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Contains fulltext : 292870.pdf (Publisher’s version ) (Open Access) Few clinical trials address efficacy of adjuvant systemic treatment in patients with in-transit melanoma (ITM). This study describes adjuvant systemic therapy of ITM patients beyond clinical trials. In this study, we included stage III adjuvant-treated melanoma patients registered in the nationwide Dutch Melanoma Treatment Registry between July 2018 and December 2020. Patients were divided into three groups: nodal disease only, ITM only and ITM and nodal disease. Recurrence patterns, recurrence-free survival (RFS) and overall survival (OS) at 12-months were analyzed. In our study population of 1037 patients, 66.8% had nodal disease only, 16.7% had ITM only and 16.2% had ITM with nodal disease. RFS at 12-months was comparable in the nodal only and ITM only group (72.2% vs70.1%, P = .97) but lower in ITM and nodal disease patients (57.8%; P = .01, P

Since the introduction of BRAF(/MEK) inhibition and immune checkpoint inhibition (ICI), the prognosis of advanced melanoma has greatly improved. Melanoma is known for its remarkably long time to first distant recurrence (TFDR), which can be decades in some patients and is partly attributed to immune-surveillance. We investigated the relationship between TFDR and patient outcomes after systemic treatment for advanced melanoma. We selected patients undergoing first-line systemic therapy for advanced melanoma from the nationwide Dutch Melanoma Treatment Registry. The association between TFDR and progression-free survival (PFS) and overall survival (OS) was assessed by Cox proportional hazard regression models. The TFDR was modeled categorically, linearly, and flexibly using restricted cubic splines. Patients received anti-PD-1-based treatment (n = 1844) or BRAF(/MEK) inhibition (n = 1618). For ICI-treated patients with a TFDR 5 years (P = .014). Patients treated with BRAF(/MEK) inhibition with a longer TFDR also had a significantly longer median OS (8.6 months for TFDR 5 years, P = .004). The hazard of dying rapidly decreased with increasing TFDR until approximately 5 years (HR 0.87), after which the hazard of dying further decreased with increasing TFDR, but less strongly (HR 0.82 for a TFDR of 10 years and HR 0.79 for a TFDR of 15 years). Results were similar when stratifying for type of treatment. Advanced melanoma patients with longer TFDR have a prolonged PFS and OS, irrespective of being treated with first-line ICI or targeted therapy.

Background: Patients diagnosed with haematologic malignancies (HMs) have a higher risk of developing subsequent solid tumours, such as melanoma. Patients with HM were mostly excluded from clinical trials but potentially derive less benefit from immune checkpoint inhibitors (ICIs) due to disease-or treatment-related T-or B-cell dysfunction.Methods: All advanced melanoma patients treated with anti-PD-1-based treatment or tar-geted therapy between 2015 and 2021 were included from the prospective nationwide Dutch Melanoma Treatment Registry. Progression-free survival (PFS) and melanoma-specific sur-vival (MSS) were analysed for patients with HM (HM+) and without HM (HM-). A cox model was used to account for confounders associated with PFS and MSS.Results: In total, 4638 advanced melanoma patients received first-line anti-PD-1 mono -therapy (n = 1763), ipilimumab-nivolumab (n = 800), or BRAF(/MEK) inhibitors (n = 2075). Concurrent HMs were present for 46 anti-PD1-treated patients, 11 ipilimumab-nivolumab-treated patients and 43 BRAF(/MEK)-inhibitor-treated patients. In anti-PD-1-treated pa-tients, the median PFS was 2.8 months for HM+ and 9.9 months for HM- (p = 0.01). MSS was 41.2 months for HM+ and 58.1 months for HM- (p = 0.00086). In multivariable analysis, the presence of an HM was significantly associated with higher risk of melanoma progression (HRadj 1.62; 95% confidence interval [95% CI] 1.15-2.29; p = 0.006) and melanoma-related death (HRadj 1.74; 95% CI 1.09-2.78; p = 0.020). Median PFS and MSS for first-line BRAF (/MEK-) inhibitor-treated HM+ and HM- patients were not significantly different.Conclusions: Patients with HM and advanced melanoma show significantly worse melanoma -related outcomes when treated with ICI, but not targeted therapy, compared to patients without HM. Clinicians should be aware of potentially altered effectiveness of ICI in patients with active HM.(c) 2023 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

