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We conducted a nationwide retrospective analysis of 116 hepatitis B virus (HBV) surface antigen (HBsAg)‐positive patients with diffuse large B‐cell lymphoma (DLBCL) and 278 HBsAg‐negative patients with DLBCL, as a control cohort, who received rituximab‐containing regimens as an induction chemotherapy at 30 Japanese medical centers between January 2004 and December 2014. Hepatitis was defined as an absolute serum alanine aminotransferase (ALT) level of ≥100 U/L. HBV reactivation‐related hepatitis was defined as hepatitis with an absolute serum HBV DNA level of ≥3.3 log IU/mL or an absolute increase of ≥2 log compared with the baseline value. HBsAg‐positive patients were divided into three groups based on anti–HBV prophylactic therapy: no nucleos(t)ide analogue (non–NA, n = 9), lamivudine (LAM, n = 20), and entecavir (ETV, n = 87). The 4‐year cumulative incidence (CI) of hepatitis in HBsAg‐positive and HBsAg‐negative patients was 21.1% and 14.6% (P = .081), respectively. The 4‐year CI of HBV reactivation‐related hepatitis was higher in HBsAg‐positive patients than in HBsAg‐negative patients (8.0% vs 0.4%; P, Prophylactic use of entecavir reduced HBV‐related hepatitis and mortality in HBsAg‐positive DLBCL treated with R‐chemotherapy. The 4‐year overall survival rate in HBsAg‐positive DLBCL patients receiving prophylactic entecavir was similar to that in HBsAg‐negative DLBCL.

The efficiency of upfront consolidation with high‐dose chemotherapy/autologous stem‐cell transplantation (HDCT/ASCT) for newly diagnosed high‐risk diffuse large B‐cell lymphoma (DLBCL) may be influenced by induction chemotherapy. To select better induction chemotherapy regimens for HDCT/ASCT, a randomized phase II study was conducted in high‐risk DLBCL patients having an age‐adjusted International Prognostic Index (aaIPI) score of 2 or 3. As induction chemotherapy, 6 cycles of R‐CHOP‐14 (arm A) or 3 cycles of R‐CHOP‐14 followed by 3 cycles of CHASER (arm B) were planned, and patients who responded proceeded to HDCT with LEED and ASCT. The primary endpoint was 2‐y progression‐free survival (PFS), and the main secondary endpoints included overall survival, overall response rate, and adverse events (AEs). In total, 71 patients were enrolled. With a median follow‐up of 40.3 mo, 2‐y PFS in arms A and B were 68.6% (95% confidence interval [CI], 50.5%‐81.2%) and 66.7% (95% CI: 48.8%‐79.5%), respectively. Overall survival at 2 y in arms A and B was 74.3% (95% CI: 56.4%‐85.7%) and 83.3% (95% CI: 66.6%‐92.1%). Overall response rates were 82.9% in arm A and 69.4% in arm B. During induction chemotherapy, 45.7% and 75.0% of patients in arms A and B, respectively, had grade ≥ 3 non‐hematologic toxicities. One patient in arm A and 6 in arm B discontinued induction chemotherapy due to AEs. In conclusion, R‐CHOP‐14 showed higher 2‐y PFS and less toxicity compared with R‐CHOP‐14/CHASER in patients with high‐risk DLBCL, suggesting the former to be a more promising induction regimen for further investigations (UMIN‐CTR, UMIN000003823)., The efficiency of upfront consolidation with high‐dose chemotherapy/autologous stem‐cell transplantation (HDCT/ASCT) for newly diagnosed high‐risk diffuse large B‐cell lymphoma (DLBCL) may be influenced by induction chemotherapy. To select better induction chemotherapy regimens for HDCT/ASCT, a randomized phase II study was conducted in patients with high‐risk DLBCL who had an age‐adjusted International Prognostic Index (aaIPI) score of 2 or 3. R‐CHOP‐14 showed higher 2‐y PFS and less toxicity compared with R‐CHOP‐14/CHASER in patients with high‐risk DLBCL, suggesting the former to be a more promising induction regimen for further investigations.

Background Circulating interferon-γ (IFN-γ) concentration may be sustained at a high level regardless of the initiation of antiretroviral therapy (ART) in some patients with HIV-1 infection. In the present study, we examined the clinical characteristics of HIV-1-infected patients with high levels of plasma IFN-γ. Methods The study subjects were patients infected with HIV-1 who were either naïve to ART with CD4+ cell count > 200 cells/μL (n = 12), or had achieved viral suppression after ART for over a year (n = 188). The levels of plasma IFN-γ and interleukin-6 (IL-6) were measured by the enzyme-linked immunosorbent assay. Patients were divided into high IFN-γ and low IFN-γ groups based on a cutoff level of 5 pg/mL. Results The high IFN-γ group included 41 patients (21%). Compared to the patients on ART with low IFN-γ levels, those on ART in the high IFN-γ group were more likely to be younger than 50 years of age (P = 0.0051) and less likely to have dyslipidemia (P = 0.0476) or to be on a protease inhibitor (P = 0.0449). There was no significant difference between groups in the median increase of CD4+ cell counts from the initiation of ART for up to 3 years. However, after 4 years, the increase in CD4+ cell counts was significantly lower in the high IFN-γ group compared with that in the low IFN-γ group. There were no such significant differences between patients with low and high (> 2 pg/mL) levels of plasma IL-6. Conclusion We concluded that HIV-1-infected patients with high levels of circulating IFN-γ did not have a higher rate of comorbidities related to immune activation. However, they exhibited lower CD4+ cell count recovery after 4 years of being on ART. This deficit could be a consequence of persistent immune activation. Electronic supplementary material The online version of this article (10.1186/s12879-018-3643-2) contains supplementary material, which is available to authorized users.

