Digital decision support for structural improvement of melanoma tumor boards: using standard cases to optimize workflow.

PURPOSE: Choosing optimal cancer treatment is challenging, and certified cancer centers must present all patients in multidisciplinary tumor boards (MDT). Our aim was to develop a decision support system (DSS) to provide treatment recommendations for apparently simple cases already at conference registration and to classify these as "standard cases". According to certification requirements, discussion of standard cases is optional and would thus allow more time for complex cases. METHODS: We created a smartphone query that simulated a tumor conference registration and requested all information needed to provide a recommendation. In total, 111 out of 705 malignant melanoma cases discussed at a skin cancer center from 2017 to 2020 were identified as potential standard cases, for which a digital twin recommendation was then generated by DSS. RESULTS: The system provided reliable advice in all 111 cases and showed 97% concordance of MDT and DSS for therapeutic recommendations, regardless of tumor stage. Discrepancies included two cases (2%) where DSS advised discussions at MDT and one case (1%) with deviating recommendation due to advanced patient age. CONCLUSIONS: Our work aimed not to replace clinical expertise but to alleviate MDT workload and enhance focus on complex cases. Overall, our DSS proved to be a suitable tool for identifying standard cases as such, providing correct treatment recommendations, and thus reducing the time burden of tumor conferences in favor for the comprehensive discussion of complex cases. The aim is to implement the DSS in routine tumor board software for further qualitative assessment of its impact on oncological care.

Impact of the COVID-19 pandemic on training conditions and education in oncologic disciplines: a survey-based analysis.

PURPOSE: The COVID-19 pandemic has led to changes in global health care. Medical societies had to update guidelines and enhance new services such as video consultations. Cancer treatment had to be modified. The aim of this study is to ensure optimal care for cancer patients with the help of high-quality training even in times of crisis. We therefore conducted a nationwide survey of physicians in training in oncological disciplines during the pandemic to assess the impact on their education. METHODS: The survey was sent to tumour centres, hospitals, specialist societies, and working and junior research groups and distributed via newsletters and homepages. Interim results and a call for participation were published as a poster (DEGRO) [26] and in the German Cancer Society (DKG) journal FORUM [42]. The survey contained 53 questions on conditions of education and training and on clinical and scientific work. Statistics were carried out with LimeSurvey and SPSS (IBM Corp., Armonk, NY, USA). RESULTS: Between February and November 2022, 450 participants answered the survey, with radio-oncologists being the largest group (28%). Most colleagues (63%) had access to digital training methods. Virtual sessions were rated as a good alternative, especially as multidisciplinary meetings (54%) as well as in-house and external training programs (48%, 47%). The time spent by training supervisors on education was rated as less than before the pandemic by 57%. Half of all participants perceived communication (54%), motivation (44%) and atmosphere (50%) in the team as bad. The participants felt strongly burdened by extra work (55%) and by a changed team atmosphere (49%). One third felt a change in the quality of training during the pandemic and rated it as negative (35%). According to 37% of the participants, this had little influence on their own quality of work. Additional subgroup analyses revealed significant differences in gender, specialty and education level. CONCLUSION: In order to improve oncology training in times of crisis, access to digital training options and meetings should be ensured. Participants wish for regular team meetings in person to enable good team spirit, compensation for overtime work and sufficient time for training supervisors for discussion and feedback.

Tebentafusp in Patients with Metastatic Uveal Melanoma: A Real-Life Retrospective Multicenter Study.

BACKGROUND: Tebentafusp has recently been approved for the treatment of metastatic uveal melanoma (mUM) after proving to have survival benefits in a first-line setting. PATIENTS AND METHODS: This retrospective, multicenter study analyzed the outcomes and safety of tebentafusp therapy in 78 patients with mUM. RESULTS: Patients treated with tebentafusp had a median PFS of 3 months (95% CI 2.7 to 3.3) and a median OS of 22 months (95% CI 10.6 to 33.4). In contrast to a published Phase 3 study, our cohort had a higher rate of patients with elevated LDH (65.4% vs. 35.7%) and included patients with prior systemic and local ablative therapies. In patients treated with tebentafusp following ICI, there was a trend for a longer median OS (28 months, 95% CI 26.9 to 29.1) compared to the inverse treatment sequence (24 months, 95% CI 13.0 to 35.0, p = 0.257). The most common treatment-related adverse events were cytokine release syndrome in 71.2% and skin toxicity in 53.8% of patients. Tumor lysis syndrome occurred in one patient. CONCLUSIONS: Data from this real-life cohort showed a median PFS/OS similar to published Phase 3 trial data. Treatment with ICI followed by tebentafusp may result in longer PFS/OS compared to the inverse treatment sequence.