This study was designed to screen for preliminary evidence of predictive markers of melanoma response to PD-1 blockade. We hypothesized that the following immune markers would be positive predictors of response: increased densities of CD103 + CD8 + T cells or Th1 lineage T-bet + T cells, high expression of CXCL9-11 and presence of tertiary lymphoid structures. Conversely, we hypothesized that the high expression of barrier molecules would be a negative predictor of response. Patients with advanced melanoma treated with pembrolizumab were identified, and clinical response as well as overall survival data were collected. Tumor samples were evaluated by multiplex immunofluorescence histology. All statistical analyses were performed in R Studio and Microsoft Excel using the Mann-Whitney U test, chi-square test, Spearman's rank correlation and Kaplan-Meier survival curves. Sixty-five advanced melanoma patients were identified, of whom 46 met inclusion criteria and were included in this study. Increased densities ( P = 0.04) and proportions ( P = 0.02) of CD8 + T cells expressing CD103 + were associated with complete response (CR) to pembrolizumab. Improved survival was associated with increased proportions of CD8 + cells expressing CD103 ( P = 0.0085) as well as decreased density of periplakin + cells ( P = 0.012) and periplakin + SOX10 + cells ( P = 0.0012). The density and proportion of CD8 + T cells expressing CD103 + positively correlated with PD-L1 expression, though PD-L1 expression was not significantly correlated with outcomes. This screening study found that increased density and proportion of CD8 + T cells expressing CD103 and decreased density of periplakin were associated with positive outcomes in patients with melanoma metastases treated with pembrolizumab and may warrant further study.

Checkpoint immunotherapies (CPIs) have improved outcomes for metastatic melanoma patients, with objective response rates to combination ipilimumab and nivolumab of ~58%. Preclinical data suggest that histone deacetylase (HDAC) inhibition enhances antitumor immune activity and may augment CPI. In a phase Ib open-label pilot trial (NCT03565406), patients with therapy-naive metastatic melanoma were treated with the class I/IV HDAC inhibitor mocetinostat orally three times a week in combination with nivolumab and ipilimumab every 3 weeks for 12 weeks followed by 12-week maintenance cycles of nivolumab every 2 weeks and mocetinostat at the same dose and schedule as induction. The endpoints of the trial were safety, definition of a recommended phase 2 dose, preliminary assessment of response, and correlative marker determination. Patient PBMC and serum samples collected at baseline and on-treatment were assessed by flow cytometry and Luminex assays for immune correlates. Ten patients were treated: nine with 70-mg and one with 50-mg mocetinostat. In the 70-mg cohort, eight patients had objective responses. The patient in the 50-mg cohort had an early progression of disease. All patients had grade 2 or higher toxicities, and six had grades 3 and 4 toxicities. Patient PBMC showed significant decreases in myeloid-derived suppressor cells and trends towards reduced anti-inflammatory monocyte phenotypes. Patient serum showed significant upregulation of granzyme A and TNF and trends towards increased granzyme B and IFNγ. Collectively, combining CPI and mocetinostat had favorable response rates but with high levels of toxicity. Assessment of immune correlates supports a shift away from immunosuppressive phenotypes towards enhanced immune responses.

PURPOSE Effective treatments are needed for melanoma that progresses on inhibitors of programmed cell death protein-1 (PD-1) or its ligand (PD-L1). We conducted the phase II LEAP-004 study to evaluate the combination of the multikinase inhibitor lenvatinib and the PD-1 inhibitor pembrolizumab in this population (ClinicalTrials.gov identifier: NCT03776136 ). METHODS Eligible patients with unresectable stage III-IV melanoma with confirmed progressive disease (PD) within 12 weeks of the last dose of a PD-1/L1 inhibitor given alone or with other therapies, including cytotoxic T-cell lymphocyte–associated antigen 4 (CTLA-4) inhibitors, received lenvatinib 20 mg orally once daily plus ≤ 35 doses of pembrolizumab 200 mg intravenously once every 3 weeks until PD or unacceptable toxicity. The primary end point was objective response rate (ORR) per RECIST, version 1.1, by independent central review. RESULTS A total of 103 patients were enrolled and treated. The median study follow-up was 15.3 months. ORR in the total population was 21.4% (95% CI, 13.9 to 30.5), with three (2.9%) complete responses and 19 (18.4%) partial responses. The median duration of response was 8.3 months (range, 3.2-15.9+). ORR was 33.3% in the 30 patients with PD on prior anti–PD-1 plus anti–CTLA-4 therapy. The median progression-free survival and overall survival in the total population were 4.2 months (95% CI, 3.8 to 7.1) and 14.0 months (95% CI, 10.8 to not reached), respectively. Grade 3-5 treatment-related adverse events occurred in 47 (45.6%) patients, most commonly hypertension (21.4%); one patient died from a treatment-related event (decreased platelet count). CONCLUSION Lenvatinib plus pembrolizumab provides clinically meaningful, durable responses in patients with advanced melanoma with confirmed PD on prior PD-1/L1 inhibitor-based therapy, including those with PD on anti–PD-1 plus anti–CTLA-4 therapy. The safety profile was as expected. These data support lenvatinib plus pembrolizumab as a potential regimen for this population of high unmet need.

