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Apilimod dimesylate is a first-in-class phosphoinositide kinase, FYVE-type zinc finger-containing (PIKfyve) inhibitor with a favourable clinical safety profile and has demonstrated activity in preclinical C9orf72 and TDP-43 amyotrophic lateral sclerosis (ALS) models. In this ALS clinical trial, the safety, tolerability, CNS penetrance and modulation of pharmacodynamic target engagement biomarkers were evaluated. This phase 2a, randomized, double-blind, placebo-controlled, biomarker-end-point clinical trial was conducted in four US centres (ClinicalTrials.gov NCT05163886). Participants with C9orf72 repeat expansions were randomly assigned (2:1) to receive twice-daily oral treatment with 125 mg apilimod dimesylate capsules or matching placebo for 12 weeks, followed by a 12-week open-label extension. Safety was measured as the occurrence of treatment-emergent or serious adverse events attributable to the study drug and tolerability at trial completion or treatment over 12 weeks. Changes from baseline in plasma and CSF and concentrations of apilimod dimesylate and its active metabolites and of pharmacodynamic biomarkers of PIKfyve inhibition [soluble glycoprotein nonmetastatic melanoma protein B (sGPNMB) upregulation] and disease-specific CNS target engagement [poly(GP)] were measured. Between 16 December 2021 and 7 July 2022, 15 eligible participants were enrolled. There were no drug-related serious adverse events reported in the trial. Fourteen (93%) participants completed the double-blind period with 99% dose compliance [ n = 9 (90%) apilimod dimesylate; n = 5 (100%) placebo]. At Week 12, apilimod dimesylate was measurable in CSF at 1.63 ng/ml [standard deviation (SD): 0.937]. At Week 12, apilimod dimesylate increased plasma sGPNMB by >2.5-fold (P < 0.001), indicating PIKfyve inhibition, and lowered CSF poly(GP) protein levels by 73% (P < 0.001), indicating CNS tissue-level proof of mechanism. Apilimod dimesylate met prespecified key safety and biomarker end-points in this phase 2a trial and demonstrated CNS penetrance and pharmacodynamic target engagement. Apilimod dimesylate was observed to result in the greatest reduction in CSF poly(GP) levels observed to date in C9orf72 clinical trials. [ABSTRACT FROM AUTHOR]

Background Increasing melanoma incidence with less increasing mortality is observed in several countries. This discrepancy is not well understood. Objectives In this study, our aim was to discuss factors [ultraviolet radiation (UVR) exposure, melanoma treatment, diagnostic activity, overdiagnosis, pathologists' diagnostic threshold and clinicians' propensity to remove suspect skin lesions] that might influence melanoma incidence and mortality in Denmark. Methods This was a register study with the number of melanocyte-related lesions and melanoma mortality based on comprehensive national pathology and mortality databases for the period 1999–2019. We investigated melanocyte-related diagnoses and mortality in a population of 5.5 million with a national healthcare system. Age-adjusted melanoma mortality and age-adjusted incidence of benign naevi, atypical lesion, or melanoma in situ and of invasive melanoma were computed for data analysis. Results In total, 1 434 798 biopsies were taken from 704 682 individuals (65% female). The mean age at biopsy was 39.8 years in males and 37.6 in females. In males and females, the incidence of invasive melanoma increased by 87% during the period 1999–2011. During the subsequent period it increased by 9% in males but remained unchanged in females. The incidence of melanoma in situ increased by 476% in males and 357% in females during the study period, while the increases for atypical melanocytic lesions were 1928% and 1686%, respectively. Biopsy rates increased by 153% in males and 118% in females from 1999 through 2011 but fell by 20% in males and 22% in females during the subsequent period. Mortality varied slightly from year to year without any significant time trend for males or females. We identified no evidence of increased UVR exposure over the latest 30 years in Denmark. Immunotherapy of advanced melanoma was introduced in Denmark in 2010 and came into general use in 2014. Conclusions Comprehensive national data demonstrate increasing melanoma incidence correlated with increasing biopsy rates, but with no change in mortality. Previously suggested explanations for such a trend are a lowered threshold of melanoma diagnosis among pathologists, increased diagnostic activity in the presence of overdiagnosis and improved melanoma treatment. Because the study is observational and we have more explanatory factors than outcomes, the findings do not warrant conclusions about causal relationships. [ABSTRACT FROM AUTHOR]

Background Only a fraction of patients with metastatic melanoma derive durable benefit from approved treatments. The clinical impact of personalized medicine strategies for melanoma, apart from BRAF , NRAS , or CKIT targeting, has rarely been reported. Materials and Methods By means of the Group of Cutaneous Oncology of the French Society of Dermatology, we retrospectively included all patients with advanced melanoma aged 18 years and older for whom molecular testing identified one or more actionable molecular alterations and who accordingly received molecularly matched therapy. We excluded patients with only BRAF , NRAS , or CKIT alterations and patients who received molecularly matched therapy for less than 15 days. Results We included 26 patients with a median follow-up of 8 months (1-54), a median age of 63 years (24-89), and a sex ratio of 2.7. These patients had been heavily pretreated, and 64% had elevated LDH levels. The disease control rate was 38%, with 4 cases of partial response (overall response rate: 15%) and 6 of stable disease for at least 6 months. The median duration of treatment was 3.1 months (0.9-13.5). Among patients with disease control, the median duration of control was 6.6 months (2.6-13.5) and 3 cases were ongoing at the end of the study. Patients with controlled disease had GNA11 , MAP2K1 , FYCO1-RAF1 , HRAS , ATM , CCND1 , MDM2/CDK4 , and CDKN2A/NRAS alterations. Conclusions High-throughput sequencing followed by matched targeted therapy is a promising approach for patients with advanced melanoma refractory to approved treatments. [ABSTRACT FROM AUTHOR]

Each year, malignant melanoma accounts for 57 000 deaths globally. If current rates continue, there will be an estimated 510 000 new cases annually and 96 000 deaths by 2040. Melanoma and keratinocyte cancers (KCs) incur a large societal burden. Using a mathematical population model, we performed an economic evaluation of the SunSmart program in the state of Western Australia (WA), a primary prevention program to reduce the incidence of skin cancer, versus no program. A societal perspective was taken combining costs to the health system, patients and lost productivity. The model combined data from pragmatic trial evidence of sun protection, epidemiological studies and national cost reports. The main outcomes modelled were societal and government costs, skin cancer counts, melanoma deaths, life years and quality-adjusted life years. Over the next 20 years, the model predicted that implementing the WA SunSmart program would prevent 13 728 KCs, 636 melanomas and 46 melanoma deaths per 100 000 population. Furthermore, 251 life years would be saved, 358 quality-adjusted life years gained and AU$2.95 million in cost savings to society per 100 000 population would be achieved. Key drivers of the model were the rate reduction of benign lesions from sunscreen use, the costs of purchasing sunscreen and the effectiveness of reducing KCs in sunscreen users. The likelihood of WA SunSmart being cost-effective was 90.1%. For the WA Government, the estimated return on investment was $8.70 gained for every $1 invested. Primary prevention of skin cancer is a cost-effective strategy for preventing skin cancers. [ABSTRACT FROM AUTHOR]

Melanoma, a cancer arising from melanocytes, requires a novel treatment strategy because of the ineffectiveness of conventional therapies in certain patients. Fustin is a flavanonol found in young fustic (Cotinus coggygria). However, little is known about its antimelanoma effects. Our study demonstrates that fustin suppresses the growth of B16 melanoma cells. Phalloidin staining of cytoskeletal actin revealed that fustin induced a conformational change in the actin structure of melanoma cells, accompanied by suppressed phosphorylation of myosin regulatory light chain 2 (MLC2), a regulator of actin structure. Furthermore, the protein kinase A (cAMP-dependent protein kinase) inhibitor H89 completely attenuated fustin-induced downregulation of phosphorylated myosin phosphatase targeting subunit 1, which is involved in dephosphorylation of MLC2. In a mouse model, administration of fustin suppressed tumor growth in B16 melanoma cells without adverse effects. In conclusion, our findings suggest that fustin effectively suppresses melanoma cell growth both in vitro and in vivo. [ABSTRACT FROM AUTHOR]