Hepatitis B virus (HBV) surface antigen (HBsAg)-positive patients treated with anti-B-cell lymphoma therapy are at high risk of HBV reactivation; indeed, the incidence is as high as 60-80% without antiviral prophylaxis. Hepatitis caused by HBV reactivation usually leads to discontinuation of chemotherapy, which in itself may be fatal. Therefore, several guidelines recommend antiviral prophylaxis for HBsAg-positive patients treated with chemotherapy. However, there is limited evidence regarding the clinical impact of antiviral prophylaxis on HBV reactivation and subsequent hepatitis and long-term outcome, particularly in patients treated with rituximab (R)-containing regimens. To answer these questions, we conducted a nationwide multicenter retrospective analysis for HBsAg-positive patients with diffuse large B-cell lymphoma (DLBCL) treated with R-chemotherapy. Data were collected from HBsAg-positive patients with DLBCL who received R-CHOP or R-THP-COP regimens as an initial chemotherapy (regardless of steroid use) at 29 participating institutions between January 2004 and December 2014. Key exclusion criteria were as follows: seropositive for HCV or HIV; alanine transaminase (ALT) levels ≥ 100 U/L at the time of diagnosis; and a history of decompensated cirrhosis or hepatocellular carcinoma. Medical data were also obtained for HBsAg-negative DLBCL patients (controls), regardless of anti-HBc or anti-HBs seropositivity; these patients were diagnosed within 2 month (before and after 1 month) of the diagnosis date of each HBsAg-positive patient. Hepatitis was defined as an absolute serum ALT level of ≥ 100 U/L. HBV reactivation-related hepatitis was defined as hepatitis accompanied by an absolute serum HBV DNA level of ≥ 3.3 Log IU/mL or an absolute increase of ≥ 2 Log compared with the baseline value. Statistical analysis was performed at the Japanese Data Center for Hematopoietic Cell Transplantation using Stata software Version 13.1 and EZR 1.35. The study was registered at UMIN (ID: 000025574). A total of 394 patients were eligible: 116 (29.4%) were HBsAg-positive and 278 (70.6%) were HBsAg-negative. The baseline characteristics of the two cohorts were similar; exceptions was HBV status (Table). R-CHOP was the most common regimen (n=337, 85.5%), followed by R-THP-COP (n=57, 14.5%). For HBsAg-positive patients with detectable and quantifiable HBV DNA (n=65, 56.0%), the median baseline HBV DNA level was 2.9 Log IU/mL (interquartile range, 2.0-3.7). HBsAg-positive patients were divided into three groups based on prophylactic nucleoside analogue (NA) therapy: no prophylactic therapy (non-NA, n=9), prophylactic therapy with lamivudine (LAM, n=20), and prophylactic therapy with entecavir (ETV, n=87). Of the HBsAg-negative patients, 64 (23.0%) were seropositive for anti-HBc or anti-HBs. The median follow-up time for HBsAg-positive and HBsAg-negative patients was 4.3 years and 4.5 years, respectively. The 4-year cumulative incidence of hepatitis in HBsAg-positive and HBsAg-negative patients was 21.1% (95% confidence interval (CI): 14.1-28.9%) and 14.6% (95% CI: 10.7-19.2%), respectively (p=0.081). Importantly, the 4-year cumulative incidence of HBV reactivation-related hepatitis was higher in HBsAg-positive patients than in HBsAg-negative patients (8.0% (95% CI: 3.9-14.0%) vs. 0.4% (95% CI: 0.0-2.0%, respectively; p Prophylactic use of entecavir reduced the incidence of HBV reactivation-related hepatitis and reduced mortality associated with HBV reactivation-related hepatitis in HBsAg-positive patients with DLBCL treated with R-chemotherapy. Disclosures Maruyama: Abbvie: Research Funding; Nippon Boehringer Ingelheim: Research Funding; Pfizer: Research Funding; Amgen Astellas BioPharma: Research Funding; Kyowa Hakko Kirin: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Fujifilm: Honoraria, Research Funding; MSD: Honoraria, Research Funding; Novartis: Research Funding; GlaxoSmithKline: Research Funding; Chugai Pharma: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Biomedis International: Honoraria, Research Funding; Solasia Pharma: Research Funding; AstraZeneca: Research Funding; Asahi Kasei Pharma: Honoraria; Dai-Nippon-Sumitomo: Honoraria; Zenyaku Kogyo: Honoraria, Research Funding; Mundipharma International: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Astellas Pharma: Research Funding; Otsuka: Research Funding; Dai-ichi-Sankyo: Honoraria. Yamamoto:Bristol-Myers Squibb: Honoraria. Igarashi:Eisai Co Ltd.: Research Funding; Celltrion Inc.: Research Funding; Zenyaku-Kogyo Co.Ltd.: Research Funding; Sanofi K.K.: Research Funding. Izutsu:Takeda: Honoraria, Research Funding; Zenyaku: Research Funding; Amgen: Research Funding; Gilead Sciences: Honoraria; Solasia: Research Funding; Sanofi: Research Funding; Otsuka: Honoraria; Mundhi: Honoraria; Kyowa Hakko Kirin: Honoraria; Abbvie: Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Symbio: Research Funding; Celltrion: Research Funding; Chugai: Honoraria, Research Funding; Nihon Medi-Physics: Honoraria; MSD: Honoraria; Celgene: Consultancy, Research Funding; Bristol- Myers Squibb: Honoraria; Daiichi Sankyo: Honoraria, Research Funding; Astellas: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; HUYA Bioscience International: Research Funding; Eisai: Honoraria, Research Funding; Novartis: Honoraria; Ono: Honoraria, Research Funding; Meiji Seika: Honoraria; Shionogi: Honoraria; Asahi Kasei: Honoraria. Uchida:Nippon Shinyaku: Honoraria; Pfizer: Honoraria; Bristol-Myers Squibb: Honoraria; Meiji Seika Pharma: Honoraria; Mundipharma: Honoraria; Celgene: Honoraria; Teijin: Honoraria; Novartis: Honoraria; Janssen Pharma: Honoraria; Takeda Pharmaceutical: Honoraria; Otsuka Pharmaceutical: Honoraria; Eisai: Honoraria; Kyowa Hakko Kirin: Honoraria; Chugai Pharmaceutical: Honoraria. Tsukamoto:Chugai: Research Funding; Eisai: Research Funding; Pfizer: Research Funding; Kyowa-Kirin: Research Funding. Nosaka:Celgene Co. LTD.,: Honoraria; Chugai Pharmaceutical Co.LTD.,: Honoraria; Kyowa Kirin Pharmaceutical Development, Inc.,: Honoraria; Eisai Co. Ltd.,: Honoraria; Ono Pharmaceutical Co.LTD.: Honoraria; Bristol-Myers Squibb: Honoraria. Ueda:Rikaken Co. Ltd.: Research Funding; Medical and Biological laboratories Co. Ltd.: Research Funding; Chugai Pharmaceutical Co. Ltd.: Research Funding; Kyowa Hakko Kirin Co. Ltd.: Honoraria, Research Funding; Terumo Co.: Consultancy; Ono Pharmaceutical Co.: Consultancy, Honoraria, Research Funding; Mundipharma K.K.: Consultancy. Mizokami:Sysmex Corporation: Honoraria; Gilead Sciences: Honoraria. Kusumoto:Bristol-Myers Squibb: Honoraria, Research Funding; Chugai Pharmaceutical Co. Ltd: Honoraria, Research Funding; Kyowa Hakko Kirin: Honoraria, Research Funding.

High human herpesvirus 8 (HHV-8) seroprevalence has been reported in men who have sex with men (MSM) and are infected with HIV-1. However, it is unclear when they become infected with HHV-8. Thus, we conducted cross-sectional and longitudinal investigations of HHV-8 seroprevalence in HIV-1-infected individuals in Osaka, Japan.Plasma was collected from 121 individuals infected with HIV-1 and the anti-HHV-8 antibody titer was measured using an enzyme-linked immunosorbent assay with whole virus lysate. Subjects were classified into those with and without a past medical history of HHV-8-associated disease; the latter group was then classified into 3 subgroups based on the assumed route of HIV-1 infection: blood products, homosexual contact, and other routes. HHV-8 seroprevalence was compared among the groups and measured again approximately 3 years after the baseline measurement. The relationship between HHV-8 seropositivity and possible associated factors was also investigated.All 15 subjects with HHV-8-associated disease were seropositive, and all 11 subjects in the blood product group were seronegative. In the MSM group, 25 (30%) of 79 subjects were HHV-8 seropositive and, in the non-MSM group, 1 (6%) of 16 subjects was (p 0.0001). In the longitudinal investigation, seroconversion was observed in 10 (19%) of 52 subjects in the MSM group who were seronegative at baseline. A correlation was observed between seroconversion and symptomatic syphilis (p = 0.0432).HHV-8 seropositivity and seroconversion rates were high in HIV-1-infected MSM, suggesting that, currently, HHV-8 is an epidemic pathogen in this population.

