Publications by authors named "Lucie Heinzerling"

120 Publications

Vier Fälle einer Erysipel-ähnlichen Entzündung bei Patienten mit metastasiertem Melanom unter Therapie mit Checkpoint-Inhibitoren.

J Dtsch Dermatol Ges 2021 Apr;19(4):598-602

Klinik für Dermatologie, Venerologie und Allergologie, Universitätsklinikum des Saarlandes, Homburg/Saar.

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http://dx.doi.org/10.1111/ddg.14304_gDOI Listing
April 2021

Combining CNN-based histologic whole slide image analysis and patient data to improve skin cancer classification.

Eur J Cancer 2021 Apr 7;149:94-101. Epub 2021 Apr 7.

Digital Biomarkers for Oncology Group, National Center for Tumor Diseases, German Cancer Research Center, Heidelberg, Germany. Electronic address:

Background: Clinicians and pathologists traditionally use patient data in addition to clinical examination to support their diagnoses.

Objectives: We investigated whether a combination of histologic whole slides image (WSI) analysis based on convolutional neural networks (CNNs) and commonly available patient data (age, sex and anatomical site of the lesion) in a binary melanoma/nevus classification task could increase the performance compared with CNNs alone.

Methods: We used 431 WSIs from two different laboratories and analysed the performance of classifiers that used the image or patient data individually or three common fusion techniques. Furthermore, we tested a naive combination of patient data and an image classifier: for cases interpreted as 'uncertain' (CNN output score <0.7), the decision of the CNN was replaced by the decision of the patient data classifier.

Results: The CNN on its own achieved the best performance (mean ± standard deviation of five individual runs) with AUROC of 92.30% ± 0.23% and balanced accuracy of 83.17% ± 0.38%. While the classification performance was not significantly improved in general by any of the tested fusions, naive strategy of replacing the image classifier with the patient data classifier on slides with low output scores improved balanced accuracy to 86.72% ± 0.36%.

Conclusion: In most cases, the CNN on its own was so accurate that patient data integration did not provide any benefit. However, incorporating patient data for lesions that were classified by the CNN with low 'confidence' improved balanced accuracy.
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http://dx.doi.org/10.1016/j.ejca.2021.02.032DOI Listing
April 2021

Inflammatory markers in autoimmunity induced by checkpoint inhibitors.

J Cancer Res Clin Oncol 2021 Apr 10. Epub 2021 Apr 10.

Department of Dermatology, Universitätsklinikum Erlangen, Ulmenweg 18, 91054, Erlangen, Germany.

Purpose: Immune checkpoint inhibitors (ICI) are highly effective in several cancer entities, but also invoke a variety of immune-related adverse events (irAE). These are mostly reversible, but can be life-threatening or even fatal. Currently, the pathogenesis is not fully understood, but crucial for effective treatment. Prediction and early detection of irAE could be facilitated and treatment optimized if relevant biomarkers and effector mechanisms were better characterized.

Methods: This study included a total of 45 irAE in patients with metastatic melanoma who were treated with ICI. All patients underwent a complete work-up with exclusion of other causes. Longitudinal blood samples were analyzed for a panel of soluble markers and compared to baseline and to patients who did not experience any irAE. Measurements included LDH, interleukin (IL)-6, IL-1β, IL-17, C-reactive protein (CRP) and tumor necrosis factor (TNF)-alpha as well as tumor markers S100 and melanoma inhibitory activity (MIA).

Results: During the early onset of irAE increases in serum IL-6 (from mean 24.4 pg/ml at baseline to 51.0 pg/ml; p = 0.003) and CRP (from mean 7.0 mg/l at baseline to 17.7 mg/l; p = 0.001) and a decrease in MIA (from mean 5.4 pg/ml at baseline to 4.8 pg/ml; p = 0.035) were detected. No changes in IL-17 were noted. These effects were observed for irAE of different organ systems.

Conclusion: Increases of a combination of IL-6 and CRP serum levels can be used for the early detection of irAE and tailored management. Interestingly, changes in MIA serum levels also correlate with irAE onset.
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http://dx.doi.org/10.1007/s00432-021-03550-5DOI Listing
April 2021

Sustainable responses in metastatic melanoma patients with and without brain metastases after elective discontinuation of anti-PD1-based immunotherapy due to complete response.

Eur J Cancer 2021 Apr 2;149:37-48. Epub 2021 Apr 2.

Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.

Background: Anti-PD1-based immunotherapy is currently used in most patients with advanced melanoma. Despite the remarkable data regarding overall survival, the optimal treatment duration is still unknown.

Methods: We evaluated the outcome of 125 patients with advanced melanoma with and without brain metastases (MBM), treated either with anti-PD1 monotherapy (N = 97) or combined with anti-CTLA4 (N = 28) after elective treatment discontinuation due to complete response (CR) (group A, N = 86), or treatment-limiting toxicity (N = 33) and investigator's decision (ID, N = 6) (group B) with subsequent CR.

