Therapeutic options for treating advanced melanoma have progressed rapidly in recent decades. Until 6 years ago, the regimen for treating advanced melanoma consisted mainly of cytotoxic agents such ...as dacarbazine and type I interferons. Since 2014, anti-programmed cell death 1 (PD1) antibodies have been recognized as anchor drugs for treating advanced melanoma, with or without additional combination drugs such as ipilimumab, but the efficacies of these immunotherapies are not fully satisfactory. In this review, we describe the development of the currently available anti-PD1 Abs-based immunotherapies for advanced melanoma, focusing on their efficacy and immune-related adverse events (AEs), as well as clinical trials still ongoing for the future treatment of advanced melanoma.
•Performed E-MPS simulations of deposition phenomena on a substrate.•Solidification phenomena of a single molten stannum (Sn) droplet was studied.•Reproduced the droplet spreading by considering the ...nonisothermal wall effect.•Rayleigh-Taylor instability generates fingers on the front of spreading droplets.•Plateau-Rayleigh instability induces the bump shape on the rim of spread droplets.
In jet engines and gas turbines, the deposition phenomenon is attributed to the adhesion of molten droplets on walls. In this study, numerical simulations of the deposition phenomena on a substrate were performed using the explicit moving particle simulation (E-MPS) method. We adopted a non-isothermal condition for the substrate using a coupling method including wall particles and a regular grid to estimate the heat conduction to and within the substrate for enhanced numerical accuracy. This coupling method was validated by comparing the theoretical values of the one-dimensional unsteady heat conduction. Simulations were performed to study the solidification phenomena of a single molten stannum (Sn) droplet impinging and solidifying on a vertical substrate. The droplet behavior from impingement to solidification shows reasonable agreement with experimental results in terms of spread factor, taking into account the heat exchange between the droplet and substrate, including the substrate temperature change. Although temperature change in the substrate is limited to areas near the impinging droplet, temperature distributions on the interface differ between the early and later stages. The high-temperature region appears near the impinging center except near the stagnation point for the former stage, while it is near the center for the latter stage. The finger and bump shapes around the impinging droplet are explained via Rayleigh–Taylor and Plateau–Rayleigh instabilities, respectively, using the actual expanding acceleration of the liquid film.
Transition metals, such as nickel (Ni), cobalt (Co), and iron (Fe), exhibit catalytic activity for electrochemical oxidation under basic conditions. In this study, we demonstrate the highly selective ...electrochemical oxidation of primary alcohols to aldehydes using Ni, Co, and Fe catalysts in an anion-exchange membrane (AEM) reactor. Our findings indicate that non-noble metal catalysts can be utilized for the electrocatalytic oxidation of primary alcohols by leveraging basic conditions that do not corrode these metals. In addition, we prepared binary metal alloys and oxide catalysts and investigated their catalytic abilities for alcohol oxidation. The results demonstrate that controlling the oxygen evolution reaction potential through the composition ratio of the binary catalyst and avoiding interference with the desired alcohol oxidation are crucial for increasing the yield of the oxidation products. Furthermore, despite the basic nature of the reaction sites, the electrocatalytic oxidation of primary alcohols selectively yielded the corresponding aldehydes, which was attributed to the unique triple-phase interfacial reaction sites in the AEM reactor.
CXCL13 recruits CXCR5+ follicular helper T (Tfh) cells in inflammatory lesions to develop secondary lymphoid organs. Tfh cells activate B cells to produce antibodies during humoral immune responses. ...Indeed, as previous reports suggested, CXCR5+ cell numbers were increased in the peripheral blood of bullous pemphigoid (BP) patients when compared with healthy donors, and the ratio of CXCR5+ cells was positively correlated with the anti‐BP180‐NC16A titers. From the above findings, in this report, we hypothesized that a chemokine related to CXCR5+ cells, namely CXCL13, may play a role in the development of BP. We performed immunohistochemical staining of CXCR5, CXCL13, LL37, CXCL10 and CCL20 for 10 cases of BP and 10 cases of pemphigus vulgaris (PV), and quantitatively analyzed the staining by digital microscopy. Moreover, we investigated the CXCL10 and CXCL13 production in BP and PV patients by enzyme‐linked immunosorbent assay. The immunomodulatory effects of LL37 on the production of T‐helper 17‐related chemokines were evaluated using monocyte‐derived M2 macrophages. Immunohistochemical staining and digital microscopic analysis showed that the ratios of CXCR5+, CXCL13+ and LL37+ cells in the dermis were significantly higher in BP patients than in PV patients. Notably, the ratio of CXCL13+ cells was positively correlated with the anti‐BP180‐NC16A titers. Moreover, the serum levels of CXCL13 were positively correlated with the anti‐BP180‐NC16A titers. Furthermore, CD163+ M2 macrophages stimulated by LL37 in vitro produced CXCL10 and CCL20. In the lesional skin of BP, CD163+ macrophages CXCL10 and CCL20 were produced. The serum levels of CXCL10 were negatively correlated with the anti‐BP180‐NC16A titers. The present study results indicate that the mechanism of the development of BP may involve the CXCL13/CXCR5‐mediated migration of Tfh cells.
