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BACKGROUND: In Germany, skin cancer screening (SCS) is available free of charge every two years to all those with statutory health insurance over the age of 35. General Practitioners (GP) can carry out the screening if they have completed an 8-hour training course. GPs play a crucial role in the implementation of SCS and act as gatekeepers between initial patient contact and referral to dermatologists. OBJECTIVE: To record how comprehensively GPs carry out SCS in terms of patient information and body examination, as well as to explore GPs opinions on the feasibility of SCS. METHODS: A cross-sectional survey was conducted. A questionnaire was sent to GPs with permission to perform SCS in two regions of Germany (Bavaria and Saxony) between August and September 2021. Data were analyzed using descriptive analysis. Subgroup analysis was performed according to regions (federal state, location of physician´s office), professional experience (experience in years, number of monthly screenings, age) and gender. Open questions were evaluated using qualitative content analysis. RESULTS: In the survey, 204 GPs responded. Genitalia (40.7%, 83/203), anal fold (62.3%, 127/204) and oral mucosa (66.7%, 136/204) were the least examined body regions during screening. Information on risks (false-positive findings: 18.6%, 38/203; false-negative findings: 13.2%, 27/203; overdiagnosis: 7.8%, 16/203) and benefits (48.0%, 98/202) were not always provided. GPs who performed screenings more frequently were more likely to provide information about the benefits of SCS (p<0.001; >10 vs. <5 screenings per month). Opinions were provided on uncertainties, knowledge requirements, structural and organizational requirements of SCS, SCS training and evaluation. The organization and remuneration of the SCS programme was seen as a barrier to implementation. GPs expressed uncertainties especially in unclear findings and in dermatoscopy. CONCLUSION: Uncertainties in the implementation of the SCS should be addressed by offering refresher courses. Good networking between GPs and dermatologists is essential to improve SCS quality.
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Detección Precoz del Cáncer , Médicos Generales , Neoplasias Cutáneas , Humanos , Alemania , Estudios Transversales , Masculino , Femenino , Encuestas y Cuestionarios , Detección Precoz del Cáncer/estadística & datos numéricos , Neoplasias Cutáneas/diagnóstico , Persona de Mediana Edad , Adulto , Actitud del Personal de Salud , Anciano , Pautas de la Práctica en Medicina/estadística & datos numéricosAsunto(s)
Porocarcinoma Ecrino , Perfilación de la Expresión Génica , Neoplasias de las Glándulas Sudoríparas , Humanos , Porocarcinoma Ecrino/genética , Porocarcinoma Ecrino/patología , Neoplasias de las Glándulas Sudoríparas/genética , Neoplasias de las Glándulas Sudoríparas/patología , Transcriptoma/genética , Lesiones Precancerosas/genética , Lesiones Precancerosas/patología , Femenino , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/patología , Masculino , Regulación Neoplásica de la Expresión Génica , Persona de Mediana EdadRESUMEN
This study investigated whether adjuvant treatments in stage III cutaneous melanoma (CM) influenced patterns of recurrence. Patients with primary (n = 1033) or relapsed CM (n = 350) who received adjuvant therapies with Nivolumab (N), Pembrolizumab (P), or Dabrafenib and Trametinib (D + T) were extracted from the prospective multicenter real-world skin cancer registry ADOReg. Endpoints were progression-free survival (PFS), distant metastasis-free survival (DMFS), organ-specific DMFS, and overall survival (OS). For primary cases, D + T indicated an improved PFS (1- and 2-year PFS: 90.9%; 82.7%) as compared to P (81.0%, 73.9%; p = .0208), or N (83.8%, 75.2%; p = .0539). BRAF-mutated(mut) CM demonstrated significantly lower PFS (p = .0022) and decreased DMFS (p = .0580) when treated with immune checkpoint inhibitor (ICI) instead of D + T. Besides, NRAS-mut CM tended to perform worse than wt CM upon ICI (PFS: p = .1349; DMFS: p = .0540). OS was similar between the groups. Relapsed cases showed decreased PFS, DMFS, and OS in comparison to primary (all: p < .001), without significant differences between the subgroups. Organ-specific DMFS was significantly altered for primary cases with bone (p = .0367) or brain metastases (p = .0202). In relapsed CM, the frequency of liver (D + T: 1.5%; P: 12%; N: 9%) and LN metastases (D + T: 1.5%; P: 12%; N: 10.2%) was significantly lower with adjuvant D + T than ICI. NRAS-mut CM showed increased recurrence in primary and relapsed cases. These data show that adjuvant D + T is superior to ICI in primary BRAF-mut CM.
