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Immune checkpoint inhibitors (ICIs) have tremendously changed the therapeutic landscape of melanoma since they are associated with a durable response, allowing for intentional discontinuation of therapy after complete or partial remission. However, a subset of patients develops a relapse after cessation of ICI treatment and may not respond to reinduction of ICIs. The aim of the present study was to identify risk factors for relapse after intentional discontinuation of ICI therapy. Patients with intentional discontinuation of ICI therapy for metastatic or unresectable melanoma from 5 German university hospitals were analyzed retrospectively. Clinicopathologic and follow-up data of 87 patients were collected and analyzed by univariate and multivariate Cox proportional-hazards models. The following parameters were associated with relapse after cessation of ICI treatment in the univariate Cox regression analysis: concurrent radiotherapy and ICI, best overall response, and presence of brain metastases. Duration of treatment, type of primary tumor, body mass index, programmed-death ligand 1 expression, and lactate dehydrogenase levels did not significantly influence the risk for relapse. In the multivariate analysis, partial remission [hazard ratio 4.217 (95% confidence interval: 1.424-12.49), P=0.009] and stable disease [3.327 (1.204-9.19), P=0.02] were associated with a significant decrease in progression-free survival compared with complete remission. Concurrent radiotherapy and ICI [3.619 (1.288-10.168), P=0.015] are additional independent risk factors for decreased progression-free survival upon ICI discontinuation, whereas the presence of brain metastasis did not reach statistical significance on multivariate analysis., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Dedifferentiated melanoma (DM) and undifferentiated melanoma (UM) is defined as a primary or metastatic melanoma showing transition between conventional and undifferentiated components (DM) or lacking histologic and immunophenotypic features of melanoma altogether (UM). The latter is impossible to verify as melanoma by conventional diagnostic tools alone. We herein describe our experience with 35 unpublished cases to expand on their morphologic, phenotypic, and genotypic spectrum, along with a review of 50 previously reported cases (total: 85) to establish the diagnostic criteria. By definition, the dedifferentiated/undifferentiated component lacked expression of 5 routinely used melanoma markers (S100, SOX10, Melan-A, HMB45, Pan-melanoma). Initial diagnoses (known in 66 cases) were undifferentiated/unclassified pleomorphic sarcoma (n=30), unclassified epithelioid malignancy (n=7), pleomorphic rhabdomyosarcoma (n=5), other specific sarcoma types (n=6), poorly differentiated carcinoma (n=2), collision tumor (n=2), atypical fibroxanthoma (n=2), and reactive osteochondromatous lesion (n=1). In only 11 cases (16.6%) was a diagnosis of melanoma considered. Three main categories were identified: The largest group (n=56) comprised patients with a history of verified previous melanoma who presented with metastatic DM or UM. Axillary or inguinal lymph nodes, soft tissue, bone, and lung were mainly affected. A melanoma-compatible mutation was detected in 35 of 48 (73%) evaluable cases: BRAF (n=20; 40.8%), and NRAS (n=15; 30.6%). The second group (n=15) had clinicopathologic features similar to group 1, but a melanoma history was lacking. Axillary lymph nodes (n=6) was the major site in this group followed by the lung, soft tissue, and multiple site involvement. For this group, NRAS mutation was much more frequent (n=9; 60%) than BRAF (n=3; 20%) and NF1 (n=1; 6.6%). The third category (n=14) comprised primary DM (12) or UM (2). A melanoma-compatible mutation was detected in only 7 cases: BRAF (n=2), NF1 (n=2), NRAS (n=2), and KIT exon 11 (n=1). This extended follow-up study highlights the high phenotypic plasticity of DM/UM and indicates significant underrecognition of this aggressive disease among general surgical pathologists. The major clues to the diagnosis of DM and UM are: (1) presence of minimal differentiated clone in DM, (2) earlier history of melanoma, (3) undifferentiated histology that does not fit any defined entity, (4) locations at sites that are unusual for undifferentiated/unclassified pleomorphic sarcoma (axilla, inguinal, neck, digestive system, etc.), (5) unusual multifocal disease typical of melanoma