Phase I Study Evaluating the Combination of Afatinib with Carboplatin and Pemetrexed After First-line EGFR-TKIs.

BACKGROUND/AIM: Promising reports have described the combination of first-generation epidermal growth factor receptor tyrosine-kinase inhibitors (EGFR-TKIs) with carboplatin plus pemetrexed or bevacizumab. However, no analysis of afatinib with platinum-doublet chemotherapies has been performed. PATIENTS AND METHODS: We evaluated the safety and antitumor efficacy of afatinib combined with carboplatin and pemetrexed in EGFR-mutated non-small-cell lung cancer (NSCLC) patients who progressed during first-generation EGFR-TKIs. RESULTS: Ten patients received 20 or 30 mg/day afatinib with carboplatin (area under the curve, 5) and pemetrexed (500 mg/m2). Dose-limiting toxicities included delay of afatinib ≥14 days, grade 3 diarrhea, grade 3 hypokalemia, grade 3 serum amylase increase and grade 4 thrombocytopenia. The recommended dose of afatinib was 20 mg/day in this combination therapy. Overall response rate was 30% and median progression-free survival was 13.7 months. CONCLUSION: This is the first study to investigate the combination of afatinib, carboplatin and pemetrexed. At the recommended dose, this combination was well tolerated and had a good clinical efficacy.

[Hange-Shashin-to for preventing diarrhea during afatinib therapy].

Afatinib is an epidermal growth factor receptor-tyrosine kinase inhibitor(EGFR-TKI). In a randomized phase III study(Lux- Lung 3 study)employing patients harboring EGFR mutations, patients administered afatinib show a significantly longer progression free survival time(PFS)than those administeredcombination chemotherapy comprising cisplatin andpemetrexed . However, most of the patients(95.2%)treatedwith afatinib experiencedd iarrhea. In the present report, 16 patients with EGFR mutations were treatedby afatinib at our institution from May 2014 to December 2014. Twelve patients were administered a diarrhea prevention herbal medicine, Hange-shashin-to. Seven of 12 patients(58%)had no diarrhea during the 28 days of therapy. All 4 of the patients who did not receive Hange-shashin-to experienced diarrhea above Grade 1 within 6 days of starting therapy. The rate of diarrhea differed significantly between the patients receiving and not receiving Hangeshashin- to. In conclusion, preventive administration of Hange-shashin-to may reduce the occurrence of diarrhea during afatinib treatment.

Enantioselective synthesis of imidazolines with quaternary stereocenters by organocatalytic reaction of N-(heteroarenesulfonyl)imines with isocyanoacetates.

An organocatalytic enantioselective Mannich-type reaction of isocyanoacetate with N-sulfonylimines catalyzed by chiral thioureas derived from quinine yielded 2-imidazolines with high diastereo- and enantioselectivities (up to >99:1 dr. and 96% ee). This reaction provided a convenient route to access various imidazolines and related α,ß-diamino acids having a quaternary carbon center in high enantiomeric purities.

[Ct findings of drug-induced pneumonitis--characteristic CT findings by histological group and subgroup].

We examined the chest CT results of 27 cases of drug-induced pneumonitis. We classified the subjects into 3 groups in accordance with the clinicopathological findings: eosinophilic pneumonia (EP) group (5 cases), diffuse alveolar damage (DAD) group (3 cases), and interstitial pneumonia (IP) group (19 cases). We evaluated the CT findings in each group, and made a further subclassification. In the EP group, the CT findings were subdivided into two, namely, type A, with diffuse distribution consistent with CT findings of acute eosinophilic pneumonia; and type B, with subpleural distribution consistent with chronic eosinophilic pneumonia. In the DAD group, the CT findings were diffuse distribution of mixed ground-glass attenuation and air-space consolidation, with or without traction bronchiectasis, and without shrinking of the lung. In the IP group, the CT findings were subdivided into 3, namely type A, with ground-glass attenuation dominant, without traction bronchiectasis or shrinking of the lung, consistent with the CT findings of IP without fibrosis; type B, with air-space consolidation dominant, with traction bronchiectasis and shrinking of the lung, consistent with the CT findings of IP with fibrosis; and type C with multiple nodules dominant. Radiological differentiation of the DAD group from IP-type B may be possible by the presence or absence of a shrinking lung pattern. We concluded that the subgroups of CT findings in drug-induced pneumonitis may be useful for diagnosis of this disease, and for prognosis.

[A case of combined hypersensitivity pneumonitis and bronchial asthma due to isocyanate (MDI)].

A 29-year-old man was admitted to our hospital complaining of cough, wheezing, dyspnea, and fever one month after handling paint spray containing isocyanate (MDI). Chest HRCT findings showed diffuse ground-glass attenuation in both lung fields. A pulmonary function test revealed restrictive impairment, and the reversibility test was positive. His symptoms, HRCT findings, and pulmonary dysfunction were improved only after the cessation of isocyanate administration. BALF showed lymphocytosis, and the pathological findings of the TBLB specimen revealed cellular alveolitis, but no Masson bodies or epitheloid cell granuloma. As a result of environmental provocation, fever, hypoxia, and reduced peak expiratory flow developed, and the environmental provocation test was positive. The specific antibodies against MDI and TDI were positive in both serum and BALF, and the lymphocyte stimulation test against MDI was positive in peripheral blood. Combined hypersensitivity pneumonitis and bronchial asthma due to isocyanate were therefore diagnosed. Pulmonary dysfunctions due to isocyanate are known to include bronchitis, bronchial asthma, and hypersensitivity pneumonitis. However, case reports of combined hypersensitivity pneumonitis and bronchial asthma due to isocyanate are rare.

