Current progress in genomics and targeted therapies for neurofibromatosis type 2

Neurofibromatosis type 2 (NF2), a multiple neoplasia syndrome, is a manifestation of an impaired expression of the merlin protein, exerting inhibitory effects on cell proliferation signals due to abnormalities of the NF2 gene located on chromosome 22. About half of patients inherit a germline mutation from a parent, and nearly 60% of de novo NF2 patients are estimated to have somatic mosaicism. The development of technical methods to detect NF2 gene mutation, including targeted deep sequencing from multiple tissues, improved the diagnostic rate of mosaic NF2. With improved understanding of genetics and pathogenesis, the diagnostic criteria for NF2 were updated to assist in identifying and diagnosing NF2 at an earlier stage. The understanding of cell signaling pathways interacting with merlin has led to the development of molecular-targeted therapies. Currently, several translational studies are searching for possible therapeutic agents targeting VEGF or VEGF receptors. Bevacizumab, an anti-VEGF monoclonal antibody, is widely used in many clinical trials aiming for hearing improvement or tumor volume control. Currently, a randomized, double-masked trial to assess bevacizumab is underway. In this randomized control trial, 12 other Japanese institutions joined the principal investigators in the clinical trial originating at Fukushima Medical University. In this review, we will be discussing the latest research developments regarding NF2 pathophysiology, including molecular biology, diagnosis, and novel therapeutics

Heterozygous B beta-chain C-terminal 12 amino acid elongation variant, B beta X462W (Kyoto VI), showed dysfibrinogenemia

A heterozygous patient with dysfibrinogenemia with slight bleeding and no thrombotic complications was diagnosed with fibrinogen Kyoto VI (K-VI). To elucidate the genetic mutation(s) and characterize the variant protein, we performed the following experiments and compared with identical and similar variants that have already been reported. The proposita's PCR-amplified DNA was analyzed by sequencing and her purified plasma fibrinogen underwent SDS-PAGE followed by immunoblotting, fibrin polymerization, and scanning electron microscopic observation of fibrin clot and fibers. Sequence analyses showed that K-VI fibrinogen substituted W (TGG) for terminal codon (TAG), resulting in 12 amino acid elongation 462-473 (WSPIRRFLLFCM) in the B beta-chain. Protein analyses indicated that the presence of some albumin-binding variant fibrinogens and a dimeric molecule of variant fibrinogens reduced fibrin polymerization, with a thinner fiber and aberrant fibrin network. These results are almost the same as for the identical variant of Magdeburg, however, different from the similar variant of Osaka VI [ 12 amino acid elongation 462-473 (KSPIRRFLLFCM) in the B beta-chain] in the presence of variant forms and clot structure. We speculate the side-chain difference at 462 residues, W in K-VI, K in Osaka VI, and/or the difference in the presence of disulfide bridged forms of variant fibrinogens, led to the notable difference in the fibrin bundle network. Although a strong evolutional and structural association between B beta-chain and gamma-chain molecules is established, the corresponding recombinant 15 residue elongation variants of the fibrinogen gamma-chain showed reduced assembly and secretion.ArticleBLOOD COAGULATION & FIBRINOLYSIS. 23(1):87-90 (2012)journal articl

Efficacy of salvage therapies for advanced acral melanoma after anti-PD-1 monotherapy failure: a multicenter retrospective study of 108 Japanese patients

BackgroundAnti-programmed cell death protein 1 (PD-1) monotherapy is one of the standard systemic therapies for advanced melanoma; however, the efficacy of salvage systemic therapies after PD-1 monotherapy failure (PD-1 MF), particularly in acral melanoma (AM), the main clinical melanoma type in Japanese patients, is unclear. This study aimed to investigate the efficacy of salvage systemic therapies in Japanese patients with AM after PD-1 MF.Patients and methodsThe study included 108 patients with advanced AM (palm and sole, 72; nail apparatus, 36) who underwent salvage systemic therapy at 24 Japanese institutions. We mainly assessed the objective response rate (ORR), progression-free survival (PFS), and overall survival (OS).ResultsThirty-six (33%) patients received ipilimumab, 23 (21%) received nivolumab and ipilimumab (nivo/ipi), 10 (9%) received cytotoxic chemotherapy, 4 (4%) received BRAF and MEK inhibitors (BRAFi/MEKi), and the remaining 35 (32%) continued with PD-1 monotherapy after disease progression. The ORRs in the ipilimumab, nivo/ipi, cytotoxic chemotherapy, and BRAFi/MEKi groups were 8, 17, 0, and 100%, respectively. The nivo/ipi group showed the longest OS (median, 18.9 months); however, differences in ORR, PFS, and OS between the groups were insignificant. The OS in the nivo/ipi group was higher in the palm and sole groups than in the nail apparatus group (median: not reached vs. 8.7 months, p < 0.001). Cox multivariate analysis demonstrated that nail apparatus melanoma independently predicted unfavorable PFS and OS (p = 0.006 and 0.001). The total OS (from PD-1 monotherapy initiation to death/last follow-up) was insignificant between the groups.ConclusionNivo/ipi was not more effective than cytotoxic chemotherapy and ipilimumab after PD-1 MF in patients with advanced AM. The prognosis after PD-1 MF would be poorer for nail apparatus melanoma than for palm and sole melanoma