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Background: As cancer cachexia (CC) is associated with cancer progression, early identification would be beneficial. The aim of this study was to establish a workflow for automated MRI-based segmentation of visceral (VAT) and subcutaneous adipose tissue (SCAT) and lean tissue water (LTW) in a B16 melanoma animal model, monitor diseases progression and transfer the protocol to human melanoma patients for therapy assessment. Methods: For in vivo monitoring of CC B16 melanoma-bearing and healthy mice underwent longitudinal three-point DIXON MRI (days 3, 12, 17 after subcutaneous tumor inoculation). In a prospective clinical study, 18 metastatic melanoma patients underwent MRI before, 2 and 12 weeks after onset of checkpoint inhibitor therapy (CIT; n = 16). We employed an in-house MATLAB script for automated whole-body segmentation for detection of VAT, SCAT and LTW. Results: B16 mice exhibited a CC phenotype and developed a reduced VAT volume compared to baseline (B16 − 249.8 µl, − 25%; controls + 85.3 µl, + 10%, p = 0.003) and to healthy controls. LTW was increased in controls compared to melanoma mice. Five melanoma patients responded to CIT, 7 progressed, and 6 displayed a mixed response. Responding patients exhibited a very limited variability in VAT and SCAT in contrast to others. Interestingly, the LTW was decreased in CIT responding patients (− 3.02% ± 2.67%; p = 0.0034) but increased in patients with progressive disease (+ 1.97% ± 2.19%) and mixed response (+ 4.59% ± 3.71%). Conclusion: MRI-based segmentation of fat and water contents adds essential additional information for monitoring the development of CC in mice and metastatic melanoma patients during CIT or other treatment approaches. [ABSTRACT FROM AUTHOR]

Background: Hepatic immune-related adverse events (irAE) including elevated liver function tests (transaminases) occur in 1.4–22.3% of melanoma patients receiving immune checkpoint inhibitors (ICPI) and constitute a potentially serious toxicity that is challenging to treat. In contrast to the liver transaminases alanine aminotransferase (ALT) and aspartate aminotransferase (AST), only little is known about the frequency and impact of gamma-glutamyl transferase (GGT) elevations. Methods: GGT determined prior to and during therapy of metastatic melanoma patients treated with ICPI were retrospectively assessed in two independent cohorts (PD-1: n = 218, Ipi + Nivo: n = 148). Overall survival (OS) and best objective response were analyzed according to baseline and immune-related GGT (irGGT) elevations during treatment. Results: In multivariate analysis, OS was reduced in patients with elevated baseline GGT (PD-1 group: hazard ratio [HR] 1.76, p =.0073; Ipi + Nivo group: HR 1.77, p =.032). Immune-related GGT elevation was recorded in 17% (PD-1 group) and 38.5% (Ipi + Nivo group). Of these patients, the majority (81 and 68%, respectively) had normal ALT and AST and showed no clinical signs of hepatotoxicity. Patients who experienced irGGT elevation had superior response (PD-1 group: odds ratio [OR] 3.57, p =.00072; Ipi + Nivo group: OR 1.74, p =.12) and OS (PD-1 group: HR 0.37, p =.0016; Ipi + Nivo group: HR 0.33, p =.00050). Conclusions: The frequency of hepatic irAE is currently underestimated. The addition of the sensitive enzyme GGT to the laboratory panel before and during therapy with ICPI allows to detect two to three times more patients developing hepatic or hepatobiliary toxicity than known so far. Immune-related GGT elevations correlate with response and favorable survival. Precis for use in the Table of Contents The frequency of hepatotoxicity under immune checkpoint blockade is currently underestimated. We suggest the addition of gamma-glutamyl transferase to the laboratory panel in checkpoint inhibitor patients for the detection of hepatobiliary toxicity. [ABSTRACT FROM AUTHOR]