Results: For group A, median duration of treatment (mDoT) was 22 months (range 5-49) and median time to CR 9 months (range 2-47). Accordingly, mDoT for group B was 3 months (range 0-36) and median time to CR 7 months (range 1-32). Seven patients from group A and three from group B experienced disease recurrence. Off-treatment survival was not reached. Median off-treatment response time (mOTRt) was 19 months (range 0-42) and 25 months (range 0-66), respectively. For MBM, mOTRt was 17 months (range 7-41) and 28 months (range 9-39), respectively. After a median follow-up of 38 months (range 9-70), seven (5.6%) patients had deceased, one (0.8%) due to melanoma.

Conclusions: Treatment discontinuation is feasible also in patients with MBM. Efficacy outcomes seemed to be similar in both groups of patients who achieved CR, regardless of reason for discontinuation. In patients who experienced disease relapse, treatment re-challenge with anti-PD1 resulted in subsequent renewed response.
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http://dx.doi.org/10.1016/j.ejca.2021.02.037DOI Listing
April 2021

Lipase elevation and type 1 diabetes mellitus related to immune checkpoint inhibitor therapy - A multicentre study of 90 patients from the German Dermatooncology Group.

Eur J Cancer 2021 Mar 30;149:1-10. Epub 2021 Mar 30.

Skin Cancer Center Hannover, Department of Dermatology, Hannover Medical School, Carl Neuberg Str. 1, 30625, Hannover, Germany. Electronic address:

Aim: Immune checkpoint inhibition (ICI) triggers immune-related adverse events (irAEs). The relevance of lipase elevation remains unclear.

Patients And Methods: Skin cancer patients with newly detected serum lipase elevation (at least twofold upper normal limit) or newly diagnosed type I diabetes mellitus upon ICI therapy were retrospectively collected at 14 German skin cancer centres.

Results: We identified 68 patients with lipase elevation occurring after a median time of 19 (range 1-181) weeks on ICI, 15 (22%) thereof had symptoms consistent with pancreatitis. Forty-seven patients (73%) had other irAE, mainly colitis. Discontinuation (n = 24, 35%) or interruption (n = 26, 38%) of ICI resulted in decrease of lipase after reinduction of ICI lipase levels increased again in 12 of 24 patients. In 18 patients (27%), ICI was continued unchanged, and in 12 (67%) of them, lipase levels normalised. Twenty-two patients were identified with newly diagnosed type I diabetes mellitus related to ICI, and 12 (55%) thereof had also lipase elevation mainly shortly before or after the diagnosis of diabetes. Fourteen (64%) patients had other irAE, mainly thyroiditis. Irrespective of lipase elevation, patients frequently showed a rapid onset with ketoacidosis, decreased c-peptide, and strongly increased blood glucose levels.

Conclusion: Increased serum lipase during ICI is often not associated with pancreatitis but with other irAE as possible cause. Therefore, it might be sufficient to regularly monitor blood glucose levels and perform further workup only in case of signs or symptoms of pancreatitis and/or exocrine pancreas insufficiency.
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http://dx.doi.org/10.1016/j.ejca.2021.02.017DOI Listing
March 2021

Upregulation of CCR4 in activated CD8 T cells indicates enhanced lung homing in patients with severe acute SARS-CoV-2 infection.

Eur J Immunol 2021 Mar 30. Epub 2021 Mar 30.

Department of Internal Medicine 5, Hematology, and Oncology, University Hospital Erlangen and Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.

COVID-19 is a life-threatening disease leading to bilateral pneumonia and respiratory failure. The underlying reasons why a smaller percentage of patients present with severe pulmonary symptoms whereas the majority is only mildly affected are to date not well understood. Comparing the immunological phenotype in healthy donors and patients with mild versus severe COVID-19 shows that in COVID-19 patients, NK-/B-cell activation and proliferation are enhanced independent of severity. As an important precondition for effective antibody responses, T-follicular helper cells and antibody secreting cells are increased both in patients with mild and severe SARS-CoV-2 infection. Beyond this, T cells in COVID-19 patients exhibit a stronger activation profile with differentiation toward effector cell phenotypes. Importantly, when looking at the rates of pulmonary complications in COVID-19 patients, the chemokine receptor CCR4 is higher expressed by both CD4 and CD8 T cells of patients with severe COVID-19. This raises the hypothesis that CCR4 upregulation on T cells in the pathogenesis of COVID-19 promotes stronger T-cell attraction to the lungs leading to increased immune activation with presumably higher pulmonary toxicity. Our study contributes significantly to the understanding of the immunological changes during COVID-19, as new therapeutic agents, preferentially targeting the immune system, are highly warranted.
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http://dx.doi.org/10.1002/eji.202049135DOI Listing
March 2021

Myocardial T1 and T2 Mapping by Magnetic Resonance in Patients With Immune Checkpoint Inhibitor-Associated Myocarditis.

J Am Coll Cardiol 2021 Mar;77(12):1503-1516

Cardiovascular Imaging Research Center, Division of Cardiology and Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts, USA; Cardio-Oncology Program, Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA. Electronic address:

Background: Myocarditis is a potentially fatal complication of immune checkpoint inhibitor (ICI) therapy. Data on the utility of cardiovascular magnetic resonance (CMR) T1 and T2 mapping in ICI myocarditis are limited.

Objectives: This study sought to assess the value of CMR T1 and T2 mapping in patients with ICI myocarditis.

