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Mikroskopisch kontrollierte Chirurgie (MKC) umfasst verschiedene Methoden, welche eine histologisch nachgewiesene vollständige Entfernung maligner Tumoren bei gleichzeitig größtmöglicher Schonung des tumorfreien Gewebes in direkter Umgebung ermöglichen. Allen unter MKC subsummierten Verfahren gemein ist die Markierung des Exzidates zur topographischen Orientierung, wodurch eine Zuordnung verbliebener Tumorreste möglich ist. Indikationen für MKC sind maligne Hauttumoren in Problemlokalisationen sowie aggressive Subtypen von Hauttumoren. Zu den etablierten Indikationen für MKC zählen unter anderem Basalzellkarzinome, kutane Plattenepithelkarzinome, Morbus Bowen sowie Bowen-Karzinome, das Dermatofibrosarcoma protuberans, Melanome in chronisch lichtgeschädigter Haut sowie akral lentiginöse Melanome und Merkelzellkarzinome. Für weitere Tumoren wie dem extramammären Morbus Paget und verschiedene kutane Sarkome liegen Hinweise vor, dass MKC Vorteile beispielsweise hinsichtlich der Lokalrezidivrate zeigt. Darüber hinaus ist MKC indiziert, wenn absehbar ist, dass eine komplexe Verschlusstechnik erforderlich ist und eine vollständige Resektion des Tumors sicher gewährleistet sein muss. Es wurden verschiedenen Methoden der MKC beschrieben, zu denen beispielsweise die 3D-Histologie, die Horizontal-Methode oder die Mohs-Chirurgie zählen. Eine enge Kooperation fachlich qualifizierter Operateure und (Dermato)-Pathologen sowie labortechnischer Mitarbeiter ist für die Durchführung der MKC unabdingbar.

The IMMUNED trial previously showed significant improvements in recurrence-free survival for adjuvant nivolumab plus ipilimumab as well as for adjuvant nivolumab alone in patients with stage IV melanoma with no evidence of disease after resection or radiotherapy. Here, we report the final analysis, including overall survival data.IMMUNED was an investigator-sponsored, double-blind, placebo-controlled, three-arm, phase 2 trial conducted in 20 academic medical centres in Germany. Eligible patients were aged 18-80 years with stage IV melanoma with no evidence of disease after surgery or radiotherapy. Patients were randomly assigned (1:1:1) to either nivolumab plus ipilimumab (nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four doses followed by nivolumab 3 mg/kg every 2 weeks), nivolumab monotherapy (nivolumab 3 mg/kg every 2 weeks), or matching placebo, for up to 1 year. The primary endpoint was recurrence-free survival in the intention-to-treat population. Secondary endpoints were time-to-recurrence, overall survival, progression-free survival or recurrence-free survival 2 (in patients in the placebo group who crossed over to nivolumab monotherapy after experiencing disease recurrence), and safety endpoints. This trial is registered on ClinicalTrials.gov (NCT02523313), and is complete.Between Sept 2, 2015, and Nov 20, 2018, 175 patients were enrolled in the study, and 167 were randomly assigned to receive either nivolumab plus ipilimumab (n=56), nivolumab plus ipilimumab-matching placebo (n=59), or double placebo control (n=52). At a median follow-up of 49·2 months (IQR 34·9-58·1), 4-year recurrence-free survival was 64·2% (95% CI 49·2-75·9) in the nivolumab plus ipilimumab group, 31·4% (19·7-43·8) in the nivolumab alone group, and 15·0% (6·7-26·6) in the placebo group. The hazard ratio (HR) for recurrence for the nivolumab plus ipilimumab group versus placebo was 0·25 (97·5% CI 0·13-0·48; p0·0001), and for the nivolumab group versus placebo was 0·60 (0·36-1·00; p=0·024). Median overall survival was not reached in any treatment group. The HR for overall survival was significantly in favour of the nivolumab plus ipilimumab group versus placebo (HR 0·41; 95% CI 0·17-0·99; p=0·040), but not for the nivolumab group versus placebo (HR 0·75; 0·36-1·56; p=0·44). 4-year overall survival was 83·8% (95% CI 68·8-91·9) in the nivolumab plus ipilimumab group, 72·6% (57·4-83·2) in the nivolumab alone group, and 63·1% (46·9-75·6) in the placebo group. The median progression-free survival or recurrence-free survival 2 of patients in the placebo group who crossed over to nivolumab monotherapy after experiencing disease recurrence was not reached (95% CI 21·2 months to not reached). Rates of grade 3-4 treatment-related adverse events remained largely unchanged compared with our previous report, occurring in 71% (95% CI 57-82) of the nivolumab plus ipilimumab group, and 29% (95% CI 17-42) of patients receiving nivolumab alone. There were no treatment-related deaths.Both active regimens continued to show significantly improved recurrence-free survival compared with placebo in patients with stage IV melanoma with no evidence of disease who were at high risk of recurrence. Overall survival was significantly improved for patients receiving nivolumab plus ipilimumab compared with placebo. Use of subsequent anti-PD-1-based therapy was high in patients in the placebo group after recurrence and most likely impacted the overall survival comparison of nivolumab alone versus placebo. The recurrence-free and overall survival benefit of nivolumab plus ipilimumab over placebo reinforces the change of practice already initiated for the treatment of patients with stage IV melanoma with no evidence of disease.Bristol-Myers Squibb.

