Dissecting the treatment-naive ecosystem of human melanoma brain metastasis.

Melanoma brain metastasis (MBM) frequently occurs in patients with advanced melanoma; yet, our understanding of the underlying salient biology is rudimentary. Here, we performed single-cell/nucleus RNA-seq in 22 treatment-naive MBMs and 10 extracranial melanoma metastases (ECMs) and matched spatial single-cell transcriptomics and T cell receptor (TCR)-seq. Cancer cells from MBM were more chromosomally unstable, adopted a neuronal-like cell state, and enriched for spatially variably expressed metabolic pathways. Key observations were validated in independent patient cohorts, patient-derived MBM/ECM xenograft models, RNA/ATAC-seq, proteomics, and multiplexed imaging. Integrated spatial analyses revealed distinct geography of putative cancer immune evasion and evidence for more abundant intra-tumoral B to plasma cell differentiation in lymphoid aggregates in MBM. MBM harbored larger fractions of monocyte-derived macrophages and dysfunctional TOX+CD8+ T cells with distinct expression of immune checkpoints. This work provides comprehensive insights into MBM biology and serves as a foundational resource for further discovery and therapeutic exploration.

Adjuvant immunotherapy with nivolumab versus observation in completely resected Merkel cell carcinoma (ADMEC-O): disease-free survival results from a randomised, open-label, phase 2 trial.

BACKGROUND: Merkel cell carcinoma (MCC) is an immunogenic but aggressive skin cancer. Even after complete resection and radiation, relapse rates are high. PD-1 and PD-L1 checkpoint inhibitors showed clinical benefit in advanced MCC. We aimed to assess efficacy and safety of adjuvant immune checkpoint inhibition in completely resected MCC (ie, a setting without an established systemic standard-of-care treatment). METHODS: In this multicentre phase 2 trial, patients (any stage, Eastern Cooperative Oncology Group performance status 0-1) at 20 academic medical centres in Germany and the Netherlands with completely resected MCC lesions were randomly assigned 2:1 to receive nivolumab 480 mg every 4 weeks for 1 year, or observation, stratified by stage (American Joint Committee on Cancer stages 1-2 vs stages 3-4), age (<65 vs ≥65 years), and sex. Landmark disease-free survival (DFS) at 12 and 24 months was the primary endpoint, assessed in the intention-to-treat populations. Overall survival and safety were secondary endpoints. This planned interim analysis was triggered when the last-patient-in was followed up for more than 1 year. This study is registered with ClinicalTrials.gov (NCT02196961) and with the EU Clinical Trials Register (2013-000043-78). FINDINGS: Between Oct 1, 2014, and Aug 31, 2020, 179 patients were enrolled (116 [65%] stage 3-4, 122 [68%] ≥65 years, 111 [62%] male). Stratification factors (stage, age, sex) were balanced across the nivolumab (n=118) and internal control group (observation, n=61); adjuvant radiotherapy was more common in the control group. At a median follow-up of 24·3 months (IQR 19·2-33·4), median DFS was not reached (between-groups hazard ratio 0·58, 95% CI 0·30-1·12); DFS rates in the nivolumab group were 85% at 12 months and 84% at 24 months, and in the observation group were 77% at 12 months and 73% at 24 months. Overall survival results were not yet mature. Grade 3-4 adverse events occurred in 48 [42%] of 115 patients who received at least one dose of nivolumab and seven [11%] of 61 patients in the observation group. No treatment-related deaths were reported. INTERPRETATION: Adjuvant therapy with nivolumab resulted in an absolute risk reduction of 9% (1-year DFS) and 10% (2-year DFS). The present interim analysis of ADMEC-O might suggest clinical use of nivolumab in this area of unmet medical need. However, overall survival events rates, with ten events in the active treatment group and six events in the half-the-size observation group, are not mature enough to draw conclusions. The explorative data of our trial support the continuation of ongoing, randomised trials in this area. ADMEC-O suggests that adjuvant immunotherapy is clinically feasible in this area of unmet medical need. FUNDING: Bristol Myers Squibb.

Melanoma of the central nervous system based on neurocutaneous melanocytosis in childhood: A rare but fatal condition.