Background Congenital melanocytic naevi (CMN) are the result of aberrations in the mitogen-activated protein kinase signal transduction pathway. The risk of melanoma is the most important concern among patients with CMN because of its poor prognosis. However, as a result of the great variability between studies, the reported risk of melanoma varies considerably, making it difficult to provide reliable information. Objectives To evaluate the prevalence, incidence density and standardized morbidity ratio (SMR) of melanoma among patients with CMN. Methods We conducted a systematic literature search of studies providing data on the risk of melanoma in patients with CMN following our registered and published protocol (PROSPERO: CRD42022383009). Results Overall, 27 studies with a total of 11 480 patients with CMN and 82 patients developing melanoma were included for analysis. The prevalence of melanoma was 1.84% [95% confidence interval (CI) 1.13–2.99] in patients with CMN and 2.73% (95% CI 1.67–4.43) in the subgroup of patients with large CMN (LCMN). The incidence of melanoma was 237.56 (95% CI 97.79–575.96) per 100 000 person-years in patients with CMN and 585.73 (95% CI 315.39–1085.29) per 100 000 person-years in the LCMN subgroup. The SMR of melanoma was 122.27 (95% CI 11.84–1262.88) among all patients with CMN and 285.97 (95% CI 50.65–1614.59) in the subgroup of patients with LCMN. Conclusions Our research suggests that the risk of melanoma in the CMN population seems to have been overestimated in previous studies, but it is still significantly higher than that in the general population. In addition to the risk of melanoma, aesthetic improvement and mental health should also be taken into account when making management decisions. [ABSTRACT FROM AUTHOR]

Melanoma is a highly malignant and drug-resistant disease that imposes a substantial economic burden on the world. There are many studies linking trace elements to diverse types of cancers, including melanoma. This review elucidates the relationship between trace elements exposure and melanoma. It was identified that copper, manganese, selenium, zinc, iron, and many other trace elements were associated with melanoma in humans. In terms of epidemiology, different elements have different correlations with melanoma. These trace elements affect the occurrence and development of melanoma through various mechanisms, such as oxidative stress and the MAPK pathway. The literature on the role of trace elements in the pathogenesis and treatment of melanoma depicts promising prospects for this field. [ABSTRACT FROM AUTHOR]

Background Inguinal lymph node dissection plays an important role in the management of melanoma, penile and vulval cancer. Inguinal lymph node dissection is associated with various intraoperative and postoperative complications with significant heterogeneity in classification and reporting. This lack of standardization challenges efforts to study and report inguinal lymph node dissection outcomes. The aim of this study was to devise a system to standardize the classification and reporting of inguinal lymph node dissection perioperative complications by creating a worldwide collaborative, the complications and adverse events in lymphadenectomy of the inguinal area (CALI) group. Methods A modified 3-round Delphi consensus approach surveyed a worldwide group of experts in inguinal lymph node dissection for melanoma, penile and vulval cancer. The group of experts included general surgeons, urologists and oncologists (gynaecological and surgical). The survey assessed expert agreement on inguinal lymph node dissection perioperative complications. Panel interrater agreement and consistency were assessed as the overall percentage agreement and Cronbach's α. Results Forty-seven experienced consultants were enrolled: 26 (55.3%) urologists, 11 (23.4%) surgical oncologists, 6 (12.8%) general surgeons and 4 (8.5%) gynaecology oncologists. Based on their expertise, 31 (66%), 10 (21.3%) and 22 (46.8%) of the participants treat penile cancer, vulval cancer and melanoma using inguinal lymph node dissection respectively; 89.4% (42 of 47) agreed with the definitions and inclusion as part of the inguinal lymph node dissection intraoperative complication group, while 93.6% (44 of 47) agreed that postoperative complications should be subclassified into five macrocategories. Unanimous agreement (100%, 37 of 37) was achieved with the final standardized classification system for reporting inguinal lymph node dissection complications in melanoma, vulval cancer and penile cancer. Conclusion The complications and adverse events in lymphadenectomy of the inguinal area classification system has been developed as a tool to standardize the assessment and reporting of complications during inguinal lymph node dissection for the treatment of melanoma, vulval and penile cancer. [ABSTRACT FROM AUTHOR]

Natural products based on their significant anti-cancer potencies have been used in cancer treatment. A natural blend of triterpenoid saponins derived from the horse chestnut (Aesculus hippocastanum L.), has been investigated in various diseases based on its main active ingredient escin. Herein, we examined the potential antiproliferative, proapoptotic, and cytotoxic activities of escin on human skin melanoma (CHL-1) cells. Cytotoxicity of escin was determined by MTT assay. Morphological changes were detected by confocal microscopy and ultrastructural changes by transmission electron microscopy studies. Phosphatidylserine translocation assay, Bcl-2 activation assessment, and oxidative stress analysis were used to determine the cell death mode of the cells. The results showed that escin reduced cell viability in a dose-dependent manner within 24 h of exposure and was highly cytotoxic at lower concentrations (IC50 value 6 μg/mL). Escin inactivated Bcl-2 signaling and triggered apoptosis by increasing the reactive oxygen species and by causing morphological and ultrastructural changes that implicate to the proapoptotic activity. Escin has been found to exert high potential for an anti-cancer drug following further in vitro and in vivo investigations. [ABSTRACT FROM AUTHOR]

Purpose To summarize the pharmacology, efficacy, safety, dosing, administration, and pharmacist perspectives related to operationalization of new and emerging bispecific therapies indicated for the treatment of various cancers. Summary In recent years, there have been significant advancements in the expansion of immunotherapeutics in the treatment of various malignancies. Bispecific T cell–engaging therapies represent an emerging therapeutic drug class for the treatment of cancer. These therapies are unique antibody constructs that bind simultaneously to 2 targets, a tumor-specific antigen and CD3 on T cells, to elicit an immune response. Recently, several bispecific therapies have been approved, including epcoritamab, glofitamab, mosunetuzumab, tebentafusp, and teclistamab. Epcoritamab and glofitamab have been approved for diffuse large B cell lymphoma, while mosunetuzumab, tebentafusp, and teclistamab have been approved for follicular lymphoma, uveal melanoma, and multiple myeloma, respectively. As a result of their mechanism of action, the approved bispecific therapies have the potential to cause cytokine release syndrome, and, along with this, they all have unique and specific monitoring parameters and operational considerations that require clinician awareness when administering these therapies. Such operational challenges include within-patient dose escalations at therapy initiation, hospitalization for monitoring, and various pharmacological strategies for prophylaxis of cytokine release syndrome. Conclusion Bispecific therapies have continued to evolve the therapeutic landscape of cancer, primarily in hematological malignancies. Health-system pharmacists have the opportunity to play a key role in the operationalization and management of this new and emerging drug class. [ABSTRACT FROM AUTHOR]

This article presents a comparative analysis of three large language models (LLMs) in answering patient questions about melanoma. The LLMs evaluated were ChatGPT 3.5, ChatGPT 4.0, and Google Bard. Dermatologists scored the responses generated by the LLMs based on accuracy, reproducibility, readability, and comprehensiveness. The results showed that ChatGPT 3.5 performed the best, highlighting the limitations of relying solely on LLMs for medical information. Larger studies are needed to fully understand the impact of LLMs on the dissemination of medical information. [Extracted from the article]

Background Use of artificial intelligence (AI), or machine learning, to assess dermoscopic images of skin lesions to detect melanoma has, in several retrospective studies, shown high levels of diagnostic accuracy on par with – or even outperforming – experienced dermatologists. However, the enthusiasm around these algorithms has not yet been matched by prospective clinical trials performed in authentic clinical settings. In several European countries, including Sweden, the initial clinical assessment of suspected skin cancer is principally conducted in the primary healthcare setting by primary care physicians, with or without access to teledermoscopic support from dermatology clinics. Objectives To determine the diagnostic performance of an AI-based clinical decision support tool for cutaneous melanoma detection, operated by a smartphone application (app), when used prospectively by primary care physicians to assess skin lesions of concern due to some degree of melanoma suspicion. Methods This prospective multicentre clinical trial was conducted at 36 primary care centres in Sweden. Physicians used the smartphone app on skin lesions of concern by photographing them dermoscopically, which resulted in a dichotomous decision support text regarding evidence for melanoma. Regardless of the app outcome, all lesions underwent standard diagnostic procedures (surgical excision or referral to a dermatologist). After investigations were complete, lesion diagnoses were collected from the patients' medical records and compared with the app's outcome and other lesion data. Results In total, 253 lesions of concern in 228 patients were included, of which 21 proved to be melanomas, with 11 thin invasive melanomas and 10 melanomas in situ. The app's accuracy in identifying melanomas was reflected in an area under the receiver operating characteristic (AUROC) curve of 0.960 [95% confidence interval (CI) 0.928–0.980], corresponding to a maximum sensitivity and specificity of 95.2% and 84.5%, respectively. For invasive melanomas alone, the AUROC was 0.988 (95% CI 0.965–0.997), corresponding to a maximum sensitivity and specificity of 100% and 92.6%, respectively. Conclusions The clinical decision support tool evaluated in this investigation showed high diagnostic accuracy when used prospectively in primary care patients, which could add significant clinical value for primary care physicians assessing skin lesions for melanoma. [ABSTRACT FROM AUTHOR]