To assess the effect of pre-germinated brown rice on metabolism of glucose and lipids, blood parameters of glucose and lipids were measured before and after 3 months of intake of test rice, which was mixed with Pre-germinated brown rice (PGBR) and white rice in a ratio of 1:1, in patients with diabetes mellitus type 2 (DM). Glycosylated hemoglobin A1c (HbA1c) was significantly decreased from 6.40+-0.23% to 6.23+-0.19 after 3 months of intake of PGBR. The fasting plasma glucose level was not changed by intake of PGBR, but serum insulin level and HOMA-IR were decreased slightly. As the decrease of LDL-cholesterol (LDL-c) and the increase of HDL-cholesterol (HDL-c) were slightly observed after 3 months of intake of PGBR, the LDL-c/HDL-c ratio was decreased significantly from 2.03+-0.13 to 1.83+-0.12. These changes were significantly larger in the high PGBR in take group than in the low PGBR in take group. These results suggested that the PGBR intake might have potentialities as one of therapeutic methods for diabetes mellitus type 2 and also be useful in the treatment of hypercholesterolemia.

Epoxyeicosatrienoic acids (EETs), including 5,6-EET, 8,9-EET, 11,12-EET, and 14,15-EET, are produced by cytochrome P450 (P450) such as CYP2C8 and 2C9; and they are hydrolyzed to dihydroxyeicosatrienoic acids (DHETs) by epoxide hydrolase. Particular interest in the epoxygenase reaction has developed because of the potent biological activities (modulation of vascular tone and anti-inflammatory activity, etc.) attributed to EETs. We focused on a new biological function of EETs and DHETs, which induce vascular endothelial growth factor (VEGF) and erythropoietin (EPO) under hypoxia. Human hepatoma cells, Hep3B, and human umbilical artery endothelial cells (HUAEC) were used in this study. An inhibitor of phospholipase A2, methyl arachidonyl fluorophosphonate (MAFP), and inhibitors of P450s inhibited the VEGF and EPO induction of HUAEC and Hep3B, respectively, under hypoxia. Overexpression of CYP2C8 in Hep3B induced EPO and VEGF under hypoxia. Sulfaphenazole, an inhibitor of CYP2C8/2C9 suppressed luciferase promoter activity with the hypoxia response element (HRE) of VEGF in HUAEC. Exogenous 11,12-EET and 14,15-DHET induced reporter activity in HUAEC and Hep3B cells concomitant with increased levels of hypoxia-inducible factor-1α (HIF-1α), which is a key factor in the hypoxia response, but 11,12-DHET and 14,15-EET did not. These results suggested that EETs and DHETs play an important role in the hypoxia response of cells. Keywords:: cytochrome P450, epoxyeicosatrienoic acid (EET), hypoxia-inducible factor (HIF), dihydroxyeicosatrienoic acid (DHET), vascular endothelial growth factor (VEGF)

Amazake is a traditional Japanese beverage made from sake cake or rice-koji produced in sake-brewing process. Recent progressive studies showed that sake cake and rice-koji had various physiological functionalities, such as anti-hypertension, anti-obesity and anti-amnesia. Such functionalities were anticipated in amazake, so we investigated the effects of amazake in mice. Administration of amazake to mice fed a high fat diet for 2 weeks suppressed increases in body weight, serum concentrations of triglycerides, and intraperitoneal adipose depots accumulations. When amazake was orally administrated to salt-induced hypertensive mice, blood pressure showed a significant decrease after 50 days of breeding. When impairment of learning and memory in mice was induced by a subcutaneous injection of scopolamine, prior oral administration of amazake prevented a decrease in performance for memory and learning even in a single dose. These results demonstrated that amazake has three types of health-promoting benefits, anti-obesity, anti-hypertension, and anti-amnesia, resulting from attributions of sake cake, rice-koji, and other elements of sake-brewing. These functionalities indicated that amazake should be newly recognized as a natural and healthy drink for the prevention of lifestyle-related diseases.

Background Estimates of the interval from HIV-1 infection to disease progression may be affected by selection bias, and data concerning asymptomatic early seroconverters are limited. We examined the interval until disease progression in HIV-1 seroconverters in whom the timing of infection could be estimated within 1 year before diagnosis. Methods Subjects included newly diagnosed patients at Osaka National Hospital between 2003 and 2010 who had either (1) symptomatic acute HIV-1 infection with a negative or intermediate reaction on Western blotting and a positive reaction on an HIV RNA test (symptomatic acute group) or (2) a positive reaction on Western blotting at diagnosis and a

The relationship between Helicobacter pylori infection and idiopathic thrombocytopenic purpura (ITP) has been investigated in several studies. We investigated the prevalence of H. pylori infection and the clinical effects of eradication in 22 Japanese patients with chronic ITP. H. pylori infection was found in 14 (63.6%) of the patients by histologic and culture examinations of biopsy samples obtained by gastrointestinal endoscopy. H. pylori was eradicated by proton pump inhibitors and 2 kinds of antibiotics in 13 (92.9%) of the 14 patients in whom the results of treatment could be evaluated. Five (38.4%) of those 13 patients had platelet recovery (platelet count of more than 100 x 10(9)/L and an increase of more than 30 x 10(9)/L with respect to the baseline value) after eradication. The median follow-up period was 15 months. One patient who had a complete response had a partial relapse after cessation of prednisolone treatment without any evidence of H. pylori reinfection. Another patient, in whom H. pylori was not eradicated even after 2 treatment sessions, had a partial response after treatment. A screening examination for H. pylori infection may be necessary for Japanese patients with newly diagnosed ITP. Although the exact mechanism underlying platelet recovery after H. pylori eradication is not clear, the results of this study indicated that H. pylori eradication treatment is a good option for some patients with chronic ITP.

Carboplatin has proven to be effective in the treatment of patients with recurrent ovarian cancer who have responded to platinum-based first-line chemotherapy. However, thrombocytopenia is a problem in heavily pretreated patients. Paclitaxel has a so-called platelet-sparing effect, but until now it was unknown whether this effect could be obtained in heavily pretreated patients. We treated four patients with recurrent epithelial ovarian cancers who had previously undergone heavy chemotherapy. Because these patients had responded to platinum-based first-line therapy, single carboplatin administration was employed. Although satisfactory tumor marker responses were obtained, thrombocytopenia occurred. When paclitaxel was administered before the carboplatin infusion in the subsequent treatments, the thrombocytopenia became milder. It was concluded that a platelet-sparing effect was also observed in patients who had undergone heavy prior chemotherapy.

Primary bone lymphoma (PBL) comprises less than 1% of all malignant lymphomas. Because few studies of PBL have been conducted in Japan, the characteristics of Japanese patients with PBL have not been fully elucidated. We retrospectively analyzed 17 patients diagnosed with PBL at our institution between 2001 and 2011. Median patient age was 60 years. Eleven patients had diffuse large B-cell lymphoma and 2 patients had T-cell lymphoma histology. The spine was the most frequently involved site at the time of presentation. There were 11 patients with stage IV disease and 11 patients with high or high-intermediate risk according to the International Prognostic Index (IPI). Thirteen patients achieved complete response (CR) after initial treatment. At a median follow-up of 31 months, the 3-year overall survival (OS) and progression free survival were 63.5 and 49.9%, respectively. Localized disease, low or low-intermediate IPI, and CR after initial treatment were associated with a good outcome in patients with PBL and significantly associated with a better OS. Spine involvement and T/NK-cell phenotype are more frequent in Japanese than in Caucasian patients with PBL.