Methods: In this retrospective study from an international registry of patients with ICI myocarditis, clinical and CMR findings (including T1 and T2 maps) were collected. Abnormal T1 and T2 were defined as 2 SD above site (vendor/field strength specific) reference values and a z-score was calculated for each patient. Major adverse cardiovascular events (MACE) were a composite of cardiovascular death, cardiogenic shock, cardiac arrest, and complete heart block.

Results: Of 136 patients with ICI myocarditis with a CMR, 86 (63%) had T1 maps and 79 (58%) also had T2 maps. Among the 86 patients (66.3 ± 13.1 years of age), 36 (41.9%) had a left ventricular ejection fraction <55%. Across all patients, mean z-scores for T1 and T2 values were 2.9 ± 1.9 (p < 0.001) and 2.2 ± 2.1 (p < 0.001), respectively. On Siemens 1.5-T scanner (n = 67), native T1 (1,079.0 ± 55.5 ms vs. 1,000.3 ± 22.1 ms; p < 0.001) and T2 (56.2 ± 4.9 ms vs. 49.8 ± 2.2 ms; p < 0.001) values were elevated compared with reference values. Abnormal T1 and T2 values were seen in 78% and 43% of the patients, respectively. Applying the modified Lake Louise Criteria, 95% met the nonischemic myocardial injury criteria and 53% met the myocardial edema criteria. Native T1 values had excellent discriminatory value for subsequent MACE, with an area under the curve of 0.91 (95% confidence interval: 0.84 to 0.98). Native T1 values (for every 1-unit increase in z-score, hazard ratio: 1.44; 95% confidence interval: 1.12 to 1.84; p = 0.004) but not T2 values were independently associated with subsequent MACE.

Conclusions: The use of T1 mapping and application of the modified Lake Louise Criteria provides important diagnostic value, and T1 mapping provides prognostic value in patients with ICI myocarditis.
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http://dx.doi.org/10.1016/j.jacc.2021.01.050DOI Listing
March 2021

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

Eur J Cancer 2021 Mar 15;148:61-75. Epub 2021 Mar 15.

Department of Dermatology, University Hospital Essen, University Duisburg-Essen, Essen, Germany. Electronic address:

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.
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http://dx.doi.org/10.1016/j.ejca.2021.01.034DOI Listing
March 2021

Hematological immune related adverse events after treatment with immune checkpoint inhibitors.

Eur J Cancer 2021 Apr 9;147:170-181. Epub 2021 Mar 9.

Department of Dermatology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany; Deutsches Zentrum Immuntherapie (DZI), Erlangen, Germany; Comprehensive Cancer Center Erlangen-European Metropolitan Area of Nürnberg (CCC ER-EMN), Erlangen, Germany; Department of Dermatology and Allergy, LMU, University Hospital, Munich, Germany. Electronic address:

Introduction: With the increasing use of checkpoint inhibitors, rare immune-related adverse events (irAE) are being identified. Haematological irAE (hem-irAE) are difficult to treat and have shown high mortality rates. In order to improve side-effect management for these potentially life-threatening events, we analysed frequency, severity and outcomes.

Patients And Methods: Patients who developed hem-irAE while being treated with immune checkpoint inhibitors (ICI) therapy were retrospectively identified from 18 international cancer centres.

Results: In total, more than 7626 patients treated with ICI were screened, and 50 patients with hem-irAE identified. The calculated incidence amounts to 0.6% and median onset was 6 weeks after the ICI initiation (range 1-128 weeks). Thrombocytopenia and leucopaenia were the most frequent hem-irAE with 34% (17/50) and 34% (17/50), respectively, followed by anaemia 28% (14/50), hemophagocytic lymphohistiocytosis (4% (2/50)), aplastic anaemia (2% (1/50)), acquired haemophilia A (2% (1/50)) and coagulation deficiency (2% (1/50)). Simultaneous thrombocytopenia and neutropenia occurred in two patients, concurrent anaemia and thrombocytopenia in one patient. Other than cessation of ICI (in 60%) and corticosteroids (in 78%), treatment included second-line immunosuppression in 24% of cases. Events resolved in 78% (39/50), while 18% (9/50) had persistent changes, and 2% (1/50) had fatal outcomes (agranulocytosis).

Conclusion: Hem-irAE can affect all haematopoietic blood cell lineages and may persist or even be fatal. Management may require immunosuppression beyond corticosteroids. Although these irAE are rare, treating physicians should be aware, monitor blood counts regularly and promptly act upon detection.
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http://dx.doi.org/10.1016/j.ejca.2021.01.013DOI Listing
April 2021

Electrocardiographic features of immune checkpoint inhibitor associated myocarditis.

J Immunother Cancer 2021 Mar;9(3)

Cardio-Oncology Program, Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA

Background: Myocarditis is a highly morbid complication of immune checkpoint inhibitor (ICI) use that remains inadequately characterized. The QRS duration and the QTc interval are standardized electrocardiographic measures that are prolonged in other cardiac conditions; however, there are no data on their utility in ICI myocarditis.