BACKGROUND: Melanomas of the central nervous system (CNS) based on neurocutaneous melanocytosis (NCM) are exceptionally rare in childhood and have been described only sporadically. Rapidly progressive disease may represent a major challenge for treating physicians, especially given the limited knowledge about this condition. This analysis aimed to increase knowledge about the occurrence and treatment of these malignancies. PROCEDURE: Data on diagnosis, treatment, and outcome of patients aged 0-18 years with CNS melanoma based on NCM recorded in the German Registry for Rare Pediatric Tumors (STEP registry) were analyzed. Additionally, published case reports on this condition were analyzed. RESULTS: In STEP, five patients with leptomeningeal melanoma based on NCM were identified, with a median age at melanoma diagnosis of 3.7 years. Various multimodal treatments were performed: (partial) resection (n = 4), irradiation (n = 2), trametinib (n = 3), different cytostatics (n = 2), and anti-GD2 immunotherapy (n = 1). All patients died between 0.3 and 0.8 years after diagnosis. Including published case reports, 27 patients were identified with a median age of 2.8 years at melanoma diagnosis (range: 0.2-16.6). Fourteen of 16 cases with reported data had a NRAS alteration (88%), particularly NRAS p.Q61K (85%). In the expanded cohort, no patient survived longer than 1 year after diagnosis despite multimodal therapy (including trametinib; n = 9), with a median survival of 0.4 years (range 0.1-0.9). CONCLUSIONS: CNS melanomas based on NCM in childhood are aggressive malignancies without curative treatment to date. Therapeutic approaches must be individualized. Genetic tumor sequencing is essential to improve understanding of tumorigenesis and potentially identify new therapeutic targets.

Histopathologic regression in patients with primary cutaneous melanoma undergoing sentinel lymph node biopsy is associated with favorable survival and, after metastasis, with improved progression-free survival on immune checkpoint inhibitor therapy: A single-institutional cohort study.

BACKGROUND: Histopathologic regression of cutaneous melanoma is considered a favorable prognostic factor, but its significance in clinical practice remains controversial. OBJECTIVE: To investigate the prognostic importance of regression in patients with primary cutaneous melanoma undergoing sentinel lymph node (SLN) biopsy and to assess its significance in patients progressing to an unresectable stage requiring systemic therapy. METHODS: We retrospectively reviewed patients with newly diagnosed melanoma undergoing SLN biopsy between 2010 and 2015 and available information on histopathologic regression (n = 1179). Survival data and associations of clinical variables with SLN status were assessed. RESULTS: Patients with regressive melanoma showed favorable relapse-free (hazard ratio [HR], 0.52; P = .00013), distant metastasis-free (HR, 0.56; P = .0020), and melanoma-specific survival (HR, 0.35; P = .00053). Regression was associated with negative SLN (odds ratio, 0.48; P = .0077). In patients who progressed to an unresectable stage, regression was associated with favorable progression-free survival under immune checkpoint inhibition (HR, 0.43; P = .031) but not under targeted therapy (HR, 1.14; P = .73) or chemotherapy (HR, 3.65; P = .0095). LIMITATIONS: Retrospective, single-institutional design. CONCLUSIONS: Regression of cutaneous melanoma is associated with improved prognosis in patients eligible for SLN biopsy as well as in patients with unresectable disease receiving systemic therapy with immune checkpoint inhibitors.

Sentinel lymph node biopsy for lentigo maligna melanoma under local anaesthesia.

BACKGROUND: Lentigo maligna melanoma is mainly localized in the head and neck region in elderly patients. Due to its slow horizontal growth, it has a good prognosis compared to other melanoma subtypes, but specific data are rare. OBJECTIVES: The aim of this study was to investigate sentinel lymph node biopsy in lentigo maligna melanoma under local anaesthesia and to discuss the benefit. METHODS: Investigation of patients with lentigo maligna melanoma and tumour thickness ≥1 mm treated at the Department of Dermatology, University Medical Centre Tuebingen, between January 2008 and October 2019. RESULTS: In total, 204 patients (126 SLNB, 78 non-SLNB) with a median age of 75.7 years (SLNB: 73.3 years, non-SLNB: 79.7 years) could be included. Sixteen of 126 (12.7%) sentinel lymph nodes were positive. Five-year overall survival was 87.9% (88.5% SLNB; 87.4% non-SLNB) and 5-year distant metastasis-free survival was 85.8% (85.4% SLNB; 86.7% non-SLNB). There was no significant difference for distant metastasis-free survival (p = 0.861) and overall survival (p = 0.247) between patients with and without sentinel lymph node biopsy. CONCLUSIONS: Sentinel lymph node biopsy in lentigo maligna melanoma under local anaesthesia is a safe and simple method, even in very old patients. However, LMM has a very good 5-year overall survival. In high-risk patients with high tumour thickness and/or ulceration, adjuvant immunotherapy can now be offered without the need to perform this procedure.

Overall survival with first-line atezolizumab in combination with vemurafenib and cobimetinib in BRAFV600 mutation-positive advanced melanoma (IMspire150): second interim analysis of a multicentre, randomised, phase 3 study.