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BACKGROUND: Melanomas lacking mutations in BRAF, NRAS and NF1 are frequently referred to as "triple wild-type" (tWT) melanomas. They constitute 5-10 % of all melanomas and remain poorly characterized regarding clinical characteristics and response to therapy. This study investigates the largest multicenter collection of tWT-melanomas to date. METHODS: Targeted next-generation sequencing of the TERT promoter and 29 melanoma-associated genes were performed on 3109 melanoma tissue samples of the prospective multicenter study ADOREG/TRIM of the DeCOG revealing 292 patients suffering from tWT-melanomas. Clinical characteristics and mutational patterns were analyzed. As subgroup analysis, we analyzed 141 tWT-melanoma patients receiving either anti-CTLA4 plus anti-PD1 or anti PD1 monotherapy as first line therapy in AJCC stage IV. RESULTS: 184 patients with cutaneous melanomas, 56 patients with mucosal melanomas, 34 patients with acral melanomas and 18 patients with melanomas of unknown origin (MUP) were included. A TERT promoter mutation could be identified in 33.2 % of all melanomas and 70.5 % of all tWT-melanomas harbored less than three mutations per sample. For the 141 patients with stage IV disease, mPFS independent of melanoma type was 6.2 months (95 % CI: 4-9) and mOS was 24.8 months (95 % CI: 14.2-53.4) after first line anti-CTLA4 plus anti-PD1 therapy. After first-line anti-PD1 monotherapy, mPFS was 4 months (95 %CI: 2.9-8.5) and mOS was 29.18 months (95 % CI: 17.5-46.2). CONCLUSIONS: While known prognostic factors such as TERT promoter mutations and TMB were equally distributed among patients who received either anti-CTLA4 plus anti-PD1 combination therapy or anti-PD1 monotherapy as first line therapy, we did not find a prolonged mPFS or mOS in either of those. For both therapy concepts, mPFS and mOS were considerably shorter than reported for melanomas with known oncogene mutations.
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Inhibidores de Puntos de Control Inmunológico , Melanoma , Mutación , Proteínas Proto-Oncogénicas B-raf , Humanos , Melanoma/tratamiento farmacológico , Melanoma/genética , Melanoma/mortalidad , Melanoma/patología , Melanoma/inmunología , Masculino , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Femenino , Persona de Mediana Edad , Proteínas Proto-Oncogénicas B-raf/genética , Anciano , Adulto , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/mortalidad , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/inmunología , Neurofibromina 1/genética , Estudios Prospectivos , Supervivencia sin Progresión , Anciano de 80 o más Años , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Telomerasa/genética , GTP Fosfohidrolasas/genética , Regiones Promotoras Genéticas , Proteínas de la MembranaRESUMEN
Introduction: Despite recent advancements in the treatment of metastatic uveal melanoma (UM), the availability of further treatment options remains limited and the prognosis continues to be poor in many cases. In addition to tebentafusp, immune checkpoint blockade (ICB, PD-1 (+/-) CTLA-4 antibodies) is commonly used for metastatic UM, in particular in HLA-A 02:01-negative patients. However, ICB comes at the cost of potentially severe immune-related adverse events (irAE). Thus, the selection of patient groups that are more likely to benefit from ICB is desirable. Methods: In this analysis, 194 patients with metastatic UM undergoing ICB were included. Patients were recruited from German skin cancer sites and the ADOReg registry. To investigate the association of irAE occurrence with treatment response, progression-free survival (PFS), and overall survival (OS) two cohorts were compared: patients without irAE or grade 1/2 irAE (n=137) and patients with grade 3/4 irAE (n=57). Results: In the entire population, the median OS was 16.4 months, and the median PFS was 2.8 months. Patients with grade 3/4 irAE showed more favorable survival than patients without or grade 1/2 irAE (p=0.0071). IrAE occurred in 44.7% (87/194), and severe irAE in 29.4% (57/194) of patients. Interestingly, irColitis and irHepatitis were significantly associated with longer OS (p=0.0031 and p=0.011, respectively). Conclusions: This data may indicate an association between irAE and favorable survival outcomes in patients with metastatic UM undergoing ICB treatment and suggests that a reduced tolerance to tumor antigens could be linked to reduced tolerance to self-antigens.
