Treatment Strategy for Recurrent and Refractory Epithelial Ovarian Cancer: Efficacy of High-Dose Chemotherapy with Hematopoietic Stem Cell Transplantation

According to population statistics in Japan, approximately 3,800 women die of ovarian ­cancer annually, and approximately 6,000 are affected by this disease. Ovarian cancer is ­referred to as a “silent tumor”, since patients have few subjective symptoms and by the time symptoms are observed, the cancer has progressed to Stage III or IV in about half of the patients. The basic treatment for advanced epithelial ovarian cancer is to remove as much of the tumor as possible, and subsequently to perform anticancer therapy using drugs such as cisplatin, carboplatin and paclitaxel, all of which have been shown to be effective for epi­thelial ovarian cancer. However, the 5-year survival rate in advanced ovarian cancer patients is still only about 20%, and a treatment that leads to long-term survival has yet to be developed. Here, we review the available treatments for ovarian cancer, and present the results of high-dose chemotherapy (HDC) performed in our hospital for recurrent and refractory ­ovarian cancer

Aprepitant plus granisetron and dexamethasone for prevention of chemotherapy-induced nausea and vomiting in patients with gastric cancer treated with S-1 plus cisplatin

Background: We aimed to evaluate the efficacy of a new combination antiemetic therapy comprising aprepitant, granisetron, and dexamethasone in gastric cancer patients undergoing chemotherapy with cisplatin and S-1. Methods: Gastric cancer patients scheduled to receive their first course of chemotherapy with cisplatin (60 mg/m2) and S-1 (80 mg/m2) were treated with a new combination antiemetic therapy aprepitant, granisetron, and dexamethasone on day 1; aprepitant and dexamethasone on days 2 and 3; and dexamethasone on day 4. The patients reported vomiting, nausea, use of rescue therapy, and change in the amount of diet intake, and completed the Functional Living Index-Emesis (FLIE) questionnaire. The primary endpoint was complete response (CR; no emesis and use of no rescue antiemetics) during the overall study phase (0-120 h after cisplatin administration). The secondary endpoints included complete protection (CP; CR plus no significant nausea); change in the amount of diet intake; and the impact of chemotherapy-induced nausea and vomiting (CINV) on daily life during the overall, acute (0-24 h), and delayed (24-120 h) phases. Results: Fifty-three patients were included. CR was achieved in 88.7, 98.1, and 88.7 % of patients in the overall, acute, and delayed phases, respectively. The corresponding rates of CP were 67.9, 96.2, and 67.9 %. Approximately half of the patients had some degree of anorexia. FLIE results indicated that 79.5 % of patients reported "minimal or no impact of CINV on daily life". Conclusions: Addition of aprepitant to standard antiemetic therapy was effective in gastric cancer patients undergoing treatment with cisplatin and S-1. © 2013 Springer Japan

Comparative Bioequivalence of Tablet and Capsule Formulations of Ulotaront and the Effect of Food on the Pharmacokinetics of the Tablet Form in Humans

Abstract Introduction Ulotaront (SEP-363856), a dual trace animeassociated receptor 1 (TAAR1) and 5-HT1A receptor agonist, is in phase 3 clinical development for the treatment of schizophrenia. This study evaluated the comparative bioequivalence (BE) between tablet and capsule formulations of ulotaront and the food effect (FE) on pharmacokinetics (PK) of tablet form in healthy adult human subjects. Methods The BE study applied an open-label two-period crossover design in 24 healthy volunteers. Subjects were randomly assigned (1:1) to dosing sequence AB or BA (A, 25 mg ulotaront tablet; B, 25 mg ulotaront capsule). The FE study also used an open-label randomized two-period crossover design in 20 healthy volunteers. Subjects were fasted overnight then randomly assigned (1:1) to dosing sequence AB or BA (A, fasted condition; B, fed condition). Dosing periods were separated by 1 week for both studies. Serial plasma samples from each period were collected and analyzed by LC–MS/MS. PK parameters were calculated using Phoenix WinNonlin® software. Results For the BE study, geometric mean ulotaront C max values were 93.28 and 86.98 ng/mL for tablet and capsule, respectively. C max ratio was 107.25% (90% CI 101.84–112.94%). Geometric mean ulotaront area under the plasma concentration–time curve from time 0 to infinity (AUC0–∞) values were 868.8 and 829.3 ng·h/mL for tablet and capsule, respectively. AUC0–∞ ratio was 104.76% (90% CI 100.68109.01%). For the FE study, geometric mean ulotaront C max was 157.89 and 157.95 ng/mL under fed and fasted conditions, respectively. Geometric mean ratio of C max was 99.96% (90% CI 94.48–105.77%). Geometric mean ulotaront AUC0–∞ was 1584.2 ng·h/mL fed and 1589.2 ng·h/mL fasted. Geometric mean ratio for AUC0–∞ was 99.69% (90% CI 95.02–104.58%). There was a delay in t max (median difference 1.47 h) in the fed condition. Conclusions The results showed geometric mean ratios and 90% CIs for both C max and AUC0–∞ for ulotaront were well within typical bioequivalence criteria of 80–125% for both the BE and FE studies, thereby confirming the bioequivalence of the two dosage forms and no significant food effect

