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Background: Goodpasture's syndrome is a rare disease that is characterized by rapidly progressive glomerulonephritis and diffuse alveolar hemorrhage.Case Presentation: A 71-year-old Japanese man who had chronic interstitial pneumonia was diagnosed as having Goodpasture's syndrome. Both anti-glomerular basement membrane antibody and myeloperoxidase anti-neutrophil cytoplasmic antibody were increased. Despite intensive treatments, including mechanical ventilation, he died from respiratory failure. Pathological findings at autopsy showed rapidly progressive glomerulonephritis in his kidneys, diffuse alveolar hemorrhage, hyaline membranes, and fibroblastic foci in his lungs. The cause of death was diagnosed as respiratory failure as a result of diffuse alveolar damage induced by a combination of diffuse alveolar hemorrhage and exacerbation of interstitial pneumonia.Conclusions: We report a case of Goodpasture's syndrome complicated with pre-existing chronic interstitial pneumonia and positive myeloperoxidase anti-neutrophil cytoplasmic antibody. We reviewed six similar cases reported in the literature and concluded that Goodpasture's syndrome with pre-existing interstitial pneumonia and myeloperoxidase anti-neutrophil cytoplasmic antibody is related to a poor prognosis. [ABSTRACT FROM AUTHOR]

Background: Immunoglobulin G4-related disease is characterized by infiltration of immunoglobulin G4-positive plasmacytes in various organs. The radiological findings of lung involvement of immunoglobulin G4-related disease include hilar and mediastinal lymphadenopathies, thickness of bronchovascular bundles, peribronchovascular consolidation, and lung nodules. Although a pathological approach is needed to diagnose immunoglobulin G4-related disease, it is ordinarily diagnosed by biopsy from one lesion even if there are multiple lesions. We reported a rare case of the coexistence of immunoglobulin G4-related disease and lung cancer in the same lung nodule. Case Presentation: A 72-year-old Japanese man visited our hospital for evaluation of a nodular shadow in the middle lobe of his right lung that was seen on chest radiograph and computed tomography scan. An abdominal computed tomography scan showed a tumefactive lesion in his anterior sacral spine. Blood examinations revealed high serum immunoglobulin G4 concentration at 346 mg/dl, renal dysfunction, and anemia. He underwent right upper lobectomy and regional lymph node dissection. Pathologic findings of the lung nodule showed lepidic pattern adenocarcinoma with infiltration of immunoglobulin G4-positive plasma cells and obliterative phlebitis. Conclusions: To date, there have been only few reports on the coexistence of immunoglobulin G4-related disease and lung cancer; here, we report such a rare case. Histologic examination should be considered in cases of suspicious immunoglobulin G4-related disease appearing in a lung nodule. [ABSTRACT FROM AUTHOR]

A 37-year-old man with fever, cough, and dyspnea with no medical history developed an eosinophilic pleural effusion and blood eosinophilia. No evidence of malignancy or pathogens was detected in the pleural effusion, and the pleural specimen obtained by thoracoscopy showed eosinophilic infiltration with inflammatory granulation tissue without fibrinoid necrosis or malignant cells. Since a myeloproliferative disorder was also excluded, the diagnosis was idiopathic eosinophilic pleurisy. Corticosteroid treatment was started and then slowly tapered, and the eosinophilic pleural effusion resolved. Considering the various etiologies of eosinophilic pleurisy, a practical clinical approach to the investigation and diagnosis of eosinophilic pleurisy is presented. [ABSTRACT FROM AUTHOR]

KRAS mutations have been recognized as predictive markers of primary resistance to anti-EGFR-antibodies in colorectal cancer patients. In addition, newly detected KRAS mutations have been reported to be related with acquired resistance to chemotherapy containing anti-EGFR antibody. Considering this evidence, monitoring of KRAS mutations is indispensable for making treatment decisions, and the method should be non-invasive allowing repeated examinations. Recently, we established a novel automated sensitive detection system for KRAS mutations, named mutation-biased PCR quenching probe system (MBP-QP). The goal of our study was to investigate the potential for monitoring KRAS mutations during treatment with anti-EGFR antibodies. The detection limit of MBP-QP using a control plasmid containing KRAS mutations was 1-9 copies, and 0.05-0.3% mutant plasmid was detectable in a mixture of wild type and mutants. One-hundred twenty colorectal cancer patients were genotyped for KRAS mutations with MBP-QP as well as polymerase chain reaction reverse sequence-specific oligonucleotide (PCR-rSSO), which has already been applied to cancer tissue samples in the clinical setting. Concordance rates between plasma DNA and cancer tissues were 68% with MBP-QP and 66% with PCR-rSSO, indicating that these systems are equivalent in terms of detecting KRAS mutations with plasma DNA. KRAS mutations in plasma DNA were frequently observed in systemic metastatic cancer patients, and in three patients KRAS mutations appeared after chemotherapy containing anti-EGFR antibody. A prospective study is needed for clarifying whether KRAS mutations detected in plasma DNA are predictive markers of treatment efficacy with anti-EGFR antibody.