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Inhibidores de Puntos de Control Inmunológico , Melanoma , Neoplasias de la Úvea , Humanos , Neoplasias de la Úvea/mortalidad , Neoplasias de la Úvea/tratamiento farmacológico , Neoplasias de la Úvea/inmunología , Neoplasias de la Úvea/patología , Melanoma/tratamiento farmacológico , Melanoma/mortalidad , Melanoma/inmunología , Masculino , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Femenino , Persona de Mediana Edad , Anciano , Adulto , Anciano de 80 o más Años , Metástasis de la NeoplasiaRESUMEN
Modern diagnostic procedures, such as three-dimensional total body photography (3D-TBP), digital dermoscopy (DD), and reflectance confocal microscopy (RCM), can improve melanoma diagnosis, particularly in high-risk patients. This study assessed the benefits of combining these advanced imaging techniques in a three-step programme in managing high-risk patients. This study included 410 high-risk melanoma patients who underwent a specialised imaging consultation in addition to their regular skin examinations in outpatient care. At each visit, the patients underwent a 3D-TBP, a DD for suspicious findings, and an RCM for unclear DD findings. The histological findings of excisions initiated based on imaging consultation and outpatient care were compared. Imaging consultation detected sixteen confirmed melanomas (eight invasive and eight in situ) in 39 excised pigmented lesions. Outpatient care examination detected seven confirmed melanomas (one invasive and six in situ) in 163 excised melanocytic lesions. The number needed to excise (NNE) in the imaging consultation was significantly lower than that in the outpatient care (2.4 vs. 23.3). The NNE was 2.6 for DD and 2.3 for RCM. DD, 3D-TBP, or RCM detected melanomas that were not detected by the other imaging methods. The three-step imaging programme improves melanoma detection and reduces the number of unnecessary excisions in high-risk patients.
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BACKGROUND AND OBJECTIVES: Malignant sweat gland tumors are rare, with the most common being eccrine porocarcinoma (EP). Approximately 18% of benign eccrine poroma (EPO) transit to EP. Previous research has provided first insights into the mutational landscape of EP. However, only few studies have performed gene expression analyses. This leaves a gap in the understanding of EP biology and potential drivers of malignant transformation from EPO to EP. METHODS: Transcriptome profiling of 23 samples of primary EP and normal skin (NS). Findings from the EP samples were then tested in 17 samples of EPO. RESULTS: Transcriptome profiling revealed diversity in gene expression and indicated biologically heterogeneous sub-entities as well as widespread gene downregulation in EP. Downregulated genes included CD74, NDGR1, SRRM2, CDC42, ANXA2, KFL9 and NOP53. Expression levels of CD74, NDGR1, SRRM2, ANXA2, and NOP53 showed a stepwise-reduction in expression from NS via EPO to EP, thus supporting the hypothesis that EPO represents a transitional state in EP development. CONCLUSIONS: We demonstrated that EP is molecularly complex and that evolutionary trajectories correspond to tumor initiation and progression. Our results provide further evidence implicating the p53 axis and the EGFR pathway. Larger samples are warranted to confirm our findings.
