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ZD1839 (‘Iressa’) is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that inhibits EGFR signaling. Emerging evidence indicates that ZD1839 has clinical potential in lung cancer, but very little is known about the molecular characteristics of lung cancers that may determine sensitivity to ZD1839. We examined a panel of 19 lung cancer cell lines to investigate possible association between ZD1839 sensitivity and histological type, expression level and constitutive phosphorylation of EGFR and K-ras gene status. Our results indicate that neither expression level nor constitutive activation status of EGFR seems to predict sensitivity to ZD1839. In addition, ZD1839 sensitivity was not associated with expression of human epidermal growth factor receptor-2 (HER-2), another member of this tyrosine kinase receptor family nor with co-expression of EGFR and HER-2. Finally, no correlation was found between the presence of activating mutations of the K-ras gene, an important downstream mediator of the EGFR-transduced signals and the relative resistance to ZD1839. These findings warrant future study to clarify how ZD1839 inhibits lung cancer cell growth and to find a useful marker for prediction of sensitivity to this novel and promising agent for the treatment of lung cancers. [Copyright &y& Elsevier]

Background: The optimal regimen for concurrent chemoradiotherapy (CCRT) of locally advanced non-squamous non-small cell lung cancer (NSCLC) was not definitive. We conducted randomized phase II study, NJLCG0601, and chemoradiotherapy with uracil/tegafur (UFT) and cisplatin achieved promising efficacy without severe toxicities. Here, we evaluated between this regimen and pemetrexed plus cisplatin in chemoradiotherapy for stage III non-squamous NSCLC., Methods: Patients with inoperable stage III non-squamous NSCLC were randomly assigned in a 1:1 ratio to UFT 400 mg/m 2 on days 1-14 and 29-42, and cisplatin 80 mg/m 2 on days 8 and 36 (UP), or cisplatin 75 mg/m 2 and pemetrexed 500 mg/m 2 on days 1, 22, and 43 (PP). Involved-field radiotherapy (IFRT) underwent from day 1 to a total dose of 66 Gy in 33 fractions. Consolidation chemotherapy after CCRT was prohibited for this study. The primary endpoint was defined as 2-year overall survival (OS). This trial was registered in the University Hospital Medical Information Network Clinical Trials Registry (UMIN000003948)., Results: From November 2010 to June 2017, 86 patients were entered from 11 institutions. Median follow-up was 54 months. Of the 85 eligible patients, the 2-year OS rate was 78.6% (95% CI, 62.8-88.3%) in UP and 85.5% (95% CI, 70.5-93.2%) in PP. Median PFS and OS was 12.3 and 64.2 months in UP, 26.2 months and not reached in PP, respectively. Grade 3/4 febrile neutropenia was more frequent in the UP group (14.0% vs. 2.0%)., Conclusions: Both UP and PP with IFRT achieved the expected 2-year OS. PP engendered more favorable OS and PFS compared to UP in terms., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tlcr-20-721). YT reports personal fees from AstraZeneca, Bristol-Myers Squibb, MSD, Ono Pharmaceutical, outside the submitted work. Atsushi Nakamura reports personal fees from MSD, AstraZeneca, Boehringer Ingelheim Japan, outside the submitted work. EM reports grants and personal fees from Chugai pharmaceutical co ltd, Ono pharmaceutical co., ltd., Boehringer Ingelheim, Eli Lilly Japan, and personal fees from AstraZeneca, Taiho pharma, Kyowa kirin, Daiichi sankyo, MSD, Bristol-Meyers Squibb, Novartis, Merck Bio, outside the submitted work. HM reports personal fees from Ono Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Eli Lilly Japan, Chugai Pharmaceutical Co., Ltd., outside the submitted work. TF reports grants from Ono Pharmaceutical Co., Bristol Myers Squibb, AstraZeneca, MSD, outside the submitted work. AI reports personal fees from Eli Lilly Japan, outside the submitted work. Shunichi Sugawara reports personal fees from Eli Lilly Japan, Taiho Pharmaceutical, MSD, AstraZeneca, Bristol-Myers Squibb, Ono Pharmaceutical, Chugai Pharma, Nippon Boehringer Ingelheim, Pfizer, Novartis, Kyowa Kirin, Yakult Honsha, outside the submitted work. MM reports personal fees from Eli Lilly Japan, grants from Taiho, outside the submitted work. The other authors have no conflicts of interest to declare., (2021 Translational Lung Cancer Research. All rights reserved.)

Background: Owing to the rarity of this tumor, there is limited information about second-line chemotherapy for patients with previously treated advanced thymic carcinoma., Material and Methods: We performed a multi-institutional, retrospective study named NEJ023 for patients with advanced thymic carcinoma. Patients without indications for curative treatment were treated with chemotherapy from 1995 to 2014 at 40 institutions in the North East Japan Study Group. Demographic and clinicopathologic characteristics, data on treatment methods, and outcomes of second-line chemotherapy were obtained from medical records., Results: In total, 191 patients were enrolled in this study. Second-line chemotherapy included platinum-based doublets in 57.6% of patients, other multidrug chemotherapy (e.g., cisplatin, doxorubicin, vincristine, and cyclophosphamide) in 13.6%, and monotherapy in 28.8%. The median follow-up time was 50.5 months, and the median overall survival (OS) from the start of second-line chemotherapy was 22.4 (95% confidence interval, 17.5-26.7) months. The average response rate (RR) was 20.0% overall; it was 21.6% for patients treated with platinum-based doublet chemotherapy, 13.6% for those treated with other multidrug chemotherapy, and 19.6% for those treated with single agent chemotherapy. There was no significant difference in OS between platinum-based doublet chemotherapy, other multidrug chemotherapy, and monotherapy (the median OS was 22.4, 25.7, and 21.4 months, respectively)., Conclusion: The median OS was 22.4 months in patients with advanced thymic carcinoma treated with second-line chemotherapy. There were no significant differences in RR and OS between monotherapy and multidrug chemotherapy in this study., Implications for Practice: Owing to the rarity of this tumor, there is limited information about second-line chemotherapy for patients with previously treated advanced thymic carcinoma. This is the largest data for those patients treated with second-line chemotherapy. This study suggests there is no significant difference in efficacy between monotherapy and multidrug chemotherapy for previously treated advanced thymic carcinoma. This result can support the adequacy to select monotherapy as treatment of those patients., (© AlphaMed Press 2019.)