BACKGROUND: Primary analysis of the phase 3 IMspire150 study showed improved investigator-assessed progression-free survival with first-line atezolizumab, vemurafenib, and cobimetinib (atezolizumab group) versus placebo, vemurafenib, and cobimetinib (control group) in patients with BRAFV600 mutation-positive melanoma. With a median follow-up of 18·9 months (IQR 10·4-23·8) at the primary analysis, overall survival data were immature. Here, we report the results from the second, prespecified, interim overall survival analysis. METHODS: The multicentre, double-blind, placebo-controlled, randomised, phase 3 IMspire150 study was done at 108 academic and community hospitals in 20 countries. Patients aged 18 years or older with previously untreated unresectable stage IIIc or stage IV melanoma and an Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible for inclusion. Patients were randomly assigned (1:1) to receive either atezolizumab (840 mg intravenously on day 1 and 15) or placebo plus vemurafenib (960 mg or 720 mg twice daily orally) and cobimetinib (60 mg once daily orally; 21 days on and 7 days off) in 28-day cycles. Atezolizumab and placebo were added to treatment regimens from cycle two onwards. Randomisation was done centrally (Durham, NC, USA) based on a permuted block randomisation scheme (block size of 4) using an interactive web-based response system and was stratified by geographical region and baseline lactate dehydrogenase concentration. Overall survival was analysed in the intention-to-treat population and safety was analysed in all patients who received at least one dose of study drug according to actual treatment received. The primary endpoint was investigator-assessed progression-free survival, which was previously reported. Here, we report the second, prespecified, interim overall survival analysis, which was planned after about 270 overall survival events had occurred. The trial is ongoing, but is no longer enrolling patients, and it is registered with ClinicalTrials.gov, NCT02908672. FINDINGS: Between Jan 13, 2017, and April 26, 2018, 514 patients (median age 54 years [IQR 43-63]; 299 [58%] men and 215 [42%] women) were enrolled in the trial and randomly assigned to the atezolizumab group (256 [50%] patients) or the control group (258 [50%] patients). At the data cutoff (Sept 8, 2021), 273 patients had died (126 in the atezolizumab group and 147 in the control group). Median follow-up was 29·1 months (IQR 10·1-45·4) for the atezolizumab group versus 22·8 months (10·6-44·1) for the control group. Median overall survival was 39·0 months (95% CI 29·9-not estimable) in the atezolizumab group versus 25·8 months (22·0-34·6) in the control group (HR 0·84 [95% CI 0·66-1·06]; p=0·14). The most common adverse events of any grade in the atezolizumab group were blood creatine phosphokinase increased (123 [53%] of 231 patients), diarrhoea (116 [50%]), and pyrexia (115 [50%]). The most common adverse events of any grade in the control group were diarrhoea (157 [56%] of 280 patients), blood creatine phosphokinase increased (135 [48%]), and rash (119 [43%]). The most common grade 3-4 adverse events were increased lipase (54 [23%] of 231 patients in the atezolizumab group vs 62 [22%] of 280 patients in the control group), increased blood creatine phosphokinase (51 [22%] vs 50 [18%]), and increased alanine aminotransferase (32 [14%] vs 26 [9%]). Serious adverse events were reported in 112 (48%) patients in the atezolizumab group and 117 (42%) patients in the control group. Grade 5 adverse events were reported in eight (3%) patients in the atezolizumab group versus six (2%) patients in the control group. Two grade 5 adverse events (hepatitis fulminant and hepatic failure) in the atezolizumab group were considered to be associated with the triplet combination, and one event in the control group (pulmonary haemorrhage) was considered to be associated with cobimetinib. INTERPRETATION: Additional follow-up of the IMspire150 trial showed that overall survival was not significantly improved with atezolizumab, vemurafenib, and cobimetinib compared with placebo, vemurafenib, and cobimetinib in patients with BRAFV600 mutation-positive advanced melanoma. Results of the final analysis are awaited to establish whether a significant improvement in overall survival can be achieved with long-term treatment with this triplet combination versus vemurafenib plus cobimetinib. FUNDING: F Hoffmann-La Roche.

Adjuvant nivolumab plus ipilimumab or nivolumab alone versus placebo in patients with resected stage IV melanoma with no evidence of disease (IMMUNED): final results of a randomised, double-blind, phase 2 trial.