Melanoma is one of the most dangerous types of cutaneous neoplasms, which are pigment-producing cells of neuroectodermal origin found all over the body. A great deal of research is focused on the mechanisms of melanoma to promote better diagnostic and treatment options for melanoma in its advanced stages. The progression of melanoma involves alteration in different levels of gene expression. With the successful implementation of next-generation sequencing technology, an increasing number of long noncoding RNAs (lncRNAs) sequences have been discovered, and a significant number of them have phenotypic effects in both in vitro and in vivo studies, implying that they play an important role in the occurrence and progression of human cancers, particularly melanoma. A number of evidence indicated that lncRNAs are important regulators in tumor cell proliferation, invasion, apoptosis, immune escape, energy metabolism, drug resistance, epigenetic regulation. To better understand the role of lncRNAs in melanoma tumorigenesis, we categorize melanoma-associated lncRNAs according to their cellular functions and associations with gene expression and signaling pathways in this review. Based on the mechanisms of lncRNA, we discuss the possibility of lncRNA-target treatments, and the application of liquid biopsies to detect lncRNAs in melanoma diagnosis and prognosis.

Antibiotic exposure is associated with worse clinical outcomes in patients receiving immune checkpoint inhibitors (ICI). We analyzed antibiotic prescription patterns in lung cancer and melanoma, two malignancies in which ICI are used broadly across stages.We performed a retrospective cohort study of adults in the U.S. Veterans Affairs (VA) medical system diagnosed with lung cancer or melanoma from 2003 to 2016. We defined antibiotic exposure as receipt of a prescription for a systemic antibacterial agent between 6 months before and 6 months after cancer diagnosis. Demographics, clinical variables, prescriptions, and diagnostic codes were abstracted from the VA Corporate Data Warehouse. Antibiotic exposure was compared using t tests, Chi-square, and multivariate analyses.A total of 310,321 patients (280,068 lung cancer, 30,253 melanoma) were included in the analysis. Antibiotic exposure was more common among patients with lung cancer (42% vs. 24% for melanoma; P.001). Among antibiotic-exposed patients, those with lung cancer were more likely to receive prescriptions for multiple antibiotics (47% vs. 30% for melanoma; P.001). In multivariate analyses, antibiotic exposure was associated with lung cancer diagnosis (HR 1.50; 95% CI, 1.46-1.55), comorbidity score (HR 1.08; 95% CI, 1.08-1.09), non-white race (HR 1.11; 95% CI, 1.06-1.17), and female gender (HR 1.31; 95% CI, 1.24-1.37).Among cancer patients, antibiotics are prescribed frequently. Antibiotic exposure is more common in certain cancer types and patient populations. Given the negative effect antibiotic exposure has on immunotherapy outcomes, these observations may have clinical and healthy policy implications.

Decellularized extracellular matrix (ECM) acts as a depot for biochemical factors when conditioned by the growth of cells that are subsequently removed, and in the case of tumors, this ECM depot is known as the matrisome. This study was undertaken to determine whether a tissue-engineered matrisome could be used as an antigenic depot to stimulate protective immunity against tumor regrowth and metastasis following surgical reduction of the tumor.Using two transplanted tumor cell models, the PAIII rat model of prostate cancer and the B16F1 mouse model of melanoma, mice were administered either media (control), a suspension of inactivated tumor cells, extracellular matrix (SIS), or a matrisome engineered through growth and removal of tumor cells on SIS that was then implanted either directly onto the resected tumor bed or at an anatomical site distant to the tumor bed. Tumor weights were determined at 21 days (rats) and at 17 days (mice), and the number of metastatic foci on the lungs were enumerated at 21 days in rats.Data showed that for both PAIII and B16F1 tumors, mean PAIII and B16F1 tumor weights were significantly reduced for vaccinated animals compared to controls. Furthermore, significantly fewer metastatic foci from PAIII tumors were present on the lungs in vaccinated rats compared to controls.Antigens within the tissue-engineered matrisome stimulated an inhibitory response to tumor growth; this strategy should be explored further as a means of cancer immunotherapy.

Exosomes secreted by various cells in the tumour microenvironment have been reported to be mediators of intercellular communication that play an important role in cancer progression. In this study, we aimed to investigate the effects of exosomes derived from cancer-associated fibroblasts (CAFs) on the proliferation of malignant melanoma (MM) cells and evaluated their clinicopathological significance.Three malignant melanoma cell lines, A375, MMAc, and COLO679, and three CAFs established from malignant melanomas at stages 1a, 2b, and 3b, were used. The expression of CD9, CD63, and CD81 in CAF-derived exosomes was examined using western blotting. The effect of exosomes on the proliferative potential of cancer cells was analysed using cell counting and MTT assays. The expression of CD9, CD63, and CD81 was also immunohistochemically analysed in 90 malignant melanoma specimens.CAF-derived exosomes were positive for CD9 and CD63 and remarkably inhibited the proliferative capacity of A375 and MMAc cells. The five-year disease-free survival was significantly better in patients with CAF-derived CD9-positive exosomes than in CD9-negative patients.CAF-derived exosomes, especially CD9-positive exosomes, have an inhibitory effect on the proliferation of malignant melanoma cells. These findings suggest that CD9 expression in CAFs is a promising prognostic marker for patients with malignant melanoma.