Plasminogen activating inhibitor‐1 (PAI‐1) is associated with poor clinical outcomes, and elevated levels of PAI‐1 in both tissue and serum are correlated with poor response to therapy in various ...cancers, including skin cancer. Cutaneous angiosarcoma (CAS) is a vascular tumor histologically characterized by detachment of endothelial cell‐derived tumor cells. Since CAS expresses multiple angiogenic growth factors and has increased expressions of angiogenic receptor tyrosine kinase transcripts including VEGFR1/2/3, angiogenesis‐promoting factors are potential drug targets in CAS. In this study, the expression of PAI‐1 was examined in 31 cases of CAS, and the immunomodulatory effects of PAI‐1 on a human CAS cell line, ISO‐HAS‐B, were evaluated. We found that, of the angiogenesis‐promoting factors, PAI‐1 was expressed in almost all cases of CAS, and PAI‐1 increased the mRNA expressions of IL‐23p19, VEGF‐C, CXCL5 and CCL20 on ISO‐HAS‐B. Moreover, PAI‐1 stimulated ISO‐HAS‐B culture supernatant promoted favourable tube networks, suggesting that these tumor‐derived factors promote the pro‐angiogenic effect on tumor development. In addition, IL‐23p19 was expressed in 61.3% of cases, whereas VEGF‐C was expressed in 41% of cases. The results of the present study suggest that PAI‐1 promotes angiogenesis that results in tumor progression in CAS.
Merkel cell carcinoma (MCC) is a rare cutaneous neuroendocrine carcinoma that tends to show local recurrence and metastasis. Typically, MCC is polyomavirus (MCPyV)‐associated and cytokeratin 20 ...(CK20) positive. However, little is known about this tumor and its origins. Here, we aimed to determine the developmental origins of MCC and to identify prognostic clinicopathologic factors. Initial examinations revealed that CK20 and MCPyV expression (CK20+, MCPyV+ (60%); CK20+, MCPyV− (10%); CK20−, and MCPyV− (30%)) did not affect overall survival. With RB1 gene sequencing of FFPE specimens, which covered an entire exon, all RB1 mutation‐positive cases showed positive regional lymph node and/or distant metastases (8/8 cases, 100%), whereas the frequency of the metastasis was statistically significantly lower in RB1 mutation‐negative cases, (10/16 cases, 62%, P = 0.033). The results were also confirmed with immunohistochemistry, and either RB1 alterations, entire exon sequencing, or immunohistochemistry was associated with the metastasis (P = 0.007). RB1 alterations may be used to access the aggressive clinical course of MCC.
Therapeutic options for treating advanced melanoma are progressing rapidly. Until six years ago, the regimen for treating advanced melanoma mainly comprised cytotoxic agents such as dacarbazine, and ...type I interferons. Since 2014, anti-programmed cell death 1 (PD1) antibodies have become recognized as anchor drugs for treating advanced melanoma with or without additional combination drugs such as ipilimumab. In addition, v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) kinase inhibitors in combination with mitogen-activated protein kinase kinase (MEK) inhibitors are among the most promising chemotherapeutic regimens for treating advanced BRAF-mutant melanoma, especially in patients with low tumor burden. Since anti-PD1 antibodies are widely applicable for the treatment of both BRAF wild-type and mutated advanced melanomas, several clinical trials for drugs in combination with anti-PD1 antibodies are ongoing. This review focuses on the development of the anti-melanoma therapies available today, and discusses the clinical trials of novel regimens for the treatment of advanced melanoma.