Brain metastasis and survival outcomes after first-line therapy in metastatic melanoma: a multicenter DeCOG study on 1704 patients from the prospective skin cancer registry ADOREG.

BACKGROUND: Despite the availability of effective systemic therapies, a significant number of advanced melanoma patients develops brain metastases. This study investigated differences in incidence and time to diagnosis of brain metastasis and survival outcomes dependent on the type of first-line therapy. METHODS: Patients with metastatic, non-resectable melanoma (AJCCv8 stage IIIC-V) without brain metastasis at start of first-line therapy (1L-therapy) were identified from the prospective multicenter real-world skin cancer registry ADOREG. Study endpoints were incidence of brain metastasis, brain metastasis-free survival (BMFS), progression-free survival (PFS), and overall survival (OS). RESULTS: Of 1704 patients, 916 were BRAF wild-type (BRAFwt) and 788 were BRAF V600 mutant (BRAFmut). Median follow-up time after start of 1L-therapy was 40.4 months. BRAFwt patients received 1L-therapy with immune checkpoint inhibitors (ICI) against CTLA-4+PD-1 (n=281) or PD-1 (n=544). In BRAFmut patients, 1L-therapy was ICI in 415 patients (CTLA-4+PD-1, n=108; PD-1, n=264), and BRAF+MEK targeted therapy (TT) in 373 patients. After 24 months, 1L-therapy with BRAF+MEK resulted in a higher incidence of brain metastasis compared with PD-1±CTLA-4 (BRAF+MEK, 30.3%; CTLA-4+PD-1, 22.2%; PD-1, 14.0%). In multivariate analysis, BRAFmut patients developed brain metastases earlier on 1L-therapy with BRAF+MEK than with PD-1±CTLA-4 (CTLA-4+PD-1: HR 0.560, 95% CI 0.332 to 0.945, p=0.030; PD-1: HR 0.575, 95% CI 0.372 to 0.888, p=0.013). Type of 1L-therapy, tumor stage, and age were independent prognostic factors for BMFS in BRAFmut patients. In BRAFwt patients, tumor stage was independently associated with longer BMFS; ECOG Performance status (ECOG-PS), lactate dehydrogenase (LDH), and tumor stage with OS. CTLA-4+PD-1 did not result in better BMFS, PFS, or OS than PD-1 in BRAFwt patients. For BRAFmut patients, multivariate Cox regression revealed ECOG-PS, type of 1L-therapy, tumor stage, and LDH as independent prognostic factors for PFS and OS. 1L-therapy with CTLA-4+PD-1 led to longer OS than PD-1 (HR 1.97, 95% CI 1.122 to 3.455, p=0.018) or BRAF+MEK (HR 2.41, 95% CI 1.432 to 4.054, p=0.001), without PD-1 being superior to BRAF+MEK. CONCLUSIONS: In BRAFmut patients 1L-therapy with PD-1±CTLA-4 ICI resulted in a delayed and less frequent development of brain metastasis compared with BRAF+MEK TT. 1L-therapy with CTLA-4+PD-1 showed superior OS compared with PD-1 and BRAF+MEK. In BRAFwt patients, no differences in brain metastasis and survival outcomes were detected for CTLA-4+PD-1 compared with PD-1.

C-Reactive Protein and Lymphocyte-to-Monocyte Ratio Predict Recurrence in Stage III Melanoma Patients with Microscopic Sentinel Lymph Node Metastasis.