Methods: From an international registry, ECG parameters were compared between 140 myocarditis cases and 179 controls across multiple time points (pre-ICI, on ICI prior to myocarditis, and at the time of myocarditis). The association between ECG values and major adverse cardiac events (MACE) was also tested.

Results: Both the QRS duration and QTc interval were similar between cases and controls prior to myocarditis. When compared with controls on an ICI (93±19 ms) or to baseline prior to myocarditis (97±19 ms), the QRS duration prolonged with myocarditis (110±22 ms, p<0.001 and p=0.009, respectively). In contrast, the QTc interval at the time of myocarditis (435±39 ms) was not increased compared with pre-myocarditis baseline (422±27 ms, p=0.42). A prolonged QRS duration conferred an increased risk of subsequent MACE (HR 3.28, 95% CI 1.98 to 5.62, p<0.001). After adjustment, each 10 ms increase in the QRS duration conferred a 1.3-fold increase in the odds of MACE (95% CI 1.07 to 1.61, p=0.011). Conversely, there was no association between the QTc interval and MACE among men (HR 1.33, 95% CI 0.70 to 2.53, p=0.38) or women (HR 1.48, 95% CI 0.61 to 3.58, p=0.39).

Conclusions: The QRS duration is increased in ICI myocarditis and is associated with increased MACE risk. Use of this widely available ECG parameter may aid in ICI myocarditis diagnosis and risk-stratification.
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http://dx.doi.org/10.1136/jitc-2020-002007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7929895PMC
March 2021

Experiences of In-Patients with Skin Cancer in a German University Hospital Setting: A Cross-Sectional Survey.

Patient Prefer Adherence 2021 12;15:41-48. Epub 2021 Jan 12.

Department of Dermatology, University Hospital Erlangen, Friedrich-Alexander-University (FAU) Erlangen-Nuremberg, Erlangen 91054, Germany.

Purpose: An important measure of hospital quality is the satisfaction of the patients receiving in-patient care. This cross-sectional study aimed to assess skin cancer patients' experiences in a university hospital setting as a measure of quality of cancer care.

Patients And Methods: Questionnaires were mailed to patients with skin cancer after receiving in-patient overnight treatment in the dermatological unit of the university hospital Erlangen (Germany) from 1 September to 30 November 2017. Patients were asked to evaluate their overall experience of this episode of care and to complete the Picker Inpatient Survey questionnaire on specific aspects of their care, such as patient satisfaction regarding contact with staff, need for information, recommendation of the hospital as well as tumor-specific questions. The results were re-coded as problems and reported as frequencies and their percentage.

Results: A total of 103 of 159 questionnaires were returned (64.8%). All patients rated the treatment and care they had received to be good or very good. Additionally, all patients would recommend our in-patient clinic to their families or friends. The patients most commonly criticized inconsistency of care delivered by the same physician (29.7%, 30/101) and feeling of insufficient involvement in the decision-making processes (21.1%, 20/95). Besides this, 19.0% (11/58) and 34.6% (18/52) of patients were not satisfied with physicians and nurses, respectively, appropriately addressing their fears or anxieties. In the cancer-specific questionnaire, the majority of patients were dissatisfied with further support regarding professional and social rehabilitation possibilities (85.7%, 30/35) and psycho-oncology (56.3%, 18/32).

Conclusion: Overall, the majority of patients were satisfied with the in-patient skin cancer treatment. However, physicians and nurses can enhance patient satisfaction by addressing patients' fears and anxieties regarding their disease and treatment. Besides, our results highlight the importance of psycho-oncological support.
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http://dx.doi.org/10.2147/PPA.S276417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811463PMC
January 2021

Current Melanoma Treatments: Where Do We Stand?

Cancers (Basel) 2021 Jan 9;13(2). Epub 2021 Jan 9.

The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

Groundbreaking research in immunology and cancer biology in the last few decades has led to the discovery and development of novel therapeutics, such as immune checkpoint inhibitors and targeted therapies, which have revolutionized the clinical care of patients with metastatic melanoma. Updated data from the largest clinical trials continue to support the use of these treatment modalities, both in the metastatic and in adjuvant settings, with studies showing the predicted plateau effect on survival curves. However, with growing evidence that neoadjuvant therapy is also associated with high rates of recurrence-free survival, the question about whether patients should receive adjuvant or neoadjuvant treatment raises new questions about therapeutic options. Finally, management after resistance and intervention with novel immunotherapies are newer challenges, particularly in the field of non-cutaneous melanoma.
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http://dx.doi.org/10.3390/cancers13020221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7827568PMC
January 2021

Dedifferentiated and Undifferentiated Melanomas: Report of 35 New Cases With Literature Review and Proposal of Diagnostic Criteria.

Am J Surg Pathol 2021 02;45(2):240-254

Institute of Pathology.

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.
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http://dx.doi.org/10.1097/PAS.0000000000001645DOI Listing
February 2021

MAPK blockade, toxicities, pathogenesis and management.

Curr Opin Oncol 2021 Mar;33(2):139-145

Department of Dermatology, Universitätsklinikum München (LMU), Munich, Germany.

Purpose Of Review: BRAF/MEK inhibitor has changed the treatment landscape in patients with advanced and metastatic melanoma with prolonged overall survival and progression-free survival. Since three treatment combinations exist with similar efficacy therapy decisions are often made based on the side effect profile. Additionally, on-target side effects or class effects have to be properly managed to ensure treatment adherence.