Background Cardiovascular imaging plays an important role in identifying pre-existing cardiac comorbidity prior to the decision on cancer therapy and serves as a reference for detecting changes during treatment and long-term follow-up and also in the further identification of a possible cardiac manifestation of the underlying oncological disease. Case summary We report the case of an 81-year-old patient with a malignant melanoma. The patient initially was presented before the start of adjuvant therapy with serine/threonine-protein kinase B-Raf/mitogen-activated extracellular signal-regulated kinase inhibitors. Cardiologic staged diagnostics using transthoracic echocardiography, transoesophageal echocardiography, and cardiovascular magnetic resonance imaging (CMR) revealed with a high probability a cardiac manifestation of the underlying disease. The echocardiographic and CMR results as well as the diagnostic workup are presented. Discussion Cardiac masses in general have a variety of differential diagnoses. Cardiac metastases are much more common than primary neoplasms in a ratio of about 10:1. Cardiovascular risk stratification is recommended in all patients with cancer before starting potentially cardiotoxic anticancer therapy. Cardiovascular imaging plays an important role for baseline risk stratification but is also the leading diagnostic tool in the differential diagnosis of cardiac tumours and the planning of a potential therapy. [ABSTRACT FROM AUTHOR]

Background CD8+ tumor-infiltrating lymphocyte (TIL) predicts response to anti-PD-(L)1 therapy. However, there remains no standardized method to assess CD8+ TIL in melanoma, and developing a specific, cost-effective, reproducible, and clinically actionable biomarker to anti-PD-(L)1 remains elusive. We report on the development of automatic CD8+ TIL density quantification via whole slide image (WSI) analysis in advanced melanoma patients treated with front-line anti-PD-1 blockade, and correlation immunotherapy response. Methods Seventy-eight patients treated with PD-1 inhibitors in the front-line setting between January 2015 and May 2023 at the University of Pittsburgh Cancer Institute were included. CD8+ TIL density was quantified using an image analysis algorithm on digitized WSI. Targeted next-generation sequencing (NGS) was performed to determine tumor mutation burden (TMB) in a subset of 62 patients. ROC curves were used to determine biomarker cutoffs and response to therapy. Correlation between CD8+ TIL density and TMB cutoffs and response to therapy was studied. Results Higher CD8+ TIL density was significantly associated with improved response to front-line anti-PD-1 across all time points measured. CD8+ TIL density ≥222.9 cells/mm2 reliably segregated responders and non-responders to front-line anti-PD-1 therapy regardless of when response was measured. In a multivariate analysis, patients with CD8+ TIL density exceeding cutoff had significantly improved PFS with a trend toward improved OS. Similarly, increasing TMB was associated with improved response to anti-PD-1, and a cutoff of 14.70 Mut/Mb was associated with improved odds of response. The correlation between TMB and CD8+ TIL density was low, suggesting that each represented independent predictive biomarkers of response. Conclusions An automatic digital analysis algorithm provides a standardized method to quantify CD8+ TIL density, which predicts response to front-line anti-PD-1 therapy. CD8+ TIL density and TMB are independent predictors of response to anti-PD-1 blockade. [ABSTRACT FROM AUTHOR]

Background Air pollution is positively associated with some childhood cancers, whereas greenness is inversely associated with some adult cancers. The interplay between air pollution and greenness in childhood cancer etiology is unclear. We estimated the association between early-life air pollution and greenness exposure and childhood cancer in Texas (1995 to 2011). Methods We included 6101 cancer cases and 109 762 controls (aged 0 to 16 years). We linked residential birth address to census tract annual average fine particulate matter <2.5 µg/m³ (PM2.5) and Normalized Difference Vegetation Index (NDVI). We estimated odds ratios (ORs) and 95% confidence intervals (CIs) between PM2.5/NDVI interquartile range increases and cancer. We assessed statistical interaction between PM2.5 and NDVI (likelihood ratio tests). Results Increasing residential early-life PM2.5 exposure was associated with all childhood cancers (OR = 1.10, 95% CI = 1.06 to 1.15), lymphoid leukemias (OR = 1.15, 95% CI = 1.07 to 1.23), Hodgkin lymphomas (OR = 1.27, 95% CI = 1.02 to 1.58), non-Hodgkin lymphomas (OR = 1.24, 95% CI = 1.02 to 1.51), ependymoma (OR = 1.27, 95% CI = 1.01 to 1.60), and others. Increasing NDVI exposure was inversely associated with ependymoma (0- to 4-year-old OR = 0.75, 95% CI = 0.58 to 0.97) and medulloblastoma (OR = 0.75, 95% CI = 0.62 to 0.91) but positively associated with malignant melanoma (OR = 1.75, 95% CI = 1.23 to 2.47) and Langerhans cell histiocytosis (OR = 1.56, 95% CI = 1.07 to 2.28). There was evidence of statistical interaction between NDVI and PM2.5 (P  < .04) for all cancers. Conclusion Increasing early-life exposure to PM2.5 increased the risk of childhood cancers. NDVI decreased the risk of 2 cancers yet increased the risk of others. These findings highlight the complexity between PM2.5 and NDVI in cancer etiology. [ABSTRACT FROM AUTHOR]

Background S100A8 is a melanoma biomarker expressed in the melanoma-associated epidermal keratinocytes, but its diagnostic utility has not been compared with other biomarkers, including PRAME. Objectives To compare the utility of S100A8 and PRAME immunohistochemistry (IHC) in the differential diagnosis of melanoma and naevi in a case–control study. Methods A previously described cohort of 209 melanomas (case samples) and naevi (control samples) dual-immunostained for S100A8 and PRAME were included. For S100A8, previously reported scores indicating the proportion of tumour-associated epidermis stained (0 = indeterminate; 1 = 0–4%; 2 = 5–25%; 3 = 26–50%; 4 = 51–75%; 5 = > 75%) were utilized. PRAME IHC was reviewed by at least two reviewers and a consensus score assigned, with score indicating the proportion of tumour stained (0 = indeterminate; 1 = 0%; 2 = 1–50%; 3 = > 50%). A positive test was defined as > 50% staining. Results The area under the receiver operating characteristic curves for S100A8 (0.833) and PRAME (0.874) were not significantly different from each other (P = 0.22). The diagnostic sensitivity and specificity were 42.4% [95% confidence interval (CI) 32.6–52.8%] and 98.2% (95% CI 93.6–99.8%) for S100A8, and 79.8% (95% CI 70.5–87.2%) and 87.3% (95% CI 79.6–92.9%) for PRAME, respectively. A combined test requiring both S100A8 and PRAME IHC positivity had a sensitivity of 39.4% (95% CI 29.7–49.7%) and specificity of 99.1% (95% CI 95.0–100.0%). Conclusions S100A8 and PRAME have utility in the diagnostic workup of melanoma, with S100A8 being more specific and PRAME being more sensitive when using this threshold. Our findings suggest that these two immunohistochemical markers may favourably complement one another to improve the detection of melanoma. [ABSTRACT FROM AUTHOR]

This article discusses the potential risk of acute kidney injury (AKI) and chronic kidney disease (CKD) in patients receiving BRAF/MEK inhibitor therapy for melanoma. Real-world data showed higher rates of AKI compared to clinical trials. The study found that patients who received BRAF/MEK inhibitors had a higher risk of CKD compared to a group of patients who underwent surgical resection alone. The study suggests that CKD is an important comorbidity in melanoma patients and further research is needed to understand the mechanisms and develop therapies to slow kidney function decline in these patients. [Extracted from the article]

The COVID-19 pandemic caused widespread disruptions in cancer care. We hypothesized that the greatest disruptions in diagnosis occurred in screen-detected cancers. We identified patients (≥18 years of age) with newly diagnosed cancer from 2019 to 2020 in the US National Cancer Database and calculated the change in proportion of early-stage to late-stage cancers using a weighted linear regression. Disruptions in early-stage diagnosis were greater than in late-stage diagnosis (17% vs 12.5%). Melanoma demonstrated the greatest relative decrease in early-stage vs late-stage diagnosis (22.9% vs 9.2%), whereas the decrease was similar for pancreatic cancer. Compared with breast cancer, cervical, melanoma, prostate, colorectal, and lung cancers showed the greatest disruptions in early-stage diagnosis. Uninsured patients experienced greater disruptions than privately insured patients. Disruptions in cancer diagnosis in 2020 had a larger impact on early-stage disease, particularly screen-detected cancers. Our study supports emerging evidence that primary care visits may play a critical role in early melanoma detection. [ABSTRACT FROM AUTHOR]

