 20 to 4.6 Mb by excluding shared haplotype regions and identified 11 nonsynonymous single-nucleotide polymorphisms in six candidate genes.

OBJECTIVES : The aim of this study was to achieve the quantitative analysis of the characteristic computed tomography (CT) findings and course of interstitial pneumonia using the volume histogram method. METHODS : Contrast (CNT), variance (VAR), and entropy (EPY) values from whole-lung volume data were compared between normal lungs and 5 diseases that have characteristic CT findings. Thirteen cases with nonspecific interstitial pneumonia (NSIP) were evaluated before and after treatment. RESULTS : In cases with thickening of the bronchovascular bundles and interlobular thickening, ground-glass attenuation, airspace consolidation, and honeycombing, the values of VAR and EPY were greater than those in the normal cases (P < 0.05). In the cases with NSIP, the CNT value after treatment was significantly greater and the values of VAR and EPY after treatment were significantly lower than those before treatment (P < 0.05). CONCLUSIONS : Volume histogram analysis is a promising method for the evaluation of diffuse lung diseases and the effectiveness of treatment.

Acute eosinophilic pneumonia (AEP) is associated with the presence of diffuse pulmonary infiltrates on the chest radiograph and an increased number of eosinophils and an elevation of interleukin (IL)-5 levels in bronchoalveolar lavage (BAL) fluid. Vascular endothelial growth factor (VEGF) is a constitutively expressed protein encoded by messenger ribonucleic acid in human eosinophils and is released following stimulation with IL-5. However, the roles of IL-5 and VEGF in the pathogenesis or activity of this disease have not been clarified. The authors investigated the cells and the levels of these two factors in BAL fluid in five AEP patients and five normal controls before and after corticosteroid treatment. The absolute number of eosinophils-mL(-1), IL-5 and VEGF levels in patients before treatment were higher than in controls (53.8 versus 0.3 x 10(4) x mL(-1), 490.1 versus 5.2 pg x mL(-1) and 643.0 versus 133.9 pg x mL(-1), respectively). IL-5 and VEGF rapidly decreased to the control level in parallel with clinical improvement. The relationship between eosinophilia and IL-5 and VEGF levels was strongly significant. Elevated interleukin-5 in the lung may initiate the recruitment of eosinophils and enhance the release of mediators, such as vascular endothelial growth factor from eosinophils, which, in turn, increases the permeability of blood vessels.

Background: The radiographic changes of Mycobacterium avium complex (MAC) pulmonary disease during therapy have not been studied well. Objective: To assess the efficacy of antituberculous drug therapy against MAC pulmonary disease using computed tomography (CT). Method: We analyzed chest CT scans before and after antituberculous therapy in 30 patients (21 women, 9 men) with MAC pulmonary disease. To evaluate radiographic changes during therapy, we defined a ‘degree of improvement’ (DI) that is calculated according to the CT appearance. Results: DI was better (1.35 ± 0.21) in patients who had converted sputum culture than in those who had not (0.44 ± 0.25) (p < 0.05). In patients who were diagnosed by bronchial washing, DI was better (1.60 ± 0.22) than in patients who were diagnosed by sputum (0.67 ± 0.20) (p < 0.01). We categorized the CT appearance into 6 types: small nodules, cavities, bronchial wall thickening, infiltration, pleural thickening and atelectasis. Patients who showed pleural thickening had a significantly worse DI (0.12 ± 0.40) than those who did not (1.23 ± 0.18) (p < 0.01). Most of the lesions that disappeared after therapy were small nodules. Conclusion: These results indicate that chest CT might be a useful tool for the prediction or assessment of drug therapy for MAC pulmonary disease.

The abundance and viability of microorganisms in groundwater were studied using a scientific borehole in the Tono uranium deposit area, central Japan. Groundwater samples were collected from scientific borehole TH-6 at four depths; 104, 132 and 153 m in sedimentary rocks and 177 m in granite rock using autoclaved geochemical water samplers. The total cell count using epifluorescence microscopy was of the order of 105 to 106 cells ml-1, showing non-systematic change in microbial parameters with depth. Viability estimated from cell membrane integrity ranged from 22.3% to almost 100%, and showed a tendency to increase with depth. In contrast, viability determined using both activities of the electron transport system (ETS) and esterase showed inconsistent depth-profiles. The ETS-active cell count corresponded to 0.57-24.7% of the total count; the minimum ETS-count was found at 153 m, just above the sediment-granite unconformity where the minimum redox potential was estimated. The esterase-active cell count corresponded to 0.4-10.3% of the total, with a maximum at 132 m, the lignite-derived organic-rich layer, and a minimum was found at 153 m, as seen for the ETS-active counts. These inconsistent profiles suggest a difference in microbial viability and activity between each depth. In addition, depth-specific microflorae may develop in response to the availability of various electron acceptors and donors in the subsurface.