Recent Findings: Sequential treatment with BRAF/MEK inhibition and immunotherapy might increase toxicity with a sepsis-like syndrome and triple therapy with concomitant BRAF/MEK inhibition and anti-PD1/PD-L1 antibody therapy induces severe side effects in the vast majority of patients.

Summary: Toxicity of combination therapy with BRAF/MEK inhibitors is generally manageable, reversible and infrequently associated with treatment discontinuation. In case of persisting off-target effects the change to another combination therapy can resolve side effects.
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http://dx.doi.org/10.1097/CCO.0000000000000710DOI Listing
March 2021

Immune Checkpoint Inhibitor-induced Bilateral Vestibulopathy.

J Immunother 2021 04;44(3):114-117

Departments of Dermatology.

Checkpoint inhibitors (CPI), such as anti-programmed death-1 and anti-cytotoxic T-lymphocyte antigen-4antibodies cause serious, rarely fatal immune-related adverse events (irAE) potentially in all organ systems. Neurological immune-related adverse events occur in 1%-5% of patients on CPI therapy and may present with dramatic clinical symptoms of the sensory organs. After exclusion of other causes, a high-dose treatment with corticosteroids is crucial for clinical outcome with lower risk of sequelae. We present a severe case of CPI-related ongoing and most likely irreversible bilateral vestibular affection. A 59-year-old male melanoma patient with brain metastasis undergoing immunotherapy with anti-cytotoxic T-lymphocyte antigen-4 and anti-programmed death-1 antibodies developed severe debilitating rotatory vertigo. Bilateral vestibulopathy was diagnosed as a result of the CPI therapy after a thorough analysis including magnetic resonance imaging, laboratory tests of blood and cerebrospinal fluid as well as neurological and otorhinolaryngology examinations. The vertigo improved slightly during a 10-day course of steroid therapy and intensive balance training but did not resolve completely.
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http://dx.doi.org/10.1097/CJI.0000000000000353DOI Listing
April 2021

Dual mTOR/DNA-PK Inhibitor CC-115 Induces Cell Death in Melanoma Cells and Has Radiosensitizing Potential.

Int J Mol Sci 2020 Dec 7;21(23). Epub 2020 Dec 7.

Department of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsstr. 27, 91054 Erlangen, Germany.

CC-115 is a dual inhibitor of the mechanistic target of rapamycin (mTOR) kinase and the DNA-dependent protein kinase (DNA-PK) that is currently being studied in phase I/II clinical trials. DNA-PK is essential for the repair of DNA-double strand breaks (DSB). Radiotherapy is frequently used in the palliative treatment of metastatic melanoma patients and induces DSBs. Melanoma cell lines and healthy-donor skin fibroblast cell lines were treated with CC‑115 and ionizing irradiation (IR). Apoptosis, necrosis, and cell cycle distribution were analyzed. Colony forming assays were conducted to study radiosensitizing effects. Immunofluorescence microscopy was performed to determine the activity of homologous recombination (HR). In most of the malign cell lines, an increasing concentration of CC-115 resulted in increased cell death. Furthermore, strong cytotoxic effects were only observed in malignant cell lines. Regarding clonogenicity, all cell lines displayed decreased survival fractions during combined inhibitor and IR treatment and supra-additive effects of the combination were observable in 5 out of 9 melanoma cell lines. CC-115 showed radiosensitizing potential in 7 out of 9 melanoma cell lines, but not in healthy skin fibroblasts. Based on our data CC-115 treatment could be a promising approach for patients with metastatic melanoma, particularly in the combination with radiotherapy.
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http://dx.doi.org/10.3390/ijms21239321DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7730287PMC
December 2020

Patterns of care and follow-up care of patients with uveal melanoma in German-speaking countries: a multinational survey of the German Dermatologic Cooperative Oncology Group (DeCOG).

J Cancer Res Clin Oncol 2020 Nov 21. Epub 2020 Nov 21.

Department of Dermatology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg (FAU), Ulmenweg 18, 91054, Erlangen, Germany.

Purpose: Uveal melanoma (UM) is an orphan cancer of high unmet medical need. Current patterns of care and surveillance remain unclear as they are situated in an interdisciplinary setting.

Methods: A questionnaire addressing the patterns of care and surveillance in the management of patients with uveal melanoma was distributed to 70 skin cancer centers in Austria, Germany and Switzerland. Frequency distributions of responses for each item of the questionnaire were calculated.

Results: 44 of 70 (62.9%) skin cancer centers completed the questionnaire. Thirty-nine hospitals were located in Germany (88.6%), three in Switzerland (6.8%) and two in Austria (4.5%). The majority (68.2%) represented university hospitals. Most patients with metastatic disease were treated in certified skin cancer centers (70.7%, 29/41). Besides, the majority of patients with UM were referred to the respective skin cancer center by ophthalmologists (87.2%, 34/39). Treatment and organization of follow-up of patients varied across the different centers. 35.1% (14/37) of the centers stated to not perform any screening measures.