Malignant melanoma is the most aggressive form of skin cancer, and it is characterized by poor prognosis in patients with metastatic diseases. Accurate prediction of prognosis is crucial for therapeutic decisions. In this study, bioinformatics analysis was used to explore the prognostic value of growth factor receptor-bound protein 2-associated binding protein 3 (GAB3) mRNA. RNA transcriptome sequencing data and clinical data from The Cancer Genome Atlas and genotype-tissue expression (GTEx) were analyzed for differentially expressed genes in high and low GAB3 mRNA expression groups in melanoma. Performing gene enrichment analysis and constructing protein-protein interaction networks. High expression of GAB3 was significantly correlated with a lower T stage, melanoma Clark level, Breslow depth, and melanoma ulceration. And high GAB3 expression was also associated with better progression-free interval in T1 and T2 stages and N0 stage and longer overall survival in T1 and T2 stages, N0 stage, and N1 stage. GAB3 promoted high levels of infiltration of macrophages and activated natural killer cells in melanoma. High expression of GAB3 predicted a positive prognosis in early-stage melanoma that may be mediated by the anticancer immune response.

International audience; Aim: Anti-PD-(L)1 immunotherapies improve survival in multiple cancers but remain ineffective for most patients. We applied machine-learning algorithms and multivariate analyses on baseline medical data to estimate their relative impact on overall survival (OS) upon anti-PD-(L)1 monotherapies. Method: This prognostic/predictive study retrospectively analysed 33 baseline routine medical variables derived from computed tomography (CT) images, clinical and biological meta-data. 695 patients with a diagnosis of advanced cancer were treated in prospective clinical trials in a single tertiary cancer centre in 3 cohorts including systemic anti-PD-(L)1 (251, 235 patients) versus other systemic therapies (209 patients). A random forest model combined variables to identify the combination (signature) which best estimated OS in patients treated with immunotherapy. The performance for estimating OS [95%CI] was measured using Kaplan–Meier Analysis and Log–Rank test. Results: Elevated serum lactate dehydrogenase (LDHhi) and presence of liver metastases (LM+) were dominant and independent predictors of short OS in independent cohorts of melanoma and non-melanoma solid tumours. Overall, LDHhiLM+ patients treated with anti-PD-(L)1 monotherapy had a poorer outcome (median OS: 3.1[2.4–7.8] months]) compared to LDHlowLM-patients (median OS: 15.3[8.9-NA] months; P < 0.0001). The OS of LDHlowLM-patients treated with immunotherapy was 28.8[17.9-NA] months (vs 13.1[10.8–18.5], P = 0.02) in the overall population and 30.3[19.93-NA] months (vs 14.1[8.69-NA], P = 0.0013) in patients with melanoma. Conclusion: LDHhiLM+ status identifies patients who shall not benefit from anti-PD-(L)1 monotherapy. It could be used in clinical trials to stratify patients and eventually address this specific medical need.

Rho small GTPases regulate cancer cell adhesion, migration and invasion through reorganization of the actin cytoskeleton. Rho GTPase Activating Protein 22 (ARHGAP22) is a Rac-specific GAP and suppresses Rac-dependent lamella formation and cell spreading. We have previously shown that ARHGAP22 localizes at endosomes in human melanoma A7 cells. The aim of the present study was to demonstrate the functional significance of its localization at the endosomes in melanoma cells.The lamella formation and cell spreading were monitored using human melanoma A7 cells. The effect of inhibition of endosome recycling pathway was examined.We found that dominant negative Rab11 S25N mutant inhibits RacGAP activity of ARHGAP22 and blocks ARHGAP22-dependent suppression of lamella formation and melanoma cell spreading. Furthermore, deletion of 19 amino acid residues at the C-terminal region of ARHGAP22 abolished the localization of ARHGAP22 at enlarged vesicles and stimulated RacGAP activity of ARHGAP22. The deletion mutant accumulated at enlarged vesicles when endosome recycling pathway was blocked either by co-transfection of the Rab11 S25N mutant or treatment of the cells with N-ethylmaleimide, which blocks endosomal vesicular fusion to the plasma membrane. On the other hand, deletion of the pleckstrin homology (PH) domain of ARHGAP22 abolished its RacGAP activity and localization at the plasma membrane.ARHGAP22 localizes at endosomes and is transported to the plasma membrane to inactivate Rac and suppresses lamella formation and spreading of melanoma cells.