BACKGROUND: The IMMUNED trial previously showed significant improvements in recurrence-free survival for adjuvant nivolumab plus ipilimumab as well as for adjuvant nivolumab alone in patients with stage IV melanoma with no evidence of disease after resection or radiotherapy. Here, we report the final analysis, including overall survival data. METHODS: IMMUNED was an investigator-sponsored, double-blind, placebo-controlled, three-arm, phase 2 trial conducted in 20 academic medical centres in Germany. Eligible patients were aged 18-80 years with stage IV melanoma with no evidence of disease after surgery or radiotherapy. Patients were randomly assigned (1:1:1) to either nivolumab plus ipilimumab (nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four doses followed by nivolumab 3 mg/kg every 2 weeks), nivolumab monotherapy (nivolumab 3 mg/kg every 2 weeks), or matching placebo, for up to 1 year. The primary endpoint was recurrence-free survival in the intention-to-treat population. Secondary endpoints were time-to-recurrence, overall survival, progression-free survival or recurrence-free survival 2 (in patients in the placebo group who crossed over to nivolumab monotherapy after experiencing disease recurrence), and safety endpoints. This trial is registered on ClinicalTrials.gov (NCT02523313), and is complete. FINDINGS: Between Sept 2, 2015, and Nov 20, 2018, 175 patients were enrolled in the study, and 167 were randomly assigned to receive either nivolumab plus ipilimumab (n=56), nivolumab plus ipilimumab-matching placebo (n=59), or double placebo control (n=52). At a median follow-up of 49·2 months (IQR 34·9-58·1), 4-year recurrence-free survival was 64·2% (95% CI 49·2-75·9) in the nivolumab plus ipilimumab group, 31·4% (19·7-43·8) in the nivolumab alone group, and 15·0% (6·7-26·6) in the placebo group. The hazard ratio (HR) for recurrence for the nivolumab plus ipilimumab group versus placebo was 0·25 (97·5% CI 0·13-0·48; p<0·0001), and for the nivolumab group versus placebo was 0·60 (0·36-1·00; p=0·024). Median overall survival was not reached in any treatment group. The HR for overall survival was significantly in favour of the nivolumab plus ipilimumab group versus placebo (HR 0·41; 95% CI 0·17-0·99; p=0·040), but not for the nivolumab group versus placebo (HR 0·75; 0·36-1·56; p=0·44). 4-year overall survival was 83·8% (95% CI 68·8-91·9) in the nivolumab plus ipilimumab group, 72·6% (57·4-83·2) in the nivolumab alone group, and 63·1% (46·9-75·6) in the placebo group. The median progression-free survival or recurrence-free survival 2 of patients in the placebo group who crossed over to nivolumab monotherapy after experiencing disease recurrence was not reached (95% CI 21·2 months to not reached). Rates of grade 3-4 treatment-related adverse events remained largely unchanged compared with our previous report, occurring in 71% (95% CI 57-82) of the nivolumab plus ipilimumab group, and 29% (95% CI 17-42) of patients receiving nivolumab alone. There were no treatment-related deaths. INTERPRETATION: Both active regimens continued to show significantly improved recurrence-free survival compared with placebo in patients with stage IV melanoma with no evidence of disease who were at high risk of recurrence. Overall survival was significantly improved for patients receiving nivolumab plus ipilimumab compared with placebo. Use of subsequent anti-PD-1-based therapy was high in patients in the placebo group after recurrence and most likely impacted the overall survival comparison of nivolumab alone versus placebo. The recurrence-free and overall survival benefit of nivolumab plus ipilimumab over placebo reinforces the change of practice already initiated for the treatment of patients with stage IV melanoma with no evidence of disease. FUNDING: Bristol-Myers Squibb.

Diagnosis of Basal Cell Carcinoma with Ex-vivo Confocal Laser Scanning Microscopy in a Real-life Setting.

Ex-vivo confocal laser scanning microscopy provides a rapid alternative to routine histological processing using haematoxylin and eosin-stained sections. Previous studies suggest high diagnostic accuracy in basal cell carcinoma. This study investigates the diagnostic accuracy of confocal laser scanning microscopy reporting of basal cell carcinoma in a real-life setting and compares reporting by dermatopathologists inexperienced in use of confocal laser scanning microscopy with reporting by an expert in confocal laser scanning microscopy. A total of 334 confocal laser scanning microscopy scans were diagnosed by 2 dermatopathologists inexperienced in the diagnosis of confocal laser scanning microscopy as well as an experienced examiner of confocal laser scanning microscopy scans. The inexperienced examiners achieved a sensitivity of 59.5/71.1% and specificity of 94.8/89.8%. The experienced examiner achieved a sensitivity of 78.5% and specificity of 84.8%. Detection of tumour remnants in margin controls showed insufficient values among inexperienced (30.1/33.3%) and experienced (41.7%) investigators. The results of this study, of real-life setting basal cell carcinoma reporting with confocal laser scanning microscopy, found a lower diagnostic accuracy than published data regarding artificial settings. A poor accuracy in tumour margin control is clinically relevant and could restrict the use of confocal laser scanning microscopy in clinical routine. Prior knowledge of haematoxylin and eosin trained pathologists can be partially transferred to the reporting of confocal laser scanning microscopy scans; however, specific training is recommended.

Radiofrequency antenna concepts for human cardiac MR at 14.0 T.