Background: Notch signaling plays an important role in tumorigenesis. Numb represses intracellular Notch signaling. Previous studies have demonstrated that Notch signaling suppresses the proliferation of small cell lung cancer (SCLC) cell lines. However, in SCLC, the association between Notch1 and Numb expression and clinicopathological factors or prognosis has remained unclear. In this study, we evaluated the expression of Notch1 and Numb in SCLC. Methods: We immunohistochemically assessed 125 SCLCs that were surgically resected at 16 institutions participating in either the Hokkaido Lung Cancer Clinical Study Group Trial (HOT) or the Fukushima Investigative Group for Healing Thoracic Malignancy (FIGHT) between 2003 and 2013. Correlations between Notch1 or Numb expression and various clinicopathological features were evaluated. Results: Notch1 expression was associated with ECOG performance status. Numb expression was associated with age, sex, and pathological histology (SCLC or Combined SCLC). Analysis of cellular biological expression did not demonstrate a significant correlation between the expression of Notch1 and of Numb. Multivariate Cox regression analysis showed that high Notch1 expression was an independent favorable prognostic factor for SCLC (hazard ratio = 0.503, P = 0.023). Conclusions: We demonstrate that Notch1 expression, but not Numb, is associated with prognosis in SCLC and may provide a novel prognostic marker of SCLC. Citation Format: Hajime Kikuchi, Jun Sakakibara-Konishi, Megumi Furuta, Hiroshi Yokouchi, Hiroshi Nishihara, Shigeo Yamazaki, Uramoto Hidetaka, Fumihiro Tanala, Masao Harada, Kenji Akie, Fumiko Sugaya, Yuka Fujita, Kei Takamura, Tetsuya Kojima, Toshiyuki Harada, Mitsunori Higuchi, Osamu Honjo, Yoshinori Minami, Naomi Watanabe, Satoshi Oizumi, Hiroyuki Suzuki, Takashi Ishida, Hiotoshi Dosaka-Akita, Hiroshi Isobe, Mitsuru Munakata, Masaharu Nishimura. Expression of Notch1 and Numb in small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4735. doi:10.1158/1538-7445.AM2017-4735

8532 Background: In the phase III JCOG0301 trial, concurrent chemoradiotherapy (CRT) was compared with radiotherapy (RT), demonstrating clinically significant survival benefits in elderly patients with locally advanced NSCLC after a median follow-up of 19.4 months. However, the long-term patterns and cumulative incidences of toxicity associated with CRT and RT are poorly understood for elderly patients. We report long-term survival data and late toxicities after a minimum follow-up of 6.4 years. Methods: Eligible patients were older than 70 years and had unresectable stage III NSCLC. They were randomly assigned to RT alone (RT arm: irradiation with 60 Gy in 30 fractions) or CRT (CRT arm: the same RT with additional concurrent use of carboplatin 30 mg/m2 per fraction up to the first 20 fractions). The primary endpoint was overall survival (OS). Prognosis and adverse events data were collected beyond those in the initial report of this trial. Kaplan-Meier survival curves and 3- and 5-year survival proportions were calculated. Late toxicities were defined as occurring later than 90 days after RT initiation. Results: From September 2003 to May 2010, 200 patients (RT arm, n = 100; CRT arm, n = 100) were enrolled. Consistent with the initial report, the CRT arm had better OS than the RT arm (HR = 0.743, 95% CI = 0.552 – 0.998, one-sided p = 0.0239 by stratified log-rank test). In the RT and CRT arms, median OS was 16.5 and 21.7 months, 3-year survival was 16.3% and 34.3%, and 5-year survival was 9.2% and 15.2%, respectively. %Grade 3/4 late toxicities were 7.4% (heart 2.1%, lung 5.3%) in the RT arm (n = 94) and 7.5% (esophagus 1.1%, lung 6.5%) in the CRT arm (n = 93). No additional cases of late toxicity (Grade 3/4) were seen since the initial report. There were 7 treatment-related deaths, all of which were recorded in the initial report: 4 (4.0%) in the RT arm and 3 (3.0%) in the CRT arm. Conclusions: Long-term follow-up confirms the survival benefits of CRT for elderly patients with locally advanced NSCLC. There was no observed increase in late toxicity with CRT, as compared with RT alone. Clinical trial information: 00132665.