Although adjuvant therapies with immune checkpoint inhibitors (ICI) and BRAF/MEK inhibitors improve recurrence-free survival (RFS) in stage III melanoma patients significantly, prognostic factors are needed to identify patients with a high risk of disease recurrence. Therefore, the aim of our study was to investigate the prognostic potential of routinely collected blood parameters for stage III melanoma patients with microscopic sentinel lymph node (SLN) metastasis. Altogether, we retrospectively analyzed 138 stage III melanoma patients who were diagnosed with microscopic SLN metastasis at the skin cancer center of the University Hospital Cologne between 2011 and 2020 and who did not receive prior adjuvant therapy with ICI or BRAF/MEK-inhibitors. Univariate and multivariate Cox regression analyses, Kaplan-Meier survival analyses and receiver operating characteristic (ROC) curves were performed to assess the impact of preoperatively collected blood parameters and blood ratios on recurrence-free survival (RFS; primary endpoint) and overall survival (OS). A high neutrophil-to-lymphocyte ratio (NLR), low lymphocyte-to-monocyte ratio (LMR) and high C-reactive protein (CRP) value were significantly associated with shorter RFS in multivariate analysis. For LMR (cut-off 3.5) and for CRP (cut-off 3.0) this effect remained after dichotomization. CRP showed a stronger association with RFS than NLR or LMR, with the highest association being detected for the combination of low LMR and high CRP. Additionally, derived NLR ≥ 2.0 was significantly associated with shorter OS in multivariate analysis. In summary, our data suggest that CRP in combination with LMR should be considered as a marker for melanoma recurrence in stage III melanoma patients with microscopic SLN metastasis.

Impact of radiotherapy and sequencing of systemic therapy on survival outcomes in melanoma patients with previously untreated brain metastasis: a multicenter DeCOG study on 450 patients from the prospective skin cancer registry ADOREG.

BACKGROUND: Despite of various therapeutic strategies, treatment of patients with melanoma brain metastasis (MBM) still is a major challenge. This study aimed at investigating the impact of type and sequence of immune checkpoint blockade (ICB) and targeted therapy (TT), radiotherapy, and surgery on the survival outcome of patients with MBM. METHOD: We assessed data of 450 patients collected within the prospective multicenter real-world skin cancer registry ADOREG who were diagnosed with MBM before start of the first non-adjuvant systemic therapy. Study endpoints were progression-free survival (PFS) and overall survival (OS). RESULTS: Of 450 MBM patients, 175 (38.9%) received CTLA-4+PD-1 ICB, 161 (35.8%) PD-1 ICB, and 114 (25.3%) BRAF+MEK TT as first-line treatment. Additional to systemic therapy, 67.3% of the patients received radiotherapy (stereotactic radiosurgery (SRS); conventional radiotherapy (CRT)) and 24.4% had surgery of MBM. 199 patients (42.2%) received a second-line systemic therapy. Multivariate Cox regression analysis revealed the application of radiotherapy (HR for SRS: 0.213, 95% CI 0.094 to 0.485, p<0.001; HR for CRT: 0.424, 95% CI 0.210 to 0.855, p=0.016), maximal size of brain metastases (HR for MBM >1 cm: 1.977, 95% CI 1.117 to 3.500, p=0.019), age (HR for age >65 years: 1.802, 95% CI 1.016 to 3.197, p=0.044), and ECOG performance status (HR for ECOG ≥2: HR: 2.615, 95% CI 1.024 to 6.676, p=0.044) as independent prognostic factors of OS on first-line therapy. The type of first-line therapy (ICB vs TT) was not independently prognostic. As second-line therapy BRAF+MEK showed the best survival outcome compared with ICB and other therapies (HR for CTLA-4+PD-1 compared with BRAF+MEK: 13.964, 95% CI 3.6 to 54.4, p<0.001; for PD-1 vs BRAF+MEK: 4.587 95% CI 1.3 to 16.8, p=0.022 for OS). Regarding therapy sequencing, patients treated with ICB as first-line therapy and BRAF+MEK as second-line therapy showed an improved OS (HR for CTLA-4+PD-1 followed by BRAF+MEK: 0.370, 95% CI 0.157 to 0.934, p=0.035; HR for PD-1 followed by BRAF+MEK: 0.290, 95% CI 0.092 to 0.918, p=0.035) compared with patients starting with BRAF+MEK in first-line therapy. There was no significant survival difference when comparing first-line therapy with CTLA-4+PD-1 ICB with PD-1 ICB. CONCLUSIONS: In patients with MBM, the addition of radiotherapy resulted in a favorable OS on systemic therapy. In BRAF-mutated MBM patients, ICB as first-line therapy and BRAF+MEK as second-line therapy were associated with a significantly prolonged OS.

Oncologic Outcome and Immune Responses of Radiotherapy with Anti-PD-1 Treatment for Brain Metastases Regarding Timing and Benefiting Subgroups.