Immune cell-driven anti-cancer activity is paramount for effective responses to checkpoint inhibitors (ICB). However, the contribution of the different immune cell subsets in the circulation and within the tumour is poorly understood.To elucidate the role of the different cell subsets in anti-tumour responses elicited by ICB, we performed single-cell analysis of the transcriptome and surface proteome of paired pre- and early on-treatment metastatic melanoma tumour biopsies and matched peripheral blood mononuclear cell samples. We next compared the survival of metastatic melanoma patients treated with ICB according to the abundance of pre-treatment tumour-infiltrating B cell clonotypes.We identified cell clusters associated with disease control or progression, defined differential expression of biological pathways likely involved in the immune awakening against the tumour and examined how cell-cell communication patterns between the tumour cell subsets change during treatment. Furthermore, we discovered that B cells (immunoglobulin expression and abundance of B cell clonotypes) discriminate the clinical response after ICB and propose that B cells likely contribute to anti-tumour immunity by antigen presentation through major histocompatibility complex molecules. Finally, we demonstrated that the abundance of tumour-infiltrating B cell clonotypes at baseline identifies two distinct risk groups, a finding that we confirmed in an independent cohort.Our exploratory translational study provides new insights on the mechanistic role of B cells in anti-melanoma immunity during treatment with ICB. Additionally, we support pre-treatment B cell tumour infiltration as a promising prognostic biomarker to be further validated as a tool for clinical risk stratification.

Management of liver metastases from uveal melanoma (LMUM) requires multimodal approach. This study describes evolution of liver resection for LMUM, reviewing current literature and institutional outcomes. Records of patients referred to the Melanoma Multi-Disciplinary Team between February 2005 and August 2018 were reviewed. All publications describing surgery for LMUM were identified from PubMed, Embase, and Google Scholar. Thirty-one of 147 patients with LMUM underwent laparoscopic liver biopsy, and 29 (14 females) had liver resections. Nineteen liver resections were performed locally [7 major (≥3 seg), 14 laparoscopic] without major complications or mortality. Overall survival positively correlated with the time from uveal melanoma to LMUM (Spearman's rho rs = 0.859, P 0.0001). Overall and recurrence-free survivals were comparable following R1 or R0 resections (OS 25 vs. 28 months, P = 0.404; RFS 13 vs. 6 months, P = 0.596). R1 resection cohort had longer lead-time (median 100 vs. 24 months, P = 0.0408). Eleven publications describing liver resection for LMUM were identified and included in the narrative review. Surgery for LMUM is safe and complements multidisciplinary management. Despite heterogeneity in literature, time from diagnosis of uveal melanoma to LMUM remains a key factor affecting survival after liver resection.

Immunotherapy with T-cell checkpoint inhibitors have changed the treatment landscape for patients with melanoma brain metastases (MBMs), offering increased survival compared with historical outcomes. We sought to identify clinical features associated with intracranial tumour responses or progression-free survival (PFS) in patients with MBMs treated with immunotherapy. Patients with MBMs treated with immunotherapy from August 2013 to March 2020 were identified through local databases. Melanoma disease burdens and immune-related adverse events (irAEs) were assessed retrospectively by review of patient medical records. Efficacy was evaluated by determining objective response rates (ORRs) in brain metastases using immune-Response Evaluation Criteria in Solid Tumours criteria, MBM-specific survival and overall PFS. Twenty-six patients were identified as eligible for this study. The presence and volume of extracranial metastases (ECM) were associated with a non-significant trend of reduced intracranial ORRs and PFS. Patients with irAEs, on the other hand, had significantly increased intracranial ORRs and PFS compared to those without irAEs. Severe, grade ≥3 irAEs and co-occurrence of ≥2 irAEs were also significantly associated with longer PFS. The presence and volume of ECM correlated inversely with development and severity of irAEs. We report a strong association between the development of irAEs and favourable melanoma-specific outcomes in patients with MBMs receiving immunotherapy. Contrary to previous studies, we found that co-occurrence of ECM in these patients was associated with fewer irAEs and reduced treatment efficacy.