Lessons Learned Weekly nanoparticle albumin-bound-paclitaxel (75 mg/m2) in combination with carboplatin (area under the curve 6 mg/mL/min) in elderly patients with previously untreated, advanced non-small cell lung cancer showed favorable efficacy, was well tolerated, and showed less neuropathic toxicity. This modified regimen offers potential for the treatment of elderly patients. Background The CA031 trial suggested weekly nanoparticle albumin-bound-paclitaxel (nab-PTX) was superior in efficacy to paclitaxel (PTX) once every 3 weeks when combined with carboplatin (CBDCA) for advanced non-small cell lung cancer (NSCLC) patients; a subgroup analysis of elderly patients looked promising. In a multicenter phase II trial, we prospectively evaluated the efficacy and tolerability of modified CBDCA plus weekly nab-PTX for elderly patients with untreated advanced NSCLC. Methods Eligible patients received CBDCA (area under the curve [AUC] 6 mg/mL/min) on day 1 and nab-PTX (75 mg/m2) on days 1, 8, and 15 every 4 weeks. The primary endpoint was an overall response rate (ORR), and secondary endpoints were progression-free survival (PFS), overall survival (OS), and toxicity. Results Of 32 patients (median age of 78 years), 84% were male, 56% had stage IV NSCLC, and 56% had squamous cell carcinoma. ORR and disease control rates were 50% (95% confidence interval (CI): 33–67) and 94% (95% CI: 85–100), respectively. Median PFS and OS were 6.4 months (95% CI: 4.8–8.0) and 17.5 months (95% CI: 11.9–23.1), respectively. Grade ≥3 toxicities were neutropenia (47%), leukopenia (38%), anemia (34%), thrombocytopenia (25%), and anorexia (9%). Febrile neutropenia and treatment-related deaths were not observed. Conclusion Modified CBDCA plus weekly nab-PTX demonstrated significant efficacy and acceptable toxicities in elderly patients with advanced NSCLC.

The reaction proceeds with trans- or cis-selectivity in the presence or absence of Bu4NF, respectively.

Objectives Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors are particularly effective in non-small cell lung cancer (NSCLC) patients harboring active EGFR mutations. However, some studies have reported survival benefits in NSCLC patients with wild-type EGFR upon erlotinib treatment. This trial was conducted to evaluate the efficacy of erlotinib monotherapy and investigate the predictive values of several biomarkers. Patients and methods Patients with previously treated NSCLC but without EGFR gene mutations that had never or light smoked were eligible for this study. Gene status screening was performed using the PNA-LNA PCR clamp method. Erlotinib was administered until disease progression or unacceptable toxicities occurred. EGFR gene status was re-evaluated using the fragment method to detect exon 19 deletions and the Cycleave-PCR method to detect point mutations. Expression of hepatocyte growth factor (HGF), Met, and thymidylate synthase (TS) were evaluated using immunohistochemistry. Results Forty-seven patients were enrolled in the study between March 2010 and November 2011. Objective response rate (ORR) and disease control rate (DCR) were 15.2% and 41.3%. Re-evaluations for EGFR gene were performed in 32 tumor samples. EGFR gene mutations were found in eight samples (5:exon 19 deletion, 2:G719X, 1:L858R). Six patients had PR and two had SD among these eight patients. A total of 24 patients were confirmed as wild-type EGFR using different methods. ORR and DCR were 4.2% and 41.7%. The median progression free survival (PFS) and median survival times were 2.0 and 6.0 months, respectively. Patients with tumors expressing HGF showed shorter PFS but not MET or TS. Conclusions Re-examination of EGFR gene status using different detecting method or different sample should be considered to grasp a chance of erlotinib treatment after first line treatment. In confirmed EGFR wild NSCLC, negative HGF staining could be a biomarker for longer PFS by erlotonib treatment.

BACKGROUND: Malignant fibrous histiocytoma (MFH) of the lung is rare. Early diagnosis is very important because of its poor prognosis. Long-term survivors of pulmonary MFH are patients who had surgical resection. When the patient can undergo surgery after a prompt diagnosis, the prognosis improves more than with other therapy. However, it is not easy to establish the diagnosis of thoracic MFH. In general, the small fragments from bronchial or percutaneous transthoracic fine needle aspiration (FNA) biopsies are inadequate for cytologic or pathologic analysis. Bronchial brushing cytology is greatly superior to FNA cytology because one can obtain a large amount of cells. Therefore, bronchial brushing cytology may play a useful role in diagnosis when endobronchial involvement is found. CASE: A 65-year-old female was admitted with a cough, yellow sputum and exertional dyspnea. A chest roentgenogram showed a 12 ×12-cm mass in the left lung field. Bronchial brushing cytology revealed many fibroblastlike, histiocytelike, bizarre and multinucleated giant cells in a background of necrosis. Atypical mitotic figures were also found. The cytologic findings strongly suggested MFH. Although the pathologic findings from FNA biopsy showed storiform clusters structured by pleomorphic, fibroblastlike cells with bizarre nuclei and mitotic figures, the material was too small to diagnose it definitively. Six months later the patient died. An autopsy confirmed the diagnosis of MFH: the typical storiform clusters were composed of many fibroblastlike and histiocytelike cells that were positive for CD68 (PGM1) antibody. CONCLUSION: Bronchial brushing cytology may be a useful method for early, definitive diagnosis of MFH. The presence of pleomorphic, spindle-shaped fibroblastlike and histiocytelike cells with the clusters showing a storiform pattern may permit the diagnosis of MFH.

