Anti-PD-1 antibody monotherapy versus anti-PD-1 plus anti-CTLA-4 combination therapy as first-line immunotherapy in unresectable or metastatic mucosal melanoma: a retrospective, multicenter study of 329 Japanese cases (JMAC study).

BACKGROUND: Anti-programmed cell death protein 1 (PD-1) antibody monotherapy (PD1) has led to favorable responses in advanced non-acral cutaneous melanoma among Caucasian populations; however, recent studies suggest that this therapy has limited efficacy in mucosal melanoma (MCM). Thus, advanced MCM patients are candidates for PD1 plus anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) combination therapy (PD1 + CTLA4). Data on the efficacy of immunotherapy in MCM, however, are limited. We aimed to compare the efficacies of PD1 and PD1 + CTLA4 in Japanese advanced MCM patients. PATIENTS AND METHODS: We retrospectively assessed advanced MCM patients treated with PD1 or PD1 + CTLA4 at 24 Japanese institutions. Patient baseline characteristics, clinical responses (RECIST), progression-free survival (PFS), and overall survival (OS) were estimated using Kaplan-Meier analysis, and toxicity was assessed to estimate the efficacy and safety of PD1 and PD1 + CTLA4. RESULTS: Altogether, 329 patients with advanced MCM were included in this study. PD1 and PD1 + CTLA4 were used in 263 and 66 patients, respectively. Baseline characteristics were similar between both treatment groups, except for age (median age 71 versus 65 years; P < 0.001). No significant differences were observed between the PD1 and PD1 + CTLA4 groups with respect to objective response rate (26% versus 29%; P = 0.26) or PFS and OS (median PFS 5.9 months versus 6.8 months; P = 0.55, median OS 20.4 months versus 20.1 months; P = 0.55). Cox multivariate survival analysis revealed that PD1 + CTLA4 did not prolong PFS and OS (PFS: hazard ratio 0.83, 95% confidence interval 0.58-1.19, P = 0.30; OS: HR 0.89, 95% confidence interval 0.57-1.38, P = 0.59). The rate of ≥grade 3 immune-related adverse events was higher in the PD1 + CTLA4 group than in the PD1 group (53% versus 17%; P < 0.001). CONCLUSIONS: First-line PD1 + CTLA4 demonstrated comparable clinical efficacy to PD1 in Japanese MCM patients, but with a higher rate of immune-related adverse events.

Anti-PD1 checkpoint inhibitor therapy in acral melanoma: a multicenter study of 193 Japanese patients.

BACKGROUND: Acral melanoma (AM) is an epidemiologically and molecularly distinct entity that is underrepresented in clinical trials on immunotherapy in melanoma. We aimed to analyze the efficacy of anti-programmed cell death 1 (anti-PD-1) antibodies in advanced AM. PATIENTS AND METHODS: We retrospectively evaluated unresectable stage III or stage IV AM patients treated with an anti-PD-1 antibody in any line at 21 Japanese institutions between 2014 and 2018. The clinicobiologic characteristics, objective response rate (ORR, RECIST), survival estimated using Kaplan-Meier analysis, and toxicity (Common Terminology Criteria for Adverse Events 4.0.) were analyzed to estimate the efficacy of the anti-PD-1 antibodies. RESULTS: In total, 193 patients (nail apparatus, 70; palm and sole, 123) were included in the study. Anti-PD-1 antibody was used as first-line therapy in 143 patients (74.1%). Baseline lactate dehydrogenase (LDH) was within the normal concentration in 102 patients (52.8%). The ORR of all patients was 16.6% (complete response, 3.1%; partial response, 13.5%), and the median overall survival (OS) was 18.1 months. Normal LDH concentrations showed a significantly stronger association with better OS than abnormal concentrations (median OS 24.9 versus 10.7 months; P < 0.001). Although baseline characteristics were similar between the nail apparatus and the palm and sole groups, ORR was significantly lower in the nail apparatus group [6/70 patients (8.6%) versus 26/123 patients (21.1%); P = 0.026]. Moreover, the median OS in this group was significantly poorer (12.8 versus 22.3 months; P = 0.03). CONCLUSIONS: Anti-PD-1 antibodies have limited efficacy in AM patients. Notably, patients with nail apparatus melanoma had poorer response and survival, making nail apparatus melanoma a strong candidate for further research on the efficacy of novel combination therapies with immune checkpoint inhibitors.

Clinical and genetic features of 20 Japanese patients with vascular-type Ehlers-Danlos syndrome.