Conclusion: Treatment patterns of patients with uveal melanoma in Germany, Austria and Switzerland remain extremely heterogeneous. A guideline for the treatment and surveillance is urgently needed.
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http://dx.doi.org/10.1007/s00432-020-03450-0DOI Listing
November 2020

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

J Immunother Cancer 2020 10;8(2)

Department of Dermatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany

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.
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http://dx.doi.org/10.1136/jitc-2020-000897DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583786PMC
October 2020

Four cases of erysipelas-like inflammation in patients with metastatic melanoma treated with checkpoint inhibitors.

J Dtsch Dermatol Ges 2021 Apr 8;19(4):598-602. Epub 2020 Oct 8.

Klinik für Dermatologie, Venerologie und Allergologie, Universitätsklinikum des Saarlandes, Homburg/Saar.

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http://dx.doi.org/10.1111/ddg.14304DOI Listing
April 2021

Trial watch : the gut microbiota as a tool to boost the clinical efficacy of anticancer immunotherapy.

Oncoimmunology 2020 06 3;9(1):1774298. Epub 2020 Jun 3.

Gustave Roussy Comprehensive Cancer Institute, Villejuif, France.

Accumulating evidence demonstrates the decisive role of the gut microbiota in determining the effectiveness of anticancer therapeutics such as immunogenic chemotherapy or immune checkpoint blockade in preclinical tumor models, as well as in cancer patients. In synthesis, it appears that a normal intestinal microbiota supports therapeutic anticancer responses, while a dysbiotic microbiota that lacks immunostimulatory bacteria or contains overabundant immunosuppressive species causes treatment failure. These findings have led to the design of clinical trials that evaluate the capacity of modulation of the gut microbiota to synergize with treatment and hence limit tumor progression. Along the lines of this Trial Watch, we discuss the rationale for harnessing the gut microbiome in support of cancer therapy and the progress of recent clinical trials testing this new therapeutic paradigm in cancer patients.
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http://dx.doi.org/10.1080/2162402X.2020.1774298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7466862PMC
June 2020

ALK Inhibitors Do Not Increase Sensitivity to Radiation in EML4-ALK Non-small Cell Lung Cancer.

Anticancer Res 2020 Sep;40(9):4937-4946

Department of Dermatology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Erlangen, Germany

Background/aim: ALK inhibitors like Crizotinib, Ceritinib and Alectinib are targeted therapies used in patients with anaplastic lymphoma kinase (ALK)-positive, advanced non-small cell lung cancer (NSCLC). Since in this tumor entity radiotherapy is employed sequentially or concomitantly, potential synergistic effects were investigated, which may support the hypothesis of induced radiosensitization by using ALK inhibitors.

Materials And Methods: Two cell lines expressing wild-type (WT) or echinoderm microtubule-associated protein-like 4 (EML4)-ALK were treated with ALK inhibitors, followed by irradiation. Cell survival, cell death, cell cycle and phosphorylation of H2A histone family, member X (H2AX) were examined.

Results: Combined treatment with ALK-inhibitors plus 10 Gy-irradiation led to effects similar to those of sole radiotherapy, but was more effective than sole drug treatment.

Conclusion: There is no clear evidence of sensitization to radiation by treating EML4-ALK mutated cells with ALK inhibitors.
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http://dx.doi.org/10.21873/anticanres.14497DOI Listing
September 2020

PARP inhibitors combined with ionizing radiation induce different effects in melanoma cells and healthy fibroblasts.

BMC Cancer 2020 Aug 18;20(1):775. Epub 2020 Aug 18.

Department of Radiation Oncology, University Hospital Erlangen, Strahlenklinik, Universitätsstraße 27, 91054, Erlangen, Germany.

Background: PARP inhibitors niraparib and talazoparib are FDA approved for special cases of breast cancer. PARP is an interesting repair protein which is frequently affected in cancer cells. We studied the combined action of talazoparib or niraparib with ionizing radiation in melanoma cells and healthy fibroblasts.

Methods: Homologous recombination (HR) status in six different melanoma cell lines and healthy fibroblasts was assessed. Cell cultures were treated with PARP inhibitors talazoparib or niraparib and ionizing radiation (IR). Apoptosis, necrosis and cell cycle distribution was analyzed via flow cytometry. Cell migration was studied by scratch assays.

Results: Studied melanoma cell cultures are HR deficient. Studied healthy fibroblasts are HR proficient. Talazoparib and niraparib have congruent effects within the same cell cultures. In all cell cultures, combined treatment increases cell death and G2/M arrest compared to IR. Combined treatment in melanoma cells distinctly increases G2/M arrest. Healthy fibroblasts are less affected by G2/M arrest. Treatment predominantly decelerates or does not modify migration. In two cell cultures migration is enhanced under the inhibitors.

Conclusions: Although the two PARP inhibitors talazoparib and niraparib appear to be suitable for a combination treatment with ionizing radiation in our in vitro studies, a combination treatment cannot generally be recommended. There are clear interindividual differences in the effect of the inhibitors on different melanoma cells. Therefore, the effect on the cancer cells should be studied prior to a combination therapy. Since melanoma cells increase more strongly than fibroblasts in G2/M arrest, the fractional application of combined treatment should be further investigated.
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http://dx.doi.org/10.1186/s12885-020-07190-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7433076PMC
August 2020

Therapy preferences in melanoma treatment-Willingness to pay and preference of quality versus length of life of patients, physicians, healthy individuals and physicians with oncological disease.

