In isolated rat pancreatic beta-cells, hypotonic stimulation elicited an increase in cytosolic Ca(2+) concentration ([Ca(2+)](c)) at 2.8 mM glucose. The hypotonically induced [Ca(2+)](c) elevation was significantly suppressed by nicardipine, a voltage-dependent Ca(2+) channel blocker, and by Gd(3+), amiloride, 2-aminoethoxydiphenylborate, and ruthenium red, all cation channel blockers. In contrast, the [Ca(2+)](c) elevation was not inhibited by suramin, a P(2) purinoceptor antagonist. Whole cell patch-clamp analyses showed that hypotonic stimulation induced membrane depolarization of beta-cells and produced outwardly rectifying cation currents; Gd(3+) inhibited both responses. Hypotonic stimulation also increased insulin secretion from isolated rat islets, and Gd(3+) significantly suppressed this secretion. Together, these results suggest that osmotic cell swelling activates cation channels in rat pancreatic beta-cells, thereby causing membrane depolarization and subsequent activation of voltage-dependent Ca(2+) channels and thus elevating insulin secretion.

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Objective: Trastuzumab emtansine significantly improved progression-free survival and overall survival when compared with lapatinib-capecitabine in pretreated human epidermal growth factor receptor 2-positive advanced breast cancer. However, data in Japanese populations are limited. Methods: In the single-arm Phase II JO22997 study, Japanese patients with human epidermal growth factor receptor 2-positive inoperable locally advanced/recurrent or metastatic breast cancer previously treated with at least one prior chemotherapy regimen for locally advanced/recurrent or metastatic breast cancer and trastuzumab in any setting received 3.6 mg/kg trastuzumab emtansine every 3 weeks until progression, unacceptable toxicity or consent withdrawal. The primary endpoint was Independent Review Committee-assessed objective response rate. Secondary endpoints included progression-free survival, overall survival, safety and pharmacokinetics. Results: The objective response rate in 73 treated patients was 38.4% (90% confidence interval, 28.8-48.6%), exceeding the prespecified boundary for an objective response rate > 20%. After 6.5 months' median follow-up, median progression-free survival was 5.6 months (95% confidence interval, 4.6-8.2). After 28.9 months' median follow-up, median overall survival was 30.5 months (95% confidence interval 25.2-not reached). There were no treatment-related deaths. The most common Grade 3/4 adverse events were thrombocytopenia (22%) and aspartate aminotransferase elevations (14%). Thrombocytopenia did not require platelet transfusion and typically recovered before the next cycle. There were no substantial differences in trastuzumab emtansine or trastuzumab pharmacokinetic parameters between this study and previous data from non-Japanese patients. Conclusions: JO22997 results suggest high activity of trastuzumab emtansine in Japanese patients, a safety profile consistent with previous studies in non-Japanese patients, no new safety signals and no evidence of pharmacokinetic differences between Japanese and non-Japanese populations. These results support trastuzumab emtansine therapy for Japanese patients with chemotherapyand trastuzumab-pretreated human epidermal growth factor receptor 2-positive locally advanced/ recurrent or metastatic breast cancer.

Bevacizumab-paclitaxel efficacy in Japanese patients was consistent with the MERiDiAN ITT population. No new safety signals were seen and tolerability was consistent with previous experience.

Abstract. Background/Aim: Tolerability and safety of trastuzumab emtansine (T-DM1) was investigated inThe human epidermal growth factor receptor 2 (HER2) has been shown to play an important role in the development and progression of certain types of breast cancer. HER2 is overexpressed in ~20% of patients with breast cancer and is associated with a more aggressive tumor growth and poor clinical outcome (1-3). Since trastuzumab, an anti-HER2 humanized monoclonal antibody, demonstrated the significant survival benefit in patients with HER2-positive metastatic breast cancer (4), combination of anti-HER2 therapy with standard chemotherapy has been used as an effective therapeutic approach for patients with HER2-positive advanced breast cancer. In addition, dual blockade of HER2 with combination of pertuzumab and trastuzumab plus chemotherapy showed significant improvement in overall survival compared to trastuzumab plus chemotherapy (5). To date, several novel anti-HER2 therapeutic agents, including trastuzumab, lapatinib, pertuzumab, and trastuzumab emtansine, have been developed.Trastuzumab emtansine, known as T-DM1, is an antibody drug conjugate incorporating trastuzumab with microtubuleinhibitory agent DM1 (derivative of maytansine); the anti-HER2 antibody and cytotoxic agent are conjugated via a 493 This article is freely accessible online.