BACKGROUND: Vascular-type Ehlers-Danlos syndrome (vEDS) is a severe autosomal dominant inherited disorder resulting from mutations within the α1 type III collagen gene (COL3A1). The majority of published mutations are base changes leading to the substitution of single glycine residues within the triple-helical domain of type III collagen. Although clinical characteristics and mutations in the COL3A1 gene have been analysed for some patients from Europe and America, similar analyses have not yet been performed for Japanese patients with vEDS. OBJECTIVES: To analyse the genetic and phenotypic findings in Japanese patients with vEDS. METHODS: We analysed the clinical features of 20 unrelated individuals with vEDS. To quantify type III collagen production, the fibroblasts were cultured with (3) H-proline, and the radiolabelled collagenous proteins were analysed using sodium dodecyl sulphate-polyacrylamide gel electrophoresis and fluorography. Mutations in COL3A1 were detected by sequence analysis of cDNA from patients' fibroblasts and subsequently by a genomic DNA sequence analysis. RESULTS: Thin and translucent skin with extensive bruising and hypermobility of the small joints were observed in about 90% of the patients, whereas the prevalence of serious clinical findings such as rupture/dissection/aneurysm of the arteries (30%) or rupture of the gastrointestinal tract (25%) was relatively low. Sequence analyses of the COL3A1 gene demonstrated heterozygous point mutations leading to glycine substitution in only nine patients (45%), while heterozygous splice-site mutations at the junction of the triple-helical exons were observed in the remaining 11 patients (55%). The average type III collagen production level in the cultured dermal fibroblasts was 14·6% of the normal value. The types of complication were not associated with specific mutations in COL3A1. CONCLUSION: The analysis in the present series revealed a low frequency of patients presenting with serious clinical findings such as arterial rupture/arterial dissection/aneurysm and perforation or rupture of the gastrointestinal tract, and revealed a higher prevalence of splice-site mutations at the junction of the triple-helical exons than of glycine substitution mutations in COL3A1.

Sound propagation and speech transmission in a branching underground tunnel.

The characteristics of sound propagation and speech transmission along a tunnel with a "T" intersection were investigated. At receivers within sight of the sound source, low frequencies were mainly attenuated around the intersection than high frequencies. At receivers out of sight of the source, high frequencies were extensively attenuated. The overall pattern of sound attenuation along the different sections of tunnel, which was calculated by the conical beam method, agreed well with the measurements in this study. Numerical calculations of reflected and diffracted waves with minimum transmission paths in a two-dimensional plane showed that reflected waves were the primary contributors to sound fields out of sight of the source. The articulation scores measured at receivers within sight of the source were high, and most of the confusion concerned syllables that could easily be misheard, even if there were a high signal-to-noise ratio. The types of syllable confusions observed at the receivers out of sight of the source appeared to have been caused by the greater deterioration in speech signals along this part of the tunnel, especially at high frequencies. The evaluation by rapid speech transmission indices (RASTI) appeared to be overestimated at the receivers out of sight of the source. Taking into account the early decay times of impulsive sound and the calculation procedures used in RASTI, it is concluded that speech intelligibility may not have been evaluated correctly by RASTI.

Xeroderma pigmentosum variant associated with multiple cancers.

A 62-year-old Japanese man with xeroderma pigmentosum (XP) variant is reported. The patient had developed at least 6 basal cell carcinomas, a squamous cell carcinoma, and a malignant melanoma on sun-exposed areas, and an atypical carcinoid on the right lung. In vivo phototesting showed a normal response. The minimal erythema dose of ultraviolet B (UVB) was not lowered and no delayed peaking of the erythema reaction was observed. His skin fibroblasts exhibited higher sensitivity to UV irradiation, but a normal level of unscheduled DNA and RNA synthesis. Cell fusions with XP group A, C, D, E, F, and G cells after UV irradiation were all complemented. Previous reports together with this case suggest that older XP variant patients have a high frequency of not only skin cancers, but also internal malignancies.

Transendothelial cell diapedesis of neutrophils in inflamed human skin.

The mode of extravasation of neutrophils (PMNs) in cutaneous inflammation was studied in sequential biopsy specimens taken from human skin. Inflammatory skin reactions were produced by intracutaneous injection of endogeneous mediators of inflammation--C5ades arg, LTB4, neutrophil-activating peptide (NAP) and interleukin-1 (IL-1). Within 30 min after injection neutrophils were observed in close contact with endothelial cells of postcapillary venules and, following cytoplasmic engulfment, the cells were found to be transported transcellulary through the endothelial layer. In a total of 20 biopsy specimens taken at various times, cell migration via interendothelial gaps was absent. Instead, the transcellular pathway appeared to be the first and foremost mode of diapedesis. During this migratory process PMNs lacked signs of degranulation and numerous electron-lucent vesicles and secondary lysosomes were found. In addition, coated pits present on leukocyte as well as endothelial-cell membranes were indicative of receptor-mediated endocytotic processes.