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Immune checkpoint inhibitors, including the anti-CTLA-4 antibody ipilimumab, the anti-PD-1 antibodies nivolumab and pembrolizumab, and the anti-PD-L1 antibody atezolizumab had produced long-lasting tumor responses in several malignancies. Immune-related Adverse Events(irAEs)which are different from adverse events of conventional chemotherapy and molecular targeted therapy, occur as a consequence of impaired self-tolerance from loss of T-cell inhibition. The main irAEs of immune checkpoint inhibitors include dermatological, gastrointestinal, pulmonary, hepatic, endocrine, renal toxicities. Every organ system can be potentially involved, but nivolumab, pembrolizumab and atezolizumab have a different toxicity profile with fewer high grade events compared with ipilimumab. In this article, we provide an approach to appropriate management for each class of irAEs.

We report a case of tuberculous pleurisy that required differentiation from pleurisy caused by Mycoplasma infection. A 28-year-old woman presented to a clinic with fever and pain on the left side of her chest. A chest radiograph revealed pleural effusion in the left thorax, and the condition was diagnosed as bacterial pleurisy. The patient was referred to our hospital because of an increase in the pleural effusion despite antibiotic treatment. Mycoplasma infection was suspected because the patient was young, the white blood cell count was not elevated, and the result of the ImmunoCard Mycoplasma test (IC) for Mycoplasma pneumoniae-specific IgM antibodies was positive. However, the fever persisted even after treatment with azithromycin and pazufloxacin. The left pleural effusion was exudative, with lymphocytosis and high adenosine deaminase (ADA) levels. The results of the QuantiFERON test were positive. Therefore, tuberculous pleurisy was diagnosed, and the effusion subsided after treatment with standard anti-tuberculosis chemotherapy. Although detection of Mycoplasma infection using the IC is rapid and simple, the accuracy of this test is poor. The patient was first diagnosed with pleurisy of Mycoplasma origin because of a single high-particle agglutination titer of 1: 320 and because of the presence of exudative pleural effusion with lymphocytosis and elevated ADA levels, which has been reported in patients with Mycoplasma infection. The results of the IC test and the ADA level of the pleural effusion might not be reliable when distinguishing between tuberculous pleurisy and pleurisy caused by Mycoplasma infection.

Ocular tuberculosis is rare. We report a case of orbital myositis suspected to be infected with tuberculosis. In January 2008, a 34-year-old man experienced discomfort in the right eye. In May 2008, this patient developed right exophthalmos, diplopia, and pain in the right eye, and he was diagnosed with idiopathic orbital myositis. The patient underwent 2 courses of steroid pulse therapy; after which, the dosage of steroids was reduced. The steroid treatment reduced the eye pain, but his diplopia and exophthalmos persisted. By November of the same year, his general malaise had increased, and chest X-ray radiography and computed tomography were performed on 3rd December. On the basis of the imaging results, we suspected active pulmonary tuberculosis of the right upper lobe. The smear made by using the sample obtained after bronchial brushing was negative for acid-fast bacilli, but a Mycobacterium tuberculosis nucleic acid amplification test of the post-bronchoscopic sputum yielded positive results. Therefore, the patient was diagnosed with pulmonary tuberculosis. After the 2HREZ/7HR regimen of treatment, the extent of the tuberculosis lesions of the lung was reduced and the exophthalmos and eye pain were alleviated. Orbital myositis is inflammation of the extraocular muscles and can be either idiopathic, without a known etiology, or secondary to conditions such as tuberculosis, sarcoidosis, or hyperthyroidism. Our patient was not definitively diagnosed with tuberculosis of the eye. A definitive diagnosis of tuberculosis of the eye would require detection of granulomatous lesions in the eye or isolation of Mycobacterium tuberculosis by puncturing the eye muscles; however, our findings suggested the possibility that it was secondary to tuberculosis. We think that a careful examination of the chest should be performed for patients with ocular abnormalities.