Das Kaposi-Sarkom (KS) ist eine seltene, maligne, von lymphatischen Endothelzellen ausgehende, multilokuläre Gefäßerkrankung, die vor allem Haut und Schleimhäute, aber auch das lymphatische System und innere Organe wie den Gastrointestinaltrakt, die Lunge oder die Leber befallen kann. Fünf epidemiologische Subtypen des KS mit variablem klinischem Verlauf und unterschiedlicher Prognose werden unterschieden, die in spezifischen Populationen vermehrt auftreten: (1) klassisches KS, (2) iatrogenes KS bei Immunsuppression, (3) endemisches (afrikanisches) lymphadenopathisches KS, (4) epidemisches, HIV-assoziiertes KS und mit einem Immunrekonstitutions-Inflammations-Syndrom (IRIS) assoziiertes KS und (5) KS bei Männern, die Sex mit Männern haben (MSM) ohne HIV-Infektion. Diese interdisziplinäre Leitlinie fasst aktuelle praxisrelevante Empfehlungen zu Diagnostik und Therapie der verschiedenen Formen des KS zusammen. Die in dieser Kurzleitlinie genannten Empfehlungen werden in der Langfassung der Leitlinie (Online-Version des JDDG) detaillierter ausgeführt.

Stevens-Johnson-Syndrom und toxisch epidermale Nekrolyse sind schwere, vorrangig arzneimittelinduzierte Haut-Schleimhaut-Reaktionen. Da sie sich im Ausmaß der Hautablösung, nicht aber in der Ätiologie unterscheiden, werden sie als epidermale Nekrolyse (EN) zusammengefasst. Durch ihre deutschlandweite Erfassung liegen im Dokumentationszentrum schwerer Hautreaktionen repräsentative Daten vor. Dabei fielen zunehmend Fallmeldungen unter der Behandlung mit neuen immunonkologischen Medikamenten, Kinaseinhibitoren und Biologika auf.Von 4150 Fallmeldungen, die zwischen Januar 2003 und Februar 2019 eingingen, wurden 102 mit diesen Medikamentengruppen exponierte Fälle einer systematischen Aufarbeitung, Validierung und Kausalitätsbeurteilung unterzogen.Bestätigt wurden zwei Fälle von EN durch Vemurafenib und je ein Fall durch Afatinib und Pembrolizumab. In 14 EN-Fällen waren andere Medikamente - mehrheitlich Allopurinol oder Cotrimoxazol - Auslöser. Vierzehn Fälle entsprachen EN-ähnlichen Reaktionen: sechs bullöse lichenoide Arzneimittelexantheme (AME) auf Pembrolizumab (2), Obinutuzumab, Nivolumab, Rituximab, Infliximab/Nivolumab und acht multiforme-artige AME auf Rituximab (2), Adalimumab, Ramucirumab, Bevacizumab, Vemurafenib und Sorafenib (2). Lichenoide AME waren histologisch und durch den protrahierten Verlauf von EN unterscheidbar, multiforme-artige AME durch ein variantenreiches Hautbild mit allenfalls geringer Epidermolyse oder Schleimhautbeteiligung.Die korrekte Diagnose ist prognoseentscheidend und durch den Einsatz dieser Medikamente in der Malignombehandlung relevant. Eine Reexposition ist bei EN kontraindiziert, bei anderen AME unter strenger Risiken-Nutzen-Abwägung möglich.

