Frank Meiss

BRAF inhibitor-associated ERK activation drives development of chronic lymphocytic leukemia.

Patients with BRAFV600E/K-driven melanoma respond to the BRAF inhibitor vemurafenib due to subsequent deactivation of the proliferative RAS/RAF/MEK/ERK pathway. In BRAF WT cells and those with mutations that activate or result in high levels of the BRAF activator RAS, BRAF inhibition can lead to ERK activation, resulting in tumorigenic transformation. We describe a patient with malignant melanoma who developed chronic lymphocytic leukemia (CLL) in the absence of RAS mutations during vemurafenib treatment. BRAF inhibition promoted patient CLL proliferation in culture and in murine xenografts and activated MEK/ERK in primary CLL cells from additional patients. BRAF inhibitor-driven ERK activity and CLL proliferation required B cell antigen receptor (BCR) activation, as inhibition of the BCR-proximal spleen tyrosine kinase (SYK) reversed ERK hyperactivation and proliferation of CLL cells from multiple patients, while inhibition of the BCR-distal Bruton tyrosine kinase had no effect. Additionally, the RAS-GTP/RAS ratio in primary CLL cells exposed to vemurafenib was reduced upon SYK inhibition. BRAF inhibition increased mortality and CLL expansion in mice harboring CLL xenografts; however, SYK or MEK inhibition prevented CLL proliferation and increased animal survival. Together, these results suggest that BRAF inhibitors promote B cell malignancies in the absence of obvious mutations in RAS or other receptor tyrosine kinases and provide a rationale for combined BRAF/MEK or BRAF/SYK inhibition.

Self-efficacy for coping with cancer in melanoma patients: its association with physical fatigue and depression.

The purpose of this study was to explore the impact of self‐efficacy for coping with cancer (SECC) on physical fatigue and depressive symptoms in melanoma patients, in comparison with objective factors, such as treatment with interferon‐alpha (IFN‐α) and medical and sociodemographic variables. Current literature shows that psychological distress in melanoma patients is generally moderate, that they experience high quality of life, and that symptoms of depression and fatigue have been mostly associated with adjuvant IFN‐α treatment

Immunotherapy for Malignant Melanoma Robert

Treatment of metastatic melanoma is a challenge for clinicians as most agents have failed to demonstrate improved survival in phase III trials. Despite the immunogenicity of this tumor entity, different immunological interventions including cytokine therapy, vaccination, biochemotherapy or allogeneic hematopoietic cell transplantation did not lead to a satisfactory response. However, continuous investigation on the immune mediated rejection of melanoma cells has led to the development of effective antibodies blocking cytotoxic T-lymphocyte antigen-4 (CTLA-4), a critical negative regulator of the antitumor T-cell response. Based on data from rodent models, the anti-CTLA-4 antibody ipilimumab was developed into clinical studies where it had encouraging activity in advanced melanoma with unusual response patterns. As in most immunostimulatory therapies, acute toxicities were severe and clearly mechanism-related. Although some patients developed signs of autoimmunity, the toxicities were overall manageable and mostly reversible. This review summarizes different immunotherapeutical approaches against melanoma that have been applied in the past and focuses on CTLA-4 blockade with respect to its mechanism, clinical effectiveness and immunological side effects.

Vemurafenib and ipilimumab: A promising combination? Results of a case series

ABSTRACT The purpose of combining targeted agents and immunotherapy is to achieve a chance of long-term tumor control in highly advanced patients. Between April 2012 and December 2013, 10 patients with metastatic melanoma were treated with a combination treatment of vemurafenib and ipilimumab as an individual treatment decision after detailed information and giving written informed consent. All the patients had advanced symptomatic disease, seven with elevated serum lactate dehydrogenase (LDH) levels and six with brain metastases on MRI. After clinical improvement under vemurafenib monotherapy (median 11.5 weeks), four cycles of ipilimumab were administered additionally. Combination treatment was tolerated well, with only two patients developing ≥ grade 3 elevation of transaminases; this was asymptomatic and resolved on cessation of BRAF inhibitor treatment. Staging 12 weeks after initiation of ipilimumab revealed partial response for five patients, stable disease for two, and disease progression for three. Of the seven patients with disease control, we stopped vemurafenib for five, to determine whether ipilimumab treatment led to disease control. Two revealed progressive disease 2 mo later, and received vemurafenib again, but for three the disease was controlled for at least a year, and two are still in partial remission without any further treatment. Progression-free survival was a median of 8.0 mo (95% CI 4.8–11.2), overall survival (OS) was 13.0 mo (95% CI 5.0–21.0), and four patients are still alive. In conclusion, the combination of vemurafenib and ipilimumab was well tolerated and clinical outcome was promising. The combination of targeted and immunotherapies is currently addressed in clinical trials.