While immune checkpoint inhibitors (ICIs) in combination with radiotherapy (RT) are widely used for patients with brain metastasis (BM), markers that predict treatment response for combined RT and ICI (RT-ICI) and their optimal dosing and sequence for the best immunogenic effects are still under investigation. The aim of this study was to evaluate prognostic factors for therapeutic outcome and to compare effects of concurrent and non-concurrent RT-ICI. We retrospectively analyzed data of 93 patients with 319 BMs of different cancer types who received PD-1 inhibitors and RT at the University Hospital Cologne between September/2014 and November/2020. Primary study endpoints were overall survival (OS), progression-free survival (PFS), and local control (LC). We included 66.7% melanoma, 22.8% lung, and 5.5% other cancer types with a mean follow-up time of 23.8 months. Median OS time was 12.19 months. LC at 6 months was 95.3% (concurrent) vs. 69.2% (non-concurrent; p = 0.008). Univariate Cox regression analysis detected following prognostic factors for OS: neutrophil-to-lymphocyte ratio NLR favoring <3 (low; HR 2.037 (1.184−3.506), p = 0.010), lactate dehydrogenase (LDH) favoring ≤ULN (HR 1.853 (1.059−3.241), p = 0.031), absence of neurological symptoms (HR 2.114 (1.285−3.478), p = 0.003), RT concept favoring SRS (HR 1.985 (1.112−3.543), p = 0.019), RT dose favoring ≥60 Gy (HR 0.519 (0.309−0.871), p = 0.013), and prior anti-CTLA4 treatment (HR 0.498 (0.271−0.914), p = 0.024). Independent prognostic factors for OS were concurrent RT-ICI application (HR 0.539 (0.299−0.971), p = 0.024) with a median OS of 17.61 vs. 6.83 months (non-concurrent), ECOG performance status favoring 0 (HR 7.756 (1.253−6.061), p = 0.012), cancer type favoring melanoma (HR 0.516 (0.288−0.926), p = 0.026), BM volume (PTV) favoring ≤3 cm3 (HR 1.947 (1.007−3.763), p = 0.048). Subgroups with the following factors showed significantly longer OS when being treated concurrently: RT dose <60 Gy (p = 0.014), PTV > 3 cm3 (p = 0.007), other cancer types than melanoma (p = 0.006), anti-CTLA4-naïve patients (p < 0.001), low NLR (p = 0.039), steroid intake ≤4 mg (p = 0.042). Specific immune responses, such as abscopal effects (AbEs), pseudoprogression (PsP), or immune-related adverse events (IrAEs), occurred more frequently with concurrent RT-ICI and resulted in better OS. Other toxicities, including radionecrosis, were not statistically different in both groups. The concurrent application of RT and ICI, the ECOG-PS, cancer type, and PTV had an independently prognostic impact on OS. In concurrently treated patients, treatment response (LC) was delayed and specific immune responses (AbE, PsP, IrAE) occurred more frequently with longer OS rates. Our results suggest that concurrent RT-ICI application is more beneficial than sequential treatment in patients with low pretreatment inflammatory status, more and larger BMs, and with other cancer types than melanoma.

Computed tomography-guided biopsy of radiologically unclear lesions in advanced skin cancer: A retrospective analysis of 47 cases.

BACKGROUND: Radiological imaging such as computed tomography (CT) is used frequently for disease staging and therapy monitoring in advanced skin cancer patients. Detected lesions of unclear dignity are a common challenge for treating physicians. The aim of this study was to assess the frequency and outcome of CT-guided biopsy (CTGB) of radiologically unclear, suspicious lesions and to depict its usefulness in different clinical settings. METHODS: This retrospective monocentric study included advanced skin cancer patients (melanoma, Merkel cell carcinoma, squamous cell carcinoma, angiosarcoma, cutaneous lymphoma) with radiologically unclear lesions who underwent CTGB between 2010 and 2018. RESULTS: Of 59 skin cancer patients who received CTGB, 47 received CTGB to clarify radiologically suspicious lesions of unclear dignity. 32 patients had no systemic therapy (cohort A), while 15 patients received systemic treatment at CTGB (cohort B). In both cohorts, CTGB revealed skin cancer metastasis in a large proportion of patients (37.5%, 40.0%, respectively), but benign tissue showing inflammation, fibrosis or infection in an equally large percentage (37.5%, 46.7%, respectively). Additionally, a significant number of other cancer entities was found (25.0%, 13.3%, respectively). In patients receiving BRAF/MEK inhibitors, CTGB confirmed suspicious lesions as skin cancer metastasis in 83.3%, leading to treatment change. In immune checkpoint inhibitor-treated patients, skin cancer metastasis was confirmed in 11.1% of patients only, whereas benign tissue changes (inflammation/fibrosis) were found in 77.8%. CONCLUSIONS: Our results highlight the relevance of clarifying radiologically unclear lesions by CTGB before start or change of an anti-tumour therapy to exclude benign alterations and secondary malignancies.