To assess efficacy and toxicity of combination immunotherapy with ipilimumab plus nivolumab in routine practice in a retrospective multicentre cohort of patients with advanced melanoma.This retrospective analysis included patients with advanced melanoma treated with ipilimumab and nivolumab between October 2015 and January 2020 at six centres in Australia, Europe and the United States of America. We describe efficacy outcomes (overall survival [OS], progression-free survival [PFS] and objective response rate [ORR]) in treatment-naïve and pre-treated patients, with and without brain metastases, plus treatment-related adverse events (trAEs) in all patients treated.A total of 697 patients were identified; 472 were treatment-naïve of which 138 (29.2%) had brain metastases, and 225 were previously treated of which 102 (45.3%) had brain metastases. At baseline, 32.3% had stage M1c and 34.4% stage M1d disease. Lactate dehydrogenase was high in 280 patients (40.2%). With a median follow-up of 25.9 months, median OS in the 334 treatment-naïve patients without brain metastases was 53.7 months (95% confidence interval [CI] 40.8-NR) and 38.7 months (95% CI 18.6-NR) for the 138 treatment-naïve patients with brain metastases. For the entire cohort the ORR was 48%, for treatment-naïve patients without brain metastases ORR was 56.6% with a median PFS of was 13.7 months (95% CI 9.6-26.5). Median PFS was 7.9 months (95% CI 5.8-10.4) and OS 38 months (95% CI 31-NR) for the entire cohort. Grade 3-4 trAE were reported in 44% of patients, and 4 (0.7%) treatment-related deaths (1 pneumonitis, 2 myocarditis and 1 colitis) were recorded.The outcome and toxicity of combination immunotherapy with ipilimumab and nivolumab in a real-world patient population are similar to those reported in pivotal trials.

Although anti-PD-1 antibody monotherapy (PD-1) is commonly used to treat advanced acral melanoma (AM), its efficacy is limited. Further, data on the efficacy of PD-1 plus anti-CTLA-4 antibody (PD-1+CTLA-4) for the treatment of AM are limited. Therefore, we compared the efficacy of PD-1+CTLA-4 and PD-1 in the treatment of Japanese patients with advanced AM.This retrospective study evaluated patients with advanced AM who were treated with PD-1 or PD-1+CTLA-4 as first-line immunotherapy in 24 Japanese institutions between 2014 and 2020. Treatment efficacy focussing on the objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) was compared between the two groups.In total, 254 patients (palm and sole melanoma [PSM], n = 180; nail apparatus melanoma [NAM], n = 74) were included. Among the patients with PSM, the ORR (19% vs. 31%; P = 0.44), PFS (5.9 vs. 3.2 months; P = 0.74), and OS (23.1 vs. not reached; P = 0.55) did not differ significantly between the PD-1 and PD-1+CTLA-4 groups. Among the patients with NAM, the ORR (61% vs. 10%; P 0.001) was significantly higher and PFS was longer (6.4 vs. 3.8 months; P = 0.10) in the PD-1+CTLA-4 group than in the PD-1 group. Cox multivariate analysis demonstrated that PD-1+CTLA-4 is an independent predictor of a favourable PFS in patients with NAM (P = 0.002).The efficacy of PD-1+CTLA-4 is not superior to that of PD-1 for the treatment of advanced PSM. However, PD-1+CTLA-4 may be more efficacious than PD-1 for the treatment of advanced NAM.

Adjuvant pembrolizumab significantly improved recurrence-free survival (RFS) versus placebo in resected stage IIB and IIC melanoma in the phase 3 KEYNOTE-716 study. Health-related quality of life (HRQoL) results are reported.Patients were randomly assigned 1:1 to pembrolizumab 200 mg (2 mg/kg, patients ≥12 to18 years) Q3W or placebo for ≤17 cycles or until disease recurrence, unacceptable toxicity, or withdrawal. Change from baseline in EORTC QLQ-C30 global health status (GHS)/quality of life (QoL) was a prespecified exploratory end point. Change in EORTC QLQ-C30 functioning, symptom, and single-item scales, and EQ-5D-5L visual analog scale (VAS) were also summarized. Primary analyses were performed at week 48 to ensure adequate completion/compliance. The HRQoL population comprised patients who received ≥1 dose of treatment and completed ≥1 assessment.The HRQoL population included 969 patients (pembrolizumab, n = 483; placebo, n = 486). Compliance at week 48 was ≥80% for both instruments. EORTC QLQ-C30 GHS/QoL, physical functioning, role functioning, and EQ-5D-5L VAS scores were stable from baseline to week 48 in both arms, with no clinically meaningful decline observed. Scores did not differ significantly between pembrolizumab and placebo. EORTC QLQ-C30 GHS/QoL, physical functioning, role functioning, and EQ-5D-5L VAS scores remained stable through week 96 in both arms.HRQoL was stable with adjuvant pembrolizumab, with no clinically meaningful decline observed. Change from baseline in HRQoL was similar between arms. These results, in conjunction with the improved RFS and manageable safety previously reported, support the use of adjuvant pembrolizumab for high-risk stage II melanoma.

