Anja Gesierich

Cutaneous, gastrointestinal, hepatic, endocrine, and renal side-effects of anti-PD-1 therapy

BACKGROUND Anti-programmed cell death receptor-1 (PD-1) antibodies represent an effective treatment option for metastatic melanoma as well as for other cancer entities. They act via blockade of the PD-1 receptor, an inhibitor of the T-cell effector mechanisms that limit immune responses against tumours. As reported for ipilimumab, the anti-PD-1 antibodies pembrolizumab and nivolumab can induce immune-related adverse events (irAEs). These side-effects affect skin, gastrointestinal tract, liver, endocrine system and other organ systems. Since life-threatening and fatal irAEs have been reported, adequate diagnosis and management are essential. METHODS AND FINDINGS In total, 496 patients with metastatic melanoma from 15 skin cancer centers were treated with pembrolizumab or nivolumab; 242 side-effects were described in 138 patients. In 116 of the 138 patients, side-effects affected the skin, gastrointestinal tract, liver, endocrine, and renal system. Rare side-effects included diabetes mellitus, lichen planus, and pancreas insufficiency due to pancreatitis. CONCLUSION Anti-PD1 antibodies can induce a plethora of irAEs. The knowledge of them will allow prompt diagnosis and improve the management resulting in decreased morbidity.

Neurological, respiratory, musculoskeletal, cardiac and ocular side-effects of anti-PD-1 therapy

BACKGROUND Anti-programmed cell death 1 (PD-1) antibodies represent an effective treatment option for metastatic melanoma and other cancer entities. They act via blockade of the PD-1 receptor, an inhibitor of the T-cell effector mechanisms that limit immune responses against tumours. As reported for ipilimumab, the anti-PD-1 antibodies pembrolizumab and nivolumab can induce immune-related adverse events (irAEs). These side-effects can involve skin, gastrointestinal tract, liver, the endocrine system and other organ systems. Since life-threatening and fatal irAEs have been reported, adequate diagnosis and management are essential. METHODS AND FINDINGS In total, 496 patients with metastatic melanoma from 15 skin cancer centres were treated with pembrolizumab or nivolumab. Two hundred forty two side-effects in 138 patients have been analysed. In 77 of the 138 patients side-effects affected the nervous system, respiratory tract, musculoskeletal system, heart, blood and eyes. Not yet reported side-effects such as meningo-(radiculitis), polyradiculitis, cardiac arrhythmia, asystolia, and paresis have been observed. Rare and difficult to manage side-effects such as myasthenia gravis are described in detail. CONCLUSION Anti-PD-1 antibodies can induce a plethora of irAEs. The knowledge of them will allow prompt diagnosis and improve the management resulting in decreased morbidity.

Cutaneous metastases as the first clinical sign of metastatic gastric carcinoma

Cutaneous metastases from gastric cancer are uncommon with a frequency of 7 % but can rarely be the presenting sign. A 54‐year‐old man complained of multiple pea‐sized scalp nodules which had been present for four months. Histology showed a metastatic adenocarcinoma. Initial evaluation revealed liver metastases and gastroscopy then identified a tumor involving the distal esophagus and gastric cardia that was diagnosed as a gastric tubular carcinoma. The patient had a good response to polychemotherapy. While gastric carcinoma generally metastasizes to the abdominal wall or lymph nodes, our patient showed an exceptional variant with distant cutaneous metastases as the first clinical sign.

Ipilimumab in metastatic melanoma patients with pre-existing autoimmune disorders

BackgroundIpilimumab and programmed death (PD) 1-antibodies are effective treatment options in metastatic melanoma. The safety and efficacy of ipilimumab in patients with pre-existing autoimmune disorders (AD) has only been evaluated in a selected number of patients.MethodsWe performed a retrospective analysis in 14 German skin cancer centers for patients with metastatic melanoma and pre-existing AD treated with ipilimumab.Results41 patients with 44 pre-existing AD were treated with ipilimumab (thyroiditis n = 15, rheumatoid n = 11, dermatologic n = 10, Crohn’s disease/ulcerative colitis n = 3, neurological n = 2, sarcoidosis n = 2, pancreatitis n = 1). 3 out of 41 patients had two AD, 11 patients required immunosuppressants at the time of induction of ipilimumab. 12 patients (29.2%) experienced a flare of their pre-existing AD, mainly patients with rheumatoid or dermatologic diseases. Additional immune-related adverse events (irAEs) occurred in 12 patients (29.2%). In 23 patients (56%) neither a change of their AD nor additional irAEs were observed. Objective responses were seen in five patients (one complete remission, four partial remissions, 12.1%).ConclusionThis is the largest series of patients with pre-existing AD and treatment with ipilimumab reported. Flares of pre-existing AD were observed but manageable. Response rates and occurrence of new irAEs were comparable to previous trials. Thus, in this patient subgroup, ipilimumab can be a treatment option after a thorough discussion of pros and cons and taking severity and activity of the preexisting AD into account.