Outcome of melanoma patients with elevated LDH treated with first-line targeted therapy or PD-1-based immune checkpoint inhibition.

BACKGROUND: Elevated lactate dehydrogenase (LDH) is a known predictive and prognostic factor for a poor outcome in patients with metastatic melanoma. It is unclear whether first-line targeted therapy (TT) or immune checkpoint inhibition (ICI) is more beneficial in melanoma patients with elevated LDH because prospective studies in this area are lacking. METHODS: This multicentre retrospective cohort study was conducted at 25 melanoma centres worldwide to analyse progression-free survival (PFS) and overall survival (OS) among melanoma patients with elevated LDH. The role of confounders was addressed by using inverse probability of treatment weighting. RESULTS: Among 173 BRAFV600-mutant patients, PFS at 12 months in the TT group was 22% compared with 52% in the combined anti-PD-1 and anti-CTLA-4 group (HR 0.6, 95% CI 0.4-1.0, p = 0.07) and 18% in the anti-PD-1 monotherapy group (HR 1.8, 95% CI 1.2-2.8, p = 0.003). Twelve months' OS was 48% in the TT group compared with 83% in the combined anti-PD-1 and anti-CTLA-4 group (HR 0.5, 95% CI 0.3-1.0, p = 0.03) and 50% in the anti-PD-1 monotherapy group (HR 1.2, 95% CI 0.8-2.0, p = 0.37). The ORR in the TT group was 63%, compared with 55% and 20% in the combined anti-PD-1 and anti-CTLA-4 and anti-PD-1 monotherapy group, respectively. Among 314 patients receiving ICI first-line, PFS at 12 months was 33% in the anti-PD-1 group versus 38% in the combined anti-PD-1 and anti-CTLA-4 group (HR 0.8, 95% CI 0.6-1.0; p = 0.07). OS at 12 months was 54% in the anti-PD-1 group versus 66% in the combined ICI group (HR 0.7, 95% CI 0.5-1.0; p = 0.03). The ORR was 30% in the anti-PD-1 monotherapy group and 43% in the combined anti-PD-1 and anti-CTLA-4 group. Results from multivariate analysis confirmed the absence of qualitative confounding. CONCLUSIONS: Among BRAF-mutant patients with elevated LDH, combined anti-PD-1 and anti-CTLA-4 blockade seems to be associated with prolonged OS compared with first-line TT. Among patients receiving ICI as a first-line treatment, OS appears to be longer for the combination of anti-PD-1 and anti-CTLA-4 than for anti-PD-1 alone.

Immune checkpoint inhibition therapy for advanced skin cancer in patients with concomitant hematological malignancy: a retrospective multicenter DeCOG study of 84 patients.

