Immune checkpoint inhibitor-based therapy for advanced acral and mucosal melanoma.

Acral melanoma (AM) and mucosal melanomas (MM) are rare clinical subtypes of melanoma. AM and MM are etiologically, biologically, and molecularly distinct from cutaneous melanoma (CM). Despite the recent development of immune checkpoint inhibitors (ICIs) for the treatment of advanced CMs, the true therapeutic efficacy of ICIs for these rare subtypes remains unclear. Since these subtypes are rare, especially in the Caucasian population, their biological features and corresponding novel therapies are underexplored than those of CM. Even in the larger phase III clinical trials for ICIs, the sample size of patients with AM and MM is limited. Consequently, establishment of standard of care for advanced AM and MM has been challenging. This review covers current update and overview on clinical efficacy of ICIs and ICI-based therapy for advanced AM and MM, based mainly on the reported clinical trials, prospective observational studies, and retrospective studies, to provide a better understanding of the current landscape of this field. In addition, we discuss the future direction of treatment for those rare clinical subtypes, focusing on issues relevant to dermatology and medical oncology.

Vascular Behcet's Disease Preceded by Fever of Unknown Origin: Usefulness of Ultrasonography for the Detection of Large-Vessel Vasculitis.

Behcet's disease is a systemic vasculitis characterized by oral and genital ulcers, erythema nodosum, and ocular involvement. Fever of unknown origin is a relatively rare event in Behcet's disease. We present the case of a 17-year-old male patient who suffered from prolonged fever for two months. The patient tested positive for HLA-B52 and levels of acute phase reactants were elevated. He complained of sore throat and neck pain that were evaluated by cervical ultrasonography, which revealed thickening of the carotid arterial wall and narrowing of the vessel lumen. The patient was diagnosed with vascular Behcet's disease and treated with glucocorticoid, which improved the clinical symptoms and thickening of the carotid arterial wall as detected by color duplex ultrasonography. Since vascular Behcet's disease may lead to morbidity and mortality, we suggest the early use of ultrasonography to help detect medium/large-vessel vasculitis. Prolonged fever in patients with Behcet's disease should be promptly evaluated for vascular involvement.

Clinicopathological analysis of mechanic's hand associated with dermatomyositis.

Mechanic's hand is often seen in the fingers of patients with dermatomyositis and is frequently associated with anti-aminoacyl-transfer RNA synthetase autoantibodies and interstitial lung disease. We analysed the clinical symptoms of 50 patients with dermatomyositis who had visited our department, 26 of whom also had mechanic's hand. A histological examination was carried out in 16 of the 26 cases, which revealed hyperkeratosis in all cases and colloid bodies in the epidermis in 15 cases. The number of cases of interstitial lung disease in patients with mechanic's hand (22/26, 85%) was significantly higher than that in those without mechanic's hand (12/24, 50%) (P < 0.05). Mechanic's hand is an important skin lesion of dermatomyositis, and increases the likelihood of interstitial lung disease.

Favorable efficacy of S-1 treatment for locoregionally advanced cutaneous squamous cell carcinoma in the head and neck region.

Cutaneous squamous cell carcinoma is usually treated with surgery; however, locoregionally advanced cutaneous squamous cell carcinoma can be difficult to resect. Although recent guidelines from Western countries recommend using anti-programmed cell death protein 1 (PD-1) antibodies, including cemiplimab and pembrolizumab, there are no approved anti-PD-1 antibodies for locoregional cutaneous squamous cell carcinoma in Asian countries. S-1 is an oral drug with a low incidence of severe toxicity that can be used for head and neck cancers, including head and neck locoregional cutaneous squamous cell carcinoma, in Japan. We retrospectively evaluated patients with head and neck locoregional cutaneous squamous cell carcinoma treated with S-1 at two Japanese institutions (2008-2022). The initial dosage was determined by the body surface area (<1.25 m2 : 80 mg/day, 1.25-1.5 m2 : 100 mg/day, ≥1.5 m2: 120 mg/day) for 28 consecutive days. The outcome measures were objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Fourteen patients were included. The ORR was 78%, and the complete response (CR) rate was 64.3%. The median PFS and OS were not reached (NR) (95% confidence interval [CI], 5.9 months-NR) and NR (95% CI, 13.8 months-NR), respectively. The 12-month PFS and OS rates were 51% and 85%, respectively. Six of the nine patients who achieved CR showed no recurrence during the follow-up period (median follow-up, 24.7 months). After CR, three patients experienced recurrence. Among these, two resumed S-1 treatment and subsequently underwent salvage surgery, resulting in a sustained absence of recurrence. One patient developed lung metastasis and died, although S-1 therapy was resumed. Only one patient (7.1%) developed grade 3 anemia. S-1 showed favorable efficacy and low toxicity in patients with head and neck locoregionally advanced cutaneous squamous cell carcinoma. S-1 may be a good alternative to the anti-PD-1 antibody for treating head and neck locoregionally advanced squamous cell carcinoma.

