Publications by authors named "Frank Meiss"

74 Publications

The value of primary and adjuvant radiotherapy for cutaneous squamous cell carcinomas of the head-and-neck region in the elderly.

Radiat Oncol 2021 Jun 12;16(1):105. Epub 2021 Jun 12.

Department of Radiation Oncology, University of Freiburg - Medical Center, Robert-Koch-Str. 3, 79106, Freiburg, Germany.

Purpose: To examine treatment patterns, oncological outcomes and toxicity rates in elderly patients receiving radiotherapy for cutaneous squamous cell carcinoma (cSCC) of the head-and-neck region.

Material And Methods: In this retrospective single-center analysis, locoregional control (LRC), progression-free survival (PFS) and overall survival (OS) of elderly patients > 65 years with cSCC of the head-and-neck region undergoing radiotherapy between 2010 and 2019 were calculated. The prognostic value of clinicopathological parameters on radiotherapy outcomes was analyzed using the Cox proportional hazards model. In addition, both acute and chronic toxicities were retrospectively quantified according to CTCAE version 5.0.

Results: A total of 69 elderly patients with cSCC of the head-and-neck region with a median age of 85 years were included in this analysis, of whom 21.7% (15 patients) presented with nodal disease. The majority of patients exhibited a good performance status, indicated by a median Karnofsky performance status (KPS) and Charlson Comorbidity Index (CCI) of 80% and 6 points, respectively. Radiotherapy was administered as primary (48%), adjuvant (32%) or palliative therapy (20%). 55 patients (79.7%) completed treatment and received the scheduled radiotherapy dose. Median EQD2 radiation doses were 58.4 Gy, 60 Gy and 51.3 Gy in the definitive, adjuvant and palliative situation, respectively. 2-year LRC, PFS and OS ranged at 54.2%, 33.5 and 40.7%, respectively. Survival differed significantly between age groups with a median OS of 20 vs. 12 months (p < 0.05) for patients aged 65-80 or above 80 years. In the multivariate analysis, positive lymph node status remained the only significant prognostic factor deteriorating OS (HR 3.73, CI 1.54-9.03, p < 0.01). Interestingly, neither KPS nor CCI impaired survival in this elderly patient cohort. Only 3 patients (4.3%) experienced acute CTCAE grade 3 toxicities, and no chronic CTCAE grade 2-5 toxicities were observed in our cohort.

Conclusion: Radiotherapy was feasible and well-tolerated in this distinct population, showing the general feasibility of radiotherapy for cSCC of the head-and-neck region also in the older and oldest olds. The very mild toxicities may allow for moderate dose escalation to improve LRC.
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http://dx.doi.org/10.1186/s13014-021-01832-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8199417PMC
June 2021

Clinical characteristics and therapy response in unresectable melanoma patients stage IIIB-IIID with in-transit and satellite metastases.

Eur J Cancer 2021 Jun 5;152:139-154. Epub 2021 Jun 5.

Dept. of Dermatology, University Hospital Essen, University of Duisburg-Essen, Hufelandstr. 55, 45122, Essen, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany.

Introduction: Cutaneous melanoma is notorious for the development of in-transit metastases (ITM). For unknown biological reasons, ITM remain the leading tumour manifestation without progression to distant sites in some patients.

Methods: In total, 191 patients with initially unresectable stage III ITM and satellite metastases from 16 skin cancer centres were retrospectively evaluated for their tumour characteristics, survival and therapy response. Three groups according to disease kinetics (no distant progress, slow (>6 months) and fast (<6 months) distant progression) were analysed separately.

Results: Median follow-up time was 30.5 (range 0.8-154.0) months from unresectable ITM. Progression to stage IV was observed in 56.5% of cases. Patients without distant metastasis were more often female, older (>70 years) and presented as stage III with lymph node or ITM at initial diagnosis in 45.7% of cases. Melanoma located on the leg had a significantly better overall survival (OS) from time of initial diagnosis compared to non-leg localised primaries (hazard ratio [HR] = 0.61, 95% confidence interval [CI] 0.40-0.91; p = 0.017), but not from diagnosis of unresectable stage III (HR = 0.67, 95% CI 0.45-1.02; p = 0.06). Forty percent of patients received local therapy for satellite and ITM. Overall response rate (ORR) to all local first-line treatments was 38%; disease control rate (DCR) was 49%. In total, 72.3% of patients received systemic therapy for unresectable stage IIIB-D. ORR for targeted therapy (n = 19) was highest with 63.2% and DCR was 84.2% compared to an ORR of 31.4% and a DCR of 54.3% in PD-1 treated patients (n = 70). Patients receiving PD-1 and intralesional talimogene laherparepvec (n = 12) had an ORR of 41.7% and a DCR of 75%.

Conclusion: Patients with unresectable ITM and without distant progression are more often female, older, and have a primary on the leg. Response to PD-1 inhibitors in this cohort was lower than expected, but further investigation is required to elucidate the biology of ITM development and the interplay with the immune system.
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http://dx.doi.org/10.1016/j.ejca.2021.04.032DOI Listing
June 2021

Long-term real-world experience with ipilimumab and non-ipilimumab therapies in advanced melanoma: the IMAGE study.

BMC Cancer 2021 May 29;21(1):642. Epub 2021 May 29.

Churchill Hospital, Oxford, OX3 7DQ, UK.