Beta-propeller protein-associated neurodegeneration (BPAN) is one of the neurodegenerative disorders characterized by iron deposition in the brain and is the only known disease in humans to be caused by an aberration in autophagocytosis. Here, we present the case of a 42-year-old woman with BPAN identified by the WDR45 mutation. From early childhood, she was recognized as having global developmental delay, and she frequently sucked her hand, which was considered to be a stereotypical movement. She had a febrile convulsion at 6 months of age but there was no history of epilepsy. The delay in language development was more severe than the delay in motor development; she was able to dress herself, walk unaided, and follow simple instructions until adolescence. After the age of 20, her movement ability rapidly declined. By the time she was 42 years old, she was bedridden and unable to communicate. Brain magnetic resonance imaging (MRI) at 21 years revealed no abnormality except non-specific cerebral atrophy. However, MRI at 39 years revealed abnormalities in the globus pallidus and substantia nigra, with neurodegeneration and iron accumulation in the brain. Genetic analysis for WDR45 revealed that she had a splice site mutation (NM_007075.3: c.830 + 2 T > C) which was previously reported, and a diagnosis of BPAN was confirmed. For specific therapies to be developed for BPAN in the future, it is necessary to establish early diagnosis, including genetic analysis.

Background: Patients receiving surgical treatment for Mycobacterium avium complex (MAC), lung disease should be followed up with careful attention paid to relapse/recurrence, but there is some debate regarding the findings based on which relapse/recurrence should be diagnosed., Purpose and Methods: We hypothesized that we might be able to use anti-GPL core IgA antibodies (MAC antibodies), which have been attracting attention as a factor that may support diagnosis of MAC lung disease, to diagnose postoperative relapse/recurrence. Therefore, we compared the levels of these antibodies before and at the time of relapse/recurrence, and also compared antibody titers before and after surgery., Result: MAC antibody titers were elevated by an average of about 50% at the time of relapse/recurrence compared to those before relapse/recurrence for 6 patients. In contrast, MAC antibody titers were about 30% lower after surgery compared to those before surgery for 37 patients., Conclusion: It may be possible to use MAC antibodies as an indicator of postoperative relapse/recurrence for MAC lung disease.

Background: Pulmonary disease caused by nontuberculous mycobacteria has a variable clinical course. Although this is possibly the result of not only host factors, but also bacterial factors, many questions remain to be answered regarding these manifestations., Methods: To assess the relationship between the progression of pulmonary Mycobacterium avium disease and bacterial factors we performed variable number tandem repeats (VNTR) typing analysis of M. avium tandem repeats (MATR) in M. avium isolates from 46 patients with different clinical courses, and furthermore, examined the association between disease progression and a pMAH135 plasmid derived from M. avium., Results: In patients whose treatment was initiated because of worsenedchest radiograph findings and/or clinical symptoms within 18 months after being diagnosed with pulmonary M. avium disease, the detection rate of 6 genes located in pMAH135 was 35.3-47.1% for 17 isolates. However, in untreated patients with a stable condition, these rates were 10.3-13.8% in 29 isolates. MATR-VNTR typing analysis showed that isolates from patients with worsened disease and those with stable disease are clustered differently. In cluster III, the number of isolates from patients with worsened disease was higher than that from patients with stable disease (p = 0.019), and furthermore, the number of isolates carrying pMAH135 genes was higher than that not carrying pMAH135 genes (p ≤ 0.001)., Conclusion: These results indicate an association between the progression of pulmonary M. avium disease and pMAH135. The presence of pMAH135 genes might be a useful prognostic indicator for pulmonary M. avium disease and may serve as one criterion for treatment initiation.

Background: In the intensive care unit, the use of continuous electroencephalography (cEEG) in children with altered mental status often results in the detection of non-convulsive seizures (NCS). Children with influenza can occasionally display altered mental status, but the prevalence of NCS in children with influenza with altered mental status is yet to be determined. This study determined the prevalence of NCS in pediatric patients with altered mental status associated with influenza A(H1N1)pdm09 infection., Methods: We retrospectively reviewed admissions to the pediatric intensive care unit between September 2009 and February 2010 and confirmed the presence of NCS on cEEG in children with influenza A(H1N1)pdm09 and with altered mental status., Results: Of the 15 patients (aged 41-159 months old), NCS was identified on cEEG in five children (33%)., Conclusions: Approximately one-third of the children infected with influenza A(H1N1)pdm09 with altered mental status had NCS. Further research is needed to determine if the detection and management of NCS improve outcome in these children., (© 2014 Japan Pediatric Society.)

Objective: This is a retrospective study on six surgical cases of Mycobacterium abscessus pulmonary disease, including a comparison with M. avium complex (MAC) disease., Subjects and Methods: We performed surgery for six cases of M. abscessus pulmonary disease between July 2012 and June 2014. In all the cases, video-assisted thoracic surgery alone was performed. Age, sex, bacillus identification method, disease type, preoperative anti-glycopeptidolipid core immunoglobulin A antibody value, preoperative chemotherapy, preoperative chemotherapy period, adaptation of the operation, surgical method, result of the bacillus culture of an organization that was extracted at operation, postoperative hospitalization period, surgical complications, and postoperative relapse were examined for the six cases of M. abscessus pulmonary disease. In addition, the cases were compared with 36 cases of MAC disease for which operation was performed during the same period., Result: None of the patients had major surgical complications or in-hospital death. Although three patients survived for more than 1 postoperative year and completed chemotherapy, relapses are not accepted in all cases at present. In the comparison with MAC disease, the mean preoperative chemotherapy period for M. abscessus pulmonary disease was 5.5 months, which was 18.9 months shorter than that for MAC disease, with a statistically significant difference. CONCLUSION AND CONSIDERATION: Surgery for M. abscessus pulmonary disease may be considered a safe and effective therapeutic procedure. Moreover, some physicians believe that surgical treatment is required at an earlier stage of M. abscessus pulmonary disease compared with MAC disease.