Background: Despite impressive response rates, most patients with advanced melanoma ultimately progress following therapy with B-Raf proto-oncogene (BRAF) inhibitors (BRAFi). Therefore, frequent radiologic assessments are necessary, and reliable serum biomarkers would be beneficial for disease monitoring. Objective: This study investigated the ability of lactate dehydrogenase (LDH) and S100 calcium-binding protein B (S100B) to detect response and disease progression during treatment with BRAFi. Patients and Methods: Baseline levels of LDH and S100B and repeated measurements during therapy were recorded retrospectively in 191 patients with metastatic melanoma. LDH and S100B levels were compared between distinct time points (baseline, first follow-up visit [FV], best objective response [BR], and progressive disease [PD]). The prognostic ability of the serum biomarkers in relation to disease-specific survival (DSS) was assessed with univariable and multivariable Cox regression analysis. Results: Elevated baseline LDH and S100B correlated with impaired DSS. In contrast with LDH (P = 0.12), S100B levels at FV correlated with response (P = 0.0030). Both markers significantly decreased during the first weeks of BRAFi treatment (LDH, P = 0.00034; S100B, P < 0.0001) and increased between BR and PD (LDH, P = 0.016; S100B, P < 0.0001). Patients with elevated S100B (P = 0.00062) but not with elevated LDH (P = 0.067) at the time point of radiologically confirmed PD showed significantly impaired DSS after PD. Interestingly, DSS after PD differed significantly according to S100B levels determined as early as 8 weeks (median) before PD (P = 0.0024). Conclusions: LDH and S100B are suitable serum biomarkers during therapy with BRAFi. S100B shows stronger correlation with response and exhibits more accuracy in predicting PD. Close biomarker monitoring with S100B is recommended during treatment with BRAFi to detect PD early. [ABSTRACT FROM AUTHOR]

Background: Immunotherapy with PD-1 antibodies has greatly increased prognosis of patients with advanced melanoma. Identifying biomarkers that predict overall survival (OS) and response to immunotherapy is important.Methods: OS and best overall response according to RECIST version 1.1 were analysed, and S100B and lactate dehydrogenase (LDH) serum levels were assessed retrospectively in 152 patients treated with anti-PD-1, and in 86 patients treated with anti-PD-1 plus anti-CTLA-4 antibodies at University Hospital Tuebingen, Germany.Results: In the pembrolizumab group, patients with elevated baseline S100B or LDH exhibited significantly impaired OS compared with patients with normal S100B (1-year OS: 51.1% vs 83.1%, log-rank P < .0001) and normal LDH (1-year OS: 44.4% vs 80.8%, P = .00022), respectively. LDH increases of >25% and S100B increases of >145% compared to baseline were significantly associated with impaired OS (both P < .0001). In patients treated with ipilimumab and nivolumab, baseline S100B and increasing S100B levels of >145% as well as baseline LDH were associated with impaired OS (P < .0001, P = .00060, and P = .0050, respectively), whereas increasing LDH of >25% was not (P = .64).Conclusions: S100B could serve as a strong baseline marker for OS in melanoma patients receiving anti-PD-1 therapy. Rising S100B levels during the first weeks of therapy could help guide treatment decisions. [ABSTRACT FROM AUTHOR]

