Nivolumab plus ipilimumab combination is currently one of the preferred regimens for advanced melanoma in recently updated clinical practice guidelines. However, the evidence on the efficacy of the ...combination for acral or mucosal subtypes remains less robust. This is the final analysis of a multicenter, open‐label, uncontrolled phase II study that investigated the long‐term efficacy and safety in treatment‐naive Japanese patients with advanced melanoma, including acral or mucosal subtypes, and subsequent therapy after discontinuation of the investigational agents. Patients received four doses of nivolumab (1 mg/kg i.v.) in combination with ipilimumab (3 mg/kg i.v.) at 3‐week intervals, followed by doses of nivolumab (3 mg/kg i.v.) at 2‐week intervals. The median follow‐up period was 20.8 months (range, 5.2–35.0). The centrally and locally assessed objective response rates were both 43.3% (13/30; 95% confidence interval CI, 25.5–62.6). Median progression‐free survival was not reached (95% CI, 3.02–not reached), and median overall survival was also not reached (95% CI, 19.52–not reached). The 30‐month progression‐free survival and overall survival rates were 50.3% and 54.2%, respectively. No new safety concerns were detected. After discontinuation of the investigational agents, 83.3% of patients received some form of subsequent therapy including 43.3% of patients who received nivolumab monotherapy and 26.7% of patients who received radiotherapy. Of the four patients who discontinued the investigational agents because of immune‐related adverse events, two received subsequent therapy (nivolumab and ipilimumab, respectively) and the other two showed long‐term treatment‐free survival (659 and 590 days, respectively). Long‐term survival with nivolumab plus ipilimumab was observed in Japanese patients with melanoma including acral and mucosal subtypes, which is consistent with the CheckMate 067 study. Many patients continued to receive some form of treatment safely after stopping treatment with nivolumab plus ipilimumab.
The aim of the study was to evaluate the efficacy and safety of nivolumab combined with ipilimumab in treatment-naïve Japanese patients with advanced melanoma.
In this multicentre, single-arm study, ...treatment-naïve Japanese patients with unresectable stage III/IV or recurrent melanoma received nivolumab (1 mg/kg) plus ipilimumab (3 mg/kg) every 3 weeks for four doses, followed by biweekly doses of nivolumab (3 mg/kg). The primary end-point was centrally assessed objective response rate (ORR). Secondary end-points included overall survival (OS), progression-free survival (PFS), disease control rate and safety.
The subtypes of the thirty patients enrolled were: 12, mucosal; eight, non-acral cutaneous; seven, acral; two, uveal and one, unknown primary melanoma. The ORR was 43.3% (95% confidence interval CI: 25.5, 62.6) with central and local assessment. The centrally and locally assessed disease control rate (95% CI) were 73.3% (54.1, 87.7) and 86.7% (69.3, 96.2), respectively. At the median follow-up period of 14.1 months (range 5.2–27.7), median OS and centrally assessed PFS were not reached. OS (95% CI) at 6, 12, 18 and 24 months was 93.3% (75.9, 98.3), 83.3% (64.5, 92.7), 72.9% (50.0, 86.5) and 65.6% (40.4, 82.2), respectively. Treatment-related adverse events (AEs) occurred in all patients. Grade III–IV and serious AEs occurred, mostly during the combination phase, in 23 (76.7%) and 20 (66.7%) patients, respectively. No treatment-related deaths occurred.
This study confirmed the efficacy and safety of nivolumab plus ipilimumab in treatment-naïve Japanese patients with advanced melanoma including rare subtypes. Incidence rates for grade III–IV AEs were high but manageable with appropriate medical attention and treatment.
JapicCTI-152869.
•This study tested the efficacy and safety of nivolumab plus ipilimumab.•Participants were treatment-naïve Japanese patients with advanced melanoma including rare subtypes.•Survival outcomes were consistent with previous studies in Western populations.•The safety profile was similar to previous reports.•Nivolumab plus ipilimumab is a viable option for Japanese melanoma patients.
The objective of this study was to elucidate whether the survival and long-term neurodevelopmental outcomes of extremely preterm infants have improved in a Japanese tertiary center with an active ...treatment policy for infants born at 22-23 weeks of gestation.
This single-centered retrospective cohort study enrolled extremely preterm infants treated at Saitama Medical Center, Saitama Medical University, from 2003 to 2014. Patients with major congenital abnormalities were excluded. Primary outcomes were in-hospital survival and severe neurodevelopmental impairment (NDI) at 6 years of age, which was defined as having severe cerebral palsy, severe cognitive impairment, severe visual impairment, or deafness. We assessed the changes in primary outcomes between the first (period 1; 2003-2008) and the second half (period 2; 2009-2014) of the study period and evaluated the association between birth-year and primary outcomes using multivariate logistic regression models.