原発性非小細胞肺癌手術例299例を対象としてbcl-2蛋白およびp53蛋白の発現と予後との関連を免疫組織化学的に検討した. 299例中, 64例 (21.4%) がbcl-2蛋白, 149例 (49.8%) がp53蛋白陽性であった. bcl-2蛋白およびp53蛋白の陽性率はいずれも腺癌に比し扁平上皮癌で高かった. 病理病期ではbcl-2蛋白の陽性率はIII, IV期に比べI, II期で高かった (p=0.032). 生存率はbcl-2蛋白陽性例は陰性例に比べ高く (p=0.012), p53蛋白陽性例が陰性例に比べ低かった (p=0.021). 病期別の検討ではI, II期ではbcl-2蛋白陽性例で有意に生存率が高かった (p=0.033). 組織型と生存率との関連では, 腺癌ではp53蛋白陰性例が, 扁平上皮癌ではbcl-2蛋白陽性例がいずれも有意 (それぞれp=0.012, p=0.012) に生存率が高かった. 腺癌におけるp53蛋白の発現, 扁平上皮癌におけるbcl-2蛋白の発現が予後因子として有用と考えられた.

Cisplatinを含む併用化学療法を行った105名の非小細胞肺癌患者 (臨床病期: III, IV期, PS: 0-3, 75歳以下) の臨床的予後因子を検討した.単因子解析では, PS: 0-1, 予後栄養因子 (PNI)*: 45

Tetrabutylammonium salts serve as templates for the Norrish-Yang cyclization of 2-benzyloxy-acylbenzenes to give trans-dihydrobenzofuranols in high stereoselectivities. The dual cation-π interactions between an ammonium with a benzene ring and a carbonyl group play a key role in changing the conformation of the substrate, which was supported by ab initio calculations.

Assessment of the efficacy of docetaxel plus carboplatin vs. paclitaxel plus carboplatin in Japanese patients with advanced non-small cell lung cancer (NSCLC).Chemotherapy-naïve patients were randomly assigned at a ratio of 2 to 1 to receive six cycles of either docetaxel (60 mg/m(2)) plus carboplatin [area under the curve (AUC)=6 mg/ml min] or paclitaxel (200 mg/m(2)) plus carboplatin (same dose), on day 1 every 21 days. The primary end-point was progression-free survival (PFS).A total of 90 patients were enrolled. Overall response rate, median PFS and median survival time in the docetaxel-plus-carboplatin group and the paclitaxel-plus-carboplatin group were 23% vs. 33%, 4.8 months vs. 5.1 months, and 17.6 months vs. 15.6 months, respectively. The docetaxel-plus-carboplatin group had a higher incidence of grade 3 or 4 neutropenia (88% vs. 60%).Both regimens were similarly effective in Japanese patients with advanced NSCLC.

To evaluate the efficacy and toxicity of triplet chemotherapy using tegafur-uracil (UFT), vinorelbine, and gemcitabine for patients with stage IIIB or IV non-small cell lung cancer.A total of 32 patients were enrolled in this study. The patients were subjected to a treatment regimen consisting of intravenous vinorelbine and gemcitabine on days 6 and 13, and oral UFT on days 1-5 and 8-12. This treatment was repeated every three weeks.All patients had an initial performance status of 0 to 1. The objective response rate was 21.9%, median survival time was 13.9 months, and the one-year survival rate was 56.7%. Grade 3/4 toxicities (% of patients) consisted of leukocytopenia (40.6%), neutropenia (56.3%), thrombocytopenia (3.1%), infection (9.4%), hypoxia (6.3%) and dyspnea (3.1%).Triplet chemotherapy using UFT, vinorelbine, and gemcitabine was well-tolerated, with an acceptable toxicity profile. However, the response rate and median survival did not encourage for additional investigation.

女性肺癌の臨床像について, とくに喫煙歴に注目して男性と比較検討した. 女性の喫煙率は男性の1/3以下, 平均喫煙指数も1/2以下であった. 女性では男性と比較して腺癌, 無自覚症状者, 臨床病期1期, IV期, PS0, 4が有意に多く, 検診発見者が多い傾向にあった. しかし, 喫煙歴別では, 非喫煙女性で非喫煙男性に比較してPS0が有意に多かったほかに男女間に有意差はなかった. また, 喫煙女性は非喫煙女性と比較し自覚症状発見者, 有自覚症状者が有意に多く, IV期, PS4が多い傾向にあった. 予後は, 全症例およびおもな予後因子で層別しても男女間に有意差はなかったが, 腺癌のIV期では女性の予後が有意に良好であった. 女性肺癌の臨床像の特徴は男性と比較して喫煙歴が少ないことによる影響が大きいと考えられた. また, 喫煙歴の有無は男性と比較して女性でより大きく臨床像に影響を与えていた.