Stevens-Johnson syndrome and toxic epidermal necrolysis are severe, primarily drug-induced reactions of skin and mucosa. Since they differ in the extent of skin detachment but not in etiology, they are grouped together as epidermal necrolysis (EN). Due to nationwide registration, representative data are available at the German Center for the Documentation of Severe Skin Reactions (dZh). Here, an increasing number of case notifications in the context with new immuno-oncologic drugs, kinase inhibitors and biologics have been observed.Of 4,150 cases notifications between January 2003 and February 2019, 102 cases with exposure to these drug groups underwent systematic analysis, validation and causality assessment.Two cases of EN to vemurafenib were confirmed and one case to afatinib and pembrolizumab, respectively. In 14 EN cases other drugs - predominantly allopurinol or cotrimoxazole - were the causative agent. Fourteen cases were EN-like reactions: six bullous lichenoid drug eruptions (DE) to pembrolizumab (2), obinutuzumab, nivolumab, rituximab, infliximab/nivolumab, and eight multiforme-like DE to rituximab (2), adalimumab, ramucirumab, bevacizumab, vemurafenib, sorafenib (2). Lichenoid DE were differentiated from EN through histopathology and by the protracted course of EN, multiforme-like DE by variable skin manifestations with only sparse epidermolysis or mucosal involvement.A correct diagnosis is highly relevant in terms of prognosis and use of these drugs in malignoma treatment. Re-exposure is contraindicated in EN, but possible in other DE after rigorous risk-benefit evaluation.

Superficial leiomyosarcomas (LMS) are rare skin cancers (2–3% of cutaneous sarcomas) that originate from dermally located hair follicle muscles, dartos or areolar muscles (cutaneous/dermal LMS), or from vascular muscle cells of the subcutaneous adipose tissue (subcutaneous LMS). These superficial LMS are distinct from LMS of the deep soft tissues. Leiomyosarcomas are typically localized at the lower extremities, trunk or capillitium, and present as painful, erythematous to brownish nodules. Diagnosis is made by histopathology. The treatment of choice for primary LMS is complete (R0) microscopically controlled excision, with safety margins of 1 cm in dermal LMS, and 2 cm in subcutaneous LMS, if possible. Non-resectable or metastatic LMS require individual treatment decisions. After R0 resection with 1 cm safety margins, the local recurrence rate of dermal LMS is very low, and metastasis is very rare. Subcutaneous LMS, very large, or incompletely excised LMS recur and metastasize more frequently. For this reason, clinical follow-up examinations are recommended every six months for cutaneous LMS, and every three months for subcutaneous LMS within the first two years (in subcutaneous LMS including locoregional lymph node sonography). Imaging such as CT/MRI is indicated only in primary tumors with special features, recurrences, or already metastasized tumors.