Background: Ipilimumab has shown long-term overall survival (OS) in patients with advanced melanoma in clinical trials, but robust real-world evidence is lacking. We present long-term outcomes from the IMAGE study (NCT01511913) in patients receiving ipilimumab and/or non-ipilimumab (any approved treatment other than ipilimumab) systemic therapies.

Methods: IMAGE was a multinational, prospective, observational study assessing adult patients with advanced melanoma treated with ipilimumab or non-ipilimumab systemic therapies between June 2012 and March 2015 with ≥3 years of follow-up. Adjusted OS curves based on multivariate Cox regression models included covariate effects. Safety and patient-reported outcomes were assessed.

Results: Among 1356 patients, 1094 (81%) received ipilimumab and 262 (19%) received non-ipilimumab index therapy (systemic therapy [chemotherapy, anti-programmed death 1 antibodies, or BRAF ± MEK inhibitors], radiotherapy, and radiosurgery). In the overall population, median age was 64 years, 60% were male, 78% were from Europe, and 78% had received previous treatment for advanced melanoma. In the ipilimumab-treated cohort, 780 (71%) patients did not receive subsequent therapy (IPI-noOther) and 314 (29%) received subsequent non-ipilimumab therapy (IPI-Other) on study. In the non-ipilimumab-treated cohort, 205 (78%) patients remained on or received other subsequent non-ipilimumab therapy (Other-Other) and 57 (22%) received subsequent ipilimumab therapy (Other-IPI) on study. Among 1151 patients who received ipilimumab at any time during the study (IPI-noOther, IPI-Other, and Other-IPI), 296 (26%) reported CTCAE grade ≥ 3 treatment-related adverse events, most occurring in year 1. Ipilimumab-treated and non-ipilimumab-treated patients who switched therapy (IPI-Other and Other-IPI) had longer OS than those who did not switch (IPI-noOther and Other-Other). Patients with prior therapy who did not switch therapy (IPI-noOther and Other-Other) showed similar OS. In treatment-naive patients, those in the IPI-noOther group tended to have longer OS than those in the Other-Other group. Patient-reported outcomes were similar between treatment cohorts.

Conclusions: With long-term follow-up (≥ 3 years), safety and OS in this real-world population of patients treated with ipilimumab 3 mg/kg were consistent with those reported in clinical trials. Patient-reported quality of life was maintained over the study period. OS analysis across both pretreated and treatment-naive patients suggested a beneficial role of ipilimumab early in treatment.

Trial Registration: ClinicalTrials.gov , NCT01511913. Registered January 19, 2012 - Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT01511913.
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http://dx.doi.org/10.1186/s12885-021-08032-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8164785PMC
May 2021

Case Report: Blurred Vision and Eruptive Nevi - Bilateral Diffuse Uveal Melanocytic Proliferation With Mucocutaneous Involvement in a Lung Cancer Patient.

Front Oncol 2021 13;11:658407. Epub 2021 Apr 13.

Eye Center, University Hospital Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

We describe a case of a 65-year old patient presenting with unusual mucocutaneous melanocytic proliferations of a Bilateral Diffuse Uveal Melanocytic Proliferation (BDUMP) imitating a multifocal melanoma in situ, which improved dramatically after plasmapheresis. The patient first presented at the dermatology department due to rapidly evolving brown and black macules on the glans penis. Further skin involvement of the perineal and perianal region, mamillae and oral mucosa was stated. Histology from a penile biopsy was compatible with a melanoma in situ. Due to the distribution pattern and elevated serum tumor marker S100B, metastatic melanoma was considered. Staging examinations using PET-CT scan however, revealed a lung tumor, later confirmed as a Non-small-cell lung cancer (NSCLC). Primary radio chemotherapy was initiated to treat NSCLC. Shortly after initiation of radio chemotherapy the patient developed massive vision impairment and a NSCLC-associated BDUMP was diagnosed which led to the correct classification of melanocytic skin lesions as mucocutaneous BDUMP manifestation. Plasmapheresis was started resulting in a rapid improvement of vision starting ten days after the first plasmapheresis. In contrast skin manifestations started to disappear with a marked delay 4 months after the last plasmapheresis cycle. This case highlights the importance of memorizing multiple rapidly progressing melanocytic skin and/or mucous membrane spots together with visual impairment as a possible paraneoplastic BDUMP that needs a fundamentally different therapeutic approach compared to multifocal melanoma in situ. What is already known about this topic? Bilateral Diffuse Uveal Melanocytic Proliferation (BDUMP) is a paraneoplastic syndrome with melanocytic uveal proliferation leading to vision impairment. Extraocular manifestation is rare, mainly affect the subepidermal compartment and is hard to treat. Plasmapheresis has been shown to be an effective treatment mainly for vision improvement in some but not all cases. What does this study add? Our BDUMP case with widespread skin and mucosal involvement initially mimicked a multifocal melanoma and showed an excellent treatment response to plasmapheresis. Improvement of mucocutaneous lesions has not been documented well in the literature so far. We show a more than one year lasting follow up still underlining the beneficial effect of plasmapheresis in this case. In-vitro data supports the hypothesis that plasma exchange eliminates a "Cultured melanocyte elongation and proliferation (CMEP)" factor out of patient blood leading to decreased melanocyte proliferation shown numerically in-vitro and clinically in-vivo. Our case clearly indicates that before establishing a definite diagnosis and therapy in patients with rapidly evolving melanocytic skin and/or mucosal lesions BDUMP mimicking multifocal melanoma should be considered making a thorough diagnostic workup mandatory.
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http://dx.doi.org/10.3389/fonc.2021.658407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8076566PMC
April 2021

Transitioning the Molecular Tumor Board from Proof of Concept to Clinical Routine: A German Single-Center Analysis.