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Porocarcinoma Ecrino , Perfilación de la Expresión Génica , Neoplasias de las Glándulas Sudoríparas , Humanos , Porocarcinoma Ecrino/genética , Porocarcinoma Ecrino/patología , Neoplasias de las Glándulas Sudoríparas/genética , Neoplasias de las Glándulas Sudoríparas/patología , Neoplasias de las Glándulas Sudoríparas/metabolismo , Lesiones Precancerosas/genética , Lesiones Precancerosas/patología , Femenino , Masculino , Transformación Celular Neoplásica/genética , Regulación Neoplásica de la Expresión Génica , Anciano , Persona de Mediana EdadRESUMEN
Elevated levels of peripheral blood and tumor tissue neutrophils are associated with poorer clinical response and therapy resistance in melanoma. The underlying mechanism and the role of neutrophils in targeted therapy is still not fully understood. Serum samples of patients with advanced melanoma were collected and neutrophil-associated serum markers were measured and correlated with response to targeted therapy. Blood neutrophils from healthy donors and patients with advanced melanoma were isolated, and their phenotypes, as well as their in vitro functions, were compared. In vitro functional tests were conducted through nonadherent cocultures with melanoma cells. Protection of melanoma cell lines by neutrophils was assessed under MAPK inhibition. Blood neutrophils from advanced melanoma patients exhibited lower CD16 expression compared to healthy donors. In vitro, both healthy-donor- and patient-derived neutrophils prevented melanoma cell apoptosis upon dual MAPK inhibition. The effect depended on cell-cell contact and melanoma cell susceptibility to treatment. Interference with protease activity of neutrophils prevented melanoma cell protection during treatment in cocultures. The negative correlation between neutrophils and melanoma outcomes seems to be linked to a protumoral function of neutrophils. In vitro, neutrophils exert a direct protective effect on melanoma cells during dual MAPK inhibition. This study further hints at a crucial role of neutrophil-related protease activity in protection.
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BACKGROUND: Immune checkpoint inhibitors (ICI) induce adverse events (irAEs) that do not respond to steroids, i.e. steroid-refractory (sr) irAEs, and irAEs in which steroids cannot be tapered, i.e. steroid-dependent (sd) irAEs, in about 10% of cases. An evidence-based analysis of the effectiveness of second-line immunosuppressive agents with regard to irAE and tumor control is lacking. METHODS: The international web-based Side Effect Registry Immuno-Oncology (SERIO; http://serio-registry.org) is a collaborative initiative with the Paul-Ehrlich-Institute to document rare, severe, complex or therapy-refractory immunotherapy-induced side effects. The registry was queried on August 1, 2023 for cases of irAEs which were treated with second-line therapies. RESULTS: From a total of 1330 cases, 217 patients (16.3%) received 249 second-line therapies. A total of 19 different second-line therapies were employed, including TNF-alpha antagonists (46.5%), intravenous immunoglobulins (IVIG; 19.1%), mycophenolate mofetil (15.9%), and methotrexate (3.6%). Therapy choices were determined by the type of irAE. The time to onset of sr-/sd-irAEs after ICI initiation did not consistently differ from steroid-responsive irAEs. While 74.3% of sr-/sd-irAEs resolved and 13.1% had improved, 4.3% persisted, 3.9% resulted in permanent sequelae, and 4.3% in death with ongoing symptoms. Infliximab exhibited potential for earlier symptom improvement compared to mycophenolate mofetil or IVIG. Tumor response in patients with second-line treated sd-/sr-irAE was similar to patients with irAEs treated with steroids only. CONCLUSION: Several second-line therapies are effective against sr-/sd-irAEs, the second-line therapies show no clear negative impact on tumor response, and infliximab shows potential for faster improvement of symptoms. However, prospective comparative data are needed.
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Inhibidores de Puntos de Control Inmunológico , Neoplasias , Humanos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Femenino , Masculino , Persona de Mediana Edad , Anciano , Neoplasias/tratamiento farmacológico , Neoplasias/inmunología , Adulto , Sistema de Registros , Anciano de 80 o más Años , Esteroides/uso terapéutico , Inmunosupresores/uso terapéutico , Inmunosupresores/efectos adversos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/etiologíaRESUMEN