Cancer Med 2020 09 10;9(17):6132-6140. Epub 2020 Jul 10.

Department of Dermatology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Erlangen, Germany.

Background: In recent years, monoclonal antibodies such as ipilimumab, nivolumab, and pembrolizumab have made a significant impact on the treatment of advanced melanoma. Combination of immune checkpoint inhibitors leads to improved survival and response rates of 58%-61% as compared to monotherapy (36%-44%). However, the price for the better response rates is also a higher frequency of severe adverse events (59%) as compared to monotherapy (17%-21%). This study examines attitudes towards melanoma therapy options of physicians, healthy individuals, melanoma patients, and physicians with oncological disease, their willingness to pay, and preference of quality versus length of life.

Methods: After obtaining ethical approval and informed consent surveys were conducted in 111 participants divided into four groups: melanoma patients (n = 30), healthy individuals as controls (n = 30), physicians (n = 27), and physicians with oncological disease (n = 24). Statistical analyses were conducted using SPSS statistics (version 25, IBM), applying the Pearson´s chi-squared test, Spearman correlation coefficient, Wilcoxon-Mann-Whitney test, and Kruskal-Wallis test.

Results: Life prolongation is more valued by melanoma patients and physicians with oncological disease compared to healthy controls and healthy physicians. In total, 30% of melanoma patients opt for a life prolonging therapy in all cases, even if this life prolongation is only marginal. Physicians are the strongest proponents of combination immunotherapy.    CONCLUSION: The valuation of the different treatment options differs in the four study groups with affected people valuing life prolongation much more. The individual value of cancer therapies is high, but differs from the societal standpoint.
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http://dx.doi.org/10.1002/cam4.3191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7476834PMC
September 2020

The Quality of Practice Guidelines for Melanoma: A Methodologic Appraisal with the AGREE II and AGREE-REX Instruments.

Cancers (Basel) 2020 Jun 18;12(6). Epub 2020 Jun 18.

Department of Dermatology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany.

Multiple guidelines on cutaneous melanoma (CM) are available from several consortia and countries. To provide up-to-date guidance in the rapidly changing field of melanoma treatment, guideline developers have to provide regular updates without compromises of quality. We performed a systematic search in guideline databases, Medline and Embase to identify guidelines on CM. The methodological quality of the identified guidelines was independently assessed by five reviewers using the instruments "Appraisal of Guidelines for Research and Evaluation" (AGREE II) and "Recommendation EXcellence" (AGREE-REX). We performed descriptive analysis, explored subgroup differences using the Kruskal-Wallis (H) test and examined the relationship between distinct domains and items of the instruments with Spearman's correlation. Six guidelines by consortia from Australia, France, Germany, Scotland, Spain and the United States of America were included. The German guideline fulfilled 71%-98% of criteria in AGREE II and 78%-96% for AGREE-REX, obtaining the highest scores. Deficiencies in the domains of "applicability" and "values and preferences" were observed in all guidelines. The German and Spanish guidelines significantly differed from each other in most of the domains. The domains "applicability" and "values and preferences" were identified as methodological weaknesses requiring careful revision and improvement in the future.
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http://dx.doi.org/10.3390/cancers12061613DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352745PMC
June 2020

Prognosis of Patients With Stage III Melanoma According to American Joint Committee on Cancer Version 8: A Reassessment on the Basis of 3 Independent Stage III Melanoma Cohorts.

J Clin Oncol 2020 08 12;38(22):2543-2551. Epub 2020 Jun 12.

Princess Máxima Center, Utrecht, the Netherlands.

Purpose: Three new therapies have been approved recently for the adjuvant treatment of stage III melanoma, substantially reducing the risk of tumor recurrences. This study evaluates 3 independent data sets to clarify the survival probabilities of patients with stage III melanoma.

Patients And Methods: The Central Malignant Melanoma Registry (CMMR) evaluated 1,553 patients with a primary diagnosis of stage III melanoma from 2000 to 2012. Studies from the European Organisation for Research and Treatment of Cancer (EORTC), of 573 patients in the observation arm of the 18991 study and 445 patients in the placebo arm of the 18071 study, were evaluated as reference cohorts. The survival outcomes were compared with the published American Joint Committee on Cancer version 8 (AJCCv8) stage III survival data.

Results: For the CMMR stage III cohort versus the AJCCv8 cohort, the melanoma-specific survival (MSS) rates at 5 years were 67% versus 77%, and at 10 years were 56% versus 69%, respectively. For stage IIIA, the MSS rates at 5 years were 80% versus 93%, and at 10 years were 71% versus 88%; for stage IIIB, the MSS rates at 5 years were 75% versus 83%, and at 10 years were 61% versus 77%. The MSS rates of the EORTC studies either overlapped with or were lower than, the CMMR data.