OBJECTIVE: To examine the feasibility of human cardiac MR (CMR) at 14.0 T using high-density radiofrequency (RF) dipole transceiver arrays in conjunction with static and dynamic parallel transmission (pTx). MATERIALS AND METHODS: RF arrays comprised of self-grounded bow-tie (SGBT) antennas, bow-tie (BT) antennas, or fractionated dipole (FD) antennas were used in this simulation study. Static and dynamic pTx were applied to enhance transmission field (B1+) uniformity and efficiency in the heart of the human voxel model. B1+ distribution and maximum specific absorption rate averaged over 10 g tissue (SAR10g) were examined at 7.0 T and 14.0 T. RESULTS: At 14.0 T static pTx revealed a minimum B1+ROI efficiency of 0.91 µT/√kW (SGBT), 0.73 µT/√kW (BT), and 0.56 µT/√kW (FD) and maximum SAR10g of 4.24 W/kg, 1.45 W/kg, and 2.04 W/kg. Dynamic pTx with 8 kT points indicate a balance between B1+ROI homogeneity (coefficient of variation < 14%) and efficiency (minimum B1+ROI > 1.11 µT/√kW) at 14.0 T with a maximum SAR10g < 5.25 W/kg. DISCUSSION: MRI of the human heart at 14.0 T is feasible from an electrodynamic and theoretical standpoint, provided that multi-channel high-density antennas are arranged accordingly. These findings provide a technical foundation for further explorations into CMR at 14.0 T.

Real-world outcomes using PD-1 antibodies and BRAF + MEK inhibitors for adjuvant melanoma treatment from 39 skin cancer centers in Germany, Austria and Switzerland.

BACKGROUND: Programmed death-1 (PD-1) antibodies and BRAF + MEK inhibitors are widely used for adjuvant therapy of fully resected high-risk melanoma. Little is known about treatment efficacy outside of phase III trials. This real-world study reports on clinical outcomes of modern adjuvant melanoma treatment in specialized skin cancer centers in Germany, Austria and Switzerland. METHODS: Multicenter, retrospective study investigating stage III-IV melanoma patients receiving adjuvant nivolumab (NIV), pembrolizumab (PEM) or dabrafenib + trametinib (D + T) between 1/2017 and 10/2021. The primary endpoint was 12-month recurrence-free survival (RFS). Further analyses included descriptive and correlative statistics, and a multivariate linear-regression machine learning model to assess the risk of early melanoma recurrence. RESULTS: In total, 1198 patients from 39 skin cancer centers from Germany, Austria and Switzerland were analysed. The vast majority received anti PD-1 therapies (n = 1003). Twelve-month RFS for anti PD-1 and BRAF + MEK inhibitor-treated patients were 78.1% and 86.5%, respectively (hazard ratio [HR] 1.998 [95% CI 1.335-2.991]; p = 0.001). There was no statistically significant difference in overall survival (OS) in anti PD-1 (95.8%) and BRAF + MEK inhibitor (96.9%) treated patients (p > 0.05) during the median follow-up of 17 months. Data indicates that anti PD-1 treated patients who develop immune-related adverse events (irAEs) have lower recurrence rates compared to patients with no irAEs (HR 0.578 [95% CI 0.443-0.754], p = 0.001). BRAF mutation status did not affect overall efficacy of anti PD-1 treatment (p > 0.05). In both, anti PD-1 and BRAF + MEK inhibitor treated cohorts, data did not show any difference in 12-month RFS and 12-month OS comparing patients receiving total lymph node dissection (TLND) versus sentinel lymph node biopsy only (p > 0.05). The recurrence prediction model reached high specificity but only low sensitivity with an AUC = 0.65. No new safety signals were detected. Overall, recorded numbers and severity of adverse events were lower than reported in pivotal phase III trials. CONCLUSIONS: Despite recent advances in adjuvant melanoma treatment, early recurrence remains a significant clinical challenge. This study shows that TLND does not reduce the risk of early melanoma recurrence and should only be considered in selected patients. Data further highlight that variables collected during clinical routine are unlikely to allow for a clinically relevant prediction of individual recurrence risk.

S2k Guideline - Merkel cell carcinoma (MCC, neuroendocrine carcinoma of the skin) - Update 2022.

Merkel cell carcinoma (MCC, ICD-O M8247/3) is a rare, malignant, primary skin tumor with epithelial and neuroendocrine differentiation. The tumor cells share many morphologic, immunohistochemical, and ultrastructural features with cutaneous Merkel cells. Nevertheless, the cell of origin of MCC is unclear. MCC appears clinically as a reddish to purple spherical tumor with a smooth, shiny surface and a soft to turgid, elastic consistency, usually showing rapid growth. Spontaneous and often complete regressions of the tumor are observed. These likely immunologically-mediated regressions explain the cases in which only lymph node or distant metastases are found at the time of initial diagnosis and why the tumor responds very well to immunomodulatory therapies even at advanced stages. Due to its aggressiveness, the usually given indication for sentinel lymph node biopsy, the indication of adjuvant therapies to be evaluated, as well as the complexity of the necessary diagnostics, clinical management should already be determined by an interdisciplinary tumor board at the time of initial diagnosis.