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

Background: Anti-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 methods: The 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). Results: Thirty-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. Conclusion: Nivo/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.

Six Cases of Erythrodermic Pemphigus Foliaceus: A Case Report.

Pemphigus foliaceus (PF) is one of the causes of erythroderma; however, to date, there have been relatively few reported cases. We herein describe 6 cases of erythrodermic PF. In all 6 cases, PF was a direct cause of erythroderma because the patients had not undergone any medical treatments and neither had any other skin diseases nor were taking any drugs that typically cause erythroderma. Serum levels of IgE and thymus and activation-regulated chemokine were elevated in 5 of the 6 cases, whereas soluble interleukin-2 receptor and squamous cell carcinoma-related antigen were markedly increased in all cases, suggesting that those markers are strong indicators of skin surface damage. All patients were treated with predonisolon (PSL), of which PSL pulse was added in 4 patients and intravenous immunoglobulin was added in 4 patients. Furthermore, all patients except for one were older adults, among whom 2 cases developed Kaposi's varicelliform eruption, and died, and another 2 patients, respectively, died of gastrointestinal bleeding and sepsis. Kaposi's varicelliform eruption is a complication of erythrodermic PF associated with poor prognosis, and thus caution is necessary when considering the diagnosis. Furthermore, elderly people are more likely to have complications due to PSL, which may result in death. Inappropriate treatment and delay in treatment may cause erythroderma, so early diagnosis and treatment are necessary.

Association between history of HBV vaccine response and anti-SARS-CoV-2 spike antibody response to the BioNTech/Pfizer's BNT162b2 mRNA SARS-CoV-2 vaccine among healthcare workers in Japan: A prospective observational study.

INTRODUCTION: Inadequate vaccine response is a common concern among healthcare workers at the frontlines of the COVID-19 pandemic. We aimed to investigate if healthcare workers with history of weak immune response to HBV vaccination are more likely to have weak responses against the BioNTech/Pfizer's BNT162b2 mRNA SARS-CoV-2 vaccine. METHODS: We prospectively tested 954 healthcare workers for the Anti-SARS-CoV-2 spike (S) protein antibody titers prior to the first and second BNT162b2 vaccination doses and after four weeks after the second dose using Roche's Elecsys® assay. We calculated the percentage of patients who seroconverted after the first and second doses. We estimated the relative risk of non-seroconversion after the first BNT162b2 vaccine (defined as anti-SARS-CoV-2-S titer <15 U/mL) among HBV vaccine non-responders (HBs-Ab titer <10 mIU/mL) and weak responders (≥10 and <100 mIU/mL) compared to normal responders (≥100 mIU/mL). RESULTS: Among 954 healthcare workers recruited between March 9 and March 24, 2021 at Osaka Medical and Pharmaceutical University, weak and normal HBV vaccine responders had comparable S-protein titers after the first BNT162b2 dose (51.4 [95% confidence interval 25.2-137.0] versus 59.7 [29.8-138.0] U/mL, respectively). HBV vaccine non-responders were more likely than normal responders to not seroconvert after a single dose (age and sex-adjusted relative risk 1.85 95% confidence interval [1.10-3.13]) although nearly all participants seroconverted after the second dose. After limiting the analysis to 382 patients with baseline comorbidity data, the comorbidity-adjusted relative risk of non-seroconversion among HBV vaccine non-responders to normal responders was 1.32 (95% confidence interval [0.59-2.98]). DISCUSSION: Long term follow-up studies are needed to understand if protective immunity against SARS-CoV-2 wanes faster among those with history of HBV vaccine non-response and when booster doses are warranted for these healthcare workers.

Comparison of surgical morbidities between LigaSure™ and conventional techniques in inguinal or ilioinguinal lymph node dissection for skin cancer: A single center retrospective study.

Skin cancer patients with clinical nodal disease or whose positive sentinel nodes had great tumor burden remain candidates for regional lymph node dissections. Among these patients, inguinal or ilioinguinal lymph node dissection is frequently required in clinical practice, which is associated with significant postoperative morbidity-including lymphatic leakage. The aim of this retrospective study was to evaluate the efficacy of LigaSure™, an electrothermal bipolar vessel sealing system, in reducing lymphatic leakage in inguinal or ilioinguinal lymph node dissection. In total, 58 patients who received inguinal or ilioinguinal lymph node dissection (conventional group, 48; LigaSure™ group, 10) and shared similar characteristics were included in this study. Lymphatic leakage after drain removal was significantly lower in the LigaSure™ group than that in the conventional group (present ratio, 0% vs. 37%; p = 0.02). The daily lymphatic drainage volume also tended to be lower in the LigaSure™ than that in the conventional group, with significant differences on postoperative day 1 (p = 0.02). Other perioperative outcomes including the operating time, intraoperative blood loss, time to drain removal, duration of hospital stay, flap necrosis, and wound infection showed no significant differences between the two groups. The use of the LigaSure™ in inguinal or ilioinguinal lymph node dissection for the treatment of skin cancer could reduce the incidence of postoperative lymphatic leakage after drain removal.