Purpose: EML4-ALK is a lung cancer oncogene, and ALK inhibitors show marked therapeutic efficacy for tumors harboring this fusion gene. It remains unsettled, however, how the fusion gene should be detected in specimens other than formalin-fixed, paraffin-embedded tissue. We here tested whether reverse transcription PCR (RT-PCR)-based detection of EML4-ALK is a sensitive and reliable approach. Experimental Design: We developed a multiplex RT-PCR system to capture ALK fusion transcripts and applied this technique to our prospective, nationwide cohort of non–small cell lung cancer (NSCLC) in Japan. Results: During February to December 2009, we collected 916 specimens from 853 patients, quality filtering of which yielded 808 specimens of primary NSCLC from 754 individuals. Screening for EML4-ALK and KIF5B-ALK with our RT-PCR system identified EML4-ALK transcripts in 36 samples (4.46%) from 32 individuals (4.24%). The RT-PCR products were detected in specimens including bronchial washing fluid (n = 11), tumor biopsy (n = 8), resected tumor (n = 7), pleural effusion (n = 5), sputum (n = 4), and metastatic lymph node (n = 1). The results of RT-PCR were concordant with those of sensitive immunohistochemistry with ALK antibodies. Conclusions: Multiplex RT-PCR was confirmed to be a reliable technique for detection of ALK fusion transcripts. We propose that diagnostic tools for EML4-ALK should be selected in a manner dependent on the available specimen types. FISH and sensitive immunohistochemistry should be applied to formalin-fixed, paraffin-embedded tissue, but multiplex RT-PCR is appropriate for other specimen types. Clin Cancer Res; 18(20); 5682–9. ©2012 AACR.

Purpose: To determine the maximum tolerated dose of amrubicin (AMR) with a fixed dose of irinotecan (CPT-11). Methods: Patients having pathologically proven small cell lung cancer (SCLC) relapsed after one or two chemotherapies, and Eastern Cooperative Oncology Group performance status of 0 to 2 were eligible for the study. CPT-11 was delivered as 50 mg/m 2 on days 1 and 8, every 21 days. AMR was delivered on day 1. Doses of AMR were level 1: 80 mg/m 2 , level 2: 90 mg/m 2 , and level 3: 100 mg/m 2 . Dose elevation was determined using the modified continuous reassessment method. Tolerability was assessed after the first cycle. Another two cycles were conducted when disease progression or unacceptable toxicities were not observed. Results: Eighteen patients (mean age: 66.3 years) were enrolled. A total of 40 courses were conducted. Grade 3/4 toxicities of the first cycle were leukocytopenia: 11 (61%, grade 3/4: 8/3); neutropenia: 15 (83%, grade 3/4: 6/9); and thrombocytopenia: three (17%, grade 3/4: 2/1). Other grade 3 toxicities observed were febrile neutropenia, one; infection, three; diarrhea, one; and dyspnea, one. Dose-limiting toxicity was observed in two of six patients at level 2 (neutropenia and febrile neutropenia) and in one of six at level 3 (thrombocytopenia and infection). The maximum tolerated dose was level 3, and so, the recommended dose for phase II trials was judged to be 90 mg/m 2 . Objective response was obtained in four of eight patients who were able to evaluate responses. Median survival time was 13 months, with 68% at 1-year survival rate. Conclusions: This combination was well tolerated and showed encouraging activities in SCLC. Randomized phase II trials are being planned in chemonaive SCLC.

Aim To evaluate the efficacy and feasibility of the consolidation therapy of the oral fluoropyrimidine agent S-1 after concurrent chemoradiotherapy for unresectable stage III non-small cell lung cancer (NSCLC). Methods Eligible patients had unresectable stage III NSCLC with performance status of 0 or 1. Chemoradiotherapy at a total dose of 60 Gy consisted of cisplatin (80 mg/m 2 ) on days 1 and 29, vinorelbine (20 mg/m 2 ) on days 1, 8, 29 and 36. Sequential consolidation S-1 therapy was commenced at a dose of 80–120 mg twice daily on day 57 with two cycles of 4 weeks administration and 2 weeks withdrawal. Results Of the 66 patients, 65 were evaluated. Chemoradiotherapy was completed in 57 (87.7%) patients, and S-1 consolidation therapy was administered in 45 (69.2%) and completed in 31 (47.6%). Grade 3 pneumonitis developed in three patients with one dying of it. The response rate was 61.5% (95% confidence interval [CI], 48.6–73.3%). The median progression-free survival was 10.2 (95% CI, 8.6–13.7) months and median survival time 21.8 (95% CI, 15.6–27.6) months. The 1- and 3-year survival rates were 73.9% and 34.0%, respectively. Conclusions Chemoradiotherapy with cisplatin and vinorelbine followed by S-1 consolidation demonstrated a reasonable overall survival in patients with stage III NSCLC. However, less than half of the patients completed this regimen, and the additional effect of S-1 was marginal compared with historical control. We concluded that chemoradiotherapy alone is still the recommended standard treatment for patients.