S3 guideline "actinic keratosis and cutaneous squamous cell carcinoma" - update 2023, part 2: epidemiology and etiology, diagnostics, surgical and systemic treatment of cutaneous squamous cell carcinoma (cSCC), surveillance and prevention.

Actinic keratosis (AK) are common lesions in light-skinned individuals that can potentially progress to cutaneous squamous cell carcinoma (cSCC). Both conditions may be associated with significant morbidity and constitute a major disease burden, especially among the elderly. To establish an evidence-based framework for clinical decision making, the guideline "actinic keratosis and cutaneous squamous cell carcinoma" was updated and expanded by the topics cutaneous squamous cell carcinoma in situ (Bowen's disease) and actinic cheilitis. The guideline is aimed at dermatologists, general practitioners, ear nose and throat specialists, surgeons, oncologists, radiologists and radiation oncologists in hospitals and office-based settings, as well as other medical specialties, policy makers and insurance funds involved in the diagnosis and treatment of patients with AK and cSCC. A separate guideline exists for patients and their relatives. In this part, we will address aspects relating to epidemiology and etiology, diagnostics, surgical and systemic treatment of cutaneous squamous cell carcinoma (cSCC), surveillance and prevention.

Real-world Treatment Patterns and Outcomes with Systemic Therapies in Unresectable Locally Advanced and Metastatic Cutaneous Squamous Cell Carcinoma in Germany.

Advanced cutaneous squamous cell carcinoma is a challenge to treat. Conventional systemic treatment options include chemotherapy and epidermal growth factor receptor-inhibitors. The aim of this study was to assess clinical outcomes with systemic treatments in advanced cutaneous squamous cell carcinoma. Patients receiving systemic treatment at the Tübingen Dermato-Oncology centre between 2007 and 2017 were identified (n = 59). Median age was 76 years (interquartile range (IQR) 71-80 years), 83.1% of patients were male, 72.9% had metastatic cutaneous squamous cell carcinoma, and 27.1% had unresectable locally advanced cutaneous squamous cell carcinoma. During median follow-up of 52 weeks (IQR 27-97 weeks), overall response rate was 14.3%, and disease control rate was 53.6%. Median progression-free survival was 15 weeks (IQR 8-42 weeks), and median overall survival was 52 weeks (IQR 27-97 weeks). Patients receiving chemoradiation vs chemotherapy alone showed better overall survival (hazard ratio 0.41, p = 0.014,) and progression-free survival (hazard ratio 0.42, p = 0.009); no differences were observed for metastatic cutaneous squamous cell carcinoma vs locally advanced cutaneous squamous cell carcinoma patients. Although chemotherapy and/or cetuximab showed limited outcomes in advanced cutaneous squamous cell carcinoma, such therapy may still be an option when anti-PD-1 treatment is contraindicated.

Local Tumor Infiltration and Locoregional Recurrence in Desmoplastic Cutaneous Squamous Cell Carcinoma.

BACKGROUND: Perusal of the literature of cutaneous squamous cell carcinoma (SCC) reveals that the role of the desmoplastic subtype is indistinct. Data on local infiltration and recurrence are inconsistent dependent on surgical technique, histological method, and investigated collective. OBJECTIVE: The aim of the study was to analyze local infiltration and locoregional recurrence of the desmoplastic subtype under a uniform procedure. METHODS AND MATERIALS: Between 2005 and 2015, 320 SCCs were analyzed and histological sections of all tumors were examined. Data collection included locoregional recurrence, metastasis rate, and tumor-specific death. The median follow-up was 36.5 months. RESULTS: The desmoplastic subtype required significant more re-excisions (70.0% vs 23.9%, p < .001), more interventions until tumor-free margins were achieved (maximal 6 vs 2; p < .001), showed more widespread tumor infiltration with larger excisional margins (median 9 mm, 2-51 mm vs median 4 mm, 1-10 mm; p < .001), and a 5-fold higher local recurrence rate (26.7% vs 5.0%, p < .001). The metastasis rate (16.6% vs 2.3%, p < .001) was increased. CONCLUSION: The desmoplastic subtype is characterized by a widespread local infiltration associated with perineural infiltration. It seems to be a marker for decreased histological detectability with a high rate of locoregional recurrence and metastasis.

Efficacy and tolerability of chemosaturation in patients with hepatic metastases from uveal melanoma.