A Polymorphism in MAPKAPK3 Affects Response to Interferon Therapy for Chronic Hepatitis C

Background & Aims: This study aimed to identify host single nucleotide polymorphisms (SNPs) that are associated with the efficacy of interferon (IFN) therapy in patients with chronic hepatitis C. Methods: We examined whether 116 tagging-SNPs from 13 genes that are involved in type I IFN signaling associate with the outcome of IFN therapy in Japanese case-control groups; the study included 468 sustained responders and 587 nonresponders. Results: We identified 2 SNPs (rs3792323 [A/T] and rs616589 [G/A]), located in intron 2 of mitogen-activated protein kinase-activated protein kinase 3 (MAPKAIPK3) that were associated with the outcome of IFN therapy in patients infected with hepatitis C virus (HCV) genotype 1b (P = 4.6 X 10(-5) and 4.8 X 10(-5), respectively). The 2 SNPs were in strong linkage disequilibrium and multivariate logistic regression analysis showed that rs3792323 is an independent factor associated with the IFN efficacy (genotype 1b; P =.0011). MAPKAPK3 is a kinase involved in the mitogen and stress responses, but the biological significance of MAPKAPK3 in IFN responses is poorly understood. By using an allele-specific transcript quantification assay in liver biopsy, we showed that allelespecific expression of MAPKAPK3 messenger RNA, corresponding to the risk allele for nonresponse, was significantly higher than that of the other allele. Luciferase reporter assay data indicated that overexpression of MAPKAPK3 inhibits IFN-alfa-induced gene transcription via IFN-stimulated response element and IFN gamma-activated site. Conclusions: The SNP rs3792323 in MAPKAPK3 associates with the outcome of IFN therapy in patients with HCV genotype 1b. Our functional analyses indicate that MAPKAPK3 inhibits IFN-alfa-induced antiviral activity

Sensing Bacterial Flagellin by Membrane and Soluble Orthologs of Toll-like Receptor 5 in Rainbow Trout (Onchorhynchus mikiss)

Rainbow trout (Onchorhynchus mikiss) possess two genes encoding putative leucine-rich repeat (LRR)-containing proteins similar to human TLR5. Molecular cloning of these two LRR proteins suggested the presence of a TLR5-like membrane form (rtTLR5M) and a soluble form (rtTLR5S). Here we elucidated the primary structures and the unique combinational functions of these fish versions of TLR5. The LRR regions of rtTLR5S and rtTLR5M exhibited 81% homology and relatively high (35.6 and 33.7%) homology to the extracellular domains of human TLR5 (huTLR5). Thus, two distinct genes encode the TLR5 orthologs in fish, one of which has a consensus intracellular domain (TIR). In order to test their functions, we constructed fusion proteins with the LRR region of rtTLR5S (S-chimera) or that of rtTLR5M and the TIR of huTLR5 (M-chimera). The S- and M-chimeras expressed in HeLa or CHO cells signaled the presence of Vibrio anguillarum flagellin, resulting in NF-κB activation. rtTLR5M was ubiquitously expressed, whereas rtTLR5S was predominantly expressed in the liver. In the hepatoma cell lines of the rainbow trout RTH-149, stimulation of rtTLR5M with V. anguillarum or its flagellin allowed the up-regulation of rtTLR5S. Flagellin-mediated NF-κB activation was more significant in the presence of or simultaneous expression of rtTLR5S. Therefore, a two-step flagellin response occurred for host defense against bacterial infection in fish: (a) flagellin first induced basal activation of NF-κB via membrane TLR5, facilitating the production of soluble TLR5 and minimal acute phase proteins, and (b) the inducible soluble TLR5 amplifies membrane TLR5-mediated cellular responses in a positive feedback fashion.Molecular Basis of Cell and Developmental Biolog