Melanoma is the most serious type of skin cancer that frequently spreads to other organs of the human body. Especially melanoma metastases to the brain (intracranial metastases) are hard to treat and a major cause of death of melanoma patients. Little is known about molecular alterations and altered mechanisms that distinguish intra- from extracranial melanoma metastases. So far, almost all existing studies compared intracranial metastases from one set of patients to extracranial metastases of an another set of melanoma patients. This neglects the important facts that each melanoma is highly individual and that intra- and extracranial melanoma metastases from the same patient are more similar to each other than to melanoma metastases from other patients in the same organ. To overcome this, we compared the gene expression profiles of 16 intracranial metastases to their corresponding 21 patient-matched extracranial metastases in a personalized way using a three-state Hidden Markov Model (HMM) to identify altered genes for each individual metastasis pair. This enabled three major findings by considering the predicted gene expression alterations across all patients: (i) most frequently altered pathways include cytokine-receptor interaction, calcium signaling, ECM-receptor interaction, cAMP signaling, Jak-STAT and PI3K/Akt signaling, (ii) immune-relevant signaling pathway genes were downregulated in intracranial metastases, and (iii) intracranial metastases were associated with a brain-like phenotype gene expression program. Further, the integration of all differentially expressed genes across the patient-matched melanoma metastasis pairs led to a set of 103 genes that were consistently down- or up-regulated in at least 11 of the 16 of the patients. This set of genes contained many genes involved in the regulation of immune responses, cell growth, cellular signaling and transport processes. An analysis of these genes in the TCGA melanoma cohort showed that the expression behavior of 11 genes was significantly associated with survival. Moreover, a comparison of the 103 genes to three closely related melanoma metastasis studies revealed a core set of eight genes that were consistently down- or upregulated in intra- compared to extracranial metastases in at least two of the three related studies (down: CILP, DPT, FGF7, LAMP3, MEOX2, TMEM119; up: GLDN, PMP2) including FGF7 that was also significantly associated with survival. Our findings contribute to a better characterization of genes and pathways that distinguish intra- from extracranial melanoma metastasis and provide important hints for future experimental studies to identify potential targets for new therapeutic approaches.
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Neoplasias Encefálicas , Melanoma , Neoplasias Cutáneas , Humanos , Melanoma/genética , Melanoma/patología , Melanoma/secundario , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/secundario , Femenino , Masculino , Persona de Mediana Edad , Anciano , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Regulación Neoplásica de la Expresión Génica/genética , Adulto , Perfilación de la Expresión Génica , Metástasis de la Neoplasia/genéticaRESUMEN
BACKGROUND: Treatment decisions in metastatic melanoma (MM) are highly dependent on patient preferences and require the patients' involvement. The complexity of treatment options with their individual advantages and disadvantages is often overwhelming. We therefore developed an online patient decision aid (PtDA) to facilitate shared decision making (SDM). METHODS: To evaluate the PtDA we conducted a two-armed, twocenter, prospective, open randomized controlled trial with MM patients who were facing a decision about first-line treatment. The patients were allotted randomly in a 1:1 ratio to an intervention group (IG) with access to the PtDA before discussion with a physician or to a control group (CG) without access to the PtDA. The primary endpoint was knowledge about the options for first-line treatment (multiple-choice test, 10 items, range 0-40 points). The secondary endpoints were the SDM (third-party ratings of audio recordings of the treatment discussions) and satisfaction with the decision at the follow-up visit. RESULTS: Of the 128 randomized patients, 120 completed the baseline questionnaire and were analyzed (59% male, median age 66 years). The primary endpoint, i.e., the mean difference in knowledge after discussion with a physician, differed significantly between the IG and the CG (-3.22, 95% CI [-6.32; -0.12], p = 0.042). No differences were found for the secondary endpoints, SDM and satisfaction with the decision. The patients in the IG rated the PtDA as very useful. CONCLUSION: The PtDA improved the knowledge of patients with MM about the options for treatment. Both groups were highly satisfied with their treatment decisions. However, additional physician training seems necessary to promote SDM.