BACKGROUND: Skin cancers are known for their strong immunogenicity, which may contribute to a high treatment efficacy of immune checkpoint inhibition (ICI). However, a considerable proportion of patients with skin cancer is immuno-compromised by concomitant diseases. Due to their previous exclusion from clinical trials, the ICI treatment efficacy is poorly investigated in these patients. The present study analyzed the ICI treatment outcome in advanced patients with skin cancer with a concomitant hematological malignancy. METHODS: This retrospective multicenter study included patients who were treated with ICI for locally advanced or metastatic melanoma (MM), cutaneous squamous cell carcinoma (cSCC), or Merkel cell carcinoma (MCC), and had a previous diagnosis of a hematological malignancy irrespective of disease activity or need of therapy at ICI treatment start. Comparator patient cohorts without concomitant hematological malignancy were extracted from the prospective multicenter skin cancer registry ADOREG. Treatment outcome was measured as best overall response, progression-free (PFS), and overall survival (OS). RESULTS: 84 patients (MM, n=52; cSCC, n=15; MCC, n=17) with concomitant hematological malignancy were identified at 20 skin cancer centers. The most frequent concomitant hematological malignancies were non-Hodgkin's lymphoma (n=70), with chronic lymphocytic leukemia (n=32) being the largest entity. While 9 patients received ICI in an adjuvant setting, 75 patients were treated for advanced non-resectable disease (55 anti-PD-1; 8 anti-PD-L1; 5 anti-CTLA-4; 7 combinations). In the latter 75 patients, best objective response (complete response+partial response) was 28.0%, disease stabilization was 25.3%, and 38.6% showed progressive disease (PD). Subdivided by skin cancer entity, best objective response was 31.1% (MM), 26.7% (cSCC), and 18.8% (MCC). Median PFS was 8.4 months (MM), 4.0 months (cSCC), and 5.7 months (MCC). 1-year OS rates were 78.4% (MM), 65.8% (cSCC), and 47.4% (MCC). Comparison with respective ADOREG patient cohorts without hematological malignancy (n=392) revealed no relevant differences in ICI therapy outcome for MM and MCC, but a significantly reduced PFS for cSCC (p=0.002). CONCLUSIONS: ICI therapy showed efficacy in advanced patients with skin cancer with a concomitant hematological malignancy. Compared with patients without hematological malignancy, the observed ICI therapy outcome was impaired in cSCC, but not in MM or MCC patients.

Artificial Intelligence and Its Effect on Dermatologists' Accuracy in Dermoscopic Melanoma Image Classification: Web-Based Survey Study.

BACKGROUND: Early detection of melanoma can be lifesaving but this remains a challenge. Recent diagnostic studies have revealed the superiority of artificial intelligence (AI) in classifying dermoscopic images of melanoma and nevi, concluding that these algorithms should assist a dermatologist's diagnoses. OBJECTIVE: The aim of this study was to investigate whether AI support improves the accuracy and overall diagnostic performance of dermatologists in the dichotomous image-based discrimination between melanoma and nevus. METHODS: Twelve board-certified dermatologists were presented disjoint sets of 100 unique dermoscopic images of melanomas and nevi (total of 1200 unique images), and they had to classify the images based on personal experience alone (part I) and with the support of a trained convolutional neural network (CNN, part II). Additionally, dermatologists were asked to rate their confidence in their final decision for each image. RESULTS: While the mean specificity of the dermatologists based on personal experience alone remained almost unchanged (70.6% vs 72.4%; P=.54) with AI support, the mean sensitivity and mean accuracy increased significantly (59.4% vs 74.6%; P=.003 and 65.0% vs 73.6%; P=.002, respectively) with AI support. Out of the 10% (10/94; 95% CI 8.4%-11.8%) of cases where dermatologists were correct and AI was incorrect, dermatologists on average changed to the incorrect answer for 39% (4/10; 95% CI 23.2%-55.6%) of cases. When dermatologists were incorrect and AI was correct (25/94, 27%; 95% CI 24.0%-30.1%), dermatologists changed their answers to the correct answer for 46% (11/25; 95% CI 33.1%-58.4%) of cases. Additionally, the dermatologists' average confidence in their decisions increased when the CNN confirmed their decision and decreased when the CNN disagreed, even when the dermatologists were correct. Reported values are based on the mean of all participants. Whenever absolute values are shown, the denominator and numerator are approximations as every dermatologist ended up rating a varying number of images due to a quality control step. CONCLUSIONS: The findings of our study show that AI support can improve the overall accuracy of the dermatologists in the dichotomous image-based discrimination between melanoma and nevus. This supports the argument for AI-based tools to aid clinicians in skin lesion classification and provides a rationale for studies of such classifiers in real-life settings, wherein clinicians can integrate additional information such as patient age and medical history into their decisions.

Clinical and genetic analysis of melanomas arising in acral sites.