Non-small-cell lung cancer with sensitive mutations of the epidermal growth factor receptor (EGFR) is highly responsive to EGFR tyrosine kinase inhibitors such as gefitinib, but little is known about how its efficacy and safety profile compares with that of standard chemotherapy.We randomly assigned 230 patients with metastatic, non-small-cell lung cancer and EGFR mutations who had not previously received chemotherapy to receive gefitinib or carboplatin-paclitaxel. The primary end point was progression-free survival; secondary end points included overall survival, response rate, and toxic effects.In the planned interim analysis of data for the first 200 patients, progression-free survival was significantly longer in the gefitinib group than in the standard-chemotherapy group (hazard ratio for death or disease progression with gefitinib, 0.36; P0.001), resulting in early termination of the study. The gefitinib group had a significantly longer median progression-free survival (10.8 months, vs. 5.4 months in the chemotherapy group; hazard ratio, 0.30; 95% confidence interval, 0.22 to 0.41; P0.001), as well as a higher response rate (73.7% vs. 30.7%, P0.001). The median overall survival was 30.5 months in the gefitinib group and 23.6 months in the chemotherapy group (P=0.31). The most common adverse events in the gefitinib group were rash (71.1%) and elevated aminotransferase levels (55.3%), and in the chemotherapy group, neutropenia (77.0%), anemia (64.6%), appetite loss (56.6%), and sensory neuropathy (54.9%). One patient receiving gefitinib died from interstitial lung disease.First-line gefitinib for patients with advanced non-small-cell lung cancer who were selected on the basis of EGFR mutations improved progression-free survival, with acceptable toxicity, as compared with standard chemotherapy. (UMIN-CTR number, C000000376.)

To evaluate radiation dermatitis objectively in patients with breast cancer who had undergone post-operative radiotherapy after breast-conserving surgery. Skin color (L*, a*, and b* values) and moisture analyses were performed for both breasts (before, after, 1 month, 6 months, and 1 year after radiotherapy) to examine irradiated and non-irradiated skin divided into four quadrants in 118 patients. These patients underwent breast conservative surgery followed by 50 Gy/25 fractions (median) of radiotherapy with or without boost irradiation (10 Gy/5 fractions). L*, a*, and moisture values were changed by irradiation and maximized at completion or 1 month after radiotherapy. One year after radiotherapy, the skin color had returned to the range observed prior to radiotherapy. However, moisture did not return to previous values even 1 year after treatment. The lateral upper side (quadrant C) showed greater changes than other quadrants in the L* value (darker) at the end of radiotherapy. The Common Toxicity Criteria version 3 scores were found to correlate well with a* and L* values at the completion and 1 month after radiotherapy. Boost radiotherapy intensified reddish and darker color changes at the completion of radiotherapy, while chemotherapy did not intensify the skin reaction caused by radiotherapy. Moisture impairment as a result of irradiation lasts longer than color alterations. Objective assessments are useful for analyzing radiation dermatitis.

According to the TNM classification revised in 1997, stage II non-small-cell lung cancer (NSCLC) has an unfavorable prognosis. The purpose of this study was to analyze the prognostic factors for pathological T1-2N1M0 patients with NSCLC and elucidate the significance of main bronchial lymph nodes involvement.This retrospective study analyzed patients in a prospective database of cases from an 11-year period (operations from 1992 to 2002, follow-up data until March 2008) obtained from the Japan National Hospital Study Group for Lung Cancer. Among them, a total of 319 patients with pathological T1-2N1M0 disease were identified, and all dissected lymph nodes were classified using the Naruke map.The cumulative overall 5-year survival rate for patients with intralobar or interlobar lymph node involvement (n = 266) was 56.8%, and that for those with main bronchial lymph node involvement (n = 53) was 40.4% (P = 0.002). Among patients with multiple-station N1 nodal involvement including the main bronchial lymph nodes, patients with a lower lobe tumor (n = 12) had a significantly worse prognosis than those with an upper lobe tumor (n = 9) (13.3% vs. 55.6%, P = 0.033). Multivariate analysis demonstrated that age, histology, tumor size, and main bronchial lymph node involvement were independent prognostic factors for patients with pathological T1-2N1M0 disease.Involvement of the main bronchial lymph nodes is a significant factor to predict a worse prognosis in pathological T1-2N1M0 patients with NSCLC.