Conclusion: The MSS rates in the CMMR and EORTC cohorts over the entire stage III are less favorable than those published in AJCCv8. This is particularly true for substages IIIA and IIIB.
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http://dx.doi.org/10.1200/JCO.19.03034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7392743PMC
August 2020

Nebenwirkungsmanagement bei Immun-Checkpoint-Blockade durch CTLA-4- und PD-1-Antikörper beim metastasierten Melanom - ein Update.

J Dtsch Dermatol Ges 2020 Jun;18(6):582-609

Klinik für Dermatologie, Allergologie und Venerologie, Hauttumorzentrum Hannover, Medizinische Hochschule Hannover.

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http://dx.doi.org/10.1111/ddg.14128_gDOI Listing
June 2020

Author Correction: Non-professional phagocytosis: a general feature of normal tissue cells.

Sci Rep 2020 Jun 4;10(1):9345. Epub 2020 Jun 4.

Department of Radiation Oncology, University Clinic Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, 91054, Germany.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41598-020-65963-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7270104PMC
June 2020

Side effect management during immune checkpoint blockade using CTLA-4 and PD-1 antibodies for metastatic melanoma - an update.

J Dtsch Dermatol Ges 2020 Jun 3;18(6):582-609. Epub 2020 Jun 3.

Department of Dermatology, Venereology and Allergology, Skin Cancer Center, Hanover Medical School, Hanover, Germany.

CTLA-4 and PD-1 play a key role in tumor-induced downregulation of lymphocytic immune responses. Immune checkpoint inhibitors have been shown to alter the immune response to various cancer types. Anti-CTLA-4 and anti-PD-1 antibodies affect the interaction between tumor, antigen-presenting cells and T lymphocytes. Clinical studies of the anti-CTLA-4 antibody ipilimumab and the anti-PD-1 antibodies nivolumab and pembrolizumab have provided evidence of their positive effects on overall survival in melanoma patients. Combined treatment using ipilimumab and nivolumab has been shown to achieve five-year survival rates of 52 %. Such enhancement of the immune response is inevitably associated with adverse events. Knowledge of the spectrum of side effects is essential, both in terms of prevention and management. Adverse events include colitis, dermatitis, hypophysitis, thyroiditis, hepatitis and other, less common autoimmune phenomena. In recent years, considerable progress has been made in the detection and treatment of the aforementioned immune-related adverse events. However, early diagnosis of rare neurological or cardiac side effects, which may be associated with increased mortality, frequently pose a challenge. The present update highlights our current understanding as well as new insights into the spectrum of side effects associated with checkpoint inhibitors and their management.
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http://dx.doi.org/10.1111/ddg.14128DOI Listing
June 2020

Impact of a preceding radiotherapy on the outcome of immune checkpoint inhibition in metastatic melanoma: a multicenter retrospective cohort study of the DeCOG.

J Immunother Cancer 2020 05;8(1)

Department of Dermatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany

Background: Immune checkpoint inhibition (ICI) is an essential treatment option in melanoma. Its outcome may be improved by a preceding radiation of metastases. This study aimed to investigate the impact of a preceding radiotherapy on the clinical outcome of ICI treatment.

Methods: This multicenter retrospective cohort study included patients who received anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) or anti-programmed cell death protein 1 (PD-1) ICI with or without preceding radiotherapy for unresectable metastatic melanoma. ICI therapy outcome was measured as best overall response (BOR), progression-free (PFS) and overall survival (OS). Response and survival analyses were adjusted for confounders identified by directed acyclic graphs. Adjusted survival curves were calculated using inverse probability treatment weighting.

Results: 835 patients who received ICI (anti-CTLA-4, n=596; anti-PD-1, n=239) at 16 centers were analyzed, whereof 235 received a preceding radiotherapy of metastatic lesions in stage IV disease. The most frequent organ sites irradiated prior to ICI therapy were brain (51.1%), lymph nodes (17.9%) and bone (17.9%). After multivariable adjustment for confounders, no relevant differences in ICI therapy outcome were observed between cohorts with and without preceding radiotherapy. BOR was 8.7% vs 13.0% for anti-CTLA-4 (adjusted relative risk (RR)=1.47; 95% CI=0.81 to 2.65; p=0.20), and 16.5% vs 25.3% for anti-PD-1 (RR=0.93; 95% CI=0.49 to 1.77; p=0.82). Survival probabilities were similar for cohorts with and without preceding radiotherapy, for anti-CTLA-4 (PFS, adjusted HR=1.02, 95% CI=0.86 to 1.25, p=0.74; OS, HR=1.08, 95% CI=0.81 to 1.44, p=0.61) and for anti-PD-1 (PFS, HR=0.84, 95% CI=0.57 to 1.26, p=0.41; OS, HR=0.73, 95% CI=0.43 to 1.25, p=0.26). Patients who received radiation last before ICI (n=137) revealed no better survival than those who had one or more treatment lines between radiation and start of ICI (n=86). In 223 patients with brain metastases, we found no relevant survival differences on ICI with and without preceding radiotherapy.

Conclusions: This study detected no evidence for a relevant favorable impact of a preceding radiotherapy on anti-CTLA-4 or anti-PD-1 ICI treatment outcome in metastatic melanoma.
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http://dx.doi.org/10.1136/jitc-2019-000395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7228559PMC
May 2020