Background: There has been no standard chemotherapy for advanced or recurrent thymic malignancies including thymic carcinoma (TC) and invasive thymoma (IT), though platinum and anthracycline have been reported as effective agents for the treatment of these diseases. The objective of this study was to evaluate the efficacy and safety of the combination of amrubicin (AMR), a new anthracycline agent, and carboplatin (CBDCA) in patients with advanced thymic malignancies., Methods: Patients with histologically confirmed thymic malignancies received AMR (35 mg/m, days 1-3) and CBDCA (area under the curve 4.0, day 1) every 3 weeks. Patients who had received previous chemotherapy were treated with a reduced dose of AMR (30 mg/m). The primary end point was objective response rate (ORR), and secondary endpoints were progression-free survival, overall survival, and toxicity profile., Results: From December 2008 to October 2012, 51 patients (33 TC and 18 IT) were enrolled. The median number of treatment cycles was four in each group. The ORR and progression-free survival were 30% (95% confidence interval, 14-46) and 7.6 months in the TC group, and 17% (95% confidence interval, 0-34) and 7.6 months in the IT group, respectively. The ORR of TC patients without previous chemotherapy (n = 19) was 42%. Although grade 3 or 4 hematological toxicities were common including neutropenia (82%) and febrile neutropenia (22%), these were transient and manageable. Nonhematological toxicities were moderate and no treatment-related death was observed., Conclusions: The combination of AMR with CBDCA was active for TC with acceptable toxicity, although it was not effective for IT. Further investigation of this regimen for advanced TC is warranted.

Background: Several reports have shown that segmentectomy is superior to lobectomy for preservation of postoperative pulmonary function. The purpose of this study was to characterize the relationship between pulmonary function and the volume of the resected lung in patients undergoing segmentectomy or lobectomy., Methods: Patients undergoing open lobectomy (n = 126) and open segmentectomy (n = 52) for stage I non-small cell lung cancer were analyzed retrospectively. Pulmonary function testing, including vital capacity (VC) and forced expiratory volume in 1 second (FEV1), was performed preoperatively and at 1 and 6 months postoperatively., Results: The postoperative reduction of VC and FEV1, as indicated by the postoperative value/preoperative value, at 6 months after surgery was significantly less in the segmentectomy group than in the lobectomy group. However, the standardized functional loss ratio, as expressed by [(measured postoperative value)-(predicted postoperative value)] / (predicted postoperative value) × 100 (%), at 1 month after surgery was significantly lower in the segmentectomy group than in the lobectomy group. No significant difference in the standardized functional loss ratio was seen at 6 months postoperatively., Conclusions: Pulmonary function at 6 months after surgery is better after segmental resection than after lobectomy. However, the absolute value of pulmonary function did not reach the predicted-postoperative value at 1 month after surgery. Thus, when segmentectomy is performed, clinicians should be aware that early postoperative pulmonary function may be significantly less than the expected value.

Background: Duchenne muscular dystrophy (DMD) is a progressive muscle wasting disease caused by muscle dystrophin deficiency. Downstream of the primary dystrophin deficiency is not well elucidated. Here, the hypothesis that prostaglandin D2 (PGD2)-mediated inflammation is involved in the pathology of DMD was examined by measuring tetranor PGDM, a major PGD2 metabolite, in urine of DMD patients., Methods: We measured tetranor PGDM in urine using LC-MS/MS. First morning urine samples were collected from genetically confirmed DMD patients and age-matched healthy controls aged 4 to 15y., Results: The urinary tetranor PGDM concentration was 3.08±0.15 and 6.90±0.35ng/mg creatinine (mean±SE) in 79 control and 191 DMD samples, respectively. The mean concentration was approximately 2.2-times higher in DMD patients than in controls (p<0.05). Remarkably, urinary tetranor PGDM concentrations in DMD patients showed chronological changes: it stayed nearly 1.5 times higher than in controls until 7y but surged at the age of 8y to a significantly higher concentration., Conclusion: Urinary tetranor PGDM concentrations were shown to be increased in DMD patients and became higher with advancing age. It was indicated that PGD2-mediated inflammation plays a role in the pathology of DMD., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Introduction: In this study, we aimed at determining the cause of resistance to tuberculosis treatment by performing genetic analyses of bacteria obtained from a patient who developed multidrug-resistant tuberculosis (MDR-TB) during the initial course of treatment for tuberculosis., Methods: Specimens obtained before and after the development of MDR-TB were subjected to spoligotyping, drug-resistance gene analysis, and variable-number tandem repeat (VNTR) typing. The patient's clinical background was also reviewed., Results: After the development of resistance, the bacterial genome had changed with regard to only 1 mutation: S531L in the rpoB gene. Spoligotyping revealed that the genotype was that of the Beijing strain. VNTR typing confirmed all 35 loci. Review of the patient's clinical background showed that diabetes mellitus was present as a complication., Discussion: There was no evidence of reinfection or polyclonal infection. The strain belonged to a sublineage of the Beijing genotype that is a common precipitating cause of MDR-TB due to this genotype. The patient had diabetes mellitus and was thus vulnerable to the development of resistance. Factors associated with both the host and bacteria, therefore, contributed to the development of resistance in this case, which seemed to result in the rapid development of MDR-TB.