Background: Ipilimumab and programmed death (PD) 1-antibodies are effective treatment options in metastatic melanoma. The safety and efficacy of ipilimumab in patients with pre-existing autoimmune disorders (AD) has only been evaluated in a selected number of patients.Methods: We performed a retrospective analysis in 14 German skin cancer centers for patients with metastatic melanoma and pre-existing AD treated with ipilimumab.Results: 41 patients with 44 pre-existing AD were treated with ipilimumab (thyroiditis n = 15, rheumatoid n = 11, dermatologic n = 10, Crohn’s disease/ulcerative colitis n = 3, neurological n = 2, sarcoidosis n = 2, pancreatitis n = 1). 3 out of 41 patients had two AD, 11 patients required immunosuppressants at the time of induction of ipilimumab. 12 patients (29.2%) experienced a flare of their pre-existing AD, mainly patients with rheumatoid or dermatologic diseases. Additional immune-related adverse events (irAEs) occurred in 12 patients (29.2%). In 23 patients (56%) neither a change of their AD nor additional irAEs were observed. Objective responses were seen in five patients (one complete remission, four partial remissions, 12.1%).Conclusion: This is the largest series of patients with pre-existing AD and treatment with ipilimumab reported. Flares of pre-existing AD were observed but manageable. Response rates and occurrence of new irAEs were comparable to previous trials. Thus, in this patient subgroup, ipilimumab can be a treatment option after a thorough discussion of pros and cons and taking severity and activity of the preexisting AD into account. [ABSTRACT FROM AUTHOR]

Objective: To assess the appearance of gastrointestinal melanoma metastases on CT and PET/CT and evaluate the diagnostic value of CT and PET/CT compared with surgery and histopathology.Methods: We retrospectively included 41 consecutive patients (aged 56.1 ± 13.5 years) with gastrointestinal melanoma metastases who underwent preoperative imaging (CT: all, PET/CT: n = 24) and metastasectomy. Two blinded radiologists assessed CT and PET/CT for gastrointestinal metastases and complications. Diagnostic accuracy and differences regarding lesion detectability and complications were assessed, using surgical findings and histopathology as standard of reference.Results: Fifty-three gastrointestinal melanoma metastases (5.0 ± 3.8 cm) were confirmed by surgery and histopathology. Lesions were located in the small bowel (81.1 %), colon (15.1 %) and stomach (3.8 %), and described as infiltrating (30.2 %), polypoid (28.3 %), cavitary (24.5 %) and exoenteric (17.0 %). Fifteen patients (37 %) had gastrointestinal complications. Higher complication rates were associated with large and polypoid lesions (p ≤ .012). Diagnostic accuracy was high for CT and PET/CT (AUC ≥ .802). For reader B (less experienced), CT yielded lower diagnostic accuracy than PET/CT (p = .044).Conclusion: Most gastrointestinal melanoma metastases were located in the small bowel. Large and polypoid metastases were associated with higher complication rates. PET/CT was superior for detection of gastrointestinal melanoma metastases and should be considered in patients with limited disease undergoing surgery.Key Points: • Gastrointestinal melanoma metastases (GI-MM) are rare but often cause serious gastrointestinal complications. • Early detection of GI-MM is important to prevent complications and guide surgery. • PET/CT is superior to CT for detection of GI-MMs. • PET/CT should be considered for patients with limited disease before surgical resection. [ABSTRACT FROM AUTHOR]

Background: Due to prolonged survival and technical advances in CT imaging, cardiac metastases in patients with malignant melanoma are observed more frequently nowadays. The aim of the present study was to assess the anatomic distribution as well as the morphologic and histologic appearance of cardiac metastases from malignant melanoma., Methods: Twenty five patients with known metastasized melanoma and with incidental finding of cardiac metastases during routine staging CT were retrospectively included in this study. CT images were assessed for the presence, localization and extent of cardiac metastases. Histological results, mutational analysis and tumor markers were reviewed., Results: Fourteen out of 25 patients presented with singular cardiac mass (56%), whereas ten patients (40%) presented with multifocal and one patient with disseminated cardiac metastases. Twelve patients presented with endocardial (48%), eight with myocardial and two with pericardial metastases. Most frequent site involved in endocardial metastases was the right atrium (67%) followed by the right ventricle (33%). There seems to be a correlation between histological subtype and location of cardiac metastasis. Median survival after diagnosis of cardiac metastases was 8 months, with no significant difference regarding the localization of metastases within the heart., Conclusion: Cardiac metastases can involve every part of the heart possibly in dependence of histological subtype. The awareness of different types of cardiac metastases and their characteristic appearance on CT images is necessary for further investigations and might contribute to targeted therapy.