Wound healing of acute full-thickness injuries and chronic non-healing ulcers leads to delayed wound closure, prolonged recovery period and hypertrophic scarring, generating a demand for an autologous cell therapy and a relevant pre-clinical research models for wound healing. In this study, an immunocompetent model for wound healing was employed using a syngeneic murine cell line of mesenchymal stem cells cultured from the mouse whisker hair follicle outer root sheath (named moMSCORS). moMSCORS were isolated using an air-liquid interface method, expanded in vitro and characterized according to the MSC definition criteria - cell viability, in vitro proliferation, MSC phenotype and multi-lineage differentiations. Moreover, upon applying moMSCORS in an in vivo full-thickness wound model in the syngeneic C57BL/6 mice, the treated wounds displayed different morphology to that of the untreated wound beds. Quantitative evaluation of angiogenesis, granulation and wound closure involving clinical scoring and software-based quantification indicated a lower degree of inflammation in the treated wounds. Histological staining of treated wounds by the means of H&E, Alcian Blue, PicroSirius Red and αSMA immune labelling showed lower cellularity, less collagen filaments as well as thinner dermal and epidermal layers compared with the untreated wounds, indicating a general reduction of hypertrophic scars. The decreased inflammation, accelerated wound closure and non-hypertrophic scarring, which were facilitated by moMSCORS, hereby address a common problem of hypertrophic scars and non-physiological tissue properties upon wound closure, and additionally offer an in vivo model for the autologous cell-based wound healing. Graphic Abstract

BACKGROUND Classification of lupus erythematosus (LE) is conflicting as it is carried out from different starting points. Whereas dermatological classifications categorize LE morphologically based on specific cutaneous lesions, rheumatologic classifications are based on symptomatic aspects. Indeed, LE is a systemic autoimmune disease with variable acuity and organ involvement. All cutaneous disease patterns may occur in both limited-cutaneous and systemic LE. PATIENTS AND METHODS 76 LE-patients with complete clinical data, clinical photographs and biopsy of cutaneous manifestations as well as paraclinical findings were retrospectively analyzed. Based on a published two-dimensional classification system that considers disease-specific skin manifestations and final disease diagnosis separately, patients' diagnoses were revised and compared with those in medical records. In addition, the extent to which patients could be clustered by diagnosis based on their LE-specific skin manifestations, corresponding histopathological changes, and paraclinical data was investigated. RESULTS After re-evaluation, the proportion of patients with limited-cutaneous LE decreased from 82% previously to 24%. More than two-thirds of patients indeed showed intermediate or systemic LE. Disease-specific skin manifestations, histologic characteristics and paraclinical data did not cluster with final diagnoses. CONCLUSIONS First, the work underlines the systemic character of the disease. Second, a two-dimensional approach can help overcome classification difficulties in LE, as skin-morphologic and symptomatic aspects can be considered separately.

Graft-versus-host disease (GvHD) is a major complication following stem-cell or solid-organ transplantation. Accurate diagnosis of cutaneous GvHD is challenging, given that drug eruptions and viral rashes may present with similar clinical/histological manifestations. Specific markers are not available. We performed the histological examination of biopsy samples from acute GvHD (aGvHD; n = 54), Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN; n = 27), maculopapular drug eruption (MDE; n = 26) and healthy controls (n = 26). Samples of aGvHD showed a decrease in Langerhans cells (LC, p = 0.0001) and an increase in macrophages (MΦ, p = 0.0001) compared to healthy skin. Compared to SJS/TEN, MDE and healthy skin, aGvHD biopsies contained greater numbers of CD4+ and CD8+ T cells. The majority of CD4+ T-helper cells were localized in the upper dermis, whereas cytotoxic CD8+ T cells were found in the epidermis. Increased numbers of CD56+ natural killer (NK) cells in the upper dermis of aGvHD skin (p = 0.007) were not observed in controls or SJS/TEN and MDE. There were no differences in elafin staining between aGvHD and the latter two conditions. Acute GvHD appears to have a distinct inflammatory cell profile (T cells/NK cells) that may aid establishing in a more accurate diagnosis, especially when used to rule out differential diagnoses such as SJS/TEN or MDE.