STUDY AIM: Melanomas arising in acral sites are associated with a poorer prognosis than other melanoma subtypes. The aim of this study was to evaluate clinical-pathological and genetic characteristics as well as therapeutic responses of a larger cohort of patients with melanomas arising in acral sites. METHODS: Clinical data of 134 patients with melanomas arising in acral sites from the Dept. of Dermatology Essen were collected and analysed with regard to clinicopathological characteristics and treatment responses. Genetic analysis with targeted next-generation sequencing was done on 50 samples. RESULTS: In our cohort, BRAF (30%), NRAS (28%), TERT promoter (26%), NF1 (14%) and KIT (6%) were frequently identified mutations. Comparing tumours situated on palms and soles with melanomas arising on dorsal acral sites, a higher frequency of NRAS (39.1% versus 25%) and NF1 (17.3% versus 0%) and lower frequencies of BRAF (21.7% versus 75%) and TERT promoter (8.6% versus 50%) mutations were observed. MAPK activating mutations were identified in 64% of tumours. Overall survival was longer in patients treated with immune checkpoint inhibitors as first-line treatment than in patients receiving other systemic therapies (i.e. BRAF/MEK inhibitors and chemotherapy). CONCLUSION: Our data suggest that the genetics of melanomas arising in acral sites varies by tumour location and may influence biological behaviour.

Deep learning outperformed 11 pathologists in the classification of histopathological melanoma images.

BACKGROUND: The diagnosis of most cancers is made by a board-certified pathologist based on a tissue biopsy under the microscope. Recent research reveals a high discordance between individual pathologists. For melanoma, the literature reports on 25-26% of discordance for classifying a benign nevus versus malignant melanoma. A recent study indicated the potential of deep learning to lower these discordances. However, the performance of deep learning in classifying histopathologic melanoma images was never compared directly to human experts. The aim of this study is to perform such a first direct comparison. METHODS: A total of 695 lesions were classified by an expert histopathologist in accordance with current guidelines (350 nevi/345 melanoma). Only the haematoxylin & eosin (H&E) slides of these lesions were digitalised via a slide scanner and then randomly cropped. A total of 595 of the resulting images were used to train a convolutional neural network (CNN). The additional 100 H&E image sections were used to test the results of the CNN in comparison to 11 histopathologists. Three combined McNemar tests comparing the results of the CNNs test runs in terms of sensitivity, specificity and accuracy were predefined to test for significance (p < 0.05). FINDINGS: The CNN achieved a mean sensitivity/specificity/accuracy of 76%/60%/68% over 11 test runs. In comparison, the 11 pathologists achieved a mean sensitivity/specificity/accuracy of 51.8%/66.5%/59.2%. Thus, the CNN was significantly (p = 0.016) superior in classifying the cropped images. INTERPRETATION: With limited image information available, a CNN was able to outperform 11 histopathologists in the classification of histopathological melanoma images and thus shows promise to assist human melanoma diagnoses.

Efficacy of PD-1-based immunotherapy after radiologic progression on targeted therapy in stage IV melanoma.

OBJECTIVES: Targeted therapy (TT) is an effective treatment for advanced BRAFV600-mutated melanoma, but most patients eventually acquire resistance and progress. Here, we evaluated the outcome of second-line immune checkpoint blockade (ICB) after progression on dual BRAF and MEK inhibition. METHODS: Patients with metastatic melanoma progressing on combined BRAF + MEK inhibition and receiving second-line ICB between 2015 and 2019 in 9 tertiary referral centres were enrolled. Demographic and clinical data and blood counts of all patients were collected retrospectively. RESULTS: We identified 99 patients with stage IV melanoma receiving ICB (nivolumab, pembrolizumab [n = 39] or ipilimumab plus nivolumab [n = 60]) after progression on combined TT. The median progression-free survival was similar in the PD-1 and ipilimumab plus nivolumab group (2.6 months [95% confidence interval {CI}, 2.0-3.1] vs. 2.0 [95% CI, 1.4-2.6], p = 0.15). The objective response rate was 18.0% in the PD-1 and 15.0% in the ipilimumab plus nivolumab group (p = 0.70). The disease control rate was 25.7% for monotherapy and 18.3% for combined ICB (p = 0.39). The median overall survival was 8.4 months (95% CI, 5.1-11.7) for patients receiving PD-1 monotherapy and 7.2 months (95% CI, 5.2-9.1) for patients receiving ipilimumab plus nivolumab (p = 0.86). The latter was associated with a higher rate of treatment-related adverse events (AEs). No significant association of laboratory values or clinicopathological characteristics with response to second-line ICB was observed. CONCLUSIONS: PD-1 monotherapy and combined ipilimumab plus nivolumab show similar activity and outcome in patients with melanoma resistant to BRAF + MEK inhibition. However, combined ipilimumab plus nivolumab was associated with a higher rate of treatment-related AEs compared with monotherapy.

Chemoirradiated neutrophils and T cells differentially affect immune functions of APCs.