BACKGROUND: Patients with hepatic metastatic uveal melanoma still have a poor outcome. PURPOSE: To evaluate overall survival (OS), progression-free survival (PFS), and response predictors in these patients treated with chemosaturation by percutaneous hepatic perfusion with melphalan (CS-PHP). MATERIAL AND METHODS: Between June 2015 and March 2020, a total of 29 patients (median age 69.7 years; age range 30-81 years; 60% women; median BMI 25.7 kg/m2; range 18.7-35.3kg/m2; 1-6 procedures per patient) were treated with 53 CS-PHPs. All patients received cross-sectional imaging for initial and follow-up examinations. Baseline tumor load, extrahepatic tumor load, tumor response, PFS, and OS were assessed. Non-parametric statistics were used. RESULTS: After the initial CS-PHP, a partial response was observed in 11 patients (41%), stable disease in 12 patients (44%) and progressive disease in 4 patients (15%); two patients died before the response was evaluated. After initial CS-PHP, median OS was 12.9 ± 7.4 months and median PFS was 7.1 ± 7.4 months. OS after one year was 50%. After the second CS-PHP, median PFS was 7.9 ± 5.7 months. Seven patients had a liver tumor burden >25%, associated with a significantly shorter OS (6.0 ± 2.4 vs. 14.1 ± 12.7 months; P = 0.008). At the time of first CS-PHP, 41% (12/29) of the patients had extrahepatic metastases that did not affect OS (11.1 ± 8.4 months vs. 12.9 ± 13.6 months; P = 0.66). CONCLUSION: CS-PHP is a safe and effective treatment for the hepatic metastatic uveal melanoma, especially for patients with a hepatic tumor burden <25%.

Atezolizumab, vemurafenib, and cobimetinib as first-line treatment for unresectable advanced BRAFV600 mutation-positive melanoma (IMspire150): primary analysis of the randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: IMspire150 aimed to evaluate first-line combination treatment with BRAF plus MEK inhibitors and immune checkpoint therapy in BRAFV600 mutation-positive advanced or metastatic melanoma. METHODS: IMspire150 was a randomised, double-blind, placebo-controlled phase 3 study done at 112 institutes in 20 countries. Patients with unresectable stage IIIc-IV, BRAFV600 mutation-positive melanoma were randomly assigned 1:1 to 28-day cycles of atezolizumab, vemurafenib, and cobimetinib (atezolizumab group) or atezolizumab placebo, vemurafenib, and cobimetinib (control group). In cycle 1, all patients received vemurafenib and cobimetinib only; atezolizumab placebo was added from cycle 2 onward. Randomisation was stratified by lactate dehydrogenase concentration and geographical region. Blinding for atezolizumab was achieved by means of an identical intravenous placebo, and blinding for vemurafenib was achieved by means of a placebo tablet. The primary outcome was investigator-assessed progression-free survival. This trial (ClinicalTrials.gov, NCT02908672) is ongoing but no longer recruiting patients. FINDINGS: Between Jan 13, 2017, and April 26, 2018, 777 patients were screened and 514 were enrolled and randomly assigned to the atezolizumab group (n=256) or control group (n=258). At a median follow-up of 18·9 months (IQR 10·4-23·8), progression-free survival as assessed by the study investigator was significantly prolonged with atezolizumab versus control (15·1 vs 10·6 months; hazard ratio [HR] 0·78; 95% CI 0·63-0·97; p=0·025). Common treatment-related adverse events (>30%) in the atezolizumab and control groups were blood creatinine phosphokinase increased (51·3% vs 44·8%), diarrhoea (42·2% vs 46·6%), rash (40·9%, both groups), arthralgia (39·1% vs 28·1%), pyrexia (38·7% vs 26·0%), alanine aminotransferase increased (33·9% vs 22·8%), and lipase increased (32·2% vs 27·4%); 13% of patients in the atezolizumab group and 16% in the control group stopped all treatment because of adverse events. INTERPRETATION: The addition of atezolizumab to targeted therapy with vemurafenib and cobimetinib was safe and tolerable and significantly increased progression-free survival in patients with BRAFV600 mutation-positive advanced melanoma. FUNDING: F Hoffmann-La Roche and Genentech.

Adjuvant nivolumab plus ipilimumab or nivolumab monotherapy versus placebo in patients with resected stage IV melanoma with no evidence of disease (IMMUNED): a randomised, double-blind, placebo-controlled, phase 2 trial.