Obesity is one of the phenotypes of severe asthma, which is considered to be a heterogeneous syndrome; however, its interaction with airway inflammation is not fully understood. The aim of this study was to clarify the role of saturated fatty acids in augmenting airway inflammation induced by house dust mite (HDM) in obesity. Subjects were Balb/c mice fed a high-fat diet (HFD) for 10 weeks, followed by sensitization and exposure to HDM. Subjects were also administered palmitic acid (PA) for 4 weeks with concurrent sensitization and exposure to HDM. Airway inflammation was assessed by quantifying the amount of inflammatory cells in bronchoalveolar lavage (BAL) and airway resistance was measured. In vitro, lipopolysaccharide (LPS)-primed macrophages were stimulated by PA. The amount of monocyte chemoattractant protein-1 (MCP-1), interleukin-1β (IL-1β), and tumor necrosis factor α (TNF-α) was examined in the supernatant. Compared to normal chow mice, HFD mice underwent significant increases in body weight; increases in number of lung macrophages, including circulating monocytes and alveolar macrophages; and increases in bronchoalveolar lavage fluid (BALF) total cell count, including neutrophils but not eosinophils, after HDM sensitization and exposure. In vitro, PA induced MCP-1 and augmented LPS-primed production of IL-1β and TNF-α in macrophages. Among HDM mice that were administered PA, there was an increase BALF total cell count, including neutrophils but not eosinophils, compared to vehicle mice. In conclusion, saturated fatty acid increased the number of lung macrophages and augmented HDM-induced neutrophilic airway inflammation in a HFD mouse model.

BRAF gene mutations have been observed in 30-50 % of malignant melanoma patients. Recent development of therapeutic intervention using BRAF inhibitors requires an accurate and rapid detection system for BRAF mutations. In addition, the clinical characteristics of the melanoma associated with BRAF mutations in Japanese patients have not been investigated on a large scale evaluation. We recently established quenching probe system (QP) for detection of an activating BRAF mutation, V600E and evaluated 113 melanoma samples diagnosed in Saga University Hospital from 1982 to 2011. The QP system includes fully automated genotyping, based on analysis of the probe DNA melting curve, which binds the target mutated site using a fluorescent guanine quenched probe. BRAF mutations were detected in 54 of 115 (47 %) including 51 of V600E and 3 of V600 K in Japanese melanoma cases. Among clinical subtypes of melanoma, nodular melanoma showed high frequency (12 of 15; 80 %) of mutation followed by superficial spreading melanoma (13 of 26; 50 %). The QP system is a simple and sensitive method to determine BRAF V600E mutation, and will be useful tool for patient-oriented therapy with BRAF inhibitors.

Background: Torin2 is a second-generation ATP-competitive inhibitor of the mammalian target of rapamycin (mTOR). Dysregulation of mTOR signaling pathway, consisting of mTOR complexes mTORC1 and mTORC2, is a promising therapeutic target in some human malignancies. We examined antitumor effects of Torin2 in adult T-cell leukemia/lymphoma (ATL)-related cell lines compared to those of rapamycin, a classical mTOR inhibitor., Materials and Methods: Cell growth was monitored by detecting viable cells with Cell Counting Kit-8 or trypan blue. Cell cycle was studied by flow cytometric analysis. The phosphorylation status of proteins in the mTOR signaling pathway was examined by western blot analysis., Results: Torin2 exhibited greater efficacy in cell growth inhibition than rapamycin, associated with a strong reduction of phosphorylated v-akt murine thymoma viral oncogene homolog (AKT) (Ser 473), that is downstream of mTORC2., Conclusion: Since mTORC2 activates AKT, Torin2 might inhibit both mTORC1 and mTORC2, resulting in stronger growth inhibition of ATL cells., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background: Poor adherence to ABL tyrosine kinase inhibitors (ABL TKIs) is associated with reduced treatment efficacy and increased healthcare costs. To examine the hazards associated with poor adherence, we implemented failure mode and effects analysis (FMEA)., Methods: We surveyed 54 chronic myeloid leukemia (CML) patients treated at Saga University Hospital from October 2012 to May 2014. The survey consisted of items regarding the type of ABL TKI used, adherence to ABL TKIs, the appearance of adverse effects, utilisation of the high cost medical care benefit system, and factors affecting adherence. Four factors that likely affected adherence were identified, including the level of understanding of ABL TKIs treatment outcomes, adverse effects, the high cost of medications, and careless slips in the taking of medicine. Results of the survey were analysed by FMEA., Results: The risk priority number was highest for careless slips in the taking of medicine at 7.0 ± 1.0 (mean ± SEM), followed in descending order by the inadequate understanding of treatment outcomes (4.9 ± 0.6), adverse effects (3.8 ± 0.8), and high medication cost (2.2 ± 0.5). Thus, the prevention of careless slips was the most important factor affecting adherence to ABL TKIs. Contrary to our preoccupation, FMEA revealed that high medication cost was the lowest risk factor for poor adherence. This finding may be attributed to the high utilisation (96.3 %) of the high cost medical care benefit system., Conclusion: These findings suggest that an inadequate medication-taking habit such as careless slips may represent a potential target to improve and maximize adherence in CML patients.