Cancers (Basel) 2021 Mar 8;13(5). Epub 2021 Mar 8.

Comprehensive Cancer Center Freiburg, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.

Molecular precision oncology faces two major challenges: first, to identify relevant and actionable molecular variants in a rapidly changing field and second, to provide access to a broad patient population. Here, we report a four-year experience of the Molecular Tumor Board (MTB) of the Comprehensive Cancer Center Freiburg (Germany) including workflows and process optimizations. This retrospective single-center study includes data on 488 patients enrolled in the MTB from February 2015 through December 2018. Recommendations include individual molecular diagnostics, molecular stratified therapies, assessment of treatment adherence and patient outcomes including overall survival. The majority of MTB patients presented with stage IV oncologic malignancies (90.6%) and underwent an average of 2.1 previous lines of therapy. Individual diagnostic recommendations were given to 487 patients (99.8%). A treatment recommendation was given in 264 of all cases (54.1%) which included a molecularly matched treatment in 212 patients (43.4%). The 264 treatment recommendations were implemented in 76 patients (28.8%). Stable disease was observed in 19 patients (25.0%), 17 had partial response (22.4%) and five showed a complete remission (6.6%). An objective response was achieved in 28.9% of cases with implemented recommendations and for 4.5% of the total population (22 of 488 patients). By optimizing the MTB workflow, case-discussions per session increased significantly while treatment adherence and outcome remained stable over time. Our data demonstrate the feasibility and effectiveness of molecular-guided personalized therapy for cancer patients in a clinical routine setting showing a low but robust and durable disease control rate over time.
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http://dx.doi.org/10.3390/cancers13051151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962829PMC
March 2021

IL17 inhibition for psoriasis vulgaris and arthritis results in clinical and serological remission of coexistent pemphigus foliaceus.

J Dermatol 2021 Jun 13;48(6):e246-e247. Epub 2021 Feb 13.

Department of Dermatology, Medical Center- University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

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http://dx.doi.org/10.1111/1346-8138.15801DOI Listing
June 2021

[Acral ulcers in a man with chronic lymphocytic leukemia].

Hautarzt 2021 Jun;72(6):557-560

Klinik für Dermatologie und Venerologie, Universitätsklinikum Freiburg, Medizinische Fakultät, Albert-Ludwigs-Universität Freiburg, Hauptstr. 7, 79104, Freiburg, Deutschland.

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http://dx.doi.org/10.1007/s00105-020-04725-wDOI Listing
June 2021

Personalized Treatment Selection and Disease Monitoring Using Circulating Tumor DNA Profiling in Real-World Cancer Patient Management.

Diagnostics (Basel) 2020 Aug 2;10(8). Epub 2020 Aug 2.

Department Medicine I, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.

Background: Circulating tumor DNA (ctDNA) in the blood plasma of cancer patients is an emerging biomarker used across oncology, facilitating noninvasive disease monitoring and genetic profiling at various disease milestones. Digital droplet PCR (ddPCR) technologies have demonstrated high sensitivity and specificity for robust ctDNA detection at relatively low costs. Yet, their value for ctDNA-based management of a broad population of cancer patients beyond clinical trials remains elusive.

Methods: We developed mutation-specific ddPCR assays that were optimized for their use in real-world cancer management, covering 12 genetic aberrations in common cancer genes, such as , , , , and . We assessed the limit of detection (LOD) and the limit of blank (LOB) for each assay and validated their performance for ctDNA detection using matched tumor sequencing.

Results: We applied our custom ddPCR assays to 352 plasma samples from 96 patients with solid tumors. Mutation detection in plasma was highly concordant with tumor sequencing, demonstrating high sensitivity and specificity across all assays. In 20 cases, radiographic cancer progression was mirrored by an increase of ctDNA concentrations or the occurrence of novel mutations in plasma. Moreover, ctDNA profiling at diagnosis and during disease progression reflected personalized treatment selection through the identification of actionable gene targets in 20 cases.

Conclusion: Collectively, our work highlights the potential of ctDNA assessment by sensitive ddPCR for accurate disease monitoring, robust identification of resistance mutations, and upfront treatment selection in patients with solid tumors. We envision an increasing future role for ctDNA profiling within personalized cancer management in daily clinical routine.
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http://dx.doi.org/10.3390/diagnostics10080550DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7459590PMC
August 2020

Vasoactive Intestinal Peptide in Checkpoint Inhibitor-Induced Pneumonitis.

N Engl J Med 2020 06;382(26):2573-2574

University Medical Center Freiburg, Freiburg, Germany

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http://dx.doi.org/10.1056/NEJMc2000343DOI Listing
June 2020

Deep abscopal response to radiotherapy and anti-PD-1 in an oligometastatic melanoma patient with unfavorable pretreatment immune signature.

Cancer Immunol Immunother 2020 Sep 29;69(9):1823-1832. Epub 2020 Apr 29.

Department of Radiation Oncology, Faculty of Medicine, University of Freiburg, Robert-Koch-Strasse 3, 79106, Freiburg, Germany.