Anti-PD-1 antibodies (Abs) are among the optimal adjuvant therapies for melanoma at high risk of recurrence, especially BRAF wild-type melanoma, but the anti-tumour effects of anti-PD-1 Abs in the ...adjuvant setting for acral melanoma have not been evaluated previously. The aim of this study was to analyse the efficacy and safety profiles of anti-PD-1 Ab monotherapy in the adjuvant setting in an Asian population including a high ratio of acral melanoma. The efficacy and safety profiles of anti-PD-1 Ab monotherapy in the adjuvant setting were retrospectively analysed in 78 Japanese patients with advanced melanoma, including 31 cases (40%) of acral melanoma. Overall relapse-free survival was 60.3% (47 of 78 cases, 95% confidence interval (CI) 49.2-70.4%), and 39.7% of patients (31 of 78 patients, 95% CI 29.6-50.8%) relapsed during the adjuvant PD-1 Ab treatment. Six cases (7.9%) discontinued the protocol due to serious adverse events. One case (1.3%) discontinued the protocol due to trauma. The relapse-free survival of acral melanoma was 25.8%, whereas that of high cumulative sun damage was 60.0%, and that of low cumulative sun damage was 57.1%. The acral type had a significantly lower 12-month relapse-free survival than other cutaneous types (p = 0.029). The acral type appeared to be an independent prognostic factor on multivariate analysis (p = 0.015). Adverse events due to anti-PD-1 antibody were observed in 37.1% overall. The results of this study suggest that anti-PD-1 Ab therapy in the adjuvant setting is less effective for acral melanoma than for other cutaneous types.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The efficacy and safety of nivolumab + ipilimumab combination therapy were retrospectively examined in Japanese patients with unresectable advanced melanoma in clinical practice. Fifty‐seven patients ...with advanced melanoma received the nivolumab + ipilimumab combination therapy. The primary site was cutaneous, mucosal, uveal and unknown in 35, 16, two and four patients, respectively. The overall response rate was 26.3%, with complete response observed in two (3.5%) patients, partial response in 13 (22.8%), stable disease in 12 (21.1%) and progressive disease in 30 (52.6%). The response rate in the treatment‐naive and prior systemic therapy group was 40.7% and 13.3%, respectively. For those treated with a single immune checkpoint inhibitor followed by the nivolumab + ipilimumab combination therapy as second‐line therapy after disease progression, the response rate was 18.8%. Median progression‐free survival (PFS) and overall survival (OS) in all patients was 3.3 and 14 months, respectively. Median PFS in the treatment‐naive and prior systemic therapy groups was 13 and 2 months, respectively. Median OS was unreached in the treatment‐naive group and was 6.3 months in prior systemic therapy groups. There was no significant difference in PFS and OS for non‐acral, acral and mucosal melanoma. Adverse events occurred in 86% of patients; 56.1% were grade 3 or worse. The response rate in an actual clinical setting, including the prior systemic therapy group, was lower than that in the global study and the Japanese phase II study. However, in the treatment‐naive group, the rate was equivalent to that in the Japanese phase II study. PFS and OS in the treatment‐naive group were comparable with those in the global study and Japanese phase II study, suggesting that the treatment was effective. The proportion of grade 3 and 4 immune‐related adverse events was as high as that in the global study and Japanese phase II study.
To describe the treatment patterns of nivolumab and ipilimumab in Japan, a retrospective observational study was conducted in melanoma patients who received nivolumab and ipilimumab sequentially. ...Patients who received nivolumab and ipilimumab in combination were excluded from this study. Efficacy was evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST) in terms of the overall response rate (ORR), progression‐free survival (PFS), and disease control rate (DCR). Overall survival (OS) was also evaluated. Safety was assessed by the Common Terminology Criteria for Adverse Events (CTCAE). The treatment for all 68 patients enrolled involved switching from nivolumab to ipilimumab in 61 patients and switching from ipilimumab to nivolumab in seven patients. Switching occurred because of progressive disease in 55 patients and adverse events in eight patients. The median number of ipilimumab doses was three. Ipilimumab treatment achieved an ORR and DCR of 4.9% and 21.3%, respectively, and the median OS from start of ipilimumab was 7.0 months. During the study period, no new safety signals were noted. Independent factors which were indicative of poor prognosis for PFS were high neutrophil‐to‐lymphocyte ratio (NLR) and high C‐reactive protein (CRP) levels before ipilimumab treatment. An evaluation over a washout period indicated that no significant relationship existed with efficacy or safety. For the sequential administration of nivolumab and ipilimumab in Japanese melanoma patients, switch from nivolumab to ipilimumab was common, and the major reason for switching was progressive disease. The major prognostic factors for ipilimumab PFS after nivolumab were NLR and CRP before ipilimumab treatment.
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