Background and Objectives: Approximately 10% of cases of diffuse large B cell lymphoma have a MYC rearrangement (MYC+ DLBCL) and these have been associated with an inferior outcome following standard therapy. Double-hit (DHL) and triple-hit (THL) lymphomas harbor concurrent rearrangements of MYC and BCL2 and/or BCL6 are associated with a very poor outcome. The role of hematopoietic stem cell transplantation (HSCT) for MYC+ DLBCL remains unclear. Autologous (Auto-) HSCT could not salvage chemosensitive relapse of MYC+ DLBCL in the CORAL study. However, other two retrospective studies showed the efficacy of Auto-HSCT as consolidation therapy for DHL who attained first complete response (CR), in contrast to the poor outcome of patients without HSCT. A retrospective study of HSCT for MYC+ DLBCL using Japanese registry-based data was conducted. Materials and Methods: The data of Japanese HSCT registry were surveyed, and 54 patients with MYC+ DLBCL were identified from 4,336 adult patients with DLBCL. These pathological and cytogenetic diagnoses including G-banding and/or fluorescence in situ hybridization (FISH) were carried out at each institution. The questionnaires were sent to collect patient data of clinical presentation and therapies, as well as pathology and cytogenetic reports. This study was approved by the ethical committees of the Japan Society for Hematopoietic Cell Transplantation (JSHCT) and Shimane University. Results: A total of 48 patient data were obtained from 36 institutions. MYC rearrangements were identified by G-banding in 44 patients and FISH in 4 patients. The median age at diagnosis was 55 (range, 21-67) years. Twenty patients were male. Six patients were transformed DLBCL from indolent lymphoma. Eleven patients had CNS involvement during clinical course. Twenty seven patients were single hit lymphoma (SHL, only MYC), 20 patients were DHL (MYC+BCL2; n = 15, MYC+BCL6; n = 5) and one patient was THL (MYC+BCL2+BCL6). Thirty-one patients (64.6%) received R-CHOP as initial therapy. The CR rate after the initial therapy was 66.7% in SHL, but was 28.6% in DHL/THL. In total, data were available for 32 Auto-HSCTs and 17 allogeneic (Allo-) HSCTs including one after relapsed of Auto-HSCT were available between 2003 and 2012 and subjected for further analysis. Median follow up time from HSCT in surviving patients was 17.1 months (range, 9.8-130.0). In Auto-HSCT in first CR, median time from diagnosis to HSCT was 6.5 months (range, 4.6-20.9). The overall survival (OS) at 2 years, the event free survival (EFS) at 2 years, the relapse rate at 1 year and the non-relapse mortality (NRM) at 1 year was 71.1% (95% CI: 51.7-83.9), 65.5% (95% CI: 46.4-79.2), 31.4% (95% CI: 16.2-47.9) and 3.1% (95% CI: 0.2-14.0), respectively. The outcome of SHL (n = 20) and DHL (n = 12) were almost similar (OS at 2 years; 73.8% vs 66.7%, P = 0.62). The disease status at HSCT was a significant adverse prognostic factor. OS of patients who received HSCT in CR (n = 23) was 82.4%, and was significantly better than that in partial response (PR, 42.9%, P = 0.04). The outcome of HSCT in first CR (n = 14) and second CR (n = 9) was similar (respective OS at 2 years; 78.6% and 88.9%, P = 0.57). In Allo-HSCT, four patients (23.5%) had poor performance status (2-4), eleven patients (64.7%) were chemoresistant prior to HSCT, and 13 patients (76.5%) received reduced intensity conditioning regimen. The median time from diagnosis to HSCT was 10.0 months (range, 2.3-54.5). Their OS at 2 years, EFS at 2 years, relapse rate at 1 year and NRM at 100 days were 29.4% (95% CI: 10.7-51.1), 17.6% (95% CI: 4.3-38.3), 41.2% (95% CI: 17.6-63.5) and 41.2% (95% CI: 17.1-64.0), respectively. The outcome of SHL (n = 8) and DHL/THL (n = 9) was almost similar (OS at 2 years; 37.5% vs 22.2%, P = 0.78). Conclusions: Auto-HSCT as consolidation therapy for MYC+ DLBCL was effective, as reported elsewhere. Auto-HSCT for chemosensitive relapse was also effective, in contrast to the CORAL study. The efficacy of Allo-HSCT was limited, particularly for chemoresistant patients. Although the present study include several limitations of retrospective nature, HSCT is not recommended for chemoresistant MYC+ DLBCL. Disclosures Suzuki: Bristol-Myers Squibb: Honoraria; Kyowa Hakko kirin: Honoraria; Chugai: Honoraria. Izutsu:Abbvie: Research Funding; Gilead: Research Funding; Celgene: Research Funding; Janssen Pharmaceutical K.K.: Honoraria; Eisai: Honoraria; Kyowa Hakko Kirin: Honoraria; Chugai Pharmaceutical: Honoraria, Research Funding; Takeda Pharmaceutical: Honoraria; Mundipharma KK: Research Funding. Kuroda:Bristol Myers Squibb: Honoraria, Research Funding; Astra Zeneca: Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria. Suzumiya:Astellas: Research Funding; Takeda: Honoraria; Chugai: Honoraria, Research Funding; Kyowa Hakko kirin: Research Funding; Toyama Chemical: Research Funding; Eisai: Honoraria, Research Funding.

Sex reversal of female isopods, Armadillidium vulgare, has been induced by implantation of the androgenic gland (AG) into individuals after the initiation of morphological sex differentiation. The focus of the present study is to examine whether female gonads are reversed by the androgenic gland hormone (AGH) during the sexually undifferentiated period through postembryonic development in A. vulgare. Instead of injections of AGH, three AGs were implanted into each genetic female at various developmental stages to induce sex reversal. Before implantation fresh AGs were treated with ethanol to stop AGH synthesis, but then still contained AGH. These AGs have been referred to as ethanol-treated AGs (t-AGs). Development of a testis was used as an indicator of gonadal sex reversal. The gonads of genetic females were transformed into testes by implantations of t-AGs during the sex differentiation period. However, when genetic females received implants at sexually undifferentiated stages, development of their gonads was not reversed in the male direction. These results suggest that after the onset of gonadal sex differentiation, AGH is a sex-reversing factor that can turn a female gonad into a male gonad. AGH cannot be a sex-determining factor in female A. vulgare, as undifferentiated gonads of genetic females are not sex reversed by the hormone.

Ovarian and hemolymph ecdysteroids in Armadillidium vulgare were analyzed at four stages of ovarian maturation through the reproductive molt cycle using high-performance liquid chromatography and radioimmunoassay. The major ecdysteroids in the ovaries and hemolymph of A. vulgare were 20-hydroxyecdysone and ecdysone in free and conjugated forms. The concentration of ovarian ecdysteroids reached a maximal level in maturing ovaries during stage D (premolt period) of the molt cycle. At the end of stage D, a high level of ecdysteroids was detected in fully matured ovaries. On the other hand, hemolymph ecdysteroid titers in reproductive females showed a peak during stage D and declined rapidly to a low level at the end of stage D. No appreciable differences in the amounts of hemolymph ecdysteroids and in molecular species of them were apparent in females in reproductive and nonreproductive molt cycles. The amounts of hemolymph ecdysteroids were about fivefold higher in females than those in males. These ecdysteroids may have a role in controlling ovarian development in female A. vulgare.

To evaluate the clinical effects of the administration of recombinant human granulocyte-stimulating factor (rhG-CSF) post chemotherapy for patients with advanced-staged intermediate-grade or high-grade non-Hodgkin's malignant lymphoma (NHL), we conducted this multicenter study and compared the responses between both the regimens, CHOP as a first-generation chemotherapy and ProMACE/CytaBOM as a third-generation chemotherapy, when combined with the rhG-CSF administration. In this multicenter study, where forty patients were registered, patients in both the CHOP and ProMACE/CytaBOM groups were treated with the original regimen designs without the necessity of reducing drug dosages when combined with the administration of rhG-CSF. The administration of rhG-CSF post both of the cytotoxic therapies brought about much higher rates of complete remission in both the groups (CHOP, 75 percent; ProMACE/CytaBOM, 75 percent), as compared with those of the previous study without the rhG-CSF administration. Regarding res...