Chronic graft-versus-host disease (cGVHD) is a major life-threatening complication of allogeneic hematopoietic stem cell transplantation. The molecular mechanisms underlying cGVHD remain poorly understood, and targeted therapies for clinical use are not well established. Here, we examined the role of the canonical WNT pathway in sclerodermatous cGVHD (sclGVHD). WNT signaling was activated in human sclGVHD with increased nuclear accumulation of the transcription factor β-catenin and a WNT-biased gene expression signature in lesional skin. Treatment with the highly selective tankryase inhibitor G007-LK, the CK1α agonist pyrvinium, or the LRP6 inhibitor salinomycin abrogated the activation of WNT signaling and protected against experimental cGVHD, without a significant impact on graft-versus-leukemia effect (GVL). Treatment with G007-LK, pyrvinium, or salinomycin almost completely prevented the development of clinical and histological features in the B10.D2 (H-2d) → BALB/c (H-2d) and LP/J (H-2b) → C57BL/6 (H-2b) models of sclGVHD. Inhibition of canonical WNT signaling reduced the release of extracellular matrix from fibroblasts and reduced leukocyte influx, suggesting that WNT signaling stimulates fibrotic tissue remodeling by direct effects on fibroblasts and by indirect inflammation-dependent effects in sclGVHD. Our findings may have direct translational potential, because pyrvinium is in clinical use, and tankyrase inhibitors are in clinical trials for other indications.

Choosing the adequate systemic treatment for melanoma is driven by clinical parameters and personal preferences.Evaluation of the impact of disease and treatment on the daily life of patients receiving systemic therapy for melanoma.A German-wide, cross-sectional comparative study was conducted at 13 specialized skin cancer centres from 08/2020 to 03/2021. A questionnaire was distributed to assess patients' perception of disease and symptoms, the impact of their current treatment on quality of life (QOL) and activities, adverse events (AEs), therapeutic visits, as well as believe in and satisfaction with their current systemic melanoma treatment. Patient-reported outcomes (PROs) were rated on a continuous numerical rating scale or selected from a given list.Four hundred and fourteen patients with systemic melanoma therapy were included. 359 (87%) received immune checkpoint inhibition (ICI) and 55 (13%) targeted therapy (TT). About 1/3 of patients were adjuvantly treated, the remaining because of unresectable/metastatic melanoma. In subgroup analyses, only in the adjuvant setting, TT patients reported a significant decrease in their treatment associated QOL compared to patients with ICI (p = 0.02). Patients with TT were 1.9 times more likely to report AEs than patients with ICI, a difference being significant just for the adjuvant setting (p = 0.01). ICI treatment intervals differed significantly between adjuvant and unresectable/metastatic setting (p = 0.04), though all patients, regardless of their specific ICI drug, evaluated their treatment frequency as adequate. TT patients with dabrafenib/trametinib (n = 37) or encorafenib/binimetinib (n = 15) did not differ regarding the strain of daily pill intake. Patients older than 63 years rated various PROs better than younger patients.Patients evaluated their treatment mainly positively. ICI might be preferred over TT regarding QOL and patient-reported AEs in the adjuvant setting. Older melanoma patients appeared to be less impacted by their disease and more satisfied with their treatment.

Pathogenic variants inTP53have been classically thought to cause Li-Fraumeni syndrome (LFS), a cancer predisposition with high risks for various childhood- and adult-onset malignancies. However, increased genetic testing has lately revealed, that pathogenic variant carriers exhibit a broader range of phenotypes and that penetrance may be dependent both on variant type and modifiers. Using next generation sequencing and short tandem repeat analysis, we identified germline pathogenic variants inTP53andRAD51Clocated incison chromosome 17 in a 43-year-old male, who has developed a rare sebaceous gland carcinoma (SGC) but so far no tumors of the LFS spectrum. This course mirrors aTrp53-Rad51c-double-mutantcismouse-model, which similarly develops SGC, while the characteristicTrp53-associated tumor spectrum occurs with significantly lower frequency. Therefore, we propose that co-occurent pathogenic variants inRAD51CandTP53may predispose to SGC, reminiscent of Muir-Torre syndrome. Further, this report supports the diversity of clinical presentations associated with germlineTP53alterations, and thus, the proposed expansion of LFS to heritableTP53-related cancer syndrome.