spread, (6) detection of a melanoma-compatible gene mutation, and (7) absence of another genuine primary (eg, anaplastic carcinoma) in other organs., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Patients with cancer who are infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are more likely to develop severe illness and die compared with those without cancer. The impact of immune checkpoint inhibition (ICI) on the severity of COVID-19 illness is unknown. The aim of this study was to investigate whether ICI confers an additional risk for severe COVID-19 in patients with cancer., Methods: We analyzed data from 110 patients with laboratory-confirmed SARS-CoV-2 while on treatment with ICI without chemotherapy in 19 hospitals in North America, Europe and Australia. The primary objective was to describe the clinical course and to identify factors associated with hospital and intensive care (ICU) admission and mortality., Findings: Thirty-five (32%) patients were admitted to hospital and 18 (16%) died. All patients who died had advanced cancer, and only four were admitted to ICU. COVID-19 was the primary cause of death in 8 (7%) patients. Factors independently associated with an increased risk for hospital admission were ECOG ≥2 (OR 39.25, 95% CI 4.17 to 369.2, p=0.0013), treatment with combination ICI (OR 5.68, 95% CI 1.58 to 20.36, p=0.0273) and presence of COVID-19 symptoms (OR 5.30, 95% CI 1.57 to 17.89, p=0.0073). Seventy-six (73%) patients interrupted ICI due to SARS-CoV-2 infection, 43 (57%) of whom had resumed at data cut-off., Interpretation: COVID-19-related mortality in the ICI-treated population does not appear to be higher than previously published mortality rates for patients with cancer. Inpatient mortality of patients with cancer treated with ICI was high in comparison with previously reported rates for hospitalized patients with cancer and was due to COVID-19 in almost half of the cases. We identified factors associated with adverse outcomes in ICI-treated patients with COVID-19., Competing Interests: Competing interests: MiM: consultant/advisor for Bristol Myers Squibb, MSD, Novartis, Roche, Pierre Fabre. AANR: fellowship funding from Alamos Gold Inc. JMG: project focused consultant/advisor for Merck/Pfizer, MSD, Amgen, Novartis, Bristol Myers Squibb and Pierre Fabre; travel support from Ultrasun, L’Oreal, MSD, Bristol Myers Squibb and Pierre Fabre outside of the submitted work. TPM: fellowship funding from Alamos Gold Inc. SDS: consultant/advisor for Janssens, Novartis and Sanofi. AMM: consultant/advisor to Bristol Myers Squibb, MSD, Novartis, Roche, Pierre Fabre and QBiotics. MSC: consultant/advisor for Bristol Myers Squibb, MSD, Amgen, Novartis, Pierre Fabre, Roche, Sanofi, Merck, Ideaya, Regeneron, Nektar, Eisai; honoraria from Bristol Myers Squibb, MSD, Novartis. CB: consultant/advisor for Amgen, Bristol Myers Squibb, MSD, Novartis Pharma AG, Regeneron Pharmaceuticals Inc, Roche Pharma, Sanofi Aventis. LiZ: consultant/advisor for Bristol Myers Squibb, Novartis, Pierre Fabre, Sunpharma, Sanofi, MSD; research funding from Novartis; travel support from Bristol Myers Squibb, Pierre Fabre, Sanofi, Amgen, Novartis, Sunpharma. DS: consultant/advisor for Roche/Genentech, Novartis, Bristol Myers Squibb, MSD, Merck Serono, Amgen, Immunocore, Incyte, 4SC, Pierre Fabre, Mologen and Sanofi/Regeneron; honoraria from Roche/Genentech, Novartis, MSD, Bristol Myers Squibb, Merck Serono, Amgen, Immunocore, Incyte, 4SC, Pierre Fabre, Sysmex, Grünenthal Group, Agenus, Array BioPharma, AstraZeneca, LEO Pharma, Pfizer, Philogen, Regeneron and Mologen; travel/accommodation expenses from Roche/Genentech, Novartis, Bristol Myers Squibb, Merck Serono, Amgen and Merck; speakers bureau for Novartis, Bristol Myers Squibb, MSD, Amgen, Incyte, Pierre Fabre and Roche; research funding from Novartis and Bristol Myers Squibb; steering committee membership for Novartis, MSD and Bristol Myers Squibb. AH: consultant/advisor for Amgen, Bristol Myers Squibb, MSD/Merck, Pfizer, NeraCare, Novartis, Philogen, Pierre Fabre, Roche and Regeneron/Sanofi-Genzyme. RD: intermittent, project focused consulting and/or advisory relationships with Novartis, MSD, Bristol-Myers Squibb, Roche, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, Catalym, Second Genome, Regeneron, Alligator, MaxiVAX SA and touchIME outside the submitted work. JH: consultant/advisor for AIMM, AchillesTx, Bristol Myers Squibb, BioNTech, GSK, Immunocore, Merck Serono, MSD, Neogene