It is well known that an acute or subacute exposure to p-dichlorobenzene (p-DCB) is capable of inducing α2u-globulin-mediated nephropathy and that its continuous administration accelerates the development of age-associated chronic progressive nephrosis (CPN). In the present study, in order to investigate the necessity of continued p-DCB exposure for CPN induction, kidneys of male F344 rats maintained for a 6 month-recovery period after cessation of 9 months exposure at concentrations of 600, 300 or 75 ppm by inhalation were histologically examined. Development of CPN lesions was accelerated as compared to the control in spite of the lack of any persisting α2u-globulin-mediated nephropathy. Therefore, the present results support the hypothesis that the induced CPN is a secondary effect of kidney tubule damage.

Background Gastrointestinal tract is one of the mostsusceptible organ systems to ischaemia. Not onlymucosal injury but also alterations of the intestinalmotility and loss of interstitial cells of Cajal (ICC)have been reported in response to ischaemia and rep-erfusion (I/R). However, there are few reports on thechanges in the gastric motility after gastric I/R. Thepresent study was designed to investigate the altera-tions in gastric emptying, the ICC and enteric nervesthat regulate smooth muscle function in response togastric I/R. Methods Seven-week-old male Wistar ratswere exposed to gastric I/R, and the gastric emptyingrates at 12 and 48 h after I/R were evaluated by thephenol red method. Expressions of gene product ofc-kit receptor tyrosine kinase (c-Kit), a marker of ICC,and of neuronal proteins were also examined. KeyResults Gastric emptying was transiently delayed at12 h after I/R, but returned to normal by 48 h.Expression of c-Kit protein as assessed by Westernblotting and immunofluorescent staining of thesmooth muscle layer, as well as expression of themRNA of stem cell factor, the ligand for c-Kit, werereduced at both 12 and 48 h after I/R. The expressionof neuronal nitric oxide synthase (nNOS) protein asassessed by Western blotting and immunofluorescentstaining was also decreased at 12 h after I/R, but wasrestored to normal by 48 h. Conclusions & Infer-ences Gastric I/R evokes transient gastroparesis withdelayed gastric emptying, associated with disruptionof the ICC network and nNOS-positive neurons.Keywords gastric emptying, gastric ischaemia andreperfusion, gastroparesis, interstitial cells of Cajal,neuronal nitric oxide synthase.Abbreviations: ChAT, choline acetyltransferase; c-Kit,gene product of c-kit receptor tyrosine kinase; GAPDH,glyceraldehyde-3-phosphate; ICC, the interstitial cells ofCajal; ICC-IM, intramuscular interstitial cells of Cajal;ICC-MY, myenteric interstitial cells of Cajal; I/R, ischae-mia and reperfusion; nNOS, neuronal nitric oxide synthase;NOD, non-obese diabetic; SCF, stem cell factor; TUNEL,terminal deoxynucleotidyl transferase-mediated dUTP nickend labelling.

The correlation between oostegite formation and ovarian maturation was investigated in the isopod Armadillidium vulgare. Females whose ovaries had been removed and males whose androgenic glands had been removed were used in these experiments. Ovariectomy of puberal females did not stop oostegite formation. Whether oostegites develop in puberal females whose ovaries have been removed depends upon the degree of maturation of the ovaries at the time of removal. On the other hand, ovariectomized juvenile females and andrectomized juvenile males were unable to form oostegites when they attained puberty. An extract of vitellogenic ovaries induced oostegite formation in ovariectomized females and andrectomized males, but not in intact males. The ability of ovarian extracts to induce oostegite formation was dose-dependent. The nature of this ovarian factor that induces oostegite formation in A. vulgare remains to be elucidated.

Evidence is presented for the first time for the complete sex-reversal of genetic males of the terrestrial isopod Armadillidium vulgare into functional females folloing partial gonadectomy. Fifth-instar males were used. The anterior half of their rudimentary reproductive organs along with the attached androgenic glands were removed. Six months later these animals formed oostegites and laid eggs, and when bred with normal males, produced only male offspring. These results show that in the absence of the androgenic gland, female sex characteristics differentiate and oogenesis occurs in genetic males.

Inchinkoto (ICKT), a herbal medicine, has been recognized in Japan and China as a “magic bullet” for jaundice. To explore potent therapeutic agents for cholestasis, the effects of ICKT or its ingredients on multidrug resistance-associated protein 2 (Mrp2/ MRP2)-mediated choleretic activity, as well as on antioxidative action, were investigated using rats and chimeric mice with livers that were almost completely repopulated with human hepatocytes. Biliary excretion of Mrp2 substrates and the protein mass, subcellular localization, and mRNA level of Mrp2 were assessed in rats after 1-wk oral administration of ICKT or genipin, a major ingredient of ICKT. Administration of ICKT or genipin to rats for 7 days increased bile flow and biliary excretion of bilirubin conjugates. Mrp2 protein and mRNA levels and Mrp2 membrane densities in the bile canaliculi and renal proximal tubules were significantly increased in ICKT- or genipin-treated rat livers and kidneys. ICKT and genipin, thereby, accelerated the disposal of intravenously infused bilirubin. The treatment also increased hepatic levels of heme oxygenase-1 and GSH by a nuclear factor-E2-related factor (Nrf2)-dependent mechanism. Similar effects of ICKT on MRP2 expression levels were observed in humanized livers of chimeric mice. In conclusion, these findings provide the rationale for therapeutic options of ICKT and its ingredients that should potentiate bilirubin disposal in vivo by enhancing Mrp2/MRP2-mediated secretory capacities in both livers and kidneys as well as Nrf2-mediated antioxidative actions in the treatment of cholestatic liver diseases associated with jaundice.

Objective We longitudinally examined the changes of brachial to ankle distensibility using pulse wave velocity (PWV) throughout pregnancy and its difference between normal pregnancy and pregnancy-induced hypertension (PIH) groups. Study design One hundred and eighty-three pregnant women were included in this study. The PWV examinations were performed in a longitudinal way during the first, second, and third trimesters of pregnancy, and immediately and 1 month after delivery. Results In normal pregnancies, the PWV significantly decreased at the second trimester, increased from the third trimester through immediately after delivery, and decreased again at 1 month after delivery. In PIH patients, it increased in proportion to the progression of gestation. Conclusion We monitored the longitudinal changes in PWV and constructed a PWV normogram during pregnancy. The predictive value of PWV and blood pressure for PIH was higher than that of blood pressure alone, suggesting the usefulness of measuring PWV to predict PIH.

The objective of this study was to provide preliminary toxicity data of multiple-cycle combination chemotherapy with intraperitoneal (IP) carboplatin and intravenous (IV) paclitaxel for further clinical trials. The toxicity data of 42 patients with müllerian carcinoma who underwent IP carboplatin therapy in combination with IV paclitaxel were retrospectively analyzed. Chemotherapy was repeated through the Bard IP port placed at initial surgery using IV paclitaxel at 175 mg/m2 followed by IP carboplatin. The doses of carboplatin were either at area under the curve (AUC) = 5, 6, 6.5, 7, or 7.5. The toxicity data in a total of 237 cycles were analyzed. The median number of cycles for IP chemotherapy was 6 (range: 3–12). The incidences of maximal grade toxicities in all cycles were: grade (G)2/3 nausea/vomiting, 23.8%; G2/3 constipation, 42.9%; G2 abdominal pain, 28.6%; G2/3 sensory neuropathy, 14.3%; motor neuropathy, 4.8%; myalgia/arthralgia 33.4%; G3/4 neutrocytopenia, 85.4%; and G3/4 anemia, 35.4%. These were not related to the dose of carboplatin. The incidences of G3 thrombocytopenia in relation to the dose of carboplatin were AUC = 5, 0%; 6, 31.6%; 6.5, 44.4%; 7, 25.0%; and 7.5, 80%. G4 thrombocytopenia did not occur. A dose of carboplatin between AUC = 6 and 7 with IV paclitaxel at 175 mg/m2 is warranted for further evaluation.