いわゆる肺硬化性血管腫の切除例2例について, 術前の経皮的肺針生検・吸引スメアの細胞像を検討したところ, 本腫瘍にみられる細胞を次のようにまとめることができた.1) 散在性または乳頭状集塊を形成する類円形細胞.2) 類円形細胞よりも小型の核と明るい細胞質を有し, 軽度の重積性をもって配列する細胞.3) 細胞質が広く, 核も大きく核小体のめだつ大型多辺形細胞.4) 小型類円形細胞の乳頭状集塊の芯にみられる紡錘形核の細胞.5) 多数のヘモジデリンを貧食している組織球.6) 炎症性細胞.このなか, 腺癌一特に末梢型一と鑑別を要する細胞は小型類円形細胞と大型多辺形細胞であり, 前者は腺癌に比べると核異型や細胞異型が一般に軽度であり, かつ, 乳頭状集塊の芯に紡錘形核のみられることが鑑別に役立つ所見であった.後者は個々の細胞所見のみでは腺癌細胞との鑑別はきわめて難しく, 上述のように多種類の細胞の出現することや, 特に多量のヘモジデリンおよびこれを貪食した組織球の多い血性背景が本腫瘍を示唆し, 腺癌細胞との鑑別に有用な所見であった.なお, 大型多辺形細胞は間葉系由来ともいわれているが, 免疫染色法により小型類円形細胞とともに肺胞上皮起源を強く示唆する所見を得た.

Background Pleomorphic carcinoma of the lung is a malignant epithelial tumor that contains carcinomatous and sarcomatoid components. Due to its rarity, few studies have been reported, and its clinical and pathological characteristics remain unclear. Method We retrospectively investigated 22 cases of pleomorphic carcinoma of the lung. Results Fifteen cases were diagnosed by surgical resection, 4 by autopsy, and 3 by transbronchial biopsy. Nineteen patients were male and 3 were female, and their mean age at diagnosis was 68.3 years (±10.1). Eighteen were current- or ex-smokers with substantial smoking histories (mean 46.4 pack-years). Sixteen patients had symptoms: hemoptysis and cough were commonly seen. Chest computed tomography (CT) findings revealed that the tumors were quite large (mean diameter 45.3 ± 21.9 mm; range 14–110 mm), and 21 tumors were peripherally located. Positron emission tomography with 18-fluorodeoxy-glucose (FDG-PET) was performed in 12 patients, and the Standardized Uptake Value (SUV) tended to be high (9.44 ± 4.98). In the 15 patients who underwent surgical resection, recurrence was common; systemic metastases were also frequently found. Patients who had received surgical treatment with proper follow-up care survived longer than those who did not undergo surgery. Responses to chemotherapy were generally poor, although 1 patient exhibited partial response to gefitinib. Conclusions Pulmonary pleomorphic carcinoma has strong malignant potential with frequent distant metastases, as has already been reported. However, this study demonstrated that surgical treatment and appropriate follow-up therapy might result in better prognoses.

We examined the impact of pretreatment neutrophil count on survival in patients with advanced non-small-cell lung cancer (NSCLC). A total of 388 chemo-naive patients with stage IIIB or IV NSCLC from a randomised controlled trial were evaluated. The effects of pretreatment peripheral blood neutrophil, lymphocyte and monocyte counts and neutrophil-lymphocyte ratio on survival were examined using the proportional hazards regression model to estimate hazard ratios after adjustment for covariates. The optimal cut-off value was determined by proportional hazards regression analysis with the minimum P-value approach and shrinkage procedure. After adjustment for prognostic factors, the pretreatment elevated neutrophil count was statistically significantly associated with short overall (P = 0.0008) and progression-free survival (P = 0.024), whereas no association was found between prognosis and lymphocyte or monocyte count. The cut-off value selected for neutrophil count was 4500 mm-3 (corrected hazard ratio, 1.67; 95% confidence interval (CI), 1.09-2.54). The median survival time was 19.3 months (95%CI, 16.5-21.4) for the low-neutrophil group (≥4500 mm-3, n = 204) and was 10.2 months (95%CI, 8.0-12.3) for the high-neutrophil group (≥4500 mm-3, n = 184). We confirmed that pretreatment elevated neutrophil count is an independent prognostic factor in patients with advanced NSCLC receiving modern chemotherapy. Neutrophil count is easily measured at low cost, and it may be a useful indicator of patient prognosis.