PURPOSE Synchrotron-generated microbeam radiotherapy (MRT) represents an innovative preclinical type of cancer radiotherapy with an excellent therapeutic ratio. Beyond local control, metastatic spread is another important endpoint to assess the effectiveness of radiotherapy treatment. Currently, no data exists on an association between MRT and metastasis. Here, we evaluated the ability of MRT to delay B16F10 murine melanoma progression and locoregional metastatic spread. METHODS AND MATERIALS We assessed the primary tumor response and the extent of metastasis in sentinel lymph nodes in two cohorts of C57BL/6J mice, one receiving a single MRT and another receiving two MRT delivered with a 10-day interval. We compared these two cohorts with synchrotron broad beam-irradiated and non-irradiated mice. In addition, using multi-plex quantitative platforms, we measured plasma concentrations of 34 pro- and anti-inflammatory cytokines and frequencies of immune cell subsets infiltrating primary tumors that received either one or two MRT treatments. RESULTS Two MRT treatments were significantly more effective for local control than single MRT. Remarkably, the second MRT also triggered a pronounced regression of out-of-radiation field locoregional metastasis. Augmentation of CXCL5, CXCL12 and CCL22 levels after the second MRT indicated that inhibition of melanoma progression could be associated with increased activity of anti-tumor neutrophils and T-cells. Indeed, we demonstrated elevated infiltration of neutrophils and activated T-cells in the tumors following the second MRT. CONCLUSIONS Our study highlights the importance of monitoring metastasis following MRT and provides the first MRT fractionation schedule that promotes local and locoregional control with the potential to manage distant metastasis.

Background: The incidence of melanoma has been increasing over the last 30 years. The most common treatments, such as surgery, chemotherapy, and radiotherapy, frequently cause serious damage to the body. It is therefore critical to develop a new therapeutic strategy for the treatment of melanoma. Objectives: This research aims to evaluate the anti-tumor effect of Neochamaejasmine A (NCA) on B16F10 melanoma cells and the underlying molecular mechanisms. Methods: The CCK-8 kit was utilized to assay the influence of NCA on the vitality of B16F10 cells. Modifications in B16F10 cells morphology were observed using a phase-contrast microscope. Apoptosis of B16F10 melanoma cells was assessed by Hoechst 33258, Annexin V and propidium iodide staining. Cell cycle was detected using a commercial kit by flow cytometry. The mRNA and protein expression levels associated with apoptosis and cell cycle arrest were detected by RT-PCR and Western blot. The expression level of pathway proteins was assessed using Western blot. Result: It was found that the proliferation of B16F10 cells was inhibited by NCA in concentration- and time-dependent manners. NCA promoted apoptosis by halting the cell cycle at the G2/M phase. After treatment with NCA, cell apoptosis was confirmed by Hoechst 33258 staining. NCA triggered the cell cycle to seize at the G2/M stage by downregulating cyclin B1 and cyclin-dependent kinase 2 (CDC2) expression. Moreover, the mRNA and protein expression of cleaved caspase- 9 and Bcl-2-associated X-protein (Bax) were increased, whereas there was a decline in the expression of B-cell lymphoma 2 (Bcl-2). The p-p38/p38 and phosphorylated c-Jun N-terminal kinase (p-JNK/JNK) ratio were also elevated by NCA. The apoptosis and G2/M cell cycle arrest were inhibited in cells co-treated with the p38 inhibitor SB203580 and JNK inhibitor SP600125. The expression of apoptosis-related proteins Bax was decreased, and Bcl-2 was increased. Conclusion: The findings of this study showed that NCA could induce apoptosis and cell cycle arrest in B16F10 melanoma cells by activating JNK and p38 MAPK signaling pathway.

Immune check point inhibitors (ICIs) have marked their existence in the field of cancer immunotherapy. Their existence dates to 2011 when the first anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4) got its FDA approval for the management of metastatic melanoma. The class of ICIs now also include antibodies against programmed cell death-1 (PD-1) and its ligand (PD-L1) which immediately gained FDA approval for use against multiple cancer types because of their effect on patient survival. These discoveries were followed by a significant rise in the identification of novel ICIs with potential anti-tumor response. Researchers have identified various novel checkpoint inhibitors which are currently under clinical trials. Despite the success of ICIs, only a small subset of patients with specific tumor types achieves a promising response. Not only efficient therapeutic response but also development of resistance, recurrence and other immune-related adverse effects limit the applicability of immune checkpoint inhibitors. These challenges can only be addressed when a directed approach is implemented at both basic and translational level. In this review, we have briefly discussed the history of ICIs, the next generation of inhibitors which are currently under clinical trial and mechanisms of resistance that can lead to treatment failure. Ultimately, by combining these insights researchers might be able to achieve a more durable and effective response in cancer patients.