Objective Currently, no long-term follow-up data are available on intraperitoneal (IP) carboplatin-based chemotherapy for ovarian carcinoma. In this study we evaluated retrospectively the survival and recurrence of a retrospective cohort of patients with epithelial ovarian cancer treated with first-line IP carboplatin-based therapy. Methods Records were reviewed of 174 patients with epithelial ovarian cancer who received IP carboplatin-based therapy between 1990 and 2000. All patients underwent surgical staging, and implantable port systems were placed regardless of residual tumor size. The pathological slides were submitted and reviewed, and then nine patients were excluded because of borderline malignancies ( n = 8), and wrong histology ( n = 1). Therefore, the records of 165 patients were analyzed for survival. Tumor grade was determined by the Universal grading system. Statistical analysis included tests for association between potential prognostic factors, and between prognostic factors and survival. Survival probabilities were estimated by Kaplan-Meier methods, and prognostic factors for survival were evaluated by a Cox regression model. Results The mean age of the patients was 53.7 years (range 21–83). The median follow-up was 41 months. The distribution by stage and histology was as follows: high risk (grade 2/3, clear cell, capsule rupture) stage I, 54; II, 21; III, 72; IV, 18; and serous, 75; clear cell, 30; mucinous, 27; endometrioid, 20; others, 13. The chemotherapy regimen was either carboplatin alone ( n = 22) or in combination with cyclophosphamide ( n = 116) or paclitaxel ( n = 27). Catheter-related complications occurred in 16 (9.7%) cases. The chemotherapeutic response in 54 patients with measurable disease was 66.4%. The 5-year survival was 94.4% for stage I, and 87.9% for stage II. The median survival for optimal and suboptimal stage III/IV patients was 51 months and 34 months, respectively. The median survival of patients with stage III/IV disease was 51 months with carboplatin doses of 400 mg/m 2 or more, but it was only 25 months with carboplatin doses smaller than 400 mg/m 2 . Poor prognostic factors, determined by Cox regression multivariate analysis, were clear cell histology ( P 2 ( P = 0.002). Conclusions Survival of patients who underwent carboplatin-based IP chemotherapy was excellent when the dose of carboplatin was higher than 400 mg/m 2 . A prospective evaluation of IP carboplatin therapy with modern combination is warranted.

We report a rare case of chronic eosinophilic leukemia (CEL) with a chromosomal abnormality of t(6;11)(q27;q23). The patient was diagnosed as having thyroid cancer with metastases to the lung and cervical lymph nodes in 1993. Percutaneous ethanol injection therapy (PEIT), total thyroidectomy, and radiotherapy were performed. The patient was also diagnosed as having prostatic cancer with bone metastasis in July 1999, and hormonal therapy was performed. At the time of the diagnosis of prostatic cancer, leukocytosis with eosinophilia was also revealed. Thereafter, cytogenetical analysis and reverse transcriptase polymerase chain reaction (RT-PCR) analysis of bone marrow showed t(6;11)(q27;q23) translocation and MLL/AF6 fusion products, respectively. No transcripts of the BCR/ABL chimeric gene were found by RT-PCR in bone marrow. Analysis of serum cytokines revealed a slight elevation of GM-CSF but no elevation of IL-3 or IL-5. Tissue damage due to infiltration of eosinophils was not observed throughout the clinical course. On the basis of the cytogenetic and molecular abnormality, the patient was diagnosed as having CEL, rather than reactive eosinophilia due to thyroid or prostatic cancer or other reactive inflammation. This is the first case report of CEL with t(6;11)(q27;q23) translocation.

The androgenic glands (AG) of crustaceans are responsible for differentiation of male sexual characters. The process of gonadal differentiation in females was studied morphologically in Armadillidium vulgare given a masculinizing AG implant. Gonadal masculinization was induced by implantation of an AG into females at various stages of postembryonic development. Functional sex reversal always occurred when an AG was implanted into females that were in stages 5 and 6 of development. Partial formation of testes was induced after implantation of an AG into stage 7 and 8 females. When an AG was implanted into a stage 9 female, development of a functional testis was not observed, but the ovaries were partially masculinized. These results show that after the onset of sex differentiation female gonads retain sexual bipotentiality through several stages of postembryonic development. Implantation of one AG into a female is enough to induce gonadal masculinization and sex reversal in this species. The AG implant up to stage 6 (3.4 mm in body length) is an experimental procedure certain to transform a genetic female into a functional male. The process of gonadal development in female A. vulgare is discussed.

Groups of 30 Wistar rats of each sex were treated with 2,2'-methylenebis(4-ethyl-6-tert-butylphenol) (MBEBP) in the diet at levels of 0, 0.03, 0.1 and 0.3% for up to 18 months. In both sexes, survival rates of treated groups were similar to those of the controls. Body weight gain was depressed (0.3% group in males, 0.1 and 0.3% groups in females). Slight anaemia (0.3% groups in both sexes) and increase of blood urea nitrogen (0.3% groups in both sexes) were observed. Histopathologically, vacuolization of the parathyroid gland cells (0.3% group in males and all treated groups in females) and degenerative changes of the kidney (0.1 and 0.3% groups in males) were observed. No neoplastic responses following MBEBP administration were noted. From these results, the no-observed-adverse-effect level (NOAEL) for MBEBP toxicity was estimated as 12 mg kg-1 body wt. day-1 in male rats. In female rats, the lowest-observed-adverse-effect level (LOAEL) was estimated as 15 mg kg-1 body wt. day-1.