Background Melanoma can metastasize to distal organs including the heart although presentation with a symptomatic cardiac metastasis is rare. The optimal management remains uncertain particularly in the era of immunotherapy. Case summary We report a case presenting with a large unresectable cardiac metastasis from melanoma that responded well to treatment with immunotherapy. Conclusion Melanoma can metastasize to the heart and is often challenging to diagnose. Combination immunotherapy can be an effective treatment option even in the setting of a symptomatic and unresectable cardiac metastasis. [ABSTRACT FROM AUTHOR]

Background To investigate the efficacy and toxicity after long-term follow-up of anti-PD-1 antibody in advanced melanoma with predominantly acral and mucosal subtypes. Methods and Patients In the POLARIS-01 phase II trial, 128 Chinese patients with advanced melanoma refractory to standard therapy received toripalimab until disease progression or unacceptable toxicity for ≤2 years. For those who progressed after discontinuation due to 2-year treatment completion, rechallenge was allowed. The primary objectives were safety and overall response rate (ORR). Results As of February 8, 2021, ORR was 17.3% (95% CI: 11.2-25.0) evaluated by the independent radiologic review committee. The median overall survival (OS) for patients with known melanoma subtypes was 16.3 m for acral, 41.5 m for nonacral cutaneous, and 10.3 m for mucosal melanoma. Thereafter, the evaluation was continued by investigators. As of November 4, 2022, 5 years after the last enrollment, median duration of response was 15.6 months (range, 3.7-64.5+), median progression-free survival (PFS) was 3.5 months (95% CI, 2.2-5.3), and 60-month OS rate was 28.5% (95% CI: 20.2-37.2). Thirteen patients completed a 2-year treatment of toripalimab, with the subtypes of acral (2/13), non-acral cutaneous (4/13), mucosal (3/13) and unknown primary (4/13). Five patients were rechallenged. Four of them, all of whom were non-mucosal, completed the rechallenge course of 2 years with PFS ≥ 24 months. Conclusions This is the largest prospective anti-PD-1 trial with mature data in advanced melanoma in China. Toripalimab demonstrated a manageable safety profile and durable clinical response in Chinese patients with metastatic melanoma who had failed in standard therapy. Immunotherapy seems less efficacious for long-term responders with mucosal primaries as rechallenge therapy. [ABSTRACT FROM AUTHOR]

Background Melanoma incidence is on the rise in East Asia, yet studies of the molecular landscape are lacking in this population. We examined patients with melanoma who underwent next-generation sequencing (NGS) at a single tertiary center in South Korea, focusing on patients harboring NRAS or RAF alterations who received belvarafenib, a pan-RAF dimer inhibitor, through the Expanded Access Program (EAP). Patients and Methods Data were collected from 192 patients with melanoma who underwent NGS between November 2017 and May 2023. Variant call format data were obtained and annotated. Patients in the EAP received 450 mg twice daily doses of belvarafenib. Results Alterations in the RAS/RTK pathway were the most prevalent, with BRAF and NRAS alteration rates of 22.4% and 17.7%, respectively. NGS enabled additional detection of fusion mutations, including 6 BRAF and 1 RAF1 fusion. Sixteen patients with NRAS or RAF alterations received belvarafenib through the EAP, and disease control was observed in 50%, with 2 patients demonstrating remarkable responses. Conclusions Our study highlights the value of NGS in detecting BRAF , NRAS mutations and RAF fusions, expanding possibilities for targeted therapies in malignant melanoma. Belvarafenib showed clinical benefit in patients harboring these alterations. Ongoing trials will provide further insights into the safety and efficacy of belvarafenib. [ABSTRACT FROM AUTHOR]

Objective Autoantibodies against MDA5 (melanoma differentiation-associated protein 5) serve as a biomarker for DM (dermatomyositis) and indicate a risk factor for interstitial lung disease (ILD). MDA5 is a protein responsible for sensing RNA virus infection and activating signalling pathways against it. However, little is known about the antigen epitopes on MDA5 autoantibodies. We aimed to determine the interaction of the MDA5 autoantibody–antigen epitope. Methods Cell-based assays (CBAs), immunoprecipitation-immunoblot assays, and various immunoblotting techniques were used in the study. Results We demonstrated that DM patient autoantibodies recognize MDA5 epitopes in a native conformation–dependent manner. Furthermore, we identified the central helicase domain （3Hel） formed by Hel1, Hel2i, Hel2, and pincer as the major epitopes. As proof of principle, the purified 3Hel efficiently absorbed MDA5 autoantibodies from patient sera through immunoprecipitation-immunoblot assay. Conclusion Our study uncovered the nature of the antigen epitopes on MDA5 and can provide guidance for diagnosis and a targeted therapeutic approach development. [ABSTRACT FROM AUTHOR]

Objectives Clinical observations in patients with dermatomyositis (DM) and autoantibodies against the melanoma differentiation–associated protein 5 (MDA5) suggest that the autoantibodies contribute to the pathogenesis of MDA5(+) DM. To gain insight into the role of the anti-MDA5 autoantibodies, we aimed to identify their binding sites on the different domains of the MDA5 protein. Methods We developed an in-house ELISA to assess the reactivity against the MDA5 domains (conformational epitopes) in plasma (n  = 8) and serum (n  = 24) samples from MDA5(+) patients with varying clinical manifestations and disease outcomes. The reactivities were also assessed using western blot (linearized epitopes). An ELISA-based depletion assay was developed to assess cross-reactivity among the different MDA5 domains. Results All eight plasma samples consistently showed reactivity towards conformational and linearized epitopes on the helicase domains of the MDA5 protein. The ELISA-based depletion assay suggests that anti-MDA5 autoantibodies specifically target each of the three helicase domains. Twenty-two of the 24 serum samples showed reactivity in the in-house ELISA and all 22 displayed reactivity towards the helicase domains of the MDA5 protein. Conclusions Our data revealed that the main immunogenic targets of anti-MDA5 autoantibodies from MDA5(+) patients are the helicase domains. Considering that the helicase domains are responsible for the enzymatic activity and subsequent triggering of an inflammatory response, our findings suggest that binding of anti-MDA5 autoantibodies could alter the canonical activity of the MDA5 protein and potentially affect the downstream induction of a pro-inflammatory cascade. [ABSTRACT FROM AUTHOR]

Primary intracranial melanocytoma is an uncommon benign pigmented tumor arising from leptomeningeal melanocytes. Neuroimaging characteristics of central nervous system melanocytoma are distinct from similarly presenting intracranial neoplasms and can aid in diagnosis prior to histopathological examination. In rare cases, there may be more than one lesion present. We report a case of a 19-year-old woman presenting with progressively worsening headaches, nausea, emesis, and generalized weakness of 2 months. Imaging revealed tumors in the parietal and ipsilateral medial temporal lobe. The patient underwent gross total resection of the parietal lesion which histopathological assessment revealed to be primary intracranial meningeal melanocytoma. This case highlights the utility of specific imaging criteria such as diffusely increased T1 signal without enhancement in the initial diagnostic evaluation of intracranial melanocytoma. We also describe the clinical characteristics, management strategy, and histopathological features of a rare case of a patient with multiple primary intracranial melanocytoma lesions. [ABSTRACT FROM AUTHOR]

Background Malignant melanoma (MM) is a highly aggressive form of skin cancer whose incidence continues to rise worldwide. If diagnosed at an early stage, it has an excellent prognosis, but mortality increases significantly at advanced stages after distant spread. Unfortunately, early detection of aggressive melanoma remains a challenge. Objectives To identify novel blood-circulating biomarkers that may be useful in the diagnosis of MM to guide patient counselling and appropriate disease management. Methods In this study, 105 serum samples from 26 healthy patients and 79 with MM were analysed using an untargeted approach by liquid chromatography coupled to high-resolution mass spectrometry (LC-HRMS) to compare the metabolomic profiles of both conditions. Resulting data were subjected to both univariate and multivariate statistical analysis to select robust biomarkers. The classification model obtained from this analysis was further validated with an independent cohort of 12 patients with stage I MM. Results We successfully identified several lipidic metabolites differentially expressed in patients with stage I MM vs. healthy controls. Three of these metabolites were used to develop a classification model, which exhibited exceptional precision (0.92) and accuracy (0.94) when validated on an independent sample. Conclusions These results demonstrate that metabolomics using LC-HRMS is a powerful tool to identify and quantify metabolites in bodily fluids that could serve as potential early diagnostic markers for MM. [ABSTRACT FROM AUTHOR]