Extracorporeal photopheresis (ECP) is known as an immunomodulatory therapy with few side effects, which is mainly used in the treatment of cutaneous T cell lymphoma, graft-versus-host disease, and allograft rejection. During ECP, leukocytes are separated from whole blood by leukapheresis, subsequently chemoirradiated with 8-methoxypsoralen and UVA light, and re-infused into the patient. Although clinically effective, its mode of action has not been fully elucidated. In the present study, we analyzed the interaction of chemoirradiated neutrophils and CD3+ lymphocytes with APC in an in vitro model. We report that chemoirradiated CD3+ T cells induced increased expression of activation markers on dendritic cells (DC), macrophages, and monocytes. Coculture of chemoirradiated CD3+ T cells with these APC also led to significantly increased secretion of TNF-α. Although less pronounced, additional activation of APC took place when APC were stimulated with LPS or IFN-γ. In contrast, chemoirradiated neutrophils did not show activating effects on APC. The presence of chemoirradiated neutrophils during LPS and IFN-γ stimulation of DC rather diminished DC and macrophage activation. In line with these findings DC cocultured with chemoirradiated CD3+ T cells, but not neutrophils, showed significantly increased activation of CD3+ responder lymphocytes in a mixed lymphocyte reaction. With this study, we demonstrate that chemoirradiated leukocytes have differential indirect immunomodulatory effects. Whereas chemoirradiated CD3+ T cells activate APC, chemoirradiated neutrophils suppress activation of APC in the presence of other activating factors, suggesting that the composition of the ECP-treated buffy coat might be of importance for its immunomodulatory effects.

Pathologist-level classification of histopathological melanoma images with deep neural networks.

BACKGROUND: The diagnosis of most cancers is made by a board-certified pathologist based on a tissue biopsy under the microscope. Recent research reveals a high discordance between individual pathologists. For melanoma, the literature reports 25-26% of discordance for classifying a benign nevus versus malignant melanoma. Deep learning was successfully implemented to enhance the precision of lung and breast cancer diagnoses. The aim of this study is to illustrate the potential of deep learning to assist human assessment for a histopathologic melanoma diagnosis. METHODS: Six hundred ninety-five lesions were classified by an expert histopathologist in accordance with current guidelines (350 nevi and 345 melanomas). Only the haematoxylin and eosin stained (H&E) slides of these lesions were digitalised using a slide scanner and then randomly cropped. Five hundred ninety-five of the resulting images were used for the training of a convolutional neural network (CNN). The additional 100 H&E image sections were used to test the results of the CNN in comparison with the original class labels. FINDINGS: The total discordance with the histopathologist was 18% for melanoma (95% confidence interval [CI]: 7.4-28.6%), 20% for nevi (95% CI: 8.9-31.1%) and 19% for the full set of images (95% CI: 11.3-26.7%). INTERPRETATION: Even in the worst case, the discordance of the CNN was about the same compared with the discordance between human pathologists as reported in the literature. Despite the vastly reduced amount of data, time necessary for diagnosis and cost compared with the pathologist, our CNN archived on-par performance. Conclusively, CNNs indicate to be a valuable tool to assist human melanoma diagnoses.

Frequent Occurrence of NRAS and BRAF Mutations in Human Acral Naevi.

Acral naevi are benign melanocytic tumors occurring at acral sites. Occasionally they can progress to become malignant tumors (melanomas). The genetics of acral naevi have not been assessed in larger studies. In our study, a large cohort of 130 acral naevi was screened for gene mutations known to be important in other naevi and melanoma subtypes by targeted next-generation sequencing. Mutation status was correlated with clinicopathological parameters. Frequent mutations in genes activating the MAP kinase pathway were identified, including n = 87 (67%) BRAF, n = 24 (18%) NRAS, and one (1%) MAP2K1 mutations. BRAF mutations were almost exclusively V600E (n = 86, 99%) and primarily found in junctional and compound naevi. NRAS mutations were either Q61K or Q61R and frequently identified in dermal naevi. Recurrent non-V600E BRAF, KIT, NF1, and TERT promoter mutations, present in acral melanoma, were not identified. Our study identifies BRAF and NRAS mutations as the primary pathogenic event in acral naevi, however, distributed differently to those in non-acral naevi. The mutational profile of acral naevi is distinct from acral melanoma, which may be of diagnostic value in distinguishing these entities.