To clarify the clinical feature of chronic necrotizing pulmonary aspergillosis (CNPA) complicated with non-tuberculous mycobacteriosis (NTM).Forty-one CNPA cases underlying NTM were analyzed according to their clinical backgrounds.Concerning the radiological type of prior NTM, CNPA cases were classified into two groups; 1) resembling pulmonary tuberculosis that usually shows cavitary lesion and 2) micronodule and bronchiectasis pattern, and more than half of cases (61.0%) were classified as the latter type. Average duration between prior NTM and CNPA was 1354 days. Isolation of Aspergillus spp. from sputum was 15 out of 41 (36.6%). Positive rates for Aspergillus galactomannan antigen and anti-aspergillus antibody were 58.5%, 46.3% respectively. With regard to subspecies of mycobacteria, M. avium was most frequent (82.9%). Since 6.8% of NTM cases develop CNPA within 10 years, careful observation of CNPA was required for the management of NTM.

きわめてまれな肺原発の良性線維性組織球腫の1例を経験したので報告した.症例は52歳女性で, 健康診断にて胸部X線写真上異常陰影を指摘され入院した. 右下葉に径30mm×25mmのだ円形で辺縁鮮明・均一な濃度を有するcoinlesionを認め, 諸検査の結果, 悪性腫瘍の疑いが否定できなかったので, 腫瘤摘出術を施行した. 腫瘤は表面平滑・弾性硬で, 組織学的にBFHと診断した. 細胞所見は, 核異型に乏しい線維芽細胞様細胞と組織球様細胞が混在して認められ, 細胞集塊はstoriform patternに類似した細胞配列を呈していた.本疾患は, 肺に原発することはきわめてまれで, さらに術前診断は容易ではないと考えられるが, 細胞診にてstoriform patternを呈する線維芽細胞様細胞および組織球様細胞を認めた場合, 本症の可能性を考慮して細胞所見を検討する必要があると考えられた.

Background: Obstructive sleep apnea (OSA) is closely related to systemic inflammation. Resistin is an adipocyte-derived cytokine (adipokine) that may link obesity with inflammation. Objective: We aimed to investigate whether incremental changes in OSA severity, from normal to severe, primarily affect the levels of resistin and other adipokines. Methods: Serum levels of resistin, interleukin-6 (IL-6) and leptin were examined in 31 men with OSA and 10 men without OSA, matched for age, body mass index (BMI) and several metabolic profiles. In 11 of the 31 men with OSA, these mediators were reexamined after 3 months of nasal continuous airway pressure (nCPAP) therapy. Results: Levels of resistin and IL-6 were simultaneously elevated in men with OSA compared with those in men without OSA (p < 0.05), while levels of leptin did not differ. The resistin and IL-6 levels tended to increase with increasing disease severity (p < 0.05), which was based on the apnea-hypopnea index (AHI). The average oxyhemoglobin saturation during sleep (p < 0.01) and IL-6 (p < 0.05) emerged as significant determinants of resistin, even after adjustments for age, BMI, leptin levels and metabolic risk factors. After nCPAP therapy, the elevated levels of resistin and IL-6 decreased, reaching almost baseline levels of controls. Before treatment, AHI correlated positively with the reduction rate in resistin (p < 0.05). Conclusion: In OSA patients, resistin production can be enhanced by hypoxic stress during sleep, possibly mediating systemic inflammatory processes. nCPAP therapy may play a beneficial role in the control of resistin production.

To retrospectively evaluate the effect of contrast medium on the three-dimensional volumetric measurement of pulmonary nodules.The study was approved by the local institutional review committee, with waiver of informed consent. Sixty pulmonary nodules in 60 patients (17 women, 43 men; age range, 29-82 years) were imaged before and after administration of contrast medium with a 64-channel multidetector computed tomographic (CT) scanner; reconstructed images with a section thickness of 0.625 mm were obtained by using a bone algorithm and a standard algorithm. Volumetric measurements of pulmonary nodules were performed by using commercially available software, and the postcontrast volume ratio was calculated by dividing the postcontrast volume by the precontrast volume. Precontrast and postcontrast volumes were then analyzed by using a Wilcoxon signed rank test.The median measured volumes of pulmonary nodules were 817 mm(3) (precontrast imaging, bone algorithm), 887 mm(3) (postcontrast imaging, bone algorithm), 812 mm(3) (precontrast imaging, standard algorithm), and 855 mm(3) (postcontrast imaging, standard algorithm). The measured volumes obtained with the bone algorithm were significantly larger than those obtained with the standard algorithm, both before and after administration of contrast medium (P.01); with both the standard algorithm and the bone algorithm, the measured postcontrast volumes were significantly larger than the precontrast volumes (P.01). The postcontrast volume ratio was more than 1.0 in 45 cases (75%) when the bone algorithm was used and in 53 cases (88%) when the standard algorithm was used. The mean postcontrast volume ratio was 1.054 with the bone algorithm and 1.065 with the standard algorithm.The measured volume of pulmonary nodules obtained by using three-dimensional volumetric software increased after administration of contrast medium. Moreover, the measured volume of pulmonary nodules that was obtained with the bone algorithm was larger than that obtained with the standard algorithm, regardless of whether contrast medium was used.