Modulation of immune responses through immune checkpoint blockade has revolutionized cutaneous melanoma treatment. However, it is still the case that not all patients respond successfully to these therapies, indicating the presence of as yet unknown resistance mechanisms. Hence, it is crucial to find novel targets to improve therapy efficacy. One of the described resistance mechanisms is regulated by immune inhibitory Siglec receptors, which are engaged by the carbohydrates sialic acids expressed on tumour cells, contributing to programmed cell death protein-1 (PD1)-like immune suppression mechanisms. In this review, we provide an overview on the regulation of sialic acid synthesis, its expression in melanoma, and the contribution of the sialic acid–Siglec axis to tumour development and immune suppressive mechanisms in the tumour microenvironment. Finally, we highlight potential sialic acid–Siglec axis-related therapeutics to improve the treatment of melanoma. [ABSTRACT FROM AUTHOR]

Background Mutant BRAF targeted therapies remain a standard of care for the treatment of metastatic malignant melanoma (MM); however, high initial response rates are tempered by the persistence of residual MM cells that eventually lead to disease recurrence and mortality. As MM recurrence during targeted therapy can present with the simultaneous occurrence of multiple tumour nodules at the original body sites, we hypothesized the presence of an intrinsically resistant MM cell subpopulation. Objectives To identify an MM cell subpopulation that is intrinsically resistant to targeted therapy and possibly responsible for MM recurrence. Methods Using melanoma cell lines, we defined culture conditions for the reproducible three-dimensional growth of melanospheres to investigate putative cancer stem cell populations. We undertook RNA sequencing and bioinformatic analysis to characterize cell populations between adherent and nonadherent culture, and cells expressing or not expressing CD20. Furthermore, we defined an in vitro assay to evaluate the killing of melanoma cancer stem cells as a therapeutic test using combination therapies targeting driver mutation and CD20. Results We described the culture conditions that promote MM cells to form melanospheres with a reproducible colony-forming efficiency rate of 0.3–1.3%. RNA sequencing of melanosphere vs. conventional MM cell cultures (n = 6), irrespective of the BRAF mutation status, showed that melanosphere formation was associated with growth and differentiation transcriptional signatures resembling MM tumours. Importantly, melanosphere formation also led to the emergence of a CD20+ MM cell subpopulation, similar to that observed in primary human MM tumours. CD20+ MM cells were resistant to BRAF inhibitor therapy and, consistent with this finding, demonstrated a Forkhead box protein M1 transcriptomic profile (n = 6). Combining BRAF inhibitor and anti-CD20 antibody treatment led to the additional killing of previously resistant CD20+   BRAF mutant MM cells. Conclusions In patients with MM that harbour a CD20+ subpopulation, combined therapy with BRAF inhibitor and anti-CD20 antibody could potentially kill residual MM cells and prevent disease recurrence. [ABSTRACT FROM AUTHOR]

Strobilurins A and X, isolated from Mucidula venosolamellata culture extracts, demonstrated potent inhibition of human melanoma G-361 cell proliferation. Strobilurin X exhibited milder inhibitory effects on human fibroblast cells (NB1RGB) compared to strobilurin A. Additional strobilurin-related compounds were isolated from the other mushroom species. Oudemansins A and B displayed weaker activities on G-361 cells than strobilurins A and B, respectively, emphasizing the importance of a conjugated double-bond structure. Among isolated compounds, strobilurin G showed the lowest IC50 value for G-361 cells. Additional strobilurins bearing various substituents on the benzene ring were synthesized. Synthetic intermediates lacking the methyl β-methoxyacrylate group and a strobilurin analogue bearing modified β-methoxyacrylate moiety showed almost no inhibitory activity against G-361 cells. The introduction of long or bulky substituents at the 4′ position of the benzene ring of strobilurins enhanced the activity and selectivity, suggesting differential recognition of the benzene ring by G-361 and NB1RGB cells. [ABSTRACT FROM AUTHOR]

Background Combined expression of the autophagy-regulatory protein AMBRA1 (activating molecule in Beclin1-regulated autophagy) and the terminal differentiation marker loricrin in the peritumoral epidermis of stage I melanomas can identify tumour subsets at low risk of -metastasis. Objectives To validate the combined expression of peritumoral AMBRA1 and loricrin (AMBLor) as a prognostic biomarker able to identify both stage I and II melanomas at low risk of tumour recurrence. Methods Automated immunohistochemistry was used to analyse peritumoral AMBRA1 and loricrin expression in geographically distinct discovery (n = 540) and validation (n = 300) cohorts of nonulcerated American Joint Committee on Cancer (AJCC) stage I and II melanomas. AMBLor status was correlated with clinical outcomes in the discovery and validation cohorts separately and combined. Results Analysis of AMBLor in the discovery cohort revealed a recurrence-free survival (RFS) rate of 95.5% in the AMBLor low-risk group vs. 81.7% in the AMBLor at-risk group (multivariate log-rank, P < 0.001) and a negative predictive value (NPV) of 96.0%. In the validation cohort, AMBLor analysis revealed a RFS rate of 97.6% in the AMBLor low-risk group vs. 78.3% in the at-risk group (multivariate log-rank, P < 0.001) and a NPV of 97.6%. In a multivariate model considering AMBLor, Breslow thickness, age and sex, analysis of the combined discovery and validation cohorts showed that the estimated effect of AMBLor was statistically significant, with a hazard ratio of 3.469 (95% confidence interval 1.403–8.580, P = 0.007) and an overall NPV of 96.5%. Conclusions These data provide further evidence validating AMBLor as a prognostic biomarker to identify nonulcerated AJCC stage I and II melanoma tumours at low risk of disease recurrence. [ABSTRACT FROM AUTHOR]

Background Cutaneous squamous cell carcinoma (cSCC) and melanoma have different associations with sun exposure. Objectives To compare trends in the incidence rates of cSCC and melanoma, to provide insight into changing patterns of exposure to ultraviolet radiation (UVR). Methods We compared trends in the incidence of cSCC and melanoma in seven susceptible populations residing at mid-to-high latitudes: Finland, Norway, Sweden, Denmark, Scotland, the Netherlands and Tasmania (Australia). We fitted Joinpoint models to describe trends in age-standardized incidence rates for melanoma and cSCC and calculated the average annual percentage rate of change for the period 1989–2020 (1989–2018 for Tasmania). We calculated the incident rate ratio (IRR) as the ratio of the age-standardized rates (European Standard Population) for cSCC to melanoma and conducted age–period–cohort modelling to compare age, period and cohort effects. Results The ratio of cSCC-to-melanoma incidence increased with proximity to the equator and over time. In the most recent time period, the incidence of cSCC was higher than the incidence of melanoma for men and women in all seven populations. While the ratio of cSCC-to-melanoma incidence was higher for men vs. women, in most countries the cSCC-to-melanoma IRR increased over time to a greater extent in women than in men. Melanoma incidence was higher among younger people and cSCC incidence was higher among older people; the age at which the incidence of cSCC overtook the incidence of melanoma was progressively younger with proximity to the equator. Conclusions Despite concerted international efforts to preserve the ozone layer over the past four decades resulting in significant reductions in surface ultraviolet B at mid-latitudes, the incidence of skin cancer, particularly cSCC, continues to rise in those regions. Our findings are consistent with a stronger association with age-associated cumulative sun exposure for cSCC vs. melanoma and suggest that women are currently receiving greater UV radiation exposure than in the past. [ABSTRACT FROM AUTHOR]

Melanoma is one of the most sensitive tumors to immune modulation, and the major challenge for melanoma patients' survival is immune checkpoint inhibitor (ICI) therapy. γδ T lymphocytes play an antitumoral role in a broad variety of tumors including melanoma and they are optimal candidates for cellular immunotherapy. Thus, a comprehensive analysis of the correlation between γδ T cells and immune checkpoint receptors in the context of melanoma was conducted, with the aim of devising an innovative combined immunotherapeutic strategy. In this study, using the GEPIA2.0 database, a significant positive correlation was observed between the expression of γδ T cell–related genes (TRGC1, TRGC2, TCRD) and immune checkpoint genes (PDCD1, HAVCR2, LAG3), highlighting the potential role of γδ T cells in the immune response within melanoma. Moreover, flow cytometry analysis unveiled a significant augmentation in the population of γδ T cells within melanoma lesions, which exhibited the expression of immune checkpoint receptors including LAG3, TIM3, and PD1. Analysis of single-cell RNA sequencing data revealed a significant enrichment and functional reprogramming of γδ T cell clusters in response to ICIs. Interestingly, the effects of ICI therapy varied between Vδ1 and Vδ2 γδ T cell subsets, with distinct changes in gene expression patterns. Last, a correlation analysis between γδ T cell abundance, immune checkpoint gene expression, and clinical outcomes in melanoma patients showed that low expression of immune checkpoint genes, including LAG3, HAVCR2, and PDCD1, was associated with improved 1-year overall survival, emphasizing the significance of these genes in predicting patient outcomes, potentially outweighing the impact of γδ T cell abundance. This study offers critical insights into the dynamic interaction between γδ T cells, immune checkpoint receptors, and melanoma, providing valuable perspectives for potential therapeutic avenues and predictive markers in this intricate interplay. A comprehensive analysis exploring the intricate correlation between γδ T cells and immune checkpoint receptors in melanoma is the focus of this study. Our findings provide a solid foundation for further exploration, suggesting the strategic combination of adoptive transfer or in vivo activation of γδ T cells with immune checkpoint inhibitor therapy as a compelling approach to enhance anti-tumor responses. [ABSTRACT FROM AUTHOR]