Abstract 2641 INTRODUCTION: Since the introduction of the anti-CD20 monoclonal antibody rituximab, the outcomes of B-cell non-Hodgkin lymphoma (B-NHL) have improved markedly. However, fulminant hepatitis due to reactivation of hepatitis B virus (HBV) infection has emerged as a serious problem. Recently, rituximab plus corticosteroid containing chemotherapy (R-chemo) has been identified as a risk factor for HBV reactivation in hepatitis B surface antigen (HBsAg)-negative B-NHL patients. Currently, there is no standard management to prevent HBV reactivation in HBV-resolved patients without HBsAg, but with antibodies against hepatitis B core antigen (anti-HBc) and/or HBsAg (anti-HBs). PATIENTS AND METHODS: We conducted a multicenter prospective observational study to estimate the incidence of HBV reactivation by serial monthly monitoring of HBV DNA in HBV-resolved patients with B-NHL during and just after R-chemo, and to establish preemptive antiviral therapy guided by this monitoring. The major eligibility criteria included previously untreated CD20-positive B-NHL with prior HBV-resolved infection, and planned treatment with 6 to 8 cycles of R-chemo defined by protocol. The baseline HBV status was evaluated on enrollment at each institute, comprising HBsAg, anti-HBc, and anti-HBs serology. Patients were excluded if they were seropositive for hepatitis C virus or human immunodeficiency virus. Plasma HBV DNA levels were measured independently at a central laboratory, using an automated real-time TaqMan polymerase chain reaction assay after enrollment. The primary end point was the incidence of HBV reactivation defined as HBV DNA levels of 1.8 log copies per mL or more. If HBV DNA levels of less than 1.8 log copies per mL were confirmed at baseline, the serial monitoring of HBV DNA (without prophylaxis of antiviral drugs) was performed with assessments every 4 weeks after enrollment for 1.5 years. Prompt antiviral treatment with an anti-HBV nucleoside analogue (entecavir, 0.5 mg per day) was highly recommended in patients with confirmed HBV reactivation. An ancillary study was conducted to identify risk factors for HBV reactivation using the preserved specimens. The protocol was approved by the Institutional Review Board of each participating institution. All patients gave written informed consent. The planned interim analysis was performed after the enrollment of 200 patients, using data available up to June 30, 2011. RESULTS: Between Sept. 2008 and Sept. 2010, a total of 187 patients (50.8% male) with a median age of 63 years (range, 26 to 79) from 45 institutes were analyzed. Histologic subtypes of B-NHL were diffuse large B-cell lymphoma (n=121, 64.7%), follicular lymphoma (n=57, 30.5%), MALT lymphoma (n=5, 2.7%) and other types (n=4, 2.0%). The number (%) of patients positive for both anti-HBc and anti-HBs was 132 (70.6%), 35 (18.7%) were positive for anti-HBc but negative for anti-HBs, and 19 (10.2%) were negative for anti-HBc but positive for anti-HBs. One patient was positive for anti-HBc but lacked anti-HBs measurement. 168 (89.8%) patients received 6 to 8 cycles of R-CHOP (n=151) or other R-chemo (n=17). With a median follow-up of 549 days (range, 35 to 939), HBV reactivation was observed in 16 out of 187 analyzed patients. The incidence of HBV reactivation at 1 year was 7.7% (95% confidence interval [CI], 4.7 to 12.7). HBV reactivation was diagnosed at a median time of 158 days (range, 33 to 490) after enrollment. No hepatitis due to HBV reactivation was observed in patients who received antiviral treatment when HBV DNA levels were 1.8 to 3.1 log copies per mL. Multivariate analysis of the ancillary study showed that an anti-HBs baseline titer less than 10 mIU per mL was an independent risk factor for HBV reactivation, compared to a titer of 100 mIU per mL or more (adjusted hazard ratio, 5.3; 95% CI, 1.3 to 21.8; p=0.02). HBV mutations of precore (G1896A) or basal core promoter (A1762T/G1764A) that enhanced HBV replication were identified in 4 patients, two of whom had both mutations. Our strategy could inhibit such highly replicative clones and prevent hepatitis. CONCLUSIONS: Monthly monitoring of HBV DNA is highly effective for preventing hepatitis due to HBV reactivation in HBV-resolved B-NHL patients treated with R-chemo. (UMIN-CTR 000001299) (This study was supported by the Ministry of Health, Labour and Welfare of Japan.) Disclosures: Kusumoto: Bristol-Myers Squibb: Honoraria; Zenyaku Kogyo: Honoraria; Chugai Pharmaceutical Co., LTD.: Honoraria, Research Funding; Abbott: Honoraria. Tanaka:Chugai Pharmaceutical Co., LTD.: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Zenyaku Kogyo: Honoraria; Abbott: Honoraria. Tanaka:Chugai Pharmaceutical Co., LTD.: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. Kinoshita:Chugai Pharmaceutical Co., LTD.: Honoraria, Research Funding; Zenyaku Kogyo: Honoraria. Ogura:Chugai Pharmaceutical Co., LTD.: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Zenyaku Kogyo: Honoraria, Research Funding. Mizokami:Chugai Pharmaceutical Co., LTD.: Honoraria; Abbott laboratories: Honoraria. Ueda:Chugai Pharmaceutical Co., LTD.: Research Funding.

G A A b st ra ct s induced gastric lesions at 6, 12 and 24 h upon 3.5 h of WRS exposure (series B). In separate series, rats with chronic gastric ulcers induced by serosal application of acetic acid (ulcer area=28 mm2) were treated daily for 9 and 15 days with: 1) vehicle (saline); 2) Hp2-20 (0.5 25 mg/kg i.g.) or 3) control peptide Hp1 (10 mg/kg i.g.) with or without non-selective and selective inhibitors of cNOS and iNOS, L-NNA (20 mg/kg-d i.p.) and L-Nil (5 mg/kgd i.p.) without or with the combination with L-arginine (200 mg/kg-d s.c.). The gastric juice was collected for acid output assessment and the number and area of WRS lesions and ulcers were determined planimetrically, the gastric blood flow (GBF) was determined by H2-gas clearance technique and luminal NOx concentration, plasma VEGF levels, the expression of mRNAs for VEGF and FPR mRNA and protein were assessed by ELISA, RTPCR and Western Blot. Hp2-20 dose-dependently inhibited the gastric acid secretion and decreased the number of WRS-induced gastric lesions at 6h, 12 h and 24 h by 16%, 38% and 46%, respectively. Hp2-20 reduced the area of acetic acid ulcers; the dose inhibiting by 50% (ID50) of ulcer area at day 9 upon ulcer induction being 10 mg/kg and this was accompanied by the rise in GBF at ulcer margin, luminal NOx levels and VEGF concentration. Treatment with L-NNA and L-Nil which by themselves increased the area of gastric ulcer significantly reduced the healing effects of Hp2-20 and accompanying rise in the GBF and plasma NOx concentration. These increase in the area of gastric ulcers and accompanying fall in GBF and NOx content induced by L-NNA and L-Nil were reversed by L-arginine added to NOS inhibitors. Upregulation of mRNA and protein for VEGF and FPR at ulcer marginwas observed inHp2-20-treated animals and these effects were significantly attenuated by L-NNA or L-Nil. We conclude that Hp2-20 enhances the mucosal recovery from WRSinduced lesions and accelerates the healing of preexisting gastric ulcers due to upregulation of FRP receptors via mechanism involving inhibition of gastric acid secretion, an activation of NO/NOS pathway and an overexpression and release of VEGF at the ulcer margin responsible for new microvessels formation.

The acute and subchronic toxicity studies on 2,2'-methylenebis (4-ethyl-6-tert-butylphenol) (MBEBP) were conducted using male and female Wistar rats. In acute toxicity test, the LD50 values were estimated to be greater than 10 g/kg BW by oral and intraperitoneal administration in each sex. In subchronic toxicity test, groups of 10 rats of each sex were fed a diet containing 0.2, 1.0 or 5.0% of MBEBP and examined at 4 and 12 weeks. Body weight gain was significantly depressed at doses of 1.0 and 5.0% in both sexes, but the depression in the 1.0% group was severer than that in the 5.0% group in males. Hematological analysis showed slight but significant decrease of hemoglobin in the 1.0 and 5.0% groups of both sexes. Urine analysis showed no remarkable changes in all treated rats of both sexes. In biochemical analysis of serum, decrease of triglyceride level and cholinesterase activity, and increase of amylase activity were observed in treated rats. Histopathologically, testicular atrophy and decrease of spermatogenesis were observed in male rats fed 1.0 or 5.0% MBEBP for 4 and 12 weeks and vacuolization of parathyroid gland cells was observed in female rats fed 1.0 and 5.0% MBEBP for 12 weeks. In subchronic test, the lowest observable adverse effect levels for MBEBP toxicity were estimated to be 171 mg/kg BW/day in male rats and 180 mg/kg BW/day in female rats.