The mechanisms of aging are still largely a mystery. However, recent studies using yeast, C. elegans, and Drosophila show that longevity can be altered by genetic manipulations. Moreover, drugs increase lifespan of these organisms have been identified. An anticonvulsant ethosuximide, antidepressants such as mianserin, antioxidants, an inhibitor of histone deacetylase, and resveratrol, a Sir2 activator, significantly extend lifespan of some organisms. Although these drugs have not been reported to extend lifespan of mammals, they provide molecular cues to elucidate aging mechanisms.

We here describe a case of multiple pyomyositis in a 62-year-old man who had systemic chemotherapy for recurrent lung cancer. His initial symptoms consisted of fever and general fatigue, followed by progressive pain and swelling in his extremities, which mimicked deep venous thrombosis along with bacterial infection. He was admitted to the hospital for intravenous administration of antibiotics. MRI appeared very useful to find the intramuscular fluid collections with circumferential inflammatory changes, which confirmed diagnosis of the multiple pyomyositis. Surgical drainage as well as intravenous administration of antibiotics worked very well and improved clinical symptoms in a few weeks after the treatments. He could resume normal activities with minimum functional impairments in the extremities. Pyomyositis should be kept in mind as one of the adverse effects after chemotherapy for malignant tumors.

Gefitinib (Iressa, ZD 1839) is an orally bioavailable small molecule that selectively inhibits epidermal growth factor receptor(EGFR) tyrosine kinase activity. Gefitinib causes a dramatic response in approximately 10% to 20% of patients with non-small-cell lung cancer (NSCLC) who receive prior chemotherapy. Studies of gefitinib in combination chemotherapy in first-line therapy of advanced NSCLC have, however, failed to show improvement of survival. Gefitinib also failed to prolong survival in a placebo controlled clinical trial for patients with pretreated advanced NSCLC. In addition, gefitinib did not improve survival as maintenance therapy after chemoradiation in patients with Stage III NSCLC. A possible explanation for the lack of a survival benefit seen in these studies might be failure to select of patients suitable for gefitinib treatment. Empirically, and also in phase II trials, a good clinical response has been observed most frequently in women, nonsmokers, patients with adenocarcinomas, and East Asian patients. Recently, mutations and amplifications of the EGFR gene identified in a subset of NSCLC have been reported to be useful for prediction of enhanced sensitivity to gefitinib. It is also known that some recurrent tumors have a secondary mutation in the EGFR kinase domain, T 790 M, conferring drug resistance. In Japan, a significant number of patients often develop fatal interstitial lung disease after the introduction of gefitinib, although it is, in general, well tolerated. In the future, we must demonstrated benefits of gefitinib treatment in prospective clinical trials by recruiting patients selected on the basis of biological characteristics. It is also important to further elucidate various issues that include other determinants of gefitinib sensitivity, other mechanisms of resistance to gefitinib or mechanisms or predictive factors of interstitial lung disease by close collaboration among clinicians and basic researchers.

The yeast silent information regulator 2 (Sir2) is an NAD-dependent histone deacetylase and silences transcription at the mating type loci, telomeres and the ribosomal DNA. Over-expression of Sir2 extends the life span of yeast and C. elegans, while Sir2 knockout shortened yeast life span to about 50%. Mammalian cells also express several Sir2 homologues. However, most of physiological functions of Sir2 homologues seem to be unknown. We found that Sir2 alpha (SIRT1) was highly expressed during embryogenesis. In the adult mouse brain, ependymal cells and some cells of subventricular zone expressed Sir2 alpha. To identify proliferating neural cells in the adult brain, BrdU was administered in the drinking water for 2 weeks. BrdU-positive and nestin-positive cells expressed Sir2 alpha. Furthermore, neurosphere cultured from E14 mouse striatum expressed Sir2 alpha. The expression of Sir2 alpha in neurosphere disappeared after differentiation. Nicotinamide, splitomicin and sirtinol, potent inhibitors of Sir2 alpha, inhibited the growth of neurosphere. FACS analysis showed that sirtinol did not increase sub-G1 population of cells. Differentiation of neurosphere into neuron and oligodendrocyte was inhibited by the addition of nicotinamide, splitomicin or sirtinol in the differentiation medium. These results suggest that Sir2 alpha has a pivotal role in the proliferation and differentiation of neural stem cells.