Prospective and between trial comparisons indicate that first-line treatment with immune checkpoint inhibitors improves survival outcomes compared to first-line therapy with combined BRAF and MEK inhibitors in metastatic melanoma containing BRAFV600E/K mutations. Long-term outcomes for BRAF/MEK inhibition after progression on immunotherapy have not been reported. Moreover, clinical variables associated with outcome from treatment with combined BRAF/MEK inhibition were previously identified in the first-line setting but have not been investigated when targeted therapies are administered after progression on immune therapy. We performed a retrospective single institution analysis of 40 metastatic melanoma patients receiving combined BRAF/MEK inhibitors after progression on an anti-PD-1 or ipilimumab plus nivolumab to assess response rate by RECIST 1.1, progression-free and overall survival (PFS and OS). Pretreatment clinical variables were analyzed for association with OS. Ipilimumab/nivolumab was the first-line immunotherapy regimen in 39 patients (97.5%), and BRAFV600E/K mutations were present in 33 (83%) and 7 (17%) patients, respectively. The median OS from start of BRAF/MEK inhibitors was 20.3 months (1.73-106.4+, 95% CI of median 13.3-30.7). Clinical characteristics associated with worse survival prior to starting BRAF/MEK inhibitors included age > 60 years (median OS 14 vs. 28 months; HR 2.5; 95% CI 0.91-6.87, P  = .023), ECOG-PS > 2 (median OS 7 vs. 33 months; HR 2.89; 95% CI 0.78-10.76, P  = .018), and presence of bone metastases (median OS 9 vs. 52 months; HR 3.17; 95% CI 1.33-7.54, P  = .002). These associations with shorter survival maintained their significance on multivariate analysis. If confirmed in larger cohorts, the identified prognostic variables can be used for stratification of patients in future randomized trials. [ABSTRACT FROM AUTHOR]

A study published in the British Journal of Dermatology found that 13% of patients developed a rash after receiving co-trimoxazole treatment while on immune checkpoint inhibitor (CPI) therapy. The severity of the rash was higher in this patient group, and they had a significantly shorter median overall survival compared to those who did not develop the rash. Prompt recognition and withdrawal of co-trimoxazole treatment is recommended in the context of CPI therapy. Further studies are needed to validate these findings and understand the mechanisms behind the increased incidence and severity of the rash. [Extracted from the article]

Anorectal mucosal melanoma is rare entity. There is currently no consensus on optimal surgical treatment for loco-regional anorectal melanoma that has a favourable outcome. Abdominoperineal resection has not shown a survival benefit over wide local excision due to the inevitable distant recurrence. With local excision considered favourable given reduced surgical morbidity and avoidance of permanent stoma. However, anorectal melanomas are often diagnosed late, with an increased tumour size and depth of primary lesions, increasing the risk of local recurrence and subsequent disease morbidity when excised locally. The decision to proceed to local excision versus abdominoperineal resection is complex, it needs to be individualized, based on primary tumour clinicopathological features and driven by multidisciplinary discussion, with the goal to improve quality and quantity of life. We present a case of a 66-year-old female with anorectal mucosal melanoma with locoregional disease and our surgical approach. [ABSTRACT FROM AUTHOR]

The article offers a perspective on lifileucel as a T-cell therapy approved by the U.S. Food and Drug Administration (FDA) for melanoma. It provides a history and evolution of tumor-infiltrating lymphocytes (TIL) for adoptive cell therapy and an overview of clinical trials supporting the use of TIL for metastatic melanoma. It considers data supporting the use of TIL prior to BRAF or MEK targeted small-molecule therapy inhibition for the treatment for metastatic melanoma.

Dabrafenib and trametinib, approved for the treatment of BRAF-mutant metastatic melanoma, are associated with a spectrum ophthalmic toxicity including pan-uveitis and serous retinopathy. Vogt–Koyanagi–Harada (VKH) is a systemic inflammatory disorder characterized by bilateral granulomatous pan-uveitis, exudative retinal detachments, and often associated with extraocular manifestations such as tinnitus, vitiligo, headaches, or encephalopathy. We present a 49-year-old woman with stage IV metastatic cutaneous melanoma developed bilateral acute pan-uveitis with multifocal serous retinal detachments, 4 months after starting combined dabrafenib and trametinib therapy. Clinical assessment, together with fluorescein angiography, optical coherence tomography, and serology led to the diagnosis of a (VKH)-like uveitis. Prompt systemic corticosteroids and modification of the dosing schedule of the suspected offending agents resulted in the resolution of intraocular inflammation and serous retinal detachments. This case underscores the importance of the prompt recognition of the association between VKH-like uveitis and BRAF/MEK inhibitors, enabling early intervention without compromising metastatic melanoma treatment. [ABSTRACT FROM AUTHOR]

Objectives Immune-related adverse events (irAEs) are common. Oral irAEs tend to cluster in patients who experience concurrent toxicities. We aimed to characterize the frequency and trajectory of non-oral irAEs in patients who developed oral irAEs, assess their relationship with non-oral irAEs, and compare those characteristics with patients without oral irAEs. Methods A retrospective chart review was conducted to identify patients who started ICIT between December 11, 2011, and September 15, 2019 (n  = 4683) in the Mass General Brigham Registered Patient Data Registry. Demographic information, cancer diagnosis, ICIT regimen, treatment duration, and time and number of infusions to irAE onset were recorded. Non-oral irAEs were categorized into 13 groups. Patients with melanoma, pulmonary cancer, or head and neck cancer who had oral irAEs were then matched with those without oral irAEs to compare the prevalence of concomitant non-oral irAEs. Results Three hundred and fourteen patients with oral irAEs with a mean age of 65.9 ± 12.6 years (43.3% females) were included. Patients with multiple oral irAEs were more likely to have non-oral irAEs (OR: 2.7, 95% CI, 1.3-3.5), including cutaneous (OR: 1.7, 95% CI, 1.1-3.0), rheumatological (OR: 2.2, 95% CI, 1.1-4.2), thyroid (OR: 2.4, 95% CI, 1.2-4.9), and neurological irAEs (OR: 2.5, 95% CI, 1.0-6.3). Compared to matched patients with non-oral irAEs, patients with oral irAEs were more likely to have cutaneous (OR: 1.7, 95% CI, 1.0-2.8) and thyroid (OR: 2.86, 95% CI, 1.1-7.5) irAEs. The development of oral and non-oral irAEs is often coincidental. Conclusion Patients who have non-oral irAEs should be monitored for development of oral irAEs for prompt management. [ABSTRACT FROM AUTHOR]

Background Specific components of lipid profile seem to differently impact on immune activity against cancer and unraveling their prognostic role in patients with solid cancer treated with immune checkpoint inhibitors (ICIs) is needed. Materials and Methods We retrospectively collected baseline clinicopathological characteristics including circulating lipid profile (total cholesterol [TC], triglycerides [TG], low-density lipoproteins [LDL], high-density lipoproteins [HDL]) of patients with consecutive solid cancer treated with ICIs, and we investigated their role in predicting clinical outcomes. Results At a median follow-up of 32.9 months, among 430 enrolled patients, those with TC ≥ 200 mg/dl showed longer median progression-free survival (mPFS; 6.6 vs. 4.7 months, P  = .4), although not reaching statistical significance, and significantly longer median overall survival (mOS; 19.4 vs. 10.8 months, P  = .02) compared to those with TC < 200 mg/dl. Conversely, patients with TG ≥150 mg/dl displayed shorter PFS (3.4 vs. 5.1 months, P  = .02) and OS (7.1 vs. 12.9 months, P  = .009) compared to those with TG <150 mg/dl. TC and TG were then combined in a "LIPID score" identifying three subgroups: good-risk (GR) (TC ≥200 mg/dl and TG <150 mg/dl), intermediate-risk (IR) (TC <200 mg/dl and TG <150 mg/dl or TC ≥200 mg/dl and TG ≥150 mg/dl) and poor-risk (PR) (TC <200 mg/dl and TG ≥150 mg/dl). The mPFS of GR, IR, and PR groups was 7.8, 4.3, and 2.5 months, respectively (P  = .005); mOS of GR, IR, and PR was 20.4, 12.4, and 5.3 months, respectively (P  < .001). At multivariable analysis, the PR profile represented an independent poor prognostic factor for both PFS and OS. Conclusions We developed a lipid score that defined subgroups of patients with cancer who differently benefit from ICIs. Further mechanistic insights are warranted to clarify the prognostic and predictive role of lipid profile components in patients treated with ICIs. [ABSTRACT FROM AUTHOR]