Background. Ghrelin is a gastrointestinal peptide that stimulates growth hormone secretion, food intake, body weight gain and upper gastrointestinal motility. Ghrelin has distinct effects on gastrointestinal motility, which may be mediated through the growth hormone secretagogue receptor (GHS-R) on the vagus nerve and enteric nerve endings. We previously reported that plasma ghrelin levels were significantly higher in patients with dysmotilitylike functional dyspepsia (Aliment Pharmacol Ther. S4:104-110, 2006). Plasma ghrelin was also increased in obese patients after gastric banding operation (Obese Surg. 15, 1024-9, 2005). The aim of the present study was to investigate the influence of delayed gastric emptying caused by surgical manipulation on the dynamics of ghrelin and GHS expression in rats.Methods. 7-week-old male Sprague-Dawley rats with or without duodenal strictures were used as models of delayed gastric emptying. After 24 hours' fasting, the rats were divided into two groups, as follows; Control group (n=14; sham operation with abdominal incision alone), impaired gastric emptying group (n=14; proximal duodenal stricture with an 18 Fr.-Nelaton catheter) As weight loss is known to increase the circulating levels of ghrelin, a pair-feeding method was applied to equalize the body weight. Rats were sacrificed 2 weeks after the operation after the 24 hours' food deprivation. Gastric emptying rate was evaluated by the phenol red method. Plasma and gastric levels of ghrelin levels were measured by radioimmunoassay. Gastric expressions of preproghrelin mRNA and GHS-R mRNA were evaluated by quantitative RT-PCR, and immunohistochemistry was performed to determine gastric ghrelin localization. Results. No significant differences in the body weight were observed among two groups. The gastric emptying rate in groups with duodenal stricture was significantly lower compared with control group (9.8%, 61.0%, p

High costs of molecule-targeted drugs such as rituximab, ibritumomab and tositumomab have given rise to an economical issue for treating patients with non-Hodgkin’s lymphoma (NHL). Granulocyte colony-stimulating factors (G-CSF), which are also expensive, are widely used for treating neutropenia after chemotherapy. In Japan, lenograstim at 2 μg/kg (almost 100 μg/body) or filgrastim at 50 μg/m2 (almost 75 μg/body) is commonly administered for patients with NHL after chemotherapy. Therefore, cost-effectiveness is an important issue in treatment for NHL. Patients with advanced-stage NHL who needed chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or a CHOP-like regimen with or without rituximab were enrolled in this randomized cross-over trial to investigate the efficacy and safety of low-dose G-CSF. Half of the patients were administered 75 μg filgrastim in the first course after neutropenia and 50 μg lenograstim in the second course, and the other half were crossed over. Forty-seven patients were enrolled in this cross-over trial, and twenty-four patients completed the trial. Frequencies of leukocytopenia and neutropenia of grade 4 were similar in patients who received filgrastim courses and those who received lenograstim courses (p=0.6366 in leukocytopenia and p=0.2207 in neutropenia, respectively). Durations of leukocytopenia and netropenia of grade 4 in each treatment course were not different statistically (p=0.3892 in leukocytopenia and p=0.1476 in neutropenia, respectively), and each period of G-CSF administration in both courses was not different statistically (p=0.0676). Frequency of fever higher than 37.5 degrees (p=0.6826) and duration of fever (p=0.7455) were also not statistically different in the two treatment courses. Documented infection containing FN after chemotherapy was not statistically different (p=0.1213). Although the administration dose of G-CSF was not determined on the basis of body weight or body surface area, eight febrile patients were not administered insufficient dose of G-CSF. Therefore, compared with the standard-dose G-CSF course (filgrastim at 75 μg), there was no statistically increased frequency of antibiotic usage in the low-dose G-CSF course (lenograstim at 50 μg) (p=0.2199). The total cost of G-CSF in the low-dose G-CSF (lenograstim at 50 μg) course was significantly lower than that in the standard-dose G-CSF (filgrastim at 75 μg) course (p

Background Rituximab, a chimeric monoclonal antibody against CD20 B-cell antigen, is widely used to treat B-cell lymphomas. One of the mechanisms through which rituximab works is antibody-dependent cellular cytotoxicity (ADCC). Granulocyte colony-stimulating factor (G-CSF) enhances the cytotoxicity of neutrophils through ADCC. The issue on the optimal timing of rituximab administration during standard CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) to exert a maximal effect against tumor cells remains to be determined. We conducted a clinical trial in which rituximab administration was synchronized with G-CSF during standard CHOP in patients with follicular (FL) or diffuse large B-cell (DLBCL) lymphomas. Methods We administered G-CSF for several days to treat neutropenia caused by CHOP regimen for patients with B-cell lymphoma (n=5). In these patients CD64 expressions on both neutrophils and monocytes and ADCC activity were examined at the several time points during one cycle of CHOP. Then, 9 patients with FL and 7 patients with DLBCL were enrolled to receive six to eight cycles of CHOP every three weeks. In each cycle from the second course, rituximab was given in synchronization with several daily administration of G-CSF. Results CD64 expression was enhanced in patients given G-CSF during CHOP, whereas CD64 expression remained unchanged in patients not given G-CSF. CD64 expression levels on both neutrophils and monocytes were significantly up-regulated by the multiple daily administration of G-CSF and reached peak levels at day5 after the start of G-CSF (p=.0007). In ADCC activity, we found that rituximab-mediated cell lysis was correspondingly enhanced at day5 after starting G-CSF (p=.01). Taken together with these finding, we speculated that the administration of rituximab synchronized with multiple daily doses of G-CSF could augment the treatment efficacy of CHOP plus rituximab. First, we commenced G-CSF on day10 of each cycle from the second course of CHOP regimen and continued for at least 5 days to treat enrolled patients who developed neutropenia. Then, we administered rituximab on day5 after the start of G-CSF in the each cycle. In 9 patients with FL, the response rate was 100%, with complete remission (CR) in 8 patients and partial remission in 1 patient. With a median follow-up of 20 months (range; 8–37 months), no relapsed or flare-up patients were observed. In 7 patients with DLBCL, the CR rate was 100%. With a median follow-up of 10.2 months (range; 7–18 months), 2 of 7 patients had relapsed. There were no significant differences in clinically adverse reactions compared with CHOP alone or R-CHOP. Conclusions The administration of rituximab synchronized with G-CSF in standard CHOP regimen may improve clinical response rate and survival without a significant increase in toxicity.

Vitellogenin synthesis in Armadillidium vulgare was investigated in tissue cultures. The synthesis of vitellogenin was assayed by the incorporation of [ 35 S]methionine into precipitin with anti-vitellin serum. The forms of synthesized vitellogenin were analyzed by polyacrylamide gel electrophoresis and fluorography. The fat body synthesized vitellogenin and its rate was correlated with the molting cycle: a maximum level at stage D and lower levels at A-C and E of the molting cycle. Four forms of vitellogenin (Vg 1–4) were synthesized; the larger forms (Vg 1–2) were prominent. The ovary also synthesized a slight amount of vitellogenin at the end of the molting cycle. The smaller forms (Vg 3–4) were synthesized under cultured condition. Through vitellogenesis in A. vulgare , the fat body must be the principal site of vitellogenin synthesis. Most vitellogenin may be transported from the fat body to the ovary through hemolymph at stage D of the molting cycle.

Multiple forms of serum cholinesterase (ChE) were compared in 8 species by electrophoretic technique and the following characteristics were noted. The first moving fraction markedly hydrolyzed butyrylthiocholine and the activity was not inhibited by 10(-5)M eserine in the serum of some rabbits tested. Electrophoretic patterns of the ChE were obtained by use of two thiocholines as substrate, and the number of fractions against acetylthiocholine were more than against butyrylthiocholine in dogs, miniature pigs, rabbits, and hamsters. The activities of ChE fractions of dogs (C3), miniature pigs (C1, C2), rabbits (C1), and hamsters (C3) were inhibited by 6.1 X 10(-2)M caffein but not by 10(-4)M ethopropazine, which suggests that the fractions are all true-ChE.