Shigenori Hoshino

Favorable response to crizotinib in three patients with echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase fusion-type oncogene-positive non-small cell lung cancer.

The echinoderm microtubule‐associated protein‐like 4 (EML4)–anaplastic lymphoma kinase (ALK) is a recently identified fusion‐type oncoprotein that exists in approximately 5% of non‐small cell lung cancer (NSCLC). It has been demonstrated that NSCLC driven by EML4‐ALK is strongly addicted to this fusion‐type oncokinase. A clinical trial of crizotinib (PF‐02341066) sponsored by Pfizer has proven this oncogene addiction in humans by demonstrating a high response rate to inhibition of ALK kinase activity. In the present study, we report on three cases harboring EML4‐ALK rearrangement who were enrolled in the trial (A8081001, NCT00585195). All three patients showed favorable responses to the ALK‐specific tyrosine kinase inhibitor. (Cancer Sci 2011; 102: 1602–1604)

Propionibacterium acnes‐induced hepatic granuloma formation is impaired in mice lacking tetraspanin CD9

The granuloma is a host defence response to persistent pathogenic irritants. In the process of granuloma formation, the activation, migration, and fusion of macrophages occur locally, but the mechanisms involved remain elusive. Tetraspanins regulate cell migration and fusion by organizing functional molecular complexes in membrane microdomains. Here we investigated the role of tetraspanin CD9 in hepatic granuloma formation. Immunostaining of the liver of untreated wild‐type mice showed that CD9 was expressed by vascular endothelial cells and perivenular hepatocytes. When intrahepatic granulomas were induced by intravenous injection of Propionibacterium acnes, hepatocyte CD9 was extensively upregulated, while inflammatory cells constituting granulomas were mostly negative for CD9. Compared with wild‐type littermates, CD9‐knockout mice showed dissemination of Propionibacterium acnes and reduced number and size of granulomas after the injection. Moreover, production of granuloma‐inducing cytokines, TNF‐α and IFN‐γ, was delayed and chemotactic activity for macrophages was suppressed in the liver of mutant mice. These results suggest that CD9 is one of the proteins that promotes granuloma formation in the liver. Copyright

Favorable response to trastuzumab plus irinotecan combination therapy in two patients with HER2-positive relapsed small-cell lung cancer

Small-cell lung cancer (SCLC) easily recurs with multidrug resistance phenotype. However, standard therapeutic strategies for relapsed-SCLC remain unestablished. Human epidermal growth factor receptor 2 (HER2) expression correlates with poor prognosis in extensive disease-SCLC. We have reported previously that HER2 expression is upregulated when HER2-positive SCLC cells acquire chemoresistance, and also demonstrated that trastuzumab exerts significant antitumor activity toward HER2-upregulated chemoresistant SCLC, mainly via antibody-dependent cell-mediated cytotoxicity mechanism. Based on these preclinical data, we treated two patients with HER2-positive SCLC by combination of trastuzumab (6 mg/kg, day 1) and irinotecan (80 mg/m(2), days 1 and 8) every 21 days as the third-line chemotherapy following two prior regimens, first-line carboplatin plus etoposide and second-line amrubicin. One patient achieved partial response after the first cycle and received 6 cycles in total without disease progression for 4.5 months. The other also received 4 cycles and kept stable disease for 3.5 months. This treatment can be continued safely at an outpatient clinic without any severe adverse event. In conclusion, trastuzumab plus irinotecan chemotherapy is promising and feasible against HER2-positive relapsed SCLC. Further clinical studies are encouraged to confirm the antitumor efficacy of trastuzumab in SCLC.

4-Hydroxy-2-nonenal induces endothelial cell injury via PKCdelta and biphasic JNK activation

Hydroxy-2-nonenal (4-HNE), a major product generated during oxidative stress, exhibits cytotoxic effects; however, the mechanisms of 4-HNE-induced endothelial cell injury are not well defined. To explore this issue, we examined how 4-HNE damages human umbilical vein endothelial cells (HUVECs) and found that 4-HNE induced biphasic activation of c-Jun N-terminal kinase (JNK). Both pre- and post-treatment of HUVECs with SP600125, a spe- cific JNK inhibitor, significantly suppressed the cytotoxic effects of 4-HNE. Inhibition of protein kinase Cδ (PKCδ), which was also phosphorylated by 4-HNE, reduced endothelial cell injury as well as late-phase JNK phosphorylation elicited by 4-HNE. Inversely, pre-treatment of HUVECs with SP600125 suppressed PKCδ activation. Taken together, these results support the concept that 4-HNE induces vascular endothelial cell injury by the interac- tion between biphasic JNK activation and the PKCδ pathway.

Successful Multimodal Treatment in a Patient with Thymoma Accompanied by Hepatic Metastasis

Despite a benign histologic appearance, thymomas have metastatic potential. Here we report a case of a patient with a Masaoka stage IVb thymoma who was successfully treated using a multimodal strategy including systemic chemotherapy, radiofrequency ablation, and thoracic surgery. Despite complete remission after treatment, the patient developed myasthenia gravis with ptosis and neck drop symptoms. Hepatic metastasis of thymoma is a relatively rare occurrence and, to the best of our knowledge, this is the first report about the application of radiofrequency ablation to thymoma.

Anti-fibrotic Effects of ONO-EF-345, a Specific Phosphodiesterase IV inhibitor, on Lung Fibroblasts

Phosphodiesterase (PDE) IV inhibitors have been shown to inhibit various inflammatory reactions in pulmonary diseases such as bronchial asthma and chronic obstructive lung diseases (COPD). However, there have been no studies evaluating the effect of PDE IV inhibitors on airway fibrosis, which is a critical feature of airway remodeling in asthma and COPD. We therefore examined whether ONO-EF-345 (ONO), a PDE IV inhibitor, affected the function of lung fibroblasts. ONO suppressed TGF-β-induced type I collagen (COL1) mRNA expression in lung fibroblasts and also inhibited TGF-β-induced α- smooth muscle actin (SMA) protein expression. ONO did not affect Smad2 phosphorylation or Smad7 expression. However, ONO reduced JNK and p38 activation, which regulates TGF-β-induced COL1 expression. These results indicate that PDE IV inhibitors exert anti-fibrotic effects through the JNK and/or p38 pathways.

IL-10 Inhibits Transforming Growth Factor-ß-Induction of Type I Collagen mRNA Expression via Both JNK and p38 Pathways in Human Lung Fibroblasts

Transforming growth factor-β (TGF-β) is a key factor for understanding the pathogenesis of fibrotic disorders such as idiopathic pulmonary fibrosis (IPF). We have demonstrated that interleukin-10 (IL-10) suppresses TGF-β-induced expression of type I collagen (COL1) mRNA in a human lung fibroblast cell line (WI-38). However, the inhibitory mechanism has not yet been clearly elucidated. Thus, in the current study, we investigate the effects of IL-10 blockade of TGF-β signaling which regulates COL1 mRNA expression. In WI-38 cells, IL-10 inhibits TGF-β-mediated phosphorylation of both, c-Jun HN2-terminal kinase (JNK) and p38, but does not suppress TGF-β-mediated phosphorylation of Smad2 or affect TGF-β-upregulation of Smad7 mRNA expression. In addition, SP600125 and SB203580, specific inhibitors of JNK and p38, respectively, attenuate TGF-β-induced COL1 mRNA expression in WI-38 cells. These results suggest that IL-10 inhibits TGF-β-induced COL1 mRNA expression via both JNK and p38 pathways but not Smad pathways in WI-38 cells. This inhibitory mechanism may provide a novel insight into therapeutic strategies for fibrotic disorders such as IPF.