Radiotherapy can elicit abscopal effects in non-irradiated metastases, particularly under immune checkpoint blockade (ICB). We report on two elderly patients with oligometastatic melanoma treated with anti-PD-1 and stereotactic body radiation therapy (SBRT). Before treatment, patient 1 showed strong tumor infiltration with exhausted CD8+ T cells and high expression of T cell-attracting chemokines. This patient rapidly mounted a complete response, now ongoing for more than 4.5 years. Patient 2 exhibited low CD8+ T cell infiltration and high expression of immunosuppressive arginase. After the first SBRT, his non-irradiated metastases did not regress and new metastases occurred although neoepitope-specific and differentiation antigen-specific CD8+ T cells were detected in the blood. A second SBRT after 10 months on anti-PD-1 induced a radiologic complete response correlating with an increase in activated PD-1-expressing CD8 T cells. Apart from a new lung lesion, which was also irradiated, this deep abscopal response lasted for more than 2.5 years. However, thereafter, his disease progressed and the activated PD-1-expressing CD8 T cells dropped. Our data suggest that oligometastatic patients, where a large proportion of the tumor mass can be irradiated, are good candidates to improve ICB responses by RT, even in the case of an unfavorable pretreatment immune signature, after progression on anti-PD-1, and despite advanced age. Besides repeated irradiation, T cell epitope-based immunotherapies (e.g., vaccination) may prolong antitumor responses even in patients with unfavorable pretreatment immune signature.
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http://dx.doi.org/10.1007/s00262-020-02587-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7413872PMC
September 2020

Combined immunotherapy with nivolumab and ipilimumab with and without local therapy in patients with melanoma brain metastasis: a DeCOG* study in 380 patients.

J Immunother Cancer 2020 03;8(1)

Center for Dermatooncology, Department of Dermatology, Eberhard Karls University of Tuebingen, Eberhard Karls University of Tuebingen, Tubingen, Germany.

Background: Nivolumab combined with ipilimumab have shown activity in melanoma brain metastasis (MBM). However, in most of the clinical trials investigating immunotherapy in this subgroup, patients with symptomatic MBM and/or prior local brain radiotherapy were excluded. We studied the efficacy of nivolumab plus ipilimumab alone or in combination with local therapies regardless of treatment line in patients with asymptomatic and symptomatic MBM.

Methods: Patients with MBM treated with nivolumab plus ipilimumab in 23 German Skin Cancer Centers between April 2015 and October 2018 were investigated. Overall survival (OS) was evaluated by Kaplan-Meier estimator and univariate and multivariate Cox proportional hazard analyses were performed to determine prognostic factors associated with OS.

Results: Three hundred and eighty patients were included in this study and 31% had symptomatic MBM (60/193 with data available) at the time of start nivolumab plus ipilimumab. The median follow-up was 18 months and the 2 years and 3 years OS rates were 41% and 30%, respectively. We identified the following independently significant prognostic factors for OS: elevated serum lactate dehydrogenase and protein S100B levels, number of MBM and Eastern Cooperative Oncology Group performance status. In these patients treated with checkpoint inhibition first-line or later, in the subgroup of patients with BRAFV600-mutated melanoma we found no differences in terms of OS when receiving first-line either BRAF and MEK inhibitors or nivolumab plus ipilimumab (p=0.085). In BRAF wild-type patients treated with nivolumab plus ipilimumab in first-line or later there was also no difference in OS (p=0.996). Local therapy with stereotactic radiosurgery or surgery led to an improvement in OS compared with not receiving local therapy (p=0.009), regardless of the timepoint of the local therapy. Receiving combined immunotherapy for MBM in first-line or at a later time point made no difference in terms of OS in this study population (p=0.119).

Conclusion: Immunotherapy with nivolumab plus ipilimumab, particularly in combination with stereotactic radiosurgery or surgery improves OS in asymptomatic and symptomatic MBM.
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http://dx.doi.org/10.1136/jitc-2019-000333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7206917PMC
March 2020

MicroRNA-146a regulates immune-related adverse events caused by immune checkpoint inhibitors.

JCI Insight 2020 03 26;5(6). Epub 2020 Mar 26.

Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, Albert Ludwigs University (ALU), Freiburg, Germany.

Immune checkpoint inhibitor (ICI) therapy has shown a significant benefit in the treatment of a variety of cancer entities. However, immune-related adverse events (irAEs) occur frequently and can lead to ICI treatment termination. MicroRNA-146a (miR-146a) has regulatory functions in immune cells. We observed that mice lacking miR-146a developed markedly more severe irAEs compared with WT mice in several irAE target organs in 2 different murine models. miR-146a-/- mice exhibited increased T cell activation and effector function upon ICI treatment. Moreover, neutrophil numbers in the spleen and the inflamed intestine were highly increased in ICI-treated miR-146a-/- mice. Therapeutic administration of a miR-146a mimic reduced irAE severity. To validate our preclinical findings in patients, we analyzed the effect of a SNP in the MIR146A gene on irAE severity in 167 patients treated with ICIs. We found that the SNP rs2910164 leading to reduced miR-146a expression was associated with an increased risk of developing severe irAEs, reduced progression-free survival, and increased neutrophil counts both at baseline and during ICI therapy. In conclusion, we characterized miR-146a as a molecular target for preventing ICI-mediated autoimmune dysregulation. Furthermore, we identified the MIR146A SNP rs2910164 as a biomarker to predict severe irAE development in ICI-treated patients.
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http://dx.doi.org/10.1172/jci.insight.132334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7213806PMC
March 2020

Extracorporeal Photopheresis for Colitis Induced by Checkpoint-Inhibitor Therapy.