Purpose: This is a retrospective study on relapse/recurrence of surgical cases of pulmonary nontuberculous mycobacteriosis (NTM). Surgical treatment was performed at one hospital and by one surgeon., Method: Fifty patients had undergone surgical treatment from August 2004 to July 2011 in hospital. From this group, 37 patients were selected after one year, and of these, 9 patients had a relapse/recurrence (group A) and the others (28 patients without relapse/recurrence, group B). Data was recorded about their age, gender, pre-operative image score, cavernous lesions, residual lesions after operation, drugs of pre-operative chemotherapy, the duration of pre-operative chemotherapy, the duration of any follow-up after operation, type of mycobacteria, the results of bacterial cultivation of surgical specimens, type of mycobacterium and operative procedure., Result: Three factors, the result of bacterial cultivation of surgical specimens, duration of chemotherapy before operation and existence of residual lesions, showed a significant difference statistically. No case with major surgical complication and hospital death was recognized., Conclusion: The visible foci should be removed as thoroughly as possible. Pre-operative chemotherapy should not be continued unnecessarily, and surgical treatment should be chosen at an early stage. The results of bacterial cultures of surgical specimens could be very useful for predicting the possibility of relapse/recurrence after operation. Surgical treatments of our patients were carried out safely. However, as the patients have a risk of relapse/recurrence, they require careful monitoring and post-operative chemotherapy over along period.

Purpose: Lymphatic spread of lung carcinoma to the mediastinum is a key determinant of prognosis. The lymph flow often carries metastases from the pulmonary segment directly into the mediastinal lymph nodes, without passing through the hilar nodes. This phenomenon is termed as "skip metastasis." This study investigated the subpleural lymphatic flow to the mediastinum using indocyanine green (ICG) with a near-infrared fluorescence imaging system., Methods: Seventeen patients with lung cancer were enrolled in this study. A 0.3 ml sample of solution containing the fluorescent dye ICG (5 mg/ml) was injected into subpleural sites near the primary tumor. Fluorescence imaging was used to monitor the flow of ICG-containing lymph from the injection site for 5 min. The relationship between the anatomical segment of the primary tumor and the lymphatic flow was assessed., Results: The lymphatic vessels draining from the injection site were revealed by the bright ICG fluorescence in 14 of the patients (82.4 %). A direct lymphatic flow to the mediastinum was confirmed in 3 of those 14 (21.4 %)., Conclusions: These findings confirm the direct flow of lymph to the mediastinum without passage through the hilum pulmonis intraoperatively. These preliminary results may provide a valuable clue for further investigations of the mechanisms underlying skip metastasis.

Background: The pulmonary disease caused by Mycobacterium avium shows diverse clinical manifestations. Little is known about the potential association between the genetic characteristics of M. avium strains and disease progression., Subjects and Methods: We enrolled 89 patients with disease caused by M. avium, from 12 hospitals in Japan and collected the corresponding M. avium isolates and clinical data. We divided the 89 patients into 2 groups: one group comprising 43 patients with progressive disease despite chemotherapy ("progressive"), and the other group comprising 46 patients with untreated disease ("untreated"). We compared clinical and bacteriological characteristics between these groups. The bacteriological characteristics that we examined were drug susceptibility, variable-number tandem-repeat (VNTR) typing, and presence of the insertion sequence ISMav6. Seventeen patients in the "untreated" group were started on chemotherapy because their condition had clinically deteriorated during follow-up., Results: The result of VNTR typing showed that there was no specific clustering according to geographical region or clinical group in the "untreated" or "progressive" groups. Six out of eight cases those of polyclonal infection, and 11 of 12 isolates that were highly resistant to clarithromycin were isolated from patients with progressive disease. The frequency of isolates with ISMav6 inserted into upstream region of the cfp29 gene, which is involved in the induction of interferon-gamma production, was significantly higher in patients with deteriorating disease than in stable patients in the "untreated" group (p = 0.002)., Conclusion: Polyclonal infection and clarithromycin resistance may be involved in disease progression. ISMav6 inserted into the cfp29 gene is also suggested to be a factor related to the deterioration of pulmonary Mycobacterium avium complex disease.

Introduction: To make more effective use of variable number tandem repeat (VNTR) typing, we identified novel VNTR loci in Mycobacterium avium and used them for modified M. avium tandem repeat-VNTR (MATR-VNTR) typing., Method: Analysis of a DNA sample extracted from a clinical isolate (strain HN135) with the FLX system genome sequencer (Roche Diagnostic System) led to discovery of several novel VNTR loci. The allelic diversity of the novel VNTR loci was evaluated for 71 clinical isolates and compared with the diversity of the MATR-VNTR loci. To improve efficacy of MATR-VNTR typing, we tested typing using 2 sets of loci selected from the newly identified loci and the MATR loci, i.e., one set containing 7 and another 16 loci. Hunter Gaston's discriminatory index (HGDI) was calculated for these sets., Results: Six VNTR loci were newly identified, of which 5 showed a high diversity. The HGDI was 0.980 for the improved new typing using a set of 7 loci, and 0.995 for another set of 16 loci, while it was 0.992 for the conventional MATR-VNTR typing., Discussion: VNTR typing with the set of the 7 loci enabled a rapid analysis, and another set of 16 loci enabled a precise analysis, as compared with conventional MATR-VNTR typing. A method that uses only VNTR loci with relatively high allelic diversity is considered to be a useful tool for VNTR typing of MAC isolates.

Introduction: To determine the characteristics of Mycobacterium avium in Japan, we compared the genetic properties of M. avium isolated in different countries., Methods: A Mycobacterium avium tandem-repeat variable-number tandem-repeat (MATR-VNTR) analysis was performed using South Korean strains (n = 119) and Japanese strains (n = 76). In addition, we compared the frequencies of a new insertion sequence, ISMav6., Results: A phylogenetic analysis identified different clusters between the two countries' strains. The prevalence of ISMav6 was significantly different between them, i.e., 75.0% in Japanese strains and 59.8% in the Korean ones (P < 0.035). The frequency of strains with IS Mav6 in the Shine-Dalgarno (SD) sequence of the cfp29 gene that is involved in the interferon-gamma induction was also different, with stronger significance (Japan: 38.2%, Korea: 12.4%, P < 0.001)., Discussion: It is possible that M. avium strains prevalent in Japan and in Korea are genetically distinct. The analyses of the presence of ISMav6, as well as the VNTR patterns of M.avium strains from many different countries would be a promising methodology in elucidating the causes of the recent increase in cases of pulmonary MAC diseases.