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.

Background: Most patients with high-risk melanomas develop metastasis within the first few years after diagnosis. However, late recurrence of melanoma is seen in patients that metastasize more than 10 years after the primary diagnosis; a metastasis after 15 years is considered an ultra-late recurrence. It is critical to better understand the clinical and biological characteristics of this subset of melanoma patients in order to offer an individual treatment plan and prevent metastasis. Methods: We retrospectively analyzed melanoma patients with recurrence ≥10 years after a primary diagnosis documented between 1993 and 2012 at the skin cancer center of the University Medical Center Leipzig, Germany. We conducted a comprehensive review of the literature and compared the results with our data. Available archived primary melanoma tissue was investigated with a seven-marker immunohistochemical signature (immunoprint®) previously validated to reliably identify high-risk patients within stages IB-III. Results: Out of 36 analyzed patients, a third metastasized ultra-late (≥15 years). The mean age at initial diagnosis was 51 years, with women being diagnosed comparatively younger than men. The largest proportion of patients with late recurrence had primary melanomas located on the trunk. The immunoprint® signature of the available primary melanomas allowed the accurate prediction of a high risk. However, it is difficult to draw a definitive conclusion from the small number of cases that could be analyzed with immunoprint® (n = 2) in this study. Apart from the primary tumor characteristics, the laboratory values at time of metastasis, comorbidities and outcome are also shown. Conclusion: Late and ultra-late recurrent melanomas seem not to differ from melanomas in general, apart from a distinctly higher proportion of lower leg localizations in ultra-late recurrent melanomas. The immunoprint® signature may help to identify high-risk primary tumors at the time of initial diagnosis. However, apart from the risk profile of the primary tumor, it seems that individual immune surveillance can control residual tumor cells for more than a decade. Advanced age and increasing comorbidities may contribute to a disturbed immunological balance.

Kaposi's sarcoma (KS) is a rare, malignant, multilocular vascular disease originating from lymphatic endothelial cells that can primarily affect the skin and mucous membranes, but also the lymphatic system and internal organs such as the gastrointestinal tract, lungs or liver. Five epidemiological subtypes of KS with variable clinical course and prognosis are distinguished, with increased incidence in specific populations: (1) Classical KS, (2) Iatrogenic KS in immunosuppression, (3) Endemic (African) lymphadenopathic KS, (4) Epidemic, HIV-associated KS and KS associated with immune reconstitution inflammatory syndrome (IRIS), and (5) KS in men who have sex with men (MSM) without HIV infection. This interdisciplinary guideline summarizes current practice-relevant recommendations on diangostics and therapy of the different forms of KS. The recommendations mentioned in this short guideline are elaborated in more detail in the extended version of the guideline (online format of the JDDG).

Conjunctival melanoma is a rare type of ocular melanoma, which is prone to local recurrence and metastasis and can lead to patient death. Novel therapeutic strategies have revolutionized cutaneous melanoma management. The efficacy of these therapies in conjunctival melanoma, however, has not been evaluated in larger patient cohorts.In this multi-center retrospective cohort study with additional screening of the ADOREG database, data were collected from 34 patients with metastatic conjunctival melanoma who received targeted therapy (TT) (BRAF ± MEK inhibitors) or immune checkpoint inhibitors (ICI) (anti-PD-1 ± anti-CTLA4). In 15 cases, tissue was available for targeted next-generation-sequencing (611 genes) and RNA sequencing. Driver mutations, tumor mutational burden, copy number variations and inflammatory/IFNγ gene expression signatures were determined.Genetic characterization identified frequent BRAF (46.7%, 7/15), NRAS (26.7%, 4/15), NF1 (20%, 3/15), and TERT promoter (46.7%, 7/15) mutations. UV associated CT and CCTT mutations were common. Median follow-up time after start of first TT or ICI therapy was 13.2 months. In 26 patients receiving first-line ICI, estimated one-year progression-free survival (PFS) rate was 42.0%, PFS and overall survival (OS) 6.2 and 18.0 months, respectively. First-line TT was given to 8 patients, estimated one-year PFS rate was 54.7%, median PFS and OS 12.6 and 29.1 months, respectively.Our findings support the role of UV irradiation in conjunctival melanoma and the genetic similarity with cutaneous melanoma. Conjunctival melanoma patients with advanced disease benefit from both targeted therapies (BRAF ± MEK inhibitors) and immune checkpoint inhibitors.