N Engl J Med 2020 01;382(3):294-296

University Medical Center Freiburg, Freiburg, Germany

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http://dx.doi.org/10.1056/NEJMc1912274DOI Listing
January 2020

EGFR inhibition for metastasized cutaneous squamous cell carcinoma in dystrophic epidermolysis bullosa.

Orphanet J Rare Dis 2019 12 3;14(1):278. Epub 2019 Dec 3.

Department of Dermatology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Hauptstrasse 7, 79104, Freiburg, Germany.

Dystrophic epidermolysis bullosa (DEB) is a hereditary skin fragility disorder, characterized by trauma-induced blistering followed by soft tissue fibrosis. One of the most feared complications is the early development of aggressive cutaneous squamous cell carcinomas (SCC). For patients with locally advanced or metastasized SCCs treatment with cetuximab, a monoclonal antibody against epidermal growth factor receptor (EGFR), has been proposed and so far, treatment of five DEB patients with cetuximab has been published. With this report, we extend the spectrum of EB patients treated with cetuximab by adding two additional patients. Taking together all DEB cases treated with cetuximab, we propose that cetuximab should be administered as early as possible, since it seems to be more efficient and is accompanied by rather mild adverse effects. We also show that EGFR is frequently expressed in DEB-associated SCCs, although there were noticeable differences in the level of expression, which may influence responsiveness to EGFR-targeting therapies. Although only limited experiences with targeted cancer treatments in EB exist, such reports highlight the treatments' effects in this specific cohort and assist our therapeutic decisions.
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http://dx.doi.org/10.1186/s13023-019-1262-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6889571PMC
December 2019

Targeted Therapy in Advanced Melanoma With Rare Mutations.

J Clin Oncol 2019 11 3;37(33):3142-3151. Epub 2019 Oct 3.

Heidelberg University Hospital, Heidelberg, Germany.

Purpose: BRAF/MEK inhibition is a standard of care for patients with V600E/K-mutated metastatic melanoma. For patients with less frequent mutations, however, efficacy data are limited.

Methods: In the current study, 103 patients with metastatic melanoma with rare, activating non-V600E/K mutations that were treated with either a BRAF inhibitor (BRAFi), MEK inhibitor (MEKi), or the combination were included. mutation, patient and disease characteristics, response, and survival data were analyzed.

Results: Fifty-eight patient tumors (56%) harbored a non-E/K V600 mutation, 38 (37%) a non-V600 mutation, and seven had both V600E and a rare mutation (7%). The most frequent mutations were V600R (43%; 44 of 103), L597P/Q/R/S (15%; 15 of 103), and K601E (11%; 11 of 103). Most patients had stage IV disease and 42% had elevated lactate dehydrogenase at BRAFi/MEKi initiation. Most patients received combined BRAFi/MEKi (58%) or BRAFi monotherapy (37%). Of the 58 patients with V600 mutations, overall response rate to BRAFi monotherapy and combination BRAFi/MEKi was 27% (six of 22) and 56% (20 of 36), respectively, whereas median progression-free survival (PFS) was 3.7 months and 8.0 months, respectively ( = .002). Of the 38 patients with non-V600 mutations, overall response rate was 0% (zero of 15) to BRAFi, 40% (two of five) to MEKi, and 28% (five of 18) to combination treatment, with a median PFS of 1.8 months versus 3.7 months versus 3.3 months, respectively. Multivariable analyses revealed superior survival (PFS and overall survival) with combination over monotherapy in rare V600 and non-V600 mutated melanoma.

Conclusion: Patients with rare mutations can respond to targeted therapy, however, efficacy seems to be lower compared with V600E mutated melanoma. Combination BRAFi/MEKi seems to be the best regimen for both V600 and non-V600 mutations. Yet interpretation should be done with care because of the heterogeneity of patients with small sample sizes for some of the reported mutations.
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http://dx.doi.org/10.1200/JCO.19.00489DOI Listing
November 2019

Successful combination therapy of systemic checkpoint inhibitors and intralesional interleukin-2 in patients with metastatic melanoma with primary therapeutic resistance to checkpoint inhibitors alone.

Cancer Immunol Immunother 2019 Sep 17;68(9):1417-1428. Epub 2019 Aug 17.

Department of Dermatology and Venereology, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, Hauptstrasse 7, 79104, Freiburg, Germany.

Systemic immunotherapy with PD-1 inhibitors is established in the treatment of metastatic melanoma. However, up to 60% of patients do not show long-term benefit from a PD-1 inhibitor monotherapy. Intralesional treatments with immunomodulatory agents such as the oncolytic herpes virus Talimogene Laherparepvec and interleukin-2 (IL-2) have been successfully used in patients with injectable metastases. Combination therapy of systemic and local immunotherapies is a promising treatment option in melanoma patients. We describe a case series of nine patients with metastatic melanoma and injectable lesions who developed progressive disease under a PD-1 inhibitor monotherapy. At the time of progressive disease, patients received intratumoral IL-2 treatment in addition to PD-1 inhibitor therapy. Three patients showed complete, three patients partial response and three patients progressive disease upon this combination therapy. IHC stainings were performed from metastases available at baseline (start of PD-1 inhibitor) and under combination therapy with IL-2. IHC results revealed a significant increase of CD4 and CD8 T cells and a higher PD-1 expression in the inflammatory infiltrate of the tumor microenvironment in metastases from patients with subsequent treatment response. All responding patients further showed a profound increase of the absolute eosinophil count (AEC) in the blood. Our case series supports the concept that patients with initial resistance to PD-1 inhibitor therapy and injectable lesions can profit from an additional intralesional IL-2 therapy which was well tolerated. Response to this therapy is accompanied by increase in AEC and a strong T cell-based inflammatory infiltrate.
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http://dx.doi.org/10.1007/s00262-019-02377-xDOI Listing
September 2019

Primary cutaneous diffuse large B-cell lymphoma, NOS and leg type: Clinical, morphologic and prognostic differences.