A 63-year-old woman was referred to our hospital because of bilateral infiltrations and nodular opacities in her chest radiograph taken in the mass radiography screening in September 2010. The chest computed tomography showed patchy infiltrations with bronchiectasis in the lower lung fields on both sides. She was diagnosed with pulmonary Mycobacterium avium complex (MAC) disease based on the bacteria recovered from the sputum and the bronchoalveolar lavage fluid. To elucidate an environmental MAC source, we investigated her home, and isolated M. avium and M. gordonae from the bathtub and shower tap, respectively, in her residential bathroom. Analysis of the hsp65-PRA variants digested with BamHI and some insertion sequences showed that the clinical strains recovered from sputum and strains from the bathtub were M. avium subsp. hominissuis. A dendrogram of the Mycobacterium avium tandem repeat loci variable-number tandem-repeat (MATR-VNTR) analysis of the MAC strains showed that the bathtub strains formed a polyclonal colonization, and that 1 of the 5 MATR-VNTR patterns was identical to the corresponding pattern of the sputum strain from the patient. In conclusion, we believe that the residential bathroom of the patient was the environmental source of her pulmonary MAC disease, as has been previously reported.

Refractory status epilepticus (RSE) is defined as persistence of seizure activity despite appropriate medical and antiepileptic drug (AED) therapy. Febrile RSE is often caused by presumed encephalitis and has a high morbidity rate. In addition, it is believed that hyperthermia aggravates epileptic brain damage. The efficacy of hypothermia/normothermia (H/N) therapy against brain damage has been proposed, but there have been limited studies reporting on the efficacy of this treatment against febrile RSE. To study the efficacy of induced H/N with general anesthesia therapy in children with febrile RSE, a retrospective review of RSE cases was conducted in 28 children hospitalized in the tertiary pediatric intensive care center of Kobe Children's Hospital, Japan, between October 2002 and August 2009. Clinical outcomes and neurological sequelae using the Pediatric Cerebral Performance Category Scale (PCPC) score were compared after one month of treatment with either H/N (34 degrees C-36 degrees C) with general anesthesia therapy or with other conventional therapies. Cases were categorized as those with good recovery (PCPC=1) or poor outcome (PCPC=2-6). Twelve children underwent H/N with general anesthesia therapy, while 16 children were treated by conventional therapy using intravenous diazepam and/or midazolam. Treatment with H/N significantly improved outcome compared to conventional therapies (p=0.024; Fisher's exact test). Five of 6 patients with poor outcome had a final diagnosis of acute encephalopathy with febrile convulsive status epilepticus (AEFCSE). Treatment with H/N therapy may reduce neurological damage in the development of AEFCSE caused by febrile RSE in children.

Introduction: Preventing the spread of drug-resistant tuberculosis is a clinically important challenge. In this effort, rifampicin (RFP)-resistant gene examination by line probe assay (LiPA) was evaluated for its clinical application for rapid detection of tuberculosis., Methods: The RFP-resistant gene was examined in a total of 110 samples of sputum obtained from patients that were definitively diagnosed with pulmonary tuberculosis by auto-LiPA. The difference in detection sensitivity between the results of the smear and culture examinations was evaluated. Culture-positive samples were compared with the results of the drug susceptibility test., Results: Smear-positive samples were LiPA positive in 69 of 73 samples (sensitivity: 94.5%), and smear-negative samples were LiPA positive in 25 of 37 samples (67.6%). More than half of the samples were LiPA positive, even those that were culture-negative or contaminated. Comparison of the 76 culture-positive samples with the results of the drug susceptibility test found that all samples were wild type among the RFP-sensitive strains. Among the 8 RFP-resistant strains, 6 were mutation type. All samples shown to be mutation type were obtained from patients with multi-drug resistant tuberculosis., Discussion: Using LiPA, the amount of smear can be used as a factor for detection of RFP-resistant genes. Detection was possible even with culture-negative and contaminated samples, allowing more rapid diagnosis of patients with multi-drug resistant tuberculosis.

A 71-year-old man who had undergone surgical resection of esophageal gastrointestinal stromal tumors (GISTs) through a right posterolateral thoracotomy 8 years earlier was referred for treatment of an anterior mediastinal mass discovered on a follow-up chest radiograph in October 2007. Computed tomography findings revealed a tumor, 82 x 49 mm, with calcification, in the anterior mediastinum. When we radically resected the tumor via a median sternectomy, we found that it was actually located in the pleural cavity, and there was a small nodule near the main tumor on other pleura. Microscopically, the tumor was comprised of uniform spindle cells with fibrillary eosinophilic cytoplasm. In addition, immunostaining showed that the tumor was positive for CD117 (c-kit). The diagnosis was pleural dissemination of esophageal GISTs 8 years after primary surgery, making this the first report of pleural dissemination of esophageal GISTs after such a prolonged postsurgical interval.