Pain: Basics and relevance in dermatology

Scientific progress in pathophysiology and differentiation of pain, functional diagnostic of pain and emerging treatments highlight this subject. Basics of development of pain, as well as differentiation of nociceptive and neuropathic pain are depicted; the latter is illustrated with the example of postherpetic neuralgia. Complex regional pain syndromes are described as a third pain complex. Principles of differentiated pain management are given. Substance groups from the WHO scheme including antipyretic analgesics, non‐steroidal antiinflammatory drugs (NSAIDs) and opioids are discussed. Recommendations of the Drug Commission of the German Medical Association concerning NSAIDs and of the International Association for the Study of Pain (IASP) concerning new treatment options for cancer pain are cited. Overviews amongst others from the Cochrane library for local anesthetics, opioids and for the treatment of postherpetic neuralgia are included. Tables are provided to simplify use in daily practice. The goal of this overview is a conceptual development of pain diagnosis and therapy in dermatology.

Identification of tissue damage, extracellular matrix remodeling and bacterial challenge as common mechanisms associated with high-risk cutaneous squamous cell carcinomas

In this study we used a genetic extracellular matrix (ECM) disease to identify mechanisms associated with aggressive behavior of cutaneous squamous cell carcinoma (cSCC). cSCC is one of the most common malignancies and usually has a good prognosis. However, some cSCCs recur or metastasize and cause significant morbidity and mortality. Known factors that are associated with aggressiveness of cSCCs include tumor grading, size, localization and microinvasive behavior. To investigate molecular mechanisms that influence biologic behavior we used global proteomic and histologic analyses of formalin-fixed paraffin-embedded tissue of primary human cSCCs. We compared three groups: non-recurring, non-metastasizing low-risk sporadic cSCCs; metastasizing sporadic cSCCs; and cSCCs from patients with recessive dystrophic epidermolysis bullosa (RDEB). RDEB is a genetic skin blistering and ECM disease caused by collagen VII deficiency. Patients commonly suffer from high-risk early onset cSCCs that frequently metastasize. The results indicate that different processes are associated with formation of RDEB cSCCs compared to sporadic cSCCs. Sporadic cSCCs show signs of UV damage, whereas RDEB cSCCs have higher mutational rates and display tissue damage, inflammation and subsequent remodeling of the dermal ECM as tumor initiating factors. Interestingly the two high-risk groups - high-risk metastasizing sporadic cSCCs and RDEB cSCCs - are both associated with tissue damage and ECM remodeling in gene-ontology enrichment and Search Tool for the Retrieval of Interacting Genes/Proteins analyses. In situ histologic analyses validate these results. The high-risk cSCCs also show signatures of enhanced bacterial challenge. Histologic analyses confirm correlation of bacterial colonization with worse prognosis. Collectively, this unbiased study - performed directly on human patient material - reveals that common microenvironmental alterations linked to ECM remodeling and increased bacterial challenges are denominators of high-risk cSCCs. The proteins identified here could serve as potential diagnostic markers and therapeutic targets in high-risk cSCCs.

Targeting of Cell Surface Proteolysis of Collagen XVII Impedes Squamous Cell Carcinoma Progression

Squamous cell carcinoma (SCC) is one of the most common skin cancers and causes significant morbidity. Although the expression of the epithelial adhesion molecule collagen XVII (ColXVII) has been linked to SCC invasion, only little is known about its mechanistic contribution. Here, we demonstrate that ColXVII expression is essential for SCC cell proliferation and motility. Moreover, it revealed that particularly the post-translational modification of ColXVII by ectodomain shedding is the major driver of SCC progression, because ectodomain-selective immunostaining was mainly localized at the invasive front of human cutaneous SCCs, and exclusive expression of a non-sheddable ColXVII mutant in SCC-25 cells inhibits their matrix-independent growth and invasiveness. This cell surface proteolysis, which is strongly elevated during SCC invasion and metastasis, releases soluble ectodomains and membrane-anchored endodomains. Both released ColXVII domains play distinct roles in tumor progression: the endodomain induces proliferation and survival, whereas the ectodomain accelerates invasiveness. Furthermore, specific blockage of shedding by monoclonal ColXVII antibodies repressed matrix-independent growth and invasion of SCC cells in organotypic co-cultures. Thus, selective inhibition of ColXVII shedding may offer a promising therapeutic strategy to prevent SCC progression.

Biglycan expression in the melanoma microenvironment promotes invasiveness via increased tissue stiffness inducing integrin-β1 expression