J Dtsch Dermatol Ges 2019 Mar 9;17(3):275-285. Epub 2019 Mar 9.

Kempf and Pfaltz, Histologische Diagnostik, Zurich, Switzerland.

Background And Objectives: Primary cutaneous diffuse large B-cell lymphoma, NOS (PCLBCL/NOS) is a rare PCLBCL. Only few data are available for this tumor. The aim of this study was to identify clinical and/or immunohistochemical markers (in addition to Bcl-2) that characterize PCLBCL/NOS, assist in differentiating it from PCLBCL, leg type (PCLBCL/LT) and help to assess the clinical course/prognosis.

Patients And Methods: Bcl-2 PCLBCL/NOS) cases (n = 14 were compared with Bcl-2 PCLBCL/LT cases (n = 29).

Results: PCLBCL/NOS patients were younger, predominantly male and had better survival rates than patients with PCLBCL/LT. Patients with PCLBCL/NOS presented more often with larger plaques limited to one or two contiguous body regions, whereas PCLBCL/LT cases often presented with disseminated lesions. Neoplastic cells had a higher proliferation rate (Ki67) in PCLBCL/LT patients. The tumor microenvironment of PCLBCL/NOS had a more prominent CD3 infiltrate. Overall survival data for the whole cohort (n = 37) revealed that female gender and Bcl-2 expression correlated with a worse survival rate. Bcl-6 expression and centroblastic subtype correlated with better outcomes. None of the other markers studied (e.g. GCB/non-GCB subtype) correlated with survival rate.

Conclusions: PCLBCL/NOS and PCLBCL/LT differ in their clinical behavior and outcomes. Bcl-2 still seems to be the best marker for discriminating between these two subgroups. Bcl-2, female gender and Bcl-6 represent prognostic markers for PCLBCL.
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http://dx.doi.org/10.1111/ddg.13773DOI Listing
March 2019

Impact of radiation, systemic therapy and treatment sequencing on survival of patients with melanoma brain metastases.

Eur J Cancer 2019 03 7;110:11-20. Epub 2019 Feb 7.

Skin Cancer Center at the University Cancer Centre, Department of Dermatology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany; National Center for Tumor Diseases (NCT), Dresden, and German Cancer Research Center (DKFZ), Heidelberg, Germany; German Cancer Consortium (DKTK), Partner Site Dresden, and German Cancer Research Center (DKFZ), Heidelberg, Germany. Electronic address:

Background: Combining stereotactic radiosurgery (SRS) and active systemic therapies (STs) achieved favourable survival outcomes in patients with melanoma brain metastases (MBMs) in retrospective analyses. However, several aspects of this treatment strategy remain poorly understood. We report on the overall survival (OS) of patients with MBM treated with a combination of radiotherapy (RT) and ST as well as the impact of the v-Raf murine sarcoma viral oncogene homolog B (BRAF)-V600 mutation (BRAFmut) status, types of RT and ST and their sequence.

Patients And Methods: Data of 208 patients treated with SRS or whole brain radiation therapy (WBRT) and either immunotherapy (IT) or targeted therapy (TT) within a 6-week interval to RT were analysed retrospectively. OS was calculated from RT to death or last follow-up. Univariate and multivariate Cox proportional hazard analyses were performed to determine prognostic features associated with OS.

Results: The median follow-up was 7.3 months. 139 patients received IT, 67 received TT and 2 received IT and TT within 6 weeks to RT (WBRT 45%; SRS 55%). One-year Kaplan-Meier OS rates were 69%, 65%, 33% and 18% (P < .001) for SRS with IT, SRS with TT, WBRT with IT and WBRT with TT, respectively. Patients with a BRAFmut receiving IT combined with RT experienced higher OS rates (88%, 65%, 50% and 18%). TT following RT or started before and continued thereafter was associated with improved median OS compared with TT solely before RT (12.2 [95% confidence interval {CI} 9.3-15.1]; 9.8 [95% CI 6.9-12.6] versus 5.1 [95% CI 2.7-7.5]; P = .03).

Conclusion: SRS and IT achieved the highest OS rates. A BRAFmut appears to be a favourable prognostic factor for OS. For the combination of RT and TT, the sequence appears to be crucial. Combinations of WBRT and ST achieved unprecedentedly high OS rates and warrant further studies.
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http://dx.doi.org/10.1016/j.ejca.2018.12.023DOI Listing
March 2019

[Psycho-oncology in dermatological practice : Evaluation of need and care structures].

Hautarzt 2019 Apr;70(4):283-289

Hautklinik, Klinikum Dortmund gGmbH, Beurhausstr. 40, 44137, Dortmund, Deutschland.

Background: Psycho-oncological care is a main component of comprehensive oncological care as stated in the National Cancer Plan of the German Federal Government. Correspondingly this goal has been adopted in the strategy of the German Skin Cancer Council. In certified skin cancer centers structural requirements for psycho-oncological care are established. Nevertheless, a large proportion of skin cancer patients are treated in dermatological practices. Up to now data on psycho-oncological care in dermatological practices are missing.