Die haufigsten Komplikationen nach allogener Stammzelltransplantation (aHSCT) sind Infektionen und die Graft-versus-host-Erkrankung (GvHD). Die GvHD ist eine komplexe Multiorganerkrankung. Die Haut ist ein in nahezu allen Krankheitsstadien betroffenes Organ und erfordert die Einbindung des Dermatologen in die interdisziplinare Behandlung der Patienten. Der vermehrte Einsatz von nicht verwandten Spendern, die Ausweitung der Indikationsgebiete und das steigende Alter transplantierter Patienten fuhrten in der Vergangenheit zu einem Anstieg der Inzidenz der GvHD. In den letzten Jahren haben jedoch neue Therapien hamoproliferativer Erkrankungen, wie unter anderem Checkpointinhibitoren, neue zielgerichtete Therapeutika und CAR-T-Zellen, deutlich an Bedeutung gewonnen, was zukunftig zu einem Ruckgang der aHSCT und damit der GvHD fuhren konnte.

To date, there have been only few studies investigating rechallenge with checkpoint inhibitors in melanoma patients. Herein, we present the first review of all internationally published, English-language articles. A total of 570 patients were included in our analysis, divided into four groups: 1) rechallenge with anti-PD1 following disease progression on anti-PD1 therapy; 2) rechallenge with anti-PD1 and anti-CTLA4 following disease progression on anti-PD1 therapy; 3) rechallenge with anti-CLTA-4 following disease progression on anti-CTLA-4 therapy; and 4) rechallenge following toxicity-related treatment discontinuation. In the first group (85 patients), the mean disease control rate (DCR) was 45.8 %, with a mean overall response rate (ORR) of 15.5 %. The second group (114 patients) showed a mean DCR of 40.6 % and an ORR of 20 %. In the third group (182 patients), the mean DCR was 50.9 %, with an ORR of 20.4 %. Thus, even patients with a history of disease progression on initial checkpoint inhibitor therapy may benefit from rechallenge. Patients in the fourth group (189 patients) showed a mean DCR of 89.5 % and an ORR of 70.2 %. Of these individuals, 18 % saw recurrence of the same toxicity; 23 % were affected by adverse events different from the ones previously experienced.

Recognizing and treating rare checkpoint inhibitor related adverse events may be a clinical challenge in melanoma therapy. One of rather rare affected organs is the pancreas. Immune-related pancreatitis is difficult to recognize due to its variable clinical characteristics. Asymptomatic elevations of serum lipase and/or amylase during therapy with immune-checkpoint blockade impede the diagnostic process. We present a patient who developed an immune-related pancreatitis within the first 4 months of immunotherapy. Treatment with high dose systemic glucocorticosteroids with very slow tapering over a total period of 6.5 months was necessary to keep the patient symptom free as well as to maintain long-term normalization of serum lipase. Checkpoint blockade related pancreatitis may occur as acute or chronic disease and may lack any radiographic signs. As in our case, very slow tapering of initially high dose systemic glucocorticosteroids seems to be a crucial requirement for lasting recovery. Even after successful treatment, late-onset secondary pancreatic insufficiency may occur and patients have to be followed up at regular intervals. Restarting immunotherapy after resolution of immune-related pancreatitis is possible but needs careful risk-benefit consideration.