Novel targeted and immunotherapeutic approaches have revolutionized the treatment of metastatic melanoma. A better understanding of the melanoma-microenvironment, in particular the interaction of cells with extracellular matrix molecules, may help to further improve these new therapeutic strategies. We observed that the extracellular matrix molecule biglycan (Bgn) was expressed in certain human melanoma cells and primary fibroblasts when evaluated by microarray-based gene expression analysis. Bgn expression in the melanoma tissues correlated with low overall-survival and low progression-free-survival in patients. To understand the functional role of Bgn we used gene-targeted mice lacking functional Bgn. Here we observed that melanoma growth, metastasis-formation and tumor-related death were reduced in Bgn−/− mice compared to Bgn+/+ mice. In vitro invasion of melanoma cells into organotypic-matrices derived from Bgn−/− fibroblasts was reduced compared to melanoma invasion into Bgn-proficient matrices. Tissue stiffness as determined by atomic-force-microscopy was reduced in Bgn−/− matrices. Isolation of melanoma cells and fibroblasts from the stiffer Bgn+/+ matrices revealed an increase in integrin-β1 expression compared to the Bgn−/− fibroblast matrices. Overexpression of integrin-β1 in B16-melanoma cells abolished the survival benefit seen in Bgn−/− mice. Consistent with the studies performed in mice, the abundance of Bgn-expression in human melanoma samples positively correlated with the expression of integrin-β1, which is in agreement with results from the organotypic invasion-assay and the in vivo mouse studies. This study describes a novel role for Bgn-related tissue stiffness in the melanoma-microenvironment via regulation of integrin-β1 expression by melanoma cells in both mice and humans.

Psychoonkologische Versorgung für Melanompatienten

ZusammenfassungDie Bereitstellung eines psychoonkologischen Behandlungsangebotes bildet einen wesentlichen, leitlinienbasierten Bestandteil der Patientenversorgung in Hauttumorzentren. Diese Arbeit stellt die Entwicklung, Implementierung und Inanspruchnahme eines spezifischen psychoonkologischen Versorgungskonzeptes für Melanompatienten an der dermatologischen Universitätsklinik Freiburg dar. Das Versorgungskonzept ist nach dem Stepped-care-Prinzip aufgebaut und besteht aus 4- bis 6-wöchig stattfindenden, interdisziplinären dermatoonkologischen und psychologischen Informationsveranstaltungen für Patienten und Angehörige zu Themen des malignen Melanoms sowie einzeltherapeutischen Behandlungsstufen, die entsprechend dem individuellen Behandlungsbedarf zum Tragen kommen. Im Untersuchungszeitraum zwischen April 2010 und Juli 2012 wurden 67 % aller stationär oder teilstationär behandelten Melanompatienten mit dem Angebot erreicht. Ein gestuftes Versorgungskonzept mit routinemäßiger Kontaktaufnahme und niederschwelligen Informationsveranstaltungen ist eine verlässliche Vorgehensweise, die Patienten auch im Hinblick auf weiterführende psychologische Maßnahmen erreicht. Es erscheint hinsichtlich Personaleinsatz und Erfolg gerechtfertigt und erwies sich in der klinischen Routine als alltagstauglich.AbstractOffering psycho-oncological care is an essential, guideline-based component of comprehensive care in skin cancer centers. This paper describes the development, implementation and utilization of a specific psycho-oncologic care concept for melanoma patients in the University Dermatology Clinic Freiburg. Based on the stepped-care principle, the concept is composed of interdisciplinary group sessions for patients and their relatives offered every 4-6 weeks addressing medical and psycho-oncological topics related to treatment of malignant melanoma and then individual psycho-oncological sessions modified for the patient’s treatment needs. Between April 2010 and July 2012, 67 % of the melanoma patients treated in the Freiburg Skin Cancer Center were reached by the program. A stepped-care concept with a routinely initiated first contact and low-threshold patient education group sessions is a reliable approach to reach patients and inform them about further psycho-oncological care. The advantages justify the allocation of resources and the approach proved successful for routine clinical practice.Offering psycho-oncological care is an essential, guideline-based component of comprehensive care in skin cancer centers. This paper describes the development, implementation and utilization of a specific psycho-oncologic care concept for melanoma patients in the University Dermatology Clinic Freiburg. Based on the stepped-care principle, the concept is composed of interdisciplinary group sessions for patients and their relatives offered every 4-6 weeks addressing medical and psycho-oncological topics related to treatment of malignant melanoma and then individual psycho-oncological sessions modified for the patients treatment needs. Between April 2010 and July 2012, 67 % of the melanoma patients treated in the Freiburg Skin Cancer Center were reached by the program. A stepped-care concept with a routinely initiated first contact and low-threshold patient education group sessions is a reliable approach to reach patients and inform them about further psycho-oncological care. The advantages justify the allocation of resources and the approach proved successful for routine clinical practice.

Insect bite-like reaction in a patient with chronic lymphocytic leukemia

A 60-year-old woman presented with widespread pruritic insect bite-like lesions, which she firstly detected 6 months before. She neither remembered any insect sting, nor were any other contact persons affected. The medical history revealed no atopic diathesis. There was no change in medications, she had not had any recent infections and did not complain of fever, chills or malaise. In 1998 she had been diagnosed with chronic lymphocytic leukemia (B-CLL) and had undergone allogeneic peripheral blood stem cell transplantation in 2010. After achieving a complete remission, she suffered a relapse in 2011, and was currently stage IV according to Rai/Binet C. She had not received any previous dermatoloInsect bite-like reaction in a patient with chronic lymphocytic leukemia Case for Diagnosis