Morbidity and oncologic outcome after saphenous vein-sparing inguinal lymphadenectomy in melanoma patients

BackgroundInguinal lymph node dissection (LND) is a surgical procedure with a high morbidity rate. Variations in surgical procedure, such as sparing of the saphenous vein, have been proposed to reduce surgical morbidity. While sparing of the saphenous vein has shown promising results in earlier studies, data for this procedure in melanoma patients are rare. In this retrospective study, we report 10-year findings on the effects of saphenous vein-sparing LND on surgical morbidity and oncologic outcomes in melanoma patients.MethodsA retrospective analysis of melanoma patients receiving inguinal LND in our facility between 2003 and 2013 was performed. Patients were divided into two groups: the saphenous vein resection group and the vein sparing group. Surgical morbidity, including wound infection, lymphatic fistula, severe bleeding, neurological complications, and chronic lymphedema, as well as regional recurrence-free survival were investigated.ResultsA total of 106 patients were included in this study; of these, the saphenous vein was spared in 41 patients (38.7%). The rate of lymphatic fistula was 51.6 vs. 48.8%, wound infection occurred in 31.3 vs. 24.4%, and patients suffered from chronic lymphedema in 30.0 vs. 26.5% in V. saphena magna resection vs. sparing group. Differences observed, however, were not significant. No difference in regional recurrence-free survival between the two study groups was detected.ConclusionsThe results of our retrospective analysis could not confirm the promising results reported in earlier studies. Thus, sparing of the saphenous vein appears to be optional.

Impact of extended lymphadenectomy on morbidity and regional recurrence-free survival in melanoma patients

Abstract Introdurction: Current guidelines for malignant melanoma do not set a concrete cutoff limit for the number of lymph nodes to be resected during regional lymph node dissection (LND). Here, we investigate if extended LND (ext-LND) has an impact on surgical morbidity and oncological outcome in melanoma patients. Material and methods: A total of 245 melanoma patients receiving axillary or inguinal LND in curative intention were investigated retrospectively. Ext-LND was defined as axillary LND with 20 or more and inguinal LND with 10 or more resected lymph nodes. Surgical morbidity and regional recurrence-free survival were investigated. Results: Ext-LND did not lead to increased surgical morbidity in the overall study collective. After ext-LND, 55.4% of the patients experienced one of the investigated complications compared to 46.2% in the limited LND group (p = .2113). There was no difference in the occurrence of lymphatic fistula, wound infection, severe bleeding or neurological complications. In addition, patients with positive lymph node status showed improved regional recurrence-free survival following ext-LND (p = .0425). Conclusion: Ext-LND can be considered a quality marker of LND in melanoma patients.

Patterns of disease control and survival in patients with melanoma brain metastases undergoing immune-checkpoint blockade

OBJECTIVES Immune-checkpoint blockers (ICBs) significantly prolong overall survival (OS) in patients with advanced melanoma. Limited data are available on the efficacy and clinical benefit in patients with melanoma brain metastases (MBMs). The aim of this study was to determine whether ICB is active in an unselected cohort treated of patients with known brain metastases and if disease control correlates with the survival. METHODS A total of 385 patients with metastatic malignant melanoma treated with ICB as monotherapy between 2005 and 2017 in two tertiary referral centres were included. Patient records were searched for the development of brain metastases. Demographic and clinical data of all patients were collected retrospectively. RESULTS We identified 177 patients with MBM who received ICBs (ipilimumab, nivolumab, pembrolizumab). Patients with and without brain metastases received similar ICB regimens. Prognosis was inferior in patients with brain metastases; patients with >1 brain metastasis showed even poorer survival. For extracranial (ec) metastases, disease control was associated with improved survival. However, when comparing patients with intracranial (ic) disease control during immunotherapy to patients with ic disease progression, no difference in OS could be observed. CONCLUSIONS In our study, ec disease control was the dominant predictive factor for OS in both patients with or without melanoma brain metastases. These data indicate that clinical trials in melanoma patients with brain metastases should address end-points such as symptom control, quality of life or OS in addition to ic response rates.