Background Lentigo maligna/lentigo maligna melanoma (LM/LMM) is usually diagnosed in older patients, when lesions are larger. However, it is important to detect it at an earlier stage to minimize the area for surgical procedure. Objectives To determine and define clinical, dermoscopic and reflectance confocal microscopy (RCM) features of LM/LMM in patients<50 years old. Methods This was a multicentre study involving tertiary referral centres for skin cancer management. The study included cases of consecutively excised LM/LMM arising in patients<50 years of age with a histopathological diagnosis of LM/LMM and a complete set of clinical and dermoscopic images; RCM images were considered when present. Results In total, 85 LM/LMM of the face from 85 patients<50 years were included in the study. A regression model showed a direct association with the size of the lesion (R2=0.08; P=0.01) and with the number of dermoscopic features at diagnosis (R2=0.12; P<0.01). In a multivariable analysis, an increasing number of dermoscopic features correlated with increased patient age (P<0.01), while the presence of grey colour was a predictor of younger age at diagnosis (P=0.03). RCM revealed the presence of melanoma diagnostic features in all cases (pagetoid cells and atypical nesting). Conclusions LM is not a disease limited to older people as previously thought. LM presenting in young adults tends to be smaller and with fewer dermoscopic features, making its diagnosis challenging. Careful evaluation of facial pigmented lesions prior to cosmetic procedures is imperative to avoid incorrectly treating early LM as a benign lesion. [ABSTRACT FROM AUTHOR]

Background Nodular melanoma (NM) is a challenge to diagnose early due to its rapid growth and more atypical clinical presentation, making it the largest contributor to melanoma mortality. Objectives Our study aim was to perform a rare-variant allele (RVA) analysis of whole-exome sequencing of patients with NM and non-NM (minor allele frequency ≤ 1% non-Finnish European) for a set of 500 candidate genes potentially implicated in melanoma. Methods This study recruited 131 participants with NM and 194 with non-NM from South-east Queensland and patients with NM from Victoria to perform a comparative analysis of possible genetic differences or similarities between the two melanoma cohorts. Results Phenotypic analysis revealed that a majority of patients diagnosed with NM were older males with a higher frequency of fair skin and red hair than is seen in the general population. The distribution of common melanoma polygenic risk scores was similar in patients with NM and non-NM, with over 28% in the highest quantile of scores. There was also a similar frequency of carriage of familial/high-penetrant melanoma gene and loss-of-function variants. We identified 39 genes by filtering 500 candidate genes based on the greatest frequency in NM compared with non-NM cases. The genes with RVAs of greatest frequency in NM included PTCH1 , ARID2 and GHR. Rare variants in the SMO gene, which interacts with PTCH1 as ligand and receptor, were also identified, providing evidence that the Hedgehog pathway may contribute to NM risk. There was a cumulative effect in carrying multiple rare variants in the NM-associated genes. A 14.8-fold increased ratio for NM compared with non-NM was seen when two RVAs of the 39 genes were carried by a patient. Conclusions This study highlights the importance of considering frequency of RVA to identify those at risk of NM in addition to known high penetrance genes. [ABSTRACT FROM AUTHOR]

Background Compared with the general population, people with a previous melanoma are at increased risk of developing another primary melanoma. Understanding the risk factors associated with multiple primary melanomas can inform patient education and tailored surveillance. Objectives To examine the risk factors for subsequent primary melanoma in people with a previous melanoma, by conducting a systematic review and meta-analysis of the available data. Methods A systematic literature search was conducted in CINAHL, Cochrane Central Register of Controlled Trials (CENTRAL), Embase and MEDLINE. Studies that reported a risk estimate or raw frequencies and conducted between 1982 and August 2022 were included. Adjusted risk estimates were prioritized over univariable risk estimates. PRISMA reporting guidelines were followed. Random effects meta-analysis was conducted to derive pooled estimates. Quality assessment was conducted by two researchers using the Newcastle-Ottawa scale. GRADE was used to rate the certainty and quality of the evidence. Results Data from 27 studies involving 413 181 participants were pooled and analysed. Risk factors assessed included age and sex, environmental, lifestyle, phenotypic, genetic and histopathological factors, and there was wide variation in how they were categorized and analysed. Independent risk factors identified from pooled analyses included male sex [hazard ratio (HR) 1.46, 95% confidence interval (CI) 1.40–1.53], increasing age per 10 years (HR 1.19, 95% CI 1.14–1.24), light skin colour (HR 1.44, 95% CI 1.23–1.70), family history [odds ratio (OR) 1.79, 95% CI 1.25–2.56], CDKN2A mutation (OR 5.29, 95% CI 2.70–10.37), a high or moderate naevus count [OR 2.63 (95% CI 1.61–4.30) and OR 1.64 (95% CI 1.07–2.51), respectively], one or more atypical naevi (OR 3.01, 95% CI 1.52–5.97), first lesions occurring on the head or neck, lentigo maligna subtype (HR 1.16, 95% CI 1.15–1.17), other subtype (HR 1.14, 95% CI 1.03–1.27) and inadequate sun protection (HR 1.85, 95% CI 0.98–3.50). Based on the GRADE criteria, there was high to very low confidence in the pooled effect estimates. Conclusions This meta-analysis identified several consistent, independent risk factors for the development of subsequent primary melanoma. These findings will help stratify the risk of subsequent melanoma, tailor skin-check schedules and inform patient education. [ABSTRACT FROM AUTHOR]

Cutaneous melanoma is an aggressive type of skin cancer with a complex genetic landscape caused by the malignant transformation of melanocytes. This study aimed at providing an in silico network model based on the systematic profiling of the melanoma-associated genes considering germline mutations, somatic mutations, and genome-wide association study signals accounting for a total of 232 unique melanoma risk genes. A protein–protein interaction network was constructed using the melanoma risk genes as seeds and evaluated to describe the functional landscape in which the melanoma genes operate within the cellular milieu. Not only were the majority of the melanoma risk genes able to interact with each other at the protein level within the core of the network, but this showed significant enrichment for genes whose expression is altered in human melanoma specimens. Functional annotation showed the melanoma risk network to be significantly associated with processes related to DNA metabolism and telomeres, DNA damage and repair, cellular ageing, and response to radiation. We further explored whether the melanoma risk network could be used as an in silico tool to predict the efficacy of anti-melanoma phytochemicals, that are considered active molecules with potentially less systemic toxicity than classical cytotoxic drugs. A significant portion of the melanoma risk network showed differential expression when SK-MEL-28 human melanoma cells were exposed to the phytochemicals harmine and berberine chloride. This reinforced our hypothesis that the network modeling approach not only provides an alternative way to identify molecular pathways relevant to disease but it may also represent an alternative screening approach to prioritize potentially active compounds. [ABSTRACT FROM AUTHOR]

Background Many women diagnosed with cancer as adolescents and young adults (AYAs, age 15-39 years) want biological children after cancer but lack information on the potential impact of their cancer history on future reproductive outcomes. We investigated the risk of adverse birth outcomes among AYA cancer survivors. Methods We identified insured women diagnosed with AYA breast cancer, thyroid cancer, gynecologic cancers, lymphoma, or melanoma from 2003 to 2016 in the state of North Carolina or the Kaiser Permanente health care systems in northern and southern California. Post-diagnosis births to cancer survivors were each matched with up to 5 births to women without cancer. Risk ratios for preterm birth (<37 completed weeks), very preterm birth (<34 completed weeks), low birth weight (<2500 g), and small for gestational age (SGA, <10th percentile of weight for gestational age) were estimated using modified Poisson regression. Results Analyses included 1648 births to 1268 AYA cancer survivors and 7879 births to 6066 women without cancer. Overall, risk of preterm birth, very preterm birth, low birth weight, and SGA did not significantly differ between births to women with and without cancer. However, births to women with gynecologic cancers had a significantly increased risk of low birth weight (risk ratio = 1.82; 95% confidence interval: 1.03 to 3.21) and suggested increased risk of preterm birth (risk ratio = 1.59; 95% confidence interval: 0.99 to 2.54). Chemotherapy exposure was not associated with increased risk of adverse birth outcomes. Conclusions Women with gynecologic cancers, but not other cancers, had an increased risk of adverse birth outcomes compared to women without cancer. [ABSTRACT FROM AUTHOR]