Materials Und Methods: We conducted a descriptive cross-sectional written survey on psycho-oncological care in dermatological practices from October 2016 to February 2017.

Results: In all, 171 practices completed the questionnaire; 19.4% of these practices have an oncological focus. The mean number of treated skin cancer patients was 554.3 ± 659.1 and 62.4 ± 73.6 for melanoma patients. Dermatologists estimated a low proportion (≤5%) of patients with need for psycho-oncological care; however, 21.9% of practices actively offer information on psycho-oncological programs and 26.1% cooperate with psycho-oncological care providers. Interest in psycho-oncological care concepts was stated by 29.3%.

Conclusions: Psycho-oncological care is only occasionally and partly deficiently provided in dermatological practices including referral to psycho-oncological care professionals. The results emphasize the necessity to raise awareness regarding psycho-oncological needs of skin cancer patients and to integrate psycho-oncological counselling into clinical routine in dermatological practices.
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http://dx.doi.org/10.1007/s00105-018-4350-zDOI Listing
April 2019

Sequenzielles Auftreten einer primären und sekundären Hypothyreose unter Therapie mit Nivolumab: Fallstricke in der immunonkologischen Therapie und endokrinologischen Diagnostik.

J Dtsch Dermatol Ges 2018 Dec;16(12):1483-1485

Klinik für Dermatologie und Venerologie, Universitätsklinikum Freiburg und Medizinische Fakultät, Universität Freiburg.

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http://dx.doi.org/10.1111/ddg.13684_gDOI Listing
December 2018

miR-146a Controls Immune Response in the Melanoma Microenvironment.

Cancer Res 2019 01 13;79(1):183-195. Epub 2018 Nov 13.

Department of Hematology, Oncology and Stem Cell Transplantation, Freiburg University Medical Center, Albert-Ludwigs-University Freiburg, Freiburg, Germany.

MicroRNAs (miR) are small noncoding RNAs that regulate gene expression, posttranscription, and manipulate immune responses in different types of cancers. In this study, we identify miR-146a as a negative regulator of immune activation, comparable to immune-checkpoint molecules. miR-146a levels were increased in melanoma microenvironmental tissue, and mice survived longer and developed less metastases in comparison with wild-type melanoma-bearing mice. T cells isolated from mice revealed higher expression levels of the miR-146a target gene Stat1 and the Stat1-regulated cytokine IFNγ. Neutralization of IFNγ in mice decreased survival and increased melanoma metastasis patterns to those of wild-type mice. , IFNγ reduced melanoma cell migration, cell-cycle activity, and basal metabolic rate. Conversely, IFNγ also increased PD-L1 levels on the melanoma cells, which may counterbalance some of the beneficial effects increasing immune escape . Combined treatment with a miR-146a antagomiR and anti-PD-1 resulted in improved survival over isotype control or anti-PD-1 treatment alone. In summary, these data show that miR-146a plays a central role within the STAT1/IFNγ axis in the melanoma microenvironment, affecting melanoma migration, proliferation, and mitochondrial fitness as well as PD-L1 levels. Additionally, combined inhibition of PD-1 and miR-146a could be a novel strategy to enhance antitumor immune response elicited by checkpoint therapy. SIGNIFICANCE: These findings identify a microRNA-based mechanism by which melanoma cells escape the immune system, providing a new therapeutic strategy to improve the current management of patients with melanoma.
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http://dx.doi.org/10.1158/0008-5472.CAN-18-1397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6330089PMC
January 2019

Sequential occurrence of primary and secondary hypothyroidism during treatment with nivolumab: pitfalls in immuno-oncological therapy and endocrinological diagnostic procedures.

J Dtsch Dermatol Ges 2018 Dec 9;16(12):1483-1485. Epub 2018 Nov 9.

Department of Dermatology and Venereology, Medical Center - University of Freiburg and Medical Faculty, University of Freiburg, Freiburg, Germany.

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http://dx.doi.org/10.1111/ddg.13684DOI Listing
December 2018

Eosinophilic dermatosis of hematologic malignancy: Correlation of molecular characteristics of skin lesions and extracutaneous manifestations of hematologic malignancy.

J Cutan Pathol 2019 Mar 17;46(3):175-181. Epub 2018 Dec 17.

Institute for Surgical Pathology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Background: Skin diseases are frequent in patients with chronic lymphocytic leukemia (CLL) and other hematological neoplasias. Eosinophilic dermatosis (ED) of hematologic malignancy has long been considered a nonspecific cutaneous reaction pattern. Recently neoplastic cells have been shown to be present in ED, thus challenging the classification as a nonspecific dermatosis.

Methods: We report five patients with ED in association with CLL. We further investigated the presence of neoplastic B-cells in the skin infiltrate by immunohistochemistry and immunoglobulin heavy chain rearrangement and compared these to extracutaneous manifestations of CLL.

Results: The phenotype of the lymphocytic infiltrate was predominately CD3+ (range: 60%-90%). CD20+ and CD79a+ lymphocytes were less frequent, accounting for up to 15% (range: absent - 15%). CD23+ lymphocytes represented up to 20% (range: absent - 20%) of the infiltrate. The analysis of the immunoglobulin heavy chain rearrangement in the skin specimens showed clonal rearrangements in 4/5 patients and in three of these four patients clones were identical to extracutaneous CLL manifestations.