Of the 403 eligible patients, 340 (84%) survived to discharge. Among 248 patients available at 6 years of age, 43 (14%) were classified as having severe NDI. Between the 2 periods, in-hospital survival improved from 155 of 198 (78%) to 185 of 205 (90%), but severe NDI increased from 11 of 108 (10%) to 32 of 140 (23%). In multivariate logistic regression models adjusted for gestational age, birthweight, sex, singleton birth, and antenatal corticosteroids, the aOR (95% CI) of birth-year for in-hospital survival and severe NDI was 1.2 (1.1-1.3) and 1.1 (1.0-1.3), respectively.
Mortality among extremely preterm infants has improved over the past 12 years; nevertheless, no significant improvement was observed in the long-term neurodevelopmental outcomes.
Objective-To examine the possible mechanisms underlying the therapeutic mode of action of glucocorticoids (GCs) in nasal polyposis.
Material and Methods-The effects of GCs on nasal polyps were ...firstly evaluated by examining the growth of fibroblasts derived from 10 nasal polyps in vitro. Subsequently, the ability of GCs to induce apoptotic cell death in fibroblasts was examined.
Results-Addition of betamethasone 21-phosphate (BET) at a concentration of > 1 × 10
−3
M to cell cultures inhibited cell growth in all cases examined. BET and dexamethasone 21-phosphate, but not testosterone or estradiol, caused apoptotic cell death in 2/10 nasal polyp fibroblasts, as assessed by agarose gel electrophoresis, when the cells were cultured with the agents for >96 h. The minimum concentration of agent needed to cause apoptosis was 1 × 10
−3
M, which is half of the recommended therapeutic dose.
Conclusion-The present findings suggest that topical application of GCs in nasal polyposis patients suppresses proliferation of fibroblasts in polyps and results in favorable modification of the clinical status of these patients.
Phenol oxidase in Drosophila melanogaster is considered as essential component of the defense system. Phenol oxidase usually occurs as precursor, prophenol oxidase, in hemolymph and activated with ...proteolysis during an immune response. Two isoforms of prophenol oxidase, Mox and Dox-3, had been purified, and cDNA coding prophenol oxidase protein, Mox and Dox-3, had been cloned and sequenced. To estimate species divergence in nine species from the primary structure, Phylogenetic tree was constructed. Mox and Dox-3 did not be included in the same cluster despite in Drosopbila. Highly conserved at the site of proteolysis for the activation and at the two active centers named A-site and B-site showed by the alignment. Rates and patterns of nucleotide substitution at cDNA of Mox and Dox-3 were estimated that mutation rate showed the highest value at the third position of protein coding region and codon usage was found. Three-dimentional structure was constructed from the data of primary-structure and its hydrophilic/hydrophobic plot . Ribbon-model suggested that the structure of isoforms is resemble totally, especially at the active center involving two copper-binding and six His-ligands and surrounded by α-helix. Active centers are suggested the location at the center of prophenol oxidase molecule.
Studies on Defrosting of Frozen Foods (Part 3) NAMBA, Atuko; JINNO, Sumiko
SEIKATSU EISEI (Journal of Urban Living and Health Association),
1980/04/20, Letnik:
24, Številka:
2
Journal Article
1.
1. The effects of a transdermal clonidine delivery system (M-5041T) on EEG sleep pattern with relation to plasma concentrations in unrestrained rabbits were investigated and compared with those of ...intravenous (i.v.) administration of clonidine.
2.
2. Although M-5041T did not affect the EEG recorded from cortex and hippocampus at doses up to 2.5 mg/kg, slow theta waves in hippocampal EEG accompanied by low-voltage slow waves in cortex were induced at a higher dose of 12.5 mg/kg. On i.v. injection (0.25 mg/kg), EEG tracings with bursts of high-voltage slow waves in cortical EEG and slow theta waves in hippocampus were observed.
3.
3. At doses of 0.5 and 2.5 mg/kg, M-5041T did not cause any alterations of the sleep-wake cycle, and plasma concentrations of 1-2 ng/ml were maintained for an 8-hr observation period. However, this delivery system significantly suppressed the incidence of rapid-eye movement sleep (REMS) from 11.9 to 4.7% and enhanced drowsiness (DW) from 9.0 to 21.0% during the 8-hr recording period at 12.5 mg/kg with a plasma concentration of up to 10 ng/ml. Contrary to transdermal administration, i.v. clonidine (0.25 mg/kg) completely blocked light and deep slow wave sleep as well as REMS with a plasma concentration indicated more than 10 ng/ml at 2 hr post administration. Recovery to a normal sleep-wake cycle was eventually established thereafter. The incidence of REMS and DW were significantly decreased from 11.9 to 6.3% and increased from 9.0 to 25.5%, respectively.
4.
4. Concurrent monitoring of clonidine concentrations in cerebrospinal fluid (CSF) indicated that CSF concentrations after patching M-5041T, as well as i.v. clonidine, were almost equal to plasma levels.
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5. These results suggest that alteration of the sleep-wake cycle with clonidine occurs depending upon brain concentrations, which increase to a level similar to that in plasma after administration, and that M-5041T at doses of less than 2.5 mg/kg could establish effective hypertensive therapy without obvious effects on the cycle.
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