Safety and efficacy of nivolumab in Japanese patients with malignant melanoma: An interim analysis of a postmarketing surveillance.

A postmarketing surveillance study is ongoing to evaluate nivolumab treatment for Japanese patients with malignant melanoma and accumulate data on all adverse events (AE) and efficacy. In this interim analysis, we evaluated data from approximately 100 Japanese medical institutions obtained from the nivolumab approval date in Japan (4 July 2014) through 3 July 2016. Patients were monitored during the first 12 months of treatment. Nivolumab was administrated by i.v. infusion (2 mg/kg every 3 weeks). A total of 680 and 610 patients were evaluated for safety and efficacy, respectively. The incidences of adverse drug reactions (ADR) and grade 3 or higher ADR were 53.53% and 12.35%, respectively. Predominant ADR included hypothyroidism (11.32%) and abnormal enzyme activity, such as increase of aspartate aminotransferase (7.79%), alanine aminotransferase (6.76%), alkaline phosphatase (6.18%) and γ-glutamyltransferase (5.44%). Grade 3 or higher ADR of special interest with an incidence of 1% or higher were hepatic function disorder (2.50%), colitis/diarrhea (2.06%) and infusion reaction (1.32%). No cases of encephalitis or venous thromboembolism, other AE of special interest, were observed. The estimated median overall survival was 379 days (95% confidence interval [CI], 290-not reached [NR]) in the overall population, NR (95% CI, 305-NR) for cutaneous melanoma and 340 days (95% CI, 275-NR) for mucosal melanoma. The improvement rate based on the antitumor response at the last evaluation was 22.2% (131/590 patients). No new safety concerns were raised, and serious ADR of special interest were infrequent. Nivolumab showed equivalent efficacy in patients with mucosal melanoma and those with cutaneous melanoma.

Stereoselective synthesis of 2-deoxy-2-fluoroarabinofuranosyl-alpha-1-phosphate and its application to the synthesis of 2'-deoxy-2'-fluoroarabinofuranosyl purine nucleosides by a chemo-enzymatic method.

Stereoselective introduction of a phosphate moiety into 2-deoxy-2-fluoroarabinofuranose derivatives at the anomeric position was investigated by two methods. One involved a stereoselective hydrolysis of 1-bromo-derivative, and the consecutive phosphorylation of 2-deoxy-2-fluoro-alpha-D-arabinofuranose via a phosphoramidite derivative. The other method involved stereoselective alpha-phosphorylation of the 1-bromo-derivative at the 1-position. The resulting alpha-1-phosphate was utilized to prepare 2'-deoxy-2'-fluoroarabinofuranosyl purine nucleosides by an enzymatic glycosylation reaction. This chemo-enzymatic method will be applicable to the synthesis of some 2'F-araNs, and three important 2'F-araNs were actually obtained in 30-40% yields from 1,3,5-tri-O-benzoyl-2-deoxy-2-fluoro-alpha-D-arabinose with high purity.

Practical synthesis of 2'-deoxy-2'-fluoroarabinofuranosyl purine nucleosides by chemo-enzymatic method.

Stereoselective introduction of a phosphate group into 2-fluorinated sugar (4) at the 1-position was developed by us for the first time. The resulting alpha-1-phosphate (1) was utilized to prepare 2'-deoxy-2'-fluoroarabinofuranosyl purine nucleosides (2), which were the key starting materials for the preparation of the 2'F-ANA-antisense molecule, by enzymatic glycosidation reaction. Next, we tried to apply this method as a practical synthesis of 2'F-araNs. Subsequently, we found an effect of additives on the direct phosphorylation of 1-bromide (4) with orthophosphoric acid. Tetra-n-butylammonium iodide was the most effective for achieving high alpha-selectivity among these additives. This reaction will be applicable for large-scale synthesis, and some 2'F-araNs were actually obtained in 30-40% yields from 1-O-benzoate (3). Thus, we proved the potency of the chemo-enzymatic synthesis of 2'F-ANs (2) by the use of alpha-1-phosphate (1).

Alternate stranded triplex formation of chimeric DNA composed of tandem alpha- and beta-anomeric strands.

A chimeric oligoDNA composed of a natural beta-anomeric oligonucleotide portion and an unnatural alpha-anomeric oligonucleotide portion forms an alternate stranded triplex possessing enhanced thermal stability compared to the triplexes composed of the parental oligomers.

Formation and stability of alternate-stranded triplex formed with alpha,beta-chimeric oligoDNA.

Chimeric oligoDNAs composed of alpha-anomeric oligonucleotide and beta-anomeric oligonucleotide with modified nucleobases and/or phosphodiester backbone are synthesized and their ability to form alternate-stranded triple helix with dsDNA was examined. Substitution of normal phosphodiester linkages with phosphorothioate linkages resulted in the prominent destabilization of the alternate-stranded triplex. Meanwhile, the introduction of cationic molecule or intercalative molecule at certain positions of the modified DNA was effective to increase the stability of the triplexes.