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Melanoma , Humanos , Melanoma/secundario , Melanoma/terapia , Masculino , Femenino , Anciano , Persona de Mediana Edad , Técnicas de Apoyo para la Decisión , Participación del Paciente/estadística & datos numéricos , Participación del Paciente/métodos , Neoplasias Cutáneas/terapia , Alemania , Estudios Prospectivos , Adulto , Satisfacción del Paciente/estadística & datos numéricos , Educación del Paciente como Asunto/métodosAsunto(s)
Inteligencia Artificial , Dermatólogos , Prioridad del Paciente , Neoplasias Cutáneas , Humanos , Neoplasias Cutáneas/diagnóstico , Estudios Prospectivos , Dermatólogos/estadística & datos numéricos , Dermatólogos/psicología , Femenino , Masculino , Prioridad del Paciente/estadística & datos numéricos , Persona de Mediana Edad , Adulto , Anciano , Encuestas y Cuestionarios/estadística & datos numéricos , Dermatología/métodosRESUMEN
BACKGROUND: Cemiplimab (Libtayo®), a human monoclonal immunoglobulin G4 antibody to the programmed cell death-1 receptor, is approved for the treatment of patients with advanced cutaneous squamous cell carcinoma (CSCC), who are not candidates for curative surgery or curative radiation, using an every-3-weeks (Q3W) dosing interval. Pharmacokinetic modeling indicated that Ctrough of extended intravenous dosing of 600 mg every 4 weeks (Q4W) would be comparable to the approved intravenous dosage of 350 mg Q3W. We examined the efficacy, pharmacokinetics, and safety of cemiplimab dosed Q4W. METHODS: In this open-label, phase II trial (ClinicalTrials.gov identifier NCT02760498), the cohort of patients ≥18 years old with advanced CSCC received cemiplimab 600 mg intravenously Q4W for up to 48 weeks. Tumor measurements were recorded every 8 weeks. The primary endpoint was objective response rate by independent central review. RESULTS: Sixty-three patients with advanced CSCC were treated with cemiplimab. The median duration of follow-up was 22.4 months (range: 1.0-39.8). An objective response was observed in 39 patients (62%; 95% CI: 48.8% to 73.9%), with 22% of patients (n=14) achieving complete response and 40% (n=25) achieving partial response. The most common treatment-emergent adverse events were diarrhea, pruritus, and fatigue. CONCLUSIONS: Extended dosing of cemiplimab 600 mg intravenously Q4W exhibited substantial antitumor activity, rapid and durable responses, and an acceptable safety profile in patients with advanced CSCC. These results confirm that cemiplimab is a highly active therapy for advanced CSCC. Additional data would help ascertain the benefit-risk profile for the 600 mg intravenous dosing regimen compared with the approved regimen.
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Carcinoma de Células Escamosas , Neoplasias Cutáneas , Humanos , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados/efectos adversos , Carcinoma de Células Escamosas/patología , Neoplasias Cutáneas/patología , AdultoRESUMEN
Melanoma, the deadliest form of skin cancer, can metastasize to different organs. Molecular differences between brain and extracranial melanoma metastases are poorly understood. Here, promoter methylation and gene expression of 11 heterogeneous patient-matched pairs of brain and extracranial metastases were analyzed using melanoma-specific gene regulatory networks learned from public transcriptome and methylome data followed by network-based impact propagation of patient-specific alterations. This innovative data analysis strategy allowed to predict potential impacts of patient-specific driver candidate genes on other genes and pathways. The patient-matched metastasis pairs clustered into three robust subgroups with specific downstream targets with known roles in cancer, including melanoma (SG1: RBM38, BCL11B, SG2: GATA3, FES, SG3: SLAMF6, PYCARD). Patient subgroups and ranking of target gene candidates were confirmed in a validation cohort. Summarizing, computational network-based impact analyses of heterogeneous metastasis pairs predicted individual regulatory differences in melanoma brain metastases, cumulating into three consistent subgroups with specific downstream target genes.