In addition to its known status as a disseminated disease in HIV-positive patients, Mycobacterium avium complex (MAC) is increasingly recognized as a causative pathogen of respiratory disease in HIV-negative patients. MAC is divided into Mycobacterium avium, and the less-epidemiologically studied Mycobacterium intracellulare. Genetic typing for M. intracellulare using variable number of tandem repeats (VNTR) has not yet been developed. The aim of this study was to identify VNTR loci in the genome of M. intracellulare and apply them as an epidemiological tool to clinical isolates. Here, we identified 25 VNTR loci on the M. intracellulare genome, of which 16 showed variations among clinical isolates in the number of tandem repeat motifs. Among the 74 M. intracellulare isolates, 50 genotypes were distinguished using the 16 VNTR loci, resulting in a Hunter Gaston's discriminatory index of 0.988. Moreover, all 16 VNTR loci were stable in different sets of isolates recovered within time intervals ranging from 2 to 1551 days from 14 separate patients. These results indicate that for use as epidemiological markers of M. intracellulare, the loci in this VNTR assay are highly discriminating and stable over time.

Mycobacterium avium complex (MAC) infections are increasing annually in various countries, including Japan, but the route of transmission and pathophysiology of the infection remain unclear. Currently, a variable-number tandem-repeat (VNTR) typing method using the Mycobacterium avium tandem repeat (MATR) loci (MATR-VNTR) is employed in Japan for epidemiological studies using clinical isolates of M. avium. In this study, the usefulness of this MATR-VNTR typing method was compared with that of the IS1245-restriction fragment length polymorphism (IS1245-RFLP) typing method and a mycobacterial interspersed repetitive-unit (MIRU)-VNTR typing method reported previously (V. C. Thibault, M. Grayon, M. L. Boschiroli, C. Hubbans, P. Overduin, K. Stevenson, M. C. Gutierrez, P. Supply, and F. Biet, J. Clin. Microbiol. 45:2404-2410, 2007). Seventy clinical isolates identified as M. avium from human immunodeficiency virus-negative patients with MAC infections were used. MATR-VNTR typing using 15 loci distinguished 56 patterns of different allele profiles, yielding a Hunter-Gaston discriminatory index (HGDI) of 0.990. However, IS1245-RFLP and MIRU-VNTR typing yielded HGDIs of 0.960 and 0.949, respectively, indicating that MATR-VNTR has an excellent discriminatory power compared with MIRU-VNTR and IS1245-RFLP typing. Moreover, concomitant use of the MATR-VNTR method and IS1245-RFLP typing increased the HGDI to 0.999. MATR-VNTR typing is inexpensive and easy to perform and could thus be useful in establishing a digital multifacility database that will greatly contribute to the clarification of the transmission route and pathophysiology of M. avium infections.

Background: Regenerating gene I alpha (REG1A) is a growth factor known to affect pancreatic islet beta cells. Although REG1A expression has also been observed in various malignant tumors, the correlation between REG1A expression and the clinicopathological characteristics of breast cancer and patient prognosis has not been evaluated., Methods: Resected breast cancer tissues obtained at surgery from 150 breast cancer patients was stained with anti-REG1A antibody, after which the relative area occupied by stained tumor cells was evaluated under a light microscope and correlated with known clinicopathological factors., Results: Whereas tumor cells were frequently stained with anti-REG1A antibody, cells from normal breast tissue were not stained. REG1A expression in tumors of breast cancer patients with HER2-positive disease was higher than those with HER2-negative disease (P = .0009). The 10-year disease-specific survival rate among patients with lower levels of REG1A was significantly better than among those with higher levels (P = .0002 by log rank test). Multivariate Cox proportional hazard analyses revealed REG1A (hazard ratio, 2.07; 95% confidence interval, 1.93 to 11.29; P = .0005) and axillary lymph node status (hazard ratio, 4.44; 95% confidence interval, 1.52 to 11.29; P = .0003) to be independent factors affecting the 10-year disease-specific survival rate., Conclusion: High levels of REG1A expression within tumors are an independent predictor of poor prognosis in patients with breast cancer.

A 63-year-old female underwent lobectomy with ND2a lymph node dissection for left lung cancer in April 1999. Histopathological examination revealed moderately-differentiated adenocarcinoma (pT2N2M0, pStage III A). She received one course of a combination of etoposide (ETP) and cisplatin(CDDP)as adjuvant therapy, followed by oral intake of UFT. At 9 months post-operatively, she received radiation therapy for lymph node recurrence, at which time new multiple lung metastases were found. After receiving 3 courses of a combination of vinorelbine (VNR) and CDDP, a complete response (CR) of all metastatic lesions was achieved. Three years after the original surgery, metastatic lesions recurred, and a total of 9 courses of a combination of VNR and carboplatin (CBDCA) and partial resection of the right lung for pulmonary metastasis were performed in succession. Following this therapy, treatment with gefitinib was initiated for about 6 months, and computed tomography (CT) showed progressive disease. For 8 years following the original operation, the patient received oral chemotherapy using S-1 and has maintained CR on CT. We conclude that oral administration of S-1 is useful as palliative chemotherapy without serious adverse events or worsening of quality of life. Patients like this case are thus able to continue chemotherapy for a long time.

Purpose: The criteria for the diagnosis of lymph node metastasis (LNM) in non-small cell lung cancer were investigated using helical computed tomography (hCT). The conventional criterion (1-cm short axis threshold) is generally accepted; however, this criterion is based on conventional CT. New criteria for LNM were investigated because the resolution of hCT is better than that of conventional CT., Methods: Ninety-seven NSCLC patients examined with hCT were enrolled. Both the long axis (LA) and short axis (SA) of the nodes were measured using hCT., Results: Based on the receiver operating characteristic curves, the thresholds that gave optimal sensitivity and specificity for LNM were 13 mm for LA and 9 mm for SA. The LNM diagnosis was re-evaluated using the combination of cutoff values. When the LA was > or =13 mm and the SA was > or =9 mm, the sensitivity, specificity, and accuracy were 56.3%, 92.1%, and 88.1%, respectively. When the LA was > or =13 mm or SA was > or =9 mm, sensitivity, specificity, and accuracy were 75.0%, 74.7%, and 74.7%, respectively. These values were not so different from the conventional criterion recalculated from these data., Conclusion: The new criteria are considered to be useful for making a LNM diagnosis. The conventional criteria for the LNM diagnosis might therefore be applicable even for hCT.