Tx, Novartis, Pfizer, Roche/Genentech, Sanofi, Seattle Genetics, Third Rock Ventures, Vaximm; research grants from Amgen, Bristol Myers Squibb, MSD, BioNTech, Novartis. CUB: consultant/advisor for Bristol Myers Squibb, MSD, Roche, Novartis, GSK, AZ, Pfizer, Lilly, GenMab, Pierre Fabre, Third Rock Ventures; research funding from Bristol Myers Squibb, Novartis, NanoString; stock ownership: Uniti Cars; co-founder: Immagene BV. CR: consultant/advisor for Bristol Myers Squibb, MSD, Roche, Novartis, CureVac, Sanofi, Pierre Fabre. RJS: consultant/advisor for Asana Biosciences, Astrazeneca, Bristol Myers Squibb, Eisai, Iovnace, Pfizer, Merck, Novartis, Replimune; research funding: Amgen, Merck. PAA: consultant/advisory for Bristol Myers Squibb, Roche/Genentech, MSD, Novartis, Array, Merck Serono, Pierre Fabre, Incyte, Medimmune, AstraZeneca, Syndax, Sun Pharma, Sanofi, Idera, Ultimovacs, Sandoz, Immunocore, 4SC, Alkermes, Italfarmaco, Nektar, Boehringer-Ingelheim, Eisai, Regeneron; research funding from Bristol Myers Squibb, Roche/Genentech, Array and travel support from MSD. FSH: consultancy/advisory for Bristol Myers Squibb, Merck, EMD Serono, Novartis, Surface, Compass Therapeutics, Apricity, Aduro, Sanofi, Pionyr, 7 Hills Pharma, Torque, Rheos, Kairos, Bicara, Psioxus Therapeutics, Pieris Pharmaceutical, Zumutor, Corner Therapeutics, Idera, Takeda, Genentech/Roche, Bioentre, Gossamer. KPMS: consulting/advisory for Bristol Myers Squibb, MSD, Abbvie, Pierre Fabre, Novartis; honoraria received from Novartis, Roche, MSD (all paid to institution). KLR: consultant/advisor for Teladoc. OER: consultant/advisor for Merck, Celgene, Five Prime, GSK, Bayer, Roche/Genentech, Puretech, Imvax, Sobi; research support from Merck; speaker for activities supported by educational grants from Bristol Myers Squibb and Merck; patent “Methods of using pembrolizumab and trebananib” pending. PCL: consultant/advisor for Bristol Myers Squibb, MSD, Pierre Fabre, Novartis, Amgen and Roche; travel support from Bristol Myers Squibb and MSD; research support from Bristol Myers Squibb. MaM: consultant advisor for Bristol Myers Squibb, MSD, Novartis, Roche, PierreFabre. GVL: consultant/advisor for Aduro Biotech Inc, Amgen Inc, Array Biopharma inc, Boehringer Ingelheim International GmbH, Bristol Myers Squibb, Highlight Therapeutics SL, MSD, Novartis Pharma AG, QBiotics Group Limited, Regeneron Pharmaceuticals Inc, SkylineDX BV, all declarations of interest are outside of the submitted work. AR, IPS, CT, CAT, JMG, MHT, SN, LZ, PB, AE, NP, MGV, JB, SR, TC, JL, AV, MOB, ME, LP, PQ, CP, WHM, RDC and SL have no conflict of interest., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Although dendritic cell (DC)-based cancer vaccines represent a promising treatment strategy, its exploration in the clinic is hampered due to the need for Good Manufacturing Practice (GMP) facilities and associated trained staff for the generation of large numbers of DCs. The Quantum bioreactor system offered by Terumo BCT represents a hollow-fiber platform integrating GMP-compliant manufacturing steps in a closed system for automated cultivation of cellular products. In the respective established protocols, the hollow fibers are coated with fibronectin and trypsin is used to harvest the final cell product, which in the case of DCs allows processing of only one tenth of an apheresis product., Materials and Results: We successfully developed a new protocol that circumvents the need for fibronectin coating and trypsin digestion, and makes the Quantum bioreactor system now suitable for generating large numbers of mature human monocyte-derived DCs (Mo-DCs) by processing a complete apheresis product at once. To achieve that, it needed a step-by-step optimization of DC-differentiation, e.g., the varying of media exchange rates and cytokine concentration until the total yield (% of input CD14 + monocytes), as well as the phenotype and functionality of mature Mo-DCs, became equivalent to those generated by our established standard production of Mo-DCs in cell culture bags., Conclusions: By using this new protocol for the Food and Drug Administration-approved Quantum system, it is now possible for the first time to process one complete apheresis to automatically generate large numbers of human Mo-DCs, making it much more feasible to exploit the potential of individualized DC-based immunotherapy., (Copyright © 2019 International Society for Cell and Gene Therapy. Published by Elsevier Inc. All rights reserved.)