In order to determine the hepatic portions by cystic vein, we carried out abdominal angiography in 153 patients. The cystic vein was recognized in eleven patients, but only in nine cystic venous flow could be measured. In this group of patients, in which the cystic venous flow was detected, hepatic angiography was performed through the right hepatic artery (RHA) in six patients, the anterior branch of RHA in one patient, and the cystic artery in two patients. Simultaneously, angiographical CT was performed in five patients. As the results, it is presumed that the cystic venous flow perfused segment 4 portal branch (P4) + segment 5 (S5) in four patients, P4 in two patients, segment 6 portal branch (P6), S5 + right portal vein (RPV) + right hepatic vein (RHV), and S5 + RHV in one patient, respectively, and we concluded that in 70% of cases cystic venous flow perfused either P4 or S5.

K+ channels play pivotal roles in maintenance of the resting membrane potential, in the regulation of the action potential duration, repolarization of the membrane potential, inhibition of the cellular excitability and transport of K+ across the cell membrane. Various kinds of K+ channels have been cloned. Mammalian K+ channels can be classified into three families according to their number of putative membrane-spanning region, i.e., six-transmembrane type, four-transmembrane type and two-transmembrane type. Each family consists of many members. These K+ channels are differentially expressed in a variety of cells. The membranes of glial cells are mainly permeable to K+. This is because glial cells express an abundant number of K+ channels. Their main function has been supposed to be aspiration and transportation of extracellular K+, which is liberated from neurons by their excitation. This regulatory function of glial cells is proposed as a spatial buffering mechanism of K+. Recently, molecular level studies on K+ channels of glial cells have been initiated. In this review, we will overview the current understanding of the features and function of K+ channels in glial cells.

Seven cases (1.9%) of simultaneous bilateral pneumothoraces were found in a retrospective study of 377 patients with spontaneous pneumothorax during the period from July, 1977 to June, 1989. Their symptoms were essentially those of unilateral pneumothorax, but with more severe dyspnea. All but two cases, both young, had underlying pulmonary diseases. Three (two lung cancers and one metastatic lung disease) had malignant pulmonary disease. During this period, five lung cancer patients were complicated with pneumothorax, and two of them had simultaneous bilateral pneumothoraces. Therefore the frequency of bilateral pneumothoraces in the lung cancer patients associated with pneumothorax is high. In these three patients with malignant disease, tube drainage was carried out but all died of respiratory failure. Two senile patients had small bilateral pneumothoraces. Bed rest without invasive treatment led to successful cure. Two younger patients without underlying pathology initially underwent tube drainage, followed by operation. We conclude that many patients with simultaneous bilateral spontaneous pneumothoraces have underlying pulmonary disease, the frequency of lung cancer being particularly high. Young patients without underlying disease should be operated on following alleviation of symptoms by tube drainage. Older patients and patients with malignancy should be treated with great care and individually.

To evaluate the efficacy of a combined therapy of prednisolone and alprazolam for controlling cisplatin-induced delayed emesis, a study involving 14 non-small cell lung cancer patients receiving cisplatin (80 mg/m2) was conducted. Seven of these patients were given oral prednisolone at a dose of 30 mg/day for 5 days, then, 15 mg/day for 2 days, and with alprazolam at a dose 1.2 mg/day for 7 days. The other 7 patients were given an oral metoclopramide at a dose of 1 mg/kg/day for 5 days, and at 0.5 mg/kg/day for 2 days. All patients received 2 courses of chemotherapy and the same assigned regimen. Five of the 7 patients who had received prednisolone and alprazolam experienced no emesis, in contrast to only 1 patient who experienced no emesis from taking oral metoclopramide (p less than 0.05). Further, the duration of anorexia was shorter in those who received oral prednisolone with alprazolam. Thus, a combined therapy of oral prednisolone and alprazolam appears to be effective for controlling cisplatin-induced delayed emesis. Further evaluation and study, however, are necessary.