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Importance: The development of artificial intelligence (AI)-based melanoma classifiers typically calls for large, centralized datasets, requiring hospitals to give away their patient data, which raises serious privacy concerns. To address this concern, decentralized federated learning has been proposed, where classifier development is distributed across hospitals. Objective: To investigate whether a more privacy-preserving federated learning approach can achieve comparable diagnostic performance to a classical centralized (ie, single-model) and ensemble learning approach for AI-based melanoma diagnostics. Design, Setting, and Participants: This multicentric, single-arm diagnostic study developed a federated model for melanoma-nevus classification using histopathological whole-slide images prospectively acquired at 6 German university hospitals between April 2021 and February 2023 and benchmarked it using both a holdout and an external test dataset. Data analysis was performed from February to April 2023. Exposures: All whole-slide images were retrospectively analyzed by an AI-based classifier without influencing routine clinical care. Main Outcomes and Measures: The area under the receiver operating characteristic curve (AUROC) served as the primary end point for evaluating the diagnostic performance. Secondary end points included balanced accuracy, sensitivity, and specificity. Results: The study included 1025 whole-slide images of clinically melanoma-suspicious skin lesions from 923 patients, consisting of 388 histopathologically confirmed invasive melanomas and 637 nevi. The median (range) age at diagnosis was 58 (18-95) years for the training set, 57 (18-93) years for the holdout test dataset, and 61 (18-95) years for the external test dataset; the median (range) Breslow thickness was 0.70 (0.10-34.00) mm, 0.70 (0.20-14.40) mm, and 0.80 (0.30-20.00) mm, respectively. The federated approach (0.8579; 95% CI, 0.7693-0.9299) performed significantly worse than the classical centralized approach (0.9024; 95% CI, 0.8379-0.9565) in terms of AUROC on a holdout test dataset (pairwise Wilcoxon signed-rank, P < .001) but performed significantly better (0.9126; 95% CI, 0.8810-0.9412) than the classical centralized approach (0.9045; 95% CI, 0.8701-0.9331) on an external test dataset (pairwise Wilcoxon signed-rank, P < .001). Notably, the federated approach performed significantly worse than the ensemble approach on both the holdout (0.8867; 95% CI, 0.8103-0.9481) and external test dataset (0.9227; 95% CI, 0.8941-0.9479). Conclusions and Relevance: The findings of this diagnostic study suggest that federated learning is a viable approach for the binary classification of invasive melanomas and nevi on a clinically representative distributed dataset. Federated learning can improve privacy protection in AI-based melanoma diagnostics while simultaneously promoting collaboration across institutions and countries. Moreover, it may have the potential to be extended to other image classification tasks in digital cancer histopathology and beyond.
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Dermatología , Melanoma , Nevo , Neoplasias Cutáneas , Humanos , Melanoma/diagnóstico , Inteligencia Artificial , Estudios Retrospectivos , Neoplasias Cutáneas/diagnóstico , Nevo/diagnósticoRESUMEN
BACKGROUND: The impact of immunosuppressive therapy (IST) on immune-checkpoint inhibition (ICI) is unclear. METHODS: Patients with unresectable advanced melanoma (MM) treated with ICI in the years 2011-2020 were identified from the prospective multicenter German skin cancer registry ADOREG. Patients with IST within 60 days before, or within 30 days after start of ICI were compared to patients without IST. End points were disease control rate (DCR), overall survival (OS) and progression-free survival (PFS) determined by Kaplan-Meier method. Prognostic factors were evaluated in a Cox regression model. RESULTS: Of 814 patients treated with ICI, 73 (9%) received concomitant IST, mainly steroids. Patients with brain metastases (BM) received IST more frequently (n = 34/130 patients; 26%), than patients without BM (39/684 patients; 6%). In patients without BM, IST initiated before, but not IST initiated after start of ICI was significantly associated with worse PFS (univariate hazard ratio (HR) 2.59, 95% confidence interval (95%-CI) 1.07-6.28, p = 0.035; multivariate HR 3.48, 95%-CI 1.26-9.6, p = 0.016). There was no association between IST and OS or DCR. In patients with BM, IST initiated before, but not after start of ICI was significantly associated with worse OS (univariate HR 2.06, 95%-CI 1.07-3.95, p = 0.031; multivariate HR 5.91, 95%-CI 1.74-20.14, p = 0.004). There was no association between IST and PFS or DCR. CONCLUSION: Patients receiving IST 60 days before start of ICI showed a tendency to an impaired therapy outcome. IST initiated within 30 days after start of ICI, mainly due to early side effects, did not affect the efficacy of ICI therapy.