A phase 1a first-in-human study evaluated the safety/tolerability, preliminary antitumour activity and pharmacokinetics of the oral MEK1/2 inhibitor FCN-159 in Chinese patients with advanced, NRAS-mutant melanoma.Patients received a single FCN-159 dose at assigned levels, proceeding to continuous dosing (once daily [QD] for 28-day cycles) if no dose-limiting toxicities (DLTs) occurred within the next 3 days. Dose escalation was initiated after review of data for the previous dose level. The primary end-point was incidence of DLTs after the first dose.Thirty-three patients were enrolled across nine FCN-159 dose groups (0.2-15 mg QD). One DLT occurred: grade 3 folliculitis in the 15-mg group. There was one gradegt;3 treatment-emergent adverse event (TEAE), death of unknown aetiology (not FCN-159 related). The most common FCN-159-related TEAE was rash (36.4%), and the incidence of grade ≥3 FCN-159-related TEAEs was 15.2%. Antitumour activity at QD doseslt;6 mg was limited; therefore, efficacy data are presented only for doses ≥6 mg (n = 21). The objective response and clinical benefit rates were 19.0% (four partial responses) and 52.4%, respectively. Median (95% confidence interval) duration of response and progression-free survival were 4.8 months (2.8-not reached) and 3.8 months (1.8-5.6), respectively. FCN-159 exposure increased dose-proportionately; geometric mean terminal half-life was 29.9-56.9 h.FCN-159 was well tolerated and demonstrated promising antitumour activity at doses ≥6 mg QD in patients with advanced, NRAS-mutant melanoma. The recommended phase 2 dose was 12 mg QD.NCT03932253. https://clinicaltrials.gov/ct2/show/NCT03932253.

The percentage of patients with metastatic non-small cell lung cancer (NSCLC) and melanoma who benefit from anti-programmed cell death protein 1 (anti-PD-1) is low owing to resistance mechanisms. SABR has a role in oligoprogressive disease and can improve responses to anti-PD-1. This multicenter prospective observational study aimed to determine whether concomitant anti-PD-1 and SABR to oligoprogressive sites enhance tumor response in metastatic NSCLC and melanoma.Patients with metastatic NSCLC or melanoma in progression to anti-PD-1 but continuing the same line owing to clinical benefit were referred for palliative SABR. All patients received concomitant pembrolizumab or nivolumab and SABR to 1 to 5 lesions, maintaining anti-PD-1 until further progression, unacceptable toxicity, or medical/patient decision. Objective response rate-complete responses and partial responses-was evaluated during all follow-up according to Response Evaluation Criteria in Solid Tumors 1.1. The abscopal response was evaluated 8 weeks after SABR as a ≥30% reduction in 1 to 2 predefined nonirradiated lesions.Of the 61 patients enrolled, 50 could be analyzed. With a median follow-up of 32.8 months, objective response rate was 42% (30% complete responses and 12% partial responses). Median progression-free survival was 14.2 months (95% confidence interval, 6.9-29 months). Median overall survival since SABR was 37.4 months (95% confidence interval, 22.9 months-not reached). Abscopal response was 65%, evaluated in 40 patients who fulfilled the criteria.Combined anti-PD-1 and SABR in oligoprogressive metastatic NSCLC or melanoma can achieve high rates of response and extend the clinical benefit of immunotherapy by delaying further progression and a new systemic therapy. This approach should be assessed in larger randomized trials.

Uveal melanoma is the most common intraocular malignancy in adults. Despite the effective primary treatment, up to 50% of patients with uveal melanoma will develop metastatic lesions mainly in the liver, which are resistant to conventional chemotherapy and lead to patient's death. To date, no orthotopic murine models of uveal melanoma which can develop spontaneous metastasis are available for preclinical studies. Here, we describe a spontaneous metastatic model of uveal melanoma based on the orthotopic injection of human uveal melanoma cells into the suprachoroidal space of immunodeficient NSG mice. All mice injected with bioluminescent OMM2.5 ( n = 23) or MP41 ( n = 19) cells developed a primary tumor. After eye enucleation, additional bioluminescence signals were detected in the lungs and in the liver. At necropsy, histopathological studies confirmed the presence of lung metastases in 100% of the mice. Liver metastases were assessed in 87 and in 100% of the mice that received OMM2.5 or MP41 cells, respectively. All tumors and metastatic lesions expressed melanoma markers and the signaling molecules insulin-like growth factor type I receptor and myristoylated alanine-rich C-kinase substrate, commonly activated in uveal melanoma. The novelty of this orthotopic mouse xenograft model is the development of spontaneous metastases in the liver from the primary site, reproducing the organoespecificity of metastasis observed in uveal melanoma patients. The faster growth and the high metastatic incidence may be attributed at least in part, to the severe immunodeficiency of NSG mice. This model may be useful for preclinical testing of targeted therapies with potential uveal melanoma antimetastatic activity and to study the mechanisms involved in liver metastasis.