Objective: The presence of a small solitary pulmonary nodule (SSPN) is a common finding on chest computed tomography (CT); however, preoperative diagnosis of SSPN is often difficult. We measured the extent of ground-glass opacity (GGO) and our own original method of circumference difference (CD) as an additional approach in classifying SSPN revealed on CT, and evaluated the likelihood of malignancy., Method: In total, 214 single SSPN with diameter <15mm were studied. All SSPN were histologically examined with surgical resection; preoperative CT findings and pathological diagnosis were evaluated retrospectively. The extent of the ratio of GGO and CD was evaluated using NIH image, where CD is defined as the ratio of the nodule margin distance to the circumference of the predicted circle with an area equal to that of the nodule., Results: The thresholds for differentiating SSPN are 70% of GGO and 68% of the CD ratio. Differentiation of malignancy from benign tumor using our algorithm had sensitivity of 96.6%, specificity of 86.1%, and positive predictive value of 94.1%., Conclusion: Combined with other malignant likelihood parameters such as extent of GGO, CD ratio is a useful additional factor for estimating the likelihood of malignancy of SSPN on CT.

Purpose and Methods: The new discharge criteria devised by the National Hospital Organization have three patterns (A, B and other). It was predicted that the hospitalization period would be markedly shortened by the pattern A. In order to judge whether these patterns were adequately applied, we used an assessment sheet. We investigated the adoption rate of the pattern A and the changes in the hospitalization period after its induction., Results: There was a low adoption rate for the pattern A; namely 18%, and the main reasons for not following it were severity illness and the presence of complications. Hospitalization for less than 4 weeks was seen in 25%, while it was over 8 weeks in 42%. The average period of hospitalization was shortened by 20 days and the average number of patients per day also decreased., Conclusion: Interpretation of discharge criteria is standardized by using the assessment sheet, allowing us to perform smooth induction of a clinical path and guide patients along it. Shortening of hospitalization raises patient turnover and allows more rational management of pulmonary tuberculosis. These results could help to refine the clinical path in the future.

Purpose: We reviewed the interaction between rifampicin (RFP) and clarithromycin (CAM) during treatment of pulmonary Mycobacterium avium complex infection., Subjects and Methods: The subjects were patients with pulmonary non-tuberculous acid-fast bacillus infection during the period from September 2004 to January 2006 who consented to this study. Drug blood concentrations were compared with the minimum inhibitory concentrations for M. avium isolated from sputum and blood levels of CAM were assessed when the time of administration was changed for RFP., Results: The blood concentration of CAM showed a marked decrease in all cases (n = 6) when administered together with RFP, but there was no significant difference in the blood concentration of 14-R-hydroxy-clarithromycin (M-5), the active metabolite of CAM. However, the total blood concentration of CAM and M-5 showed a significant fall, similar to the blood concentration of CAM alone. When the blood concentration and bacterial MIC were compared for RFP, the blood concentration exceeded five MIC(s) in six samples as did the CAM+M-5 level in four out of six samples. There was no significant difference in the blood concentration of CAM (n = 5) when the time of RFP administration was altered. CONCLUSION; Because the total blood concentration of CAM+M-5 fell markedly by co-administration of RFP, this might have an influence on the antibacterial effect of CAM. In addition, examination of the administration of RFP and CAM at different times showed that the blood concentration of CAM did not increase and the influence of induction of hepatic drug-metabolizing enzymes by RFP could not be avoided.

Rifampicin (RFP) induces hepatic drug-metabolizing enzymes, making drug interactions a very important clinical problem. Clarithromycin (CAM) metabolism is reportedly enhanced by induction of hepatic drug-metabolizing enzymes (CYP3A4) by RFP, so that the blood lend of CAM decreases when RFP is administered concurrently. We connected an electrochemical detector to a high-performance liquid chromatograph (HPLC) for simple, rapid, easy measurement of blood concentrations of RFP and CAM. Using samples of patient serum, normal serum, and reference standards, we compared HPLC by an external laboratory and the results of LC/MS/MS analysis with those of this new assay. A strong correlation was seen between our HPLC results and those of the external laboratory in RFP levels (r=0.975, p<0.01). A strong correlation was also seen between results we obtained for CAM with the electrochemical detector in this assay and values measured by LC/MS/MS analysis (r=0.995, p<0.01). Our method enabled simple, rapid measurement of RFP and CAM by connecting the HPLC and electrochemical detector in tandem. This system was used to modulate dosage during combined therapy with RFP and CAM. The therapeutic effect for nontuberculous mycobacteriosis is expected to improve, and our HPLC is expected to be useful for simple, rapid, easy measurement of blood concentrations.

Objectives: We evaluated the usefulness of Variable Numbers of Tandem Repeats (VNTR) analysis, which was recently reported as a new typing method of Mycobacterium avium strains of animal origin, for strain differentiation of clinical isolates of M. avium in comparison with the standard IS1245-RFLP typing method. In addition, forty M. avium isolates recovered from sputum samples of same patient in different times were analyzed with VNTR typing method., Subjects and Methods: The subjects were twenty-four clinical isolates of M. avium stocked at Higashi Nagoya National Hospital and discriminatory power was evaluated with Hunter Gaston Discriminatory Index (HGDI). Furthermore, forty M. avium isolates recovered from sputum samples of one patient obtained at four different times were analyzed by using this VNTR typing method., Results: VNTR typing showed better discriminatory power for twenty-four clinical isolates than IS1245-RFLP method (HGDI: 0.975 vs 0.866). In the second study, polyclonal infection of four genotype strains with different allele profiles were detected. The ratio of mixture of the four different genotype strains varied during clinical course., Conclusion: We considered that VNTR typing method was very useful for discriminatory examination of M. avium.