Diagnostik im Spektrum: Vor, in und jenseits der Praxis

Jedem Dermatologen in der Ausbildung kommt dieses Bild bekannt vor: Im Dienst stellt sich ein Patient notfallmäßig mit juckenden Quaddeln vor. Der Patient hat das Schema 1-4-Oma (einfach-vierfach-Antihistaminika-Omalizumab) bereits durchlaufen, doch die Symptome persistieren. Spätestens jetzt wäre es hilfreich einen Fahrplan zu Differentialdiagnosen der chronischen Urtikaria parat zu haben. Dr. med. Thomas Buttgereit von der Charité Berlin gibt uns in dieser Ausgabe einen solchen an die Hand – und eröffnet damit unsere Serie zur dermatologischen Differenzialdiagnostik, die wir in den folgenden Ausgaben fortsetzen werden. Die überwundene Herausforderung, differentialdiagnostisch ins Schwarze getroffen zu haben, mag für den ein oder anderen von uns mit dem Moment zusammenfallen, über den Einstieg oder die Übernahme einer Praxis nachzudenken. Das Resümee nach einem Jahr in der Niederlassung lesen wir von Frau Dr. med. Anja Weber, niedergelassene Dermatologin in Groß-Gerau, Hessen. Eine ganz andere Art des Know-how ist bei der Diagnostik wissenschaftlicher Texte gefragt. Dr. Sven Riestenpatt gibt in seinem letzten Beitrag zum wissenschaftlichen Schreiben Einblicke in die hohe Kunst der Begutachtung wissenschaftlicher Artikel.

Interleukin-2 und Checkpoint-Inhibition als erfolgreiche Therapiesequenz beim metastasierten Melanom: Fallbericht und retrospektive Analyse an 52 Patienten

Eine Fehlregulation des microRNA-Expressionsmusters fi ndet sich in zahlreichen Tumorarten, unter anderem auch im malignen Melanom, und beeinfl usst wichtige zelluläre Prozesse, wie Proliferation, Invasion und Angiogenese. MicroRNAs sind Teil des sogenannten „RNA induced silencing complex“ (RISC), der die Expression von Ziel-Genen auf post-transkriptioneller Ebene moduliert. Der humane RISC besteht aus einem von vier Argonaute-Proteinen (Ago1-4). Diese vermitteln zusammen mit weiteren Cofaktoren die Inhibition der Translation von Ziel-mRNAs. Wir konnten mit Hilfe einer spezifi schen Affi nitätsaufreinigung und anschließender massenspektrometrischer Analyse zeigen, dass in Zellen des malignen Melanoms der Proteingehalt der vier Argonaute-Proteine im Vergleich zu anderen Tumorzelllinien verringert ist. Hierbei ist insbesondere Ago2 signifi kant reduziert. Eine Reexpression von Ago2 führt zu schwächeren tumorigenen Eigenschaften der Melanomzellen. Auffällig ist, dass die Ago2-Proteinmenge auch nach ektopischer Expression im Vergleich zu anderen Zelllinien nur sehr schwach ansteigt. Im Gegensatz zur Proteinmenge unterscheidet sich der Ago2 mRNA-Gehalt jedoch nur wenig. Dies legt nahe, dass Ago2 im Melanom post-transkriptionell reguliert ist. Durch eine Immunpräzipitation des RISC mit anschließender Isolation und Analyse der ko-präzipitierten RNAs konnten wir mittels cDNA-Microarray eine Bindung der Ago2-mRNA an den RISC nachweisen. Dies deutet auf eine Autoregulation der eigenen mRNA durch Ago2 hin. Um den Bereich in der Ago2-mRNA zu identifi zieren, der durch microRNAs reguliert wird, haben wir einzelne Ago2-Domänen in verschiedenen Melanomzelllinien exprimiert. Wir konnten zeigen, dass die exprimierte Proteinmenge der N-, PAZund MID-Domäne höher ist als die der PIWI-Domäne, die mRNA-Menge jedoch für alle Domänen vergleichbar ist. Diese Ergebnisse legen eine post-transkriptionelle Regulation der PIWI-Domäne nahe. Ziel ist es, mit Hilfe der Sequenz der PIWI-Domäne die microRNA zu fi nden, die für die Bindung des RISC an die gesamte Ago2-mRNA verantwortlich ist. Durch eine Inhibition dieser microRNA könnten invasive Eigenschaften des Tumors, die durch die Fehlregulation des RISC im malignen Melanom verursacht werden, antagonisiert werden.

Seriously saRComa: Neurofibrosarcoma

A 24-year-old male presented with a subcutaneous tumour measuring approximately 10 cm in diameter on his left thigh. The tumour appeared firm on palpation and did not show epidermal alterations (figure 1A). The patient reported that the lesion had been slowly growing in size over a period of a few months. He denied symptoms such as pain, itching or bleeding. Since the patient had already been diagnosed with neurofibromatosis type 1 (NF1) several years before, and since he suffered from multiple [...]