Conclusion: Our data show that neoplastic B-cells are very frequently found in ED when systematically evaluated. This findings support the hypothesis that leukemic cells play a pathogenetic role in ED of hematologic malignancy.
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http://dx.doi.org/10.1111/cup.13389DOI Listing
March 2019

The efficacy of re-challenge with BRAF inhibitors after previous progression to BRAF inhibitors in melanoma: A retrospective multicenter study.

Oncotarget 2018 Sep 28;9(76):34336-34346. Epub 2018 Sep 28.

Department of Dermatology and Allergy, University Hospital Munich (LMU), 80337 Munich, Germany.

BRAF and MEK inhibition is efficient in patients with BRAF V600-mutated metastatic melanoma, but due to acquired resistance the duration of response (DoR) is often only short-lived. In this retrospective multicenter study with 60 patients suffering from inoperable or metastatic melanoma we evaluated the efficacy of re-challenge with a BRAF inhibitor (BRAF2) with or without MEK-inhibition after progressive disease upon previous treatment with a BRAF inhibitor (BRAF1) with or without MEK inhibition. Treatment with BRAF1 led to a disease control rate (DCR) of 90% with 12% complete responses (CR), 58% partial responses (PR) and 20% stable diseases (SD), the median progression-free survival (PFS) was 9.9 and DoR 10.7 months. BRAF2 with (68%) or without (32%) additional MEK inhibition was initiated after a median interval of 3.4 months. DCR after re-challenge with BRAF2 was 57%, 8% CR, 20% PR and 28% SD, median PFS was 5.0 and DoR 14.0 months. The duration of the treatment interval or the treatment in the interval did not influence the DCR or PFS to BRAF2. The only predictive factor for response to BRAF2 was previous response to BRAF1; all patients with CR to BRAF1 achieved disease control with BRAF2, but only 60% of the patients with PR to BRAF1 (p=0.002). Addition of MEK inhibition to BRAF2 after treatment with BRAF1 as monotherapy did not significantly increase the DCR or PFS compared to patients treated solely with mono- or combination therapy. In conclusion re-challenge with a BRAF inhibitor is a meaningful therapeutic option for patients with BRAF V600-mutated metastatic melanoma.
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http://dx.doi.org/10.18632/oncotarget.26149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6188134PMC
September 2018

Rezidivierende ulzeronekrotische Plaques und Knoten mit spontaner Remission.

J Dtsch Dermatol Ges 2018 Sep;16(9):1155-1158

Klinik für Dermatologie und Venerologie, Universitätsklinikum Freiburg, Medizinische Fakultät, Albert-Ludwigs-Universität, Freiburg, Germany.

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http://dx.doi.org/10.1111/ddg.13626_gDOI Listing
September 2018

Personalized Clinical Decision Making Through Implementation of a Molecular Tumor Board: A German Single-Center Experience.

JCO Precis Oncol 2018 16;2. Epub 2018 Aug 16.

University of Freiburg, Freiburg; , , , , , , , , , and , German Cancer Consortium, partner site Freiburg, and German Cancer Research Center, Heidelberg; , Augsburg Medical Center, Augsburg; and , University of Lübeck, Lübeck, Germany.

Purpose: Dramatic advances in our understanding of the molecular pathophysiology of cancer, along with a rapidly expanding portfolio of molecular targeted drugs, have led to a paradigm shift toward personalized, biomarker-driven cancer treatment. Here, we report the 2-year experience of the Comprehensive Cancer Center Freiburg Molecular Tumor Board (MTB), one of the first interdisciplinary molecular tumor conferences established in Europe. The role of the MTB is to recommend personalized therapy for patients with cancer beyond standard-of-care treatment.

Methods: This retrospective case series includes 198 patients discussed from March 2015 through February 2017. The MTB guided individual molecular diagnostics, assessed evidence of actionability of molecular alterations, and provided therapy recommendations, including approved and off-label treatments as well as available matched clinical trials.

Results: The majority of patients had metastatic solid tumors (73.7%), mostly progressive (77.3%) after a mean of 2.0 lines of standard treatment. Diagnostic recommendations resulted in 867 molecular diagnostic tests for 172 patients (five per case), including exome analysis in 36 cases (18.2%). With a median turnaround time of 28 days, treatment recommendations were given to 104 patients (52.5%). These included single-agent targeted therapies (42.3%), checkpoint inhibitors (37.5%), and combination therapies (18.3%). Treatment recommendations were implemented in 33 of 104 patients (31.7%), of whom 19 (57.6%) showed stable disease or partial response, including 14 patients (7.1% of the entire population) receiving off-label treatments.

Conclusion: Personalized extended molecular-guided patient care is effective for a small but clinically meaningful proportion of patients in challenging clinical situations. Limited access to targeted drugs, lack of trials, and submission at late disease stage prevents broader applicability, whereas genome-wide analyses are not a strict requirement for predictive molecular testing.
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http://dx.doi.org/10.1200/PO.18.00105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446498PMC
August 2018

Recurrent ulceronecrotic plaques and nodules with spontaneous remission.

J Dtsch Dermatol Ges 2018 Sep 9;16(9):1155-1158. Epub 2018 Aug 9.

Department of Dermatology and Venereology, Freiburg University Medical Center, Albert Ludwigs University, Freiburg, Germany.

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http://dx.doi.org/10.1111/ddg.13626DOI Listing
September 2018