Background: Spindle cell oncocytoma (SCO) is a rare non-neuroendocrine neoplasm of the pituitary gland. In general, surgical excision and radiation therapy is performed. However, local recurrences are frequently seen, requiring repeated surgical and radio-oncological interventions. Thus, mutational analysis of the tumor and targeted therapy may represent a valuable therapy option in these patients., Case Report: A 38-year-old female patient with past medical history of 6 surgeries (two transsphenoidal and four transcranial), radiation therapy, and chemoradiation therapy due to several recurrences of a SCO, presented for follow-up imaging. MRI of the brain showed growth of a tumor in the right parasellar region consistent with a new local recurrence, which due to its size and location was considered to be not resectable. Molecular analysis of a previously surgically removed tumor showed a BRAF V600E mutation and thus, combined targeted inhibition of the MAPK/ERK signaling pathway using a BRAF inhibitor and a MEK inhibitor was started. Due to drug-induced panniculitis, MEK inhibitor had to be stopped and BRAF inhibitor only was continued, which was well tolerated by the patient. Subsequent imaging revealed tumor regression already four weeks after therapy initiation and no disease progression has been observed to date., Conclusion: A SCO patient with BRAF V600E mutation was successfully treated using targeted inhibition of the MAPK/ERK signaling pathway. Under therapy, tumor regression was observed and the patient has been free of progressive disease for more than two years now. Thus, mutational analysis and targeted inhibition may offer an effective treatment option for SCO patients, while potential side-effects to this therapy, like observed in our case, can occur and needs to be adequately treated., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: In patients with melanoma, early dissemination via lymphatic and hematogenous routes is frequently seen. Thus, besides clinical follow-up examination and imaging, reliable melanoma-specific serological tumor markers are needed., Patients and Methods: We retrospectively compared two serum markers for melanoma, S100 and melanoma-inhibitory activity (MIA), for monitoring of patients with metastatic melanoma under either adjuvant or therapeutic vaccination immunotherapy with dendritic cells (DC). Serum was obtained from a total of 100 patients (28 patients in stage III and 72 patients in stage IV, according to the American Joint Committee on Cancer 2002) at regular intervals during therapy, accompanied by follow-up imaging., Results: When relapse was detected, both markers often remained within normal range. In contrast, in patients with metastatic measurable disease receiving therapeutic and not adjuvant DC vaccination, an increase of both markers was a strong indicator for disease progression. When comparing both markers in the whole study population, MIA showed a superior sensitivity to detect disease progression., Conclusion: S100 and MIA are highly sensitive tumor markers for monitoring of patients with melanoma with current metastases, but less sensitive for monitoring of tumor-free patients. In the current study, MIA had a slightly superior sensitivity to detect progressive disease compared to S100 and seems to be more useful in monitoring of patients with metastatic melanoma receiving immunotherapy., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Sarcoidosis, a chronic inflammatory disorder, results from increased immune responses. Its development can be triggered in patients under immunotherapy, as activation of the immune system in these patients is desired. Since 1997, 249 patients with metastasized cutaneous melanoma (stage III and IV, AJCC 2009) have been treated with dendritic cell (DC)-based vaccines at our hospital. Three out of these patients were diagnosed with sarcoidosis after or during long-term DC vaccination therapy (1.20%). Metastatic disease was initially suspected based on the radiographic manifestation of lung masses or bilateral hilar lymphadenopathy. Histological assessment, however, revealed the appropriate diagnosis. Interestingly, all three patients are long-term responders and have remained free of metastatic or progressive disease for over a period of at least 4 years. In summary, sarcoidosis can occur in patients with cancer who have benefited from DC-based therapeutic vaccination and thus, its development, even with substantial delay, may be associated with successful anticancer immunotherapy., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

For more than one decade patients have been treated with dendritic cell (DC) immunotherapy against malignancies and infectious diseases. Proof of principle studies demonstrated immunogenicity and clinical responses were observed in a fraction of patients. Overlooking more than 200 publications one realizes, however, that it is almost impossible to compare many of these trials even in a given clinical setting or disease. This is primarily due to the fact that dendritic cell generation procedures are highly variable. There is a requirement for a standardized DC generation protocol which provides 'reference dendritic cells' to which other dendritic cells (e.g. differently matured ones) can be compared to in order to further optimize this promising vaccination approach. In this chapter, we describe in detail our standard DC generation protocols established during the last decade with over 200 melanoma patients treated and over 2,000 vaccinations applied in clinical studies at our hospital. We do not claim that these dendritic cells are the best ones, but the generation procedure is highly reliable and reproducible and provides a standardized reference DC vaccine.