Objective: The purpose of this study was to elucidate retrospectively the clinical effects of using RFP, EB, CAM, LVFX, and SM for pulmonary Mycobacterium avium-intracellulare complex infection., Materials and Methods: During 9-year (1995-2003) period, 72 patients diagnosed according to the criteria of the Japanese Society for Tuberculosis Guidelines and treated for at least 6 months were available for this study., Results: The age averaged 68 (range, 32-92) years. The male to female ratio was approximately 2 : 3. The follow-up period averaged 344 (190-365) days. 59 of 72 patients were treated for the first time. 58 of 72 patients were diagnosed as primary infection type. Among them, 20, 38, and 14 patients were treated by RFP, EB, and CAM (REC group), RFP, EB, CAM and LVFX (LVFX group), and RFP, EB, CAM, and SM (SM group), respectively. Comparing the baseline patient characteristics among three groups, we found significant difference (measured by ANOVA) in gender (male/female, REC group: 8/12, LVFX group: 20/18, and SM group: 2/12, p < 0.05), age (REC group: 75.2 +/- 9.1, LVFX group : 66.5 +/- 12.5, and SM group: 63.9 +/- 11.9, p < 0.01) and body mass index (REC group: 17.2 +/- 2.9, LVFX group: 18.9 +/- 2.8, and SM group: 19.7 +/- 2.4, p < 0.05). However, we did not find any significant difference in the clinical outcomes (improving rate of the symptoms, change of the erythrocyte sedimentation rate, improving rate of the chest X-ray, and the results of follow-up on bacteriological effect). In the 60 of 72 patients treated for 1 year, the results were superior to those of some previous reports (1-year improving rate of the symptoms, 1-year improving rate of the chest X-ray, 1-year improving rate of the sputum conversion, and 1-year rate of the relapse were 54.3%, 65.0%, 60.0%, and 15.3%, respectively)., Conclusion: Further study was warranted that no advantage was shown by an additional use of LVFX or SM on REC from the point of view of the clinical effects for pulmonary Mycobacterium avium-intracellulare complex infection, in spite of the higher age and deteriorated nutritional status of REC group.

We report a case of mediastinal neurofibroma originating from the left phrenic nerve in a 42-year-old woman who was referred to us after a routine chest X-ray showed a smooth, round abnormal shadow in the left middle lung field adjacent to the heart. We resected a 25 x 20 x 20-mm tumor by video-assisted thoracic surgery. Histopathological examination confirmed that the lesion was a mediastinal neurofibroma originating from the left phrenic nerve without von Recklinghausen's disease. Neurogenic mediastinal tumors originating from the phrenic nerve are very rare, and to the best of our knowledge, no other case of a mediastinal neurofibroma originating from the phrenic nerve in a patient without von Recklinghausen's disease has ever been reported.

Purpose: Tissue factor (TF), an initiator of the extrinsic coagulation cascade, is also expressed in a wide range of cancer cells and plays an important role in cancer progression and metastasis, as well as in processes independent of the blood coagulation pathway. For example, by acting as an adhesion molecule enabling tissue invasion, TF may play a key role in the metastatic process and angiogenesis in non-small cell lung cancer (NSCLC)., Methods: To further investigate the role of TF on tumor cell invasion in NSCLC, we measured the TF mRNA expression in the tumors of 42 NSCLC patients using real-time quantitative reverse transcription - polymerase chain reaction carried out in a LightCycler. We then compared the TF mRNA expression with histological evidence of invasion of blood and lymphatic vessels by tumor cells., Results: Although there was no significant relationship between the TF mRNA expression and the invasion of lymphatic vessels, the TF mRNA expression was significantly higher in tumors that invaded blood vessels (Log(10) TF mRNA/GAPDH mRNA = 2.16 +/- 0.18) than in those that did not (1.59 +/- 0.16; P = 0.03)., Conclusion: These results suggest that TF plays a major role in blood vessel invasion by tumor cells in NSCLC.

A 73-year-old male underwent lobectomy with ND2a lymph node dissection and resection of the superior vena cava for right lung cancer in December 1998 at Akita University Hospital. Histopathological examination demonstrated moderately differentiated adenocarcinoma (pT4 (SVC) N2M0, Stage IIIB). He received 1 course of a combination of cisplatin (CDDP) and etoposide (ETP) as postoperative adjuvant therapy. In March 2001, he again underwent partial resection of the right lung (S8) due to recurrence. In December 2001, a new left lung metastatic tumor was found. The patient was transferred to our hospital, where he was given 1 course of vinorelbine (NVB) 25 mg/m2 (day 1, 8) and CDDP 80 mg/m2 (day 1). Subsequently, he received 2 courses of vinorelbine (NVB) 25 mg/m2 (day 1, 8) and carboplatin (CBDCA) 430 mg/body (day 1). After the chemotherapy, a complete response (CR) of metastatic lesions was achieved. Adverse reactions were grade 3 neutropenia, grade 2 alopecia and grade 1 nausea/vomiting. The combination of vinorelbine and platinum agent (CDDP/CBDCA) is a useful regimen in treating recurrent non-small-cell lung cancer.

Accumulating evidence suggests that a coordinately controlled G(2) checkpoint prevents cells with damaged DNA from entering mitosis, thus playing an important role in the maintenance of chromosomal integrity. In the study presented here, we identified a homozygous deletion of the 14-3-3epsilon gene, which resides within a previously identified, commonly deleted region at 17p13.3 in lung cancers, in two small cell lung cancer cell lines that originate from distinct metastatic sites of the same patients. The introduction of 14-3-3epsilon induced significantly restored G(2) checkpoint responses, which resulted in the reduction of mitotic cells as well as of aberrant mitotic figures in the X-ray-irradiated 14-3-3epsilon-null small cell lung cancer cell line. Interestingly, we also found that the G(2) checkpoint response is frequently impaired to various degrees in a large fraction of small cell lung cancer cell lines. These findings suggest the possible involvement of the perturbed G(2) checkpoint in the pathogenesis of this aggressive form of human lung cancers.