Rationale and Objectives: Lesion volume is considered as a promising alternative to Response Evaluation Criteria in Solid Tumors (RECIST) to make tumor measurements more accurate and consistent, which would enable an earlier detection of temporal changes. In this article, we report the results of a pilot study aiming at evaluating the effects of a consensual lesion selection on volume-based response (VBR) assessments., Materials and Methods: Eleven patients with lung computed tomography scans acquired at three time points were selected from Reference Image Database to Evaluate Response to therapy in lung cancer (RIDER) and proprietary databases. Images were analyzed according to RECIST 1.1 and VBR criteria by three readers working in different geographic locations. Cloud solutions were used to connect readers and carry out a consensus process on the selection of lesions used for computing response. Because there are not currently accepted thresholds for computing VBR, we have applied a set of thresholds based on measurement variability (-35% and +55%). The benefit of this consensus was measured in terms of multiobserver agreement by using Fleiss kappa (κfleiss) and corresponding standard errors (SE)., Results: VBR after consensual selection of target lesions allowed to obtain κfleiss = 0.85 (SE = 0.091), which increases up to 0.95 (SE = 0.092), if an extra consensus on new lesions is added. As a reference, the agreement when applying RECIST without consensus was κfleiss = 0.72 (SE = 0.088). These differences were found to be statistically significant according to a z-test., Conclusions: An agreement on the selection of lesions allows reducing the inter-reader variability when computing VBR. Cloud solutions showed to be an interesting and feasible strategy for standardizing response evaluations, reducing variability, and increasing consistency of results in multicenter clinical trials., (Copyright © 2015 AUR. Published by Elsevier Inc. All rights reserved.)

Monitoring of molecular markers is indispensable for deciding subsequent treatment after acquired resistance to molecular-targeted therapy. According to results using re-biopsy, EGFR T790M mutation and overexpression of hepatocyte growth factor (HGF) are major mechanisms of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). The aim of the present study was to assess whether quantification of HGF using peripheral blood in addition to detection of T790M with plasma DNA is useful for monitoring as an alternative to invasive re-biopsy. HGF levels in plasma were determined using ELISA and T790M mutation was detected using mutation-biased PCR and quenched probe system (MBP-QP). The median level of HGF in plasma at baseline was 140 pg/ml and was significantly higher in the advanced stage of cancer and in smokers and predicted poor survival as determined using 315 plasma samples from 225 lung cancer patients. T790M was detected with plasma DNA in 9 of 16 patients who acquired resistance to EGFR-TKIs and a greater than 1.5-fold elevation compared with pretreatment HGF levels was observed in 6 patients after acquired resistance. Eleven of 16 patients (69%) showed either HGF elevation or T790M in plasma samples, with both outcomes observed in 25% of patients; this is consistent with results based on re-biopsy reported from other laboratories. Considering these results, assessing HGF and T790M using peripheral blood could be useful for monitoring mechanisms of acquired resistance to EGFR-TKIs.

A 54-year-old man was admitted to Saga University hospital with dyspnea on effort and a sensation of pressure in the chest. Chest CT images showed a low-density mass in the mediastinum surrounding the carina and left hilus, causing narrowing of both the left pulmonary artery and left main bronchus. The pathological findings from a surgical biopsy showed markedly fibrotic tissue with lymphocytes and plasmacytes, and we diagnosed idiopathic fibrosing mediastinitis, stage II. Oral glucocorticoid treatment of 30 mg/day prednisolone reduced the mass and improved the narrowing of the left pulmonary artery and left main bronchus. The patient was given low-dosage glucocorticoids as maintenance treatment. Previous reports indicated that idiopathic fibrosing mediastinitis with severe tissue fibrosis is difficult to control with glucocorticoid monotherapy. Here, we report a case of idiopathic fibrosing mediastinitis that was effectively treated with glucocorticoids.

KRAS mutations are detected in tumors of various organs, and they are also markers of resistance for epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors and monoclonal antibodies against the EGFR. Thus, the accurate and rapid detection of KRAS mutations is crucial, not only for screening, but also for the prediction of the efficacy of molecular-targeted therapy. The aim of the present study was to establish a novel automated detection system for KRAS mutations. One hundred and thirty-six lung adenocarcinoma patients were genotyped for KRAS mutations with both the conventional direct sequence (DS) method and with the newly developed quenching probe (QP) method that obtains data automatically within 60 min. The detection limit of the QP method using a control plasmid containing the KRAS mutation was 50 copies, and 10% mutant plasmid was detected in the mixture of wild-type and mutants. The results obtained by the QP and DS methods were identical in all but two of the 136 cases. The two differentially identified samples, which consisted of substantially fewer lung cancer cells, were positive according to the QP method but negative as determined by DS for KRAS mutations. These findings characterize the QP method as an accurate and rapid detection system for KRAS mutations.