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Neoplasias Encefálicas , Melanoma , Neoplasias Primarias Secundarias , Neoplasias Cutáneas , Humanos , Melanoma/tratamiento farmacológico , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Estudios Prospectivos , Neoplasias Cutáneas/tratamiento farmacológico , Sistema de Registros , Terapia de Inmunosupresión , Estudios RetrospectivosRESUMEN
INTRODUCTION: Non-melanoma skin cancer (NMSC) is a cause of significant morbidity and mortality in high-risk individuals. Total body photography (TBP) is currently used to monitor melanocytic lesions in patients with high risk for melanoma. The authors examined if three-dimensional (3D)-TBP could be useful for diagnosis of NMSC. METHODS: Patients (n = 129; 52 female, 77 male) with lesions suspicious for NMSC who had not yet had a biopsy underwent clinical examination followed by examination of each lesion with 3D-TBP Vectra®WB360 (Canfield Scientific, Parsippany, NJ, USA) and dermoscopy. RESULTS: The 129 patients had a total of 182 lesions. Histological examination was performed for 158 lesions; the diagnoses included basal cell carcinoma (BCC; n = 107), squamous cell carcinoma (SCC; n = 27), in-situ SCC (n = 15). Lesions were located in the head/neck region (n = 138), trunk (n = 21), and limbs (n = 23). Of the 182 lesions examined, 12 were not visible on 3D-TBP; reasons for not being visible included location under hair and on septal of nose. Two lesions appeared only as erythema in 3D-TBP but were clearly identifiable on conventional photographs. Sensitivity of 3D-TBP was lower than that of dermoscopy for BCC (73% vs. 79%, p = 0.327), higher for SCC (81% vs. 74%, p = 0.727), and lower for in-situ SCC (0% vs. 33%, p = 125). Specificity of 3D-TBP was lower than that of dermoscopy for BCC (77% vs. 82%, 0.581), lower for SCC (75% vs. 84%, p = 0.063), and higher for in-situ SCC (97% vs. 94%, p = 0.344). Diagnostic accuracy of 3D-TBP was lower than that of dermoscopy for BCC (75% vs. 80%), lower for SCC (76% vs. 82%), and lower for in-situ SCC (88% vs. 89%). Lesion location was not associated with diagnostic confidence in dermoscopy (p = 0.152) or 3D-TBP (p = 0.353). If only lesions with high confidence were included in the calculation, diagnostic accuracy increased for BCC (n = 27; sensitivity 85%, specificity 85%, diagnostic accuracy 85%), SCC (n = 10; sensitivity 90%, specificity 80%, diagnostic accuracy 83%), and for in-situ SCC (n = 2; sensitivity 0%, specificity 100%, diagnostic accuracy 95%). CONCLUSION: Diagnostic accuracy appears to be slightly lower for 3D-TBP in comparison to dermoscopy. However, there is no statistically significant difference in the sensitivity and specificity of 3D-TBP and dermoscopy for NMSC. Diagnostic accuracy increases, if only lesions with high confidence are included in the calculation. Further studies are necessary to determine if 3D-TBP can improve management of NMSC.
Asunto(s)
Carcinoma Basocelular , Melanoma , Neoplasias Cutáneas , Humanos , Femenino , Masculino , Dermoscopía/métodos , Neoplasias Cutáneas/diagnóstico por imagen , Neoplasias Cutáneas/patología , Melanoma/diagnóstico por imagen , Melanoma/patología , Carcinoma Basocelular/diagnóstico por imagen , Carcinoma Basocelular/patología , FotograbarRESUMEN
Cobimetinib/vemurafenib combination therapy is approved for treatment of adults with unresectable or metastatic BRAF V600 mutated malignant melanoma (mM). The non-interventional post-authorisation safety study coveNIS collected real-world data on cobimetinib/vemurafenib treatment focussing on overall survival (OS), safety and utilization. MM patients with brain metastases are usually excluded from clinical studies. coveNIS observed 2 cohorts: mM patients without (Cohort A) and with cerebral metastases (Cohort B), aiming to close the data gap for the latter population. A direct comparison of the 2 cohorts was not intended. The primary effectiveness objective was OS; the safety objective was the incidence of all and of serious adverse events (AEs). Secondary objectives included progression-free survival (PFS), time to development of cerebral metastasis (Cohort A) and time to central nervous system relapse (Cohort B). All statistical analyses were descriptive. Between 2017 and 2021, 95 patients were included (Cohort A: 54, Cohort B: 41 patients) at 32 sites in Germany. Median OS was 21.6 months in Cohort A, 7.4 months in Cohort B. Median PFS was 6.9 months in Cohort A, 5.2 months in Cohort B. The proportion of patients experiencing any AEs was 83.3% (Cohort A) and 87.8% (Cohort B). The two most common AEs in Cohort A were 'diarrhoea' (37%), 'vomiting' (20.4%) and 'pyrexia' (20.4%); in Cohort B 'diarrhoea' (36.6%) and 'fatigue' (22%). In conclusion, the OS rates in Cohort A and Cohort B of coveNIS are in line with the OS data from other trials with BRAF/MEK inhibitors for mM. No new safety signals were observed.