Background: Wide local excision (WLE) is standard practice in the management of melanoma, but no national or international guidelines exist regarding its technique. Objectives: To assess variation in the practice of WLE and to explore the effect of clinicians' specialty and grade on such variation. Methods: This was an international, anonymized, cross-sectional study. An online questionnaire was distributed to the Irish Association of Dermatologists, British Association of Dermatologists, British Association of Plastic and Reconstructive and Aesthetic Surgeons, Melanoma Focus and BioGenoMEL members. Results: Of 128 respondents, 57% were dermatologists and 38% plastic surgeons. Most (80%) were consultants. Almost all clinicians learned their technique from colleagues (99%) 'on the job', although 21% also used textbooks or other media as part of WLE training. There was significant variation in planning and performing WLE: 59% considered margins already achieved, 71% marked margins with the skin relaxed. For 1 cm WLE, 84% delineated 1 cm from the edge of the scar; with a greater proportion of plastic surgeons than dermatologists marking from the centre of the scar (P < 0.05). Most followed a longitudinal/oblique axis on the limbs for WLE (81%). Only 40% sent 'dog ears' for histology. Most (70%) incised through the marked line, 27% incised outside it. Most (79%) excised to deep fascia, 18% to the next biological margin. Conclusions: This study demonstrates significant variation among clinicians performing WLE, an essential component of melanoma management. We postulate that this could have an impact on patient outcomes. A consensus statement should be developed, to achieve more consistency in the practice of WLE. Wide local excision (WLE) is standard practice in the management of melanoma, but no national or international guidelines exist regarding its technique. The aims of this study were to assess variation in the practice of WLE and to explore the effect of clinicians' specialty and grade on such variation. This study demonstrated significant variation among clinicians performing WLE, an essential component of melanoma management. [ABSTRACT FROM AUTHOR]

Background: The 2022 National Institute for Health and Care Excellence melanoma guideline update made significant changes to follow-up. The aim of this study was to assess the impact these changes will have on a national melanoma cohort over a 5-year follow-up interval. Methods: Anonymized, individual-level, population-scale, linkable primary and secondary care National Health Service data for an 18-year interval (2000–2018) in Wales, UK were analysed. These data were used to predict the number of patients over a 10-year interval (2020–2030) that would be diagnosed with melanoma. Follow-up schedules for the 2015 and 2022 National Institute for Health and Care Excellence melanoma guidelines were then used to calculate the number of clinician-led appointments, the number of radiological investigations, and the total healthcare cost between 2025 and 2030, corresponding to a 5-year patient follow-up interval, for those with stage IA–IIC melanoma. Results: Between 2025 and 2030 it is predicted that implementation of the 2022 guidelines would lead to 21 122 (range 19 194–23 083) fewer clinician-led appointments for patients with stage IA–IIC melanoma. However, there would be a significant increase in the number of radiological investigations (7812; range 7444–8189). These changes would lead to a €2.74 million (€1.87 million–€3.61 million) reduction in the total cost of follow-up over the interval 2025–2030. Conclusion: Melanoma follow-up guideline changes will result in a substantial reduction in the number of clinical follow-up appointments, but a significant additional burden to radiological services. The overall cost of follow-up at a national level will be reduced. Changes to the National Institute for Health and Care Excellence melanoma follow-up guidelines in 2022 will result in approximately 20 000 fewer clinician-led appointments over a 5-year interval in Wales. Despite the increase in radiology requirements, there will be a €2.74 million reduction in healthcare cost. [ABSTRACT FROM AUTHOR]

Objectives: The co-occurrence of melanoma and Parkinson's disease (PD) is higher than expected. We review the relationship between melanoma and PD, then proffer a hypothesis of how dysregulated human tyrosinase could be involved in both diseases via the loss of dopamine and neuromelanin-positive neurons in PD and the genesis alterations in melanin content during melanoma. Key findings: There are a surprising number of links between skin disorders and neurodegenerative diseases. Some risk factors related to the co-occurrence of PD and melanoma have been extensively investigated over the past 15 years. It has been proposed that human tyrosinase, an enzyme participating in the biosynthesis of neuromelanin in the brain and of melanin in the skin, plays a role. Abnormally dysregulated human tyrosinase impacts the genesis and progression of melanoma and PD. Summary: The dual role of human tyrosinase places it as the potential critical link between these seemingly distinct conditions. Detecting and monitoring human tyrosinase activity in the progression of melanoma and PD opens new opportunities for early diagnosis and treatment of both diseases. Graphical Abstract [ABSTRACT FROM AUTHOR]

Background Adjuvant therapies have been approved for resected melanoma based on improved recurrence-free survival. We present early findings from a real-world study on adjuvant treatments for melanoma. Methods A comprehensive chart review was conducted for patients receiving adjuvant systemic therapy for resected high-risk stages III and IV melanoma. Statistical analysis was performed to assess recurrence-free survival and subgroup differences. Results A total of 149 patients (median age = 58.0 years, 61.1% men, 49.7% with BRAF V600E/K genotypes) were included, with 94.6% having resected stage III melanoma. Anti-PD-1 immunotherapy was received by 86.5% of patients, while 13.4% received BRAF-targeted therapy. At a median follow-up of 22.4 months, the recurrence rate was 31.5%, with 1-year and 2-year recurrence-free survival rates of 79% and 62%, respectively. Similar recurrence rates were observed between anti-PD-1 immunotherapy and BRAF-targeted therapy. Long-term toxicity affected 27.4% of patients, with endocrinopathies and late-emergent immune-related adverse events being common. Conclusions Real-world adjuvant systemic therapy aligns with clinical trial practice. Recurrence rates remain high despite treatment, and long-term toxicities, including endocrinopathies and chronic inflammatory conditions, are not uncommon. [ABSTRACT FROM AUTHOR]

Background Immune checkpoint inhibitors (ICIs) have demonstrated efficacy over previous cytotoxic chemotherapies in clinical trials among various tumors. Despite their favorable outcomes, they are associated with a unique set of toxicities termed as immune-related adverse events (irAEs). Among the toxicities, ICI-related pneumonitis has poor outcomes with little understanding of its risk factors. This retrospective study aimed to investigate whether pre-existing interstitial lung abnormality (ILA) is a potential risk factor for ICI-related pneumonitis. Materials and Methods Patients with non-small cell lung cancer, malignant melanoma, renal cell carcinoma, and gastric cancer, who was administered either nivolumab, pembrolizumab, or atezolizumab between September 2014 and January 2019 were retrospectively reviewed. Information on baseline characteristics, computed tomography findings before administration of ICIs, clinical outcomes, and irAEs were collected from their medical records. Pre-existing ILA was categorized based on previous studies. Results Two-hundred-nine patients with a median age of 68 years were included and 23 (11.0%) developed ICI-related pneumonitis. While smoking history and ICI agents were associated with ICI-related pneumonitis (P =.005 and.044, respectively), the categories of ILA were not associated with ICI-related pneumonitis (P =.428). None of the features of lung abnormalities were also associated with ICI-related pneumonitis. Multivariate logistic analysis indicated that smoking history was the only significant predictor of ICI-related pneumonitis (P =.028). Conclusion This retrospective study did not demonstrate statistically significant association between pre-existing ILA and ICI-related pneumonitis, nor an association between radiologic features of ILA and ICI-related pneumonitis. Smoking history was independently associated with ICI-related pneumonitis. Further research is warranted for further understanding of the risk factors of ICI-related pneumonitis. [ABSTRACT FROM AUTHOR]

A study compared the carbon footprint of the National Institute for Health and Care Excellence (NICE) melanoma follow-up pathways in England in 2015 and 2022. The researchers found that the 2022 pathway had a lower carbon footprint than the 2015 pathway, suggesting that transitioning to the 2022 pathway could be more environmentally sustainable. However, the study did not evaluate the clinical outcomes of the different pathways and the findings may not be applicable to other settings. The text provides a table comparing the carbon footprints of the two pathways based on outpatient clinics and scans required, along with assumptions made for patient travel. The research did not receive specific funding and data can be requested from the corresponding author, but conflicts of interest exist for one of the authors. [Extracted from the article]

Urinary bladder with concurrent colonic melanoma is an exceptionally uncommon occurrence, posing a diagnostic challenge for clinicians. While rare, it warrants consideration as a potential differential diagnosis, particularly in patients without a history of melanoma who present with persistent hematuria due to its aggressive nature. We present a case of a 55-year-old female with malignant melanoma involving the colon and urinary bladder presenting with hematuria. Given the scarcity of cases and variability in clinical management approaches, there is a pressing need for research efforts to establish standardized protocols and conduct trials to guide clinical practice in this rare entity. [ABSTRACT FROM AUTHOR]