Inhalation of hydrogen gas attenuates left ventricular remodeling induced by intermittent hypoxia in mice.

Sleep apnea syndrome increases the risk of cardiovascular morbidity and mortality. We previously reported that intermittent hypoxia increases superoxide production in a manner dependent on nicotinamide adenine dinucleotide phosphate and accelerates adverse left ventricular (LV) remodeling. Recent studies have suggested that hydrogen (H(2)) may have an antioxidant effect by reducing hydroxyl radicals. In this study, we investigated the effects of H(2) gas inhalation on lipid metabolism and LV remodeling induced by intermittent hypoxia in mice. Male C57BL/6J mice (n = 62) were exposed to intermittent hypoxia (repetitive cycle of 1-min periods of 5 and 21% oxygen for 8 h during daytime) for 7 days. H(2) gas (1.3 vol/100 vol) was given either at the time of reoxygenation, during hypoxic conditions, or throughout the experimental period. Mice kept under normoxic conditions served as controls (n = 13). Intermittent hypoxia significantly increased plasma levels of low- and very low-density cholesterol and the amount of 4-hydroxy-2-nonenal-modified protein adducts in the LV myocardium. It also upregulated mRNA expression of tissue necrosis factor-α, interleukin-6, and brain natriuretic peptide, increased production of superoxide, and induced cardiomyocyte hypertrophy, nuclear deformity, mitochondrial degeneration, and interstitial fibrosis. H(2) gas inhalation significantly suppressed these changes induced by intermittent hypoxia. In particular, H(2) gas inhaled at the timing of reoxygenation or throughout the experiment was effective in preventing dyslipidemia and suppressing superoxide production in the LV myocardium. These results suggest that inhalation of H(2) gas was effective for reducing oxidative stress and preventing LV remodeling induced by intermittent hypoxia relevant to sleep apnea.

Endothelin ETB receptor is involved in sex differences in the development of balloon injury-induced neointimal formation.

The purpose of this study was to evaluate the involvement of endothelin (ET)(B) receptor-mediated action in the sex differences in balloon injury-induced neointimal formation using the spotting-lethal rat, which carries a naturally occurring deletion in its ET(B) receptor gene. Male and female ET(B)-deficient and wild-type rats underwent balloon injury of the carotid artery. In the wild-type rats, the neointima/media ratio was significantly lower in females than in males, but this sex difference was attenuated by ovariectomy and restored by treatment with 17ß-estradiol (20 µg/kg/day). In the ET(B)-deficient rats, the neointima/media ratio of the male and female rats was markedly increased to the same level, and this increase was not affected by ovariectomy or 17ß-estradiol treatment. Treatment with (+)-(5S,6R,7R)-2-butyl-7-[2-((2S)-2-carboxypropyl)-4-methoxyphenyl]-5-(3,4-methylenedioxyphenyl)cyclopenteno[1,2-b]pyridine-6-carboxylic acid (J-104132) (10 mg/kg/day), an ET(A)/ET(B) dual receptor antagonist, markedly decreased the neointima/media ratio of the male wild-type rats and the male and female ET(B)-deficient rats, but not the female wild-type rats. In addition, 2R-(4-propoxyphenyl)-4S-(1,3-benzodioxol-5-yl)-1-(N-(2,6-diethylphenyl)aminocarbonyl-methyl)-pyrrolidine-3R-carboxylic acid (A-192621) (30 mg/kg/day), a selective ET(B) receptor antagonist, abolished the sex difference of balloon injury-induced neointimal formation. 2R-(4-methoxyphenyl)-4S-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonyl-methyl)-pyrrolidine-3R-carboxylic acid (ABT-627) (10 mg/kg/day), a selective ET(A) receptor antagonist, and J-104132 (10 mg/kg/day) markedly decreased the neointima/media ratio to the same extent in males but not intact females. These results indicate that the sex difference in balloon injury-induced neointimal formation was abolished by genetic ET(B) receptor deficiency or its pharmacological blockade. The lack of a vasoprotective effect of estrogen and the augmentation of ET(A) receptor-mediated action seem to be responsible for the abolition of sex differences in the ET(B) receptor-inhibited condition.