[A case of chronic pigeon breeder's disease accompanied with progressive pulmonary cysts and recurrent pneumothorax].

We followed up a case of chronic pigeon breeder's disease with progressive pulmonary cysts and recurrent pneumothorax. The patient was a 48-year-old man who started to breed pigeons 14 years ago. He was diagnosed 7 years ago as having hypersensitivity pneumonitis due to pigeons, but he refused to stay away from the birds until he experienced episodes of dyspnea on exertion 3 years ago. A chest CT scan showed multiple cysts and peribronchial fibrosis in both lungs. The pathological findings of video-assisted-tracheoscopic surgery showed a centribronchial granuloma with lymphocyte infiltrations. Tests for antibodies against pigeon extracts of droppings were positive. Even after steroid treatment and avoidance of pigeons 3 years ago, there have been progressive cysts and fibrosis in the lungs. Progressive pulmonary cysts with recurrent pneumothorax is a rare manifestation as a chronic pigeon breeder's disease.

Increased serum thymidine kinase activity in acute sarcoidosis.

This is the first case report of acute sarcoidosis with increased serum thymidine kinase (TK) activity. A 43-year-old male presented fever, swelling of parotid glands, lymphadenopathy, and peripheral neuropathy. Sarcoidosis was pathologically diagnosed by lung and parotid gland biopsy. His serum TK, which was increased to 11.2 U/l at diagnosis (normal <5 U/l), normalized after glucocorticoid therapy. Serum TK has been considered as a good marker of the proliferative activity of various types of neoplasms. Its rise in sarcoidosis has, however, not been described. Because acute sarcoidosis sometimes resembles malignant lymphoma, the possible rise of serum TK in sarcoidosis may be worthy of note.

Stimulation of vascular endothelial growth factor gene transcription by all trans retinoic acid through Sp1 and Sp3 sites in human bronchioloalveolar carcinoma cells.

In this study, we examined the effects of all trans-retinoic acid (at-RA) on the vascular endothelial growth factor (VEGF) expression in human bronchioloalveolar carcinoma NCI-H322 cells to evaluate the potential of at-RA to affect tumor progression. Northern blot and enzyme-linked immunosorbent assay analyses indicate that VEGF production is significantly increased by 1 microM of at-RA. A series of 5'-deletion and site-directed mutation analyses indicated that G+C-rich sequence located at -81 and -52 was required for at-RA- and retinoic acid receptor alpha-mediated induction of VEGF promoter. Electrophoretic mobility shift and supershift assays showed that major constituents of nuclear factors binding to G+C-rich sequences are Sp1 and Sp3. Pretreatment with cycloheximide, a protein synthesis inhibitor, prevented the at-RA-mediated induction of VEGF mRNA expression. Likewise, at-RA-mediated VEGF expression was completely blocked in the presence of genistein, an inhibitor for tyrosine kinases. These results suggest that an increase in transcription of the VEGF promoter by at-RA is mediated through Sp1 site, and both new protein synthesis and tyrosine kinase activation are necessary for this induction. Because VEGF can promote neovascularization in cancer cells, an induction of VEGF by at-RA may preclude the therapeutic application of at-RA to cancer patients.

Inducible expression of endothelial PAS domain protein-1 by hypoxia in human lung adenocarcinoma A549 cells. Role of Src family kinases-dependent pathway.

Hypoxia is a potent inducer of tumor angiogenesis, the process of which is mostly mediated by induction of vascular endothelial growth factor (VEGF). In this study, we investigated the effect of hypoxia on the expression of hypoxia-inducible factor-1alpha (HIF-1alpha) and endothelial PAS domain protein-1 (EPAS1). These two similar but distinct basic helix-loop-helix-PAS proteins have been postulated to activate VEGF expression in response to hypoxia. We showed that EPAS1, but not HIF-1alpha, is abundantly expressed in human lung adenocarcinoma A549 cells. Exposure of cultured A549 cells to hypoxia increased EPAS1 mRNA and protein levels. A specific inhibitor for Src family kinases, PP1, abolished the hypoxia-induced expression of EPAS1. Transient transfection assays revealed that forced expression of EPAS1 increased the reporter gene activity driven by EPAS1 promoter as well as by VEGF promoter. Finally, overexpression of EPAS1 by infection of adenoviral vector expressing EPAS1 cDNA evidently induced the endogenous EPAS1 gene expression. Together, these data demonstrate Src family kinases mediate the hypoxia-mediated EPAS1 gene expression, which in turn positively autoregulates its own expression. Given an EPAS1 as a potent activator of the VEGF gene, these findings will provide a novel insight into the mechanisms underlying the enhancement of growth property of EPAS1-expressing tumor cells under the hypoxic environment.