BACKGROUND: Nivolumab and ipilimumab, alone or in combination, are widely used immunotherapeutic treatment options for patients with advanced-ie, unresectable or metastatic-melanoma. This criterion, however, excludes patients with stage IV melanoma with no evidence of disease. We therefore aimed to evaluate the safety and efficacy of adjuvant nivolumab plus ipilimumab or nivolumab monotherapy versus a placebo in this patient population. METHODS: We did a randomised, double-blind, placebo-controlled, phase 2 trial in 20 German academic medical centres. Eligible patients were aged 18-80 years with stage IV melanoma with no evidence of disease after surgery or radiotherapy. Key exclusion criteria included uveal or mucosal melanoma, previous therapy with checkpoint inhibitors, and any previous immunosuppressive therapy within the 30 days before study drug administration. Eligible patients were randomly assigned (1:1:1), using a central, interactive, online system, to the nivolumab plus ipilimumab group (1 mg/kg of intravenous nivolumab every 3 weeks plus 3 mg/kg of intravenous ipilimumab every 3 weeks for four doses, followed by 3 mg/kg of nivolumab every 2 weeks), nivolumab monotherapy group (3 mg/kg of intravenous nivolumab every 2 weeks plus ipilimumab-matching placebo during weeks 1-12), or double-matching placebo group. The primary endpoint was the recurrence-free survival in the intention-to-treat population. The results presented in this report reflect the prespecified interim analysis of recurrence-free survival after 90 events had been reported. This study is registered with ClinicalTrials.gov, NCT02523313, and is ongoing. FINDINGS: Between Sept 2, 2015, and Nov 20, 2018, 167 patients were randomly assigned to receive nivolumab plus ipilimumab (n=56), nivolumab (n=59), or placebo (n=52). As of July 2, 2019, at a median follow-up of 28·4 months (IQR 17·7-36·8), median recurrence-free survival was not reached in the nivolumab plus ipilimumab group, whereas median recurrence-free survival was 12·4 months (95% CI 5·3-33·3) in the nivolumab group and 6·4 months (3·3-9·6) in the placebo group. The hazard ratio for recurrence for the nivolumab plus ipilimumab group versus placebo group was 0·23 (97·5% CI 0·12-0·45; p<0·0001), and for the nivolumab group versus placebo group was 0·56 (0·33-0·94; p=0·011). In the nivolumab plus ipilimumab group, recurrence-free survival at 1 year was 75% (95% CI 61·0-84·9) and at 2 years was 70% (55·1-81·0); in the nivolumab group, 1-year recurrence-free survival was 52% (38·1-63·9) and at 2 years was 42% (28·6-54·5); and in the placebo group, this rate was 32% (19·8-45·3) at 1 year and 14% (5·9-25·7) at 2 years. Treatment-related grade 3-4 adverse events were reported in 71% (95% CI 57-82) of patients in the nivolumab plus ipilimumab group and in 27% (16-40) of those in the nivolumab group. Treatment-related adverse events of any grade led to treatment discontinuation in 34 (62%) of 55 patients in the nivolumab plus ipilimumab group and seven (13%) of 56 in the nivolumab group. Three deaths from adverse events were reported but were considered unrelated to the study treatment. INTERPRETATION: Adjuvant therapy with nivolumab alone or in combination with ipilimumab increased recurrence-free survival significantly compared with placebo in patients with stage IV melanoma with no evidence of disease. The rates of grade 3-4 treatment-related adverse events in both active treatment groups were higher than the rates reported in previous pivotal trials done in advanced melanoma with measurable disease. FUNDING: Bristol-Myers Squibb.

Noninvasive, longitudinal imaging-based analysis of body adipose tissue and water composition in a melanoma mouse model and in immune checkpoint inhibitor-treated metastatic melanoma patients.

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.

Prognostic role of gamma-glutamyl transferase in metastatic melanoma patients treated with immune checkpoint inhibitors.

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.

32-Channel self-grounded bow-tie transceiver array for cardiac MR at 7.0T.

PURPOSE: Design, implementation, evaluation, and application of a 32-channel Self-Grounded Bow-Tie (SGBT) transceiver array for cardiac MR (CMR) at 7.0T. METHODS: The array consists of 32 compact SGBT building blocks. Transmission field ( B1+ ) shimming and radiofrequency safety assessment were performed with numerical simulations and benchmarked against phantom experiments. In vivo B1+ efficiency mapping was conducted with actual flip angle imaging. The array's applicability for accelerated high spatial resolution 2D FLASH CINE imaging of the heart was examined in a volunteer study (n = 7). RESULTS: B1+ shimming provided a uniform field distribution suitable for female and male subjects. Phantom studies demonstrated an excellent agreement between simulated and measured B1+ efficiency maps (7% mean difference). The SGBT array afforded a spatial resolution of (0.8 × 0.8 × 2.5) mm3 for 2D CINE FLASH which is by a factor of 12 superior to standardized cardiovascular MR (CMR) protocols. The density of the SGBT array supports 1D acceleration of up to R = 4 (mean signal-to-noise ratio (whole heart) ≥ 16.7, mean contrast-to-noise ratio ≥ 13.5) without impairing image quality significantly. CONCLUSION: The compact SGBT building block facilitates a modular high-density array that supports accelerated and high spatial resolution CMR at 7.0T. The array provides a technological basis for future clinical assessment of parallel transmission techniques.