European Organisation for Research and Treatment of Cancer consensus recommendations for the treatment of mycosis fungoides/Sézary syndrome - Update 2017.

In order to provide a common standard for the treatment of mycosis fungoides (MF) and Sézary syndrome (SS), the European Organisation for Research and Treatment of Cancer-Cutaneous Lymphoma Task Force (EORTC-CLTF) published in 2006 its consensus recommendations for the stage-adapted selection of management options for these neoplasms. Since then, the understanding of the pathophysiology and epidemiology of MF/SS has advanced, the staging system has been revised, new outcome data have been published and novel treatment options have been introduced. The purpose of the present document is to update the original recommendations bearing in mind that there are still only a limited number of controlled studies to support treatment decisions for MF/SS and that often treatment is determined by institutional experience and availability. This consensus on treatment recommendations was established among the authors through a series of consecutive consultations in writing and a round of discussion. Recommended treatment options are presented according to disease stage, whenever possible categorised into first- and second-line options and supported with levels of evidence as devised by the Oxford Centre for Evidence-Based Medicine (OCEBM). Skin-directed therapies are still the most appropriate option for early-stage MF, and most patients can look forward to a normal life expectancy. For patients with advanced disease, prognosis is still grim, and only for a highly selected subset of patients, prolonged survival can be achieved with allogeneic stem cell transplantation (alloSCT). There is a high need for the development and investigation in controlled clinical trials of treatment options that are based on our increasing understanding of the molecular pathology of MF/SS.

Two faces of gamma-delta mycosis fungoides: before and after renal transplantation.

We describe a patient with a 30-year history of mycosis fungoides (MF) and renal transplantation performed 3 years before he presented with an ulcerated tumour in the lumbosacral area. Biopsy revealed a lymphatic infiltrate of medium-sized, pleomorphic T cells expressing the gamma-delta T-cell receptor. Radiological staging and bone marrow biopsy revealed no extracutaneous involvement. Despite reduction in systemic immunosuppressants, total skin electron beam radiotherapy and systemic chemotherapy, the disease followed a highly aggressive course and the patient died 31 years after initial diagnosis of MF. Pre-existing MF is not listed as a contraindication for solid organ transplantation. With an ever-increasing number of organ recipients, the number of MF patients undergoing solid organ transplantation will be likely to increase. Systematic collection and analysis of such cases is thus warranted to lead to a better understanding to what kind MF gets influenced by solid organ transplantation and ongoing immunosuppression.

Mast Cells Are Abundant in Primary Cutaneous T-Cell Lymphomas: Results from a Computer-Aided Quantitative Immunohistological Study.

BACKGROUND: Mast cells (MC) are bone marrow derived haematopoetic cells playing a crucial role not only in immune response but also in the tumor microenvironment with protumorigenic and antitumorigenic functions. The role of MC in primary cutaneous T-cell lymphomas (CTCL), a heterogeneous group of non-Hodgkin lymphomas with initial presentation in the skin, is largely unknown. OBJECTIVE: To gain more accurate information about presence, number, distribution and state of activation (degranulated vs. non-degranulated) of MC in CTCL variants and clinical stages. MATERIALS AND METHODS: We established a novel computer-aided tissue analysis method on digitized skin sections. Immunohistochemistry with an anti-MC tryptase antibody was performed on 34 biopsies of different CTCL subtypes and on control skin samples. An algorithm for the automatic detection of the epidermis and of cell density based CTCL areas was developed. Cells were stratified as being within the CTCL infiltrate, in P1 (a surrounding area 0-30 µm away from CTCL), or in P2 (30-60 µm away from CTCL) area. RESULTS: We found high MC counts within CTCL infiltrates and P1 and a decreased MC number in the surrounding dermis P2. Higher MC numbers were found in MF compared to all other CTCL subgroups. Regarding different stages of MF, we found significantly higher mast cell counts in stages IA and IB than in stages IIA and IIB. Regarding MC densities, we found a higher density of MC in MF compared to all other CTCL subgroups. More MC were non-degranulated than degranulated. CONCLUSION: Here for the first time an automated method for MC analysis on tissue sections and its use in CTCL is described. Eliminating error from investigator bias, the method allows for precise cell identification and counting. Our results provide new insights on MC distribution in CTCL reappraising their role in the pathophysiology of CTCL.

Illness Perception in Primary Cutaneous T-cell Lymphomas: What Patients Believe About Their Disease.

There is currently no information available on illness perception in primary cutaneous T-cell lymphomas (CTCL). The aim of this study was therefore to gather initial information on disease understanding and interpretation in patients with CTCL. Consecutive patients from a hospital-based primary cutaneous lymphoma ward completed the Revised Illness Perception Questionnaire (IPQ-R) on 2 consecutive visits. A total of 24 patients with different variants of CTCL were included in the study. Patients experienced their condition as being long-lasting, but not fundamentally affecting their lives. Patients had poor belief in personal control, but strong belief in treatment control. They did not show a good understanding of their disease, and had a moderately negative emotional response to their illness. In conclusion, the IPQ-R provides a feasible and reproducible tool for measurement and better understanding of illness perception in patients with CTCL. Knowledge of patients' attitudes towards their disease should enable optimization of the patient-physician relationship and patient care.

SNPase-ARMS qPCR: Ultrasensitive Mutation-Based Detection of Cell-Free Tumor DNA in Melanoma Patients.

Cell-free circulating tumor DNA in the plasma of cancer patients has become a common point of interest as indicator of therapy options and treatment response in clinical cancer research. Especially patient- and tumor-specific single nucleotide variants that accurately distinguish tumor DNA from wild type DNA are promising targets. The reliable detection and quantification of these single-base DNA variants is technically challenging. Currently, a variety of techniques is applied, with no apparent "gold standard". Here we present a novel qPCR protocol that meets the conditions of extreme sensitivity and specificity that are required for detection and quantification of tumor DNA. By consecutive application of two polymerases, one of them designed for extreme base-specificity, the method reaches unprecedented sensitivity and specificity. Three qPCR assays were tested with spike-in experiments, specific for point mutations BRAF V600E, PTEN T167A and NRAS Q61L of melanoma cell lines. It was possible to detect down to one copy of tumor DNA per reaction (Poisson distribution), at a background of up to 200 000 wild type DNAs. To prove its clinical applicability, the method was successfully tested on a small cohort of BRAF V600E positive melanoma patients.

Biogeography of Mediterranean Hotspot Biodiversity: Re-Evaluating the 'Tertiary Relict' Hypothesis of Macaronesian Laurel Forests.

The Macaronesian laurel forests (MLF) are dominated by trees with a laurophyll habit comparable to evergreen humid forests which were scattered across Europe and the Mediterranean in the Paleogene and Neogene. Therefore, MLF are traditionally regarded as an old, 'Tertiary relict' vegetation type. Here we address the question if key taxa of the MLF are relictual. We evaluated the relict hypothesis consulting fossil data and analyses based on molecular phylogenies of 18 representative species. For molecular dating we used the program BEAST, for ancestral trait reconstructions BayesTraits and Lagrange to infer ancestral areas. Our molecular dating showed that the origins of four species date back to the Upper Miocene while 14 originated in the Plio-Pleistocene. This coincides with the decline of fossil laurophyllous elements in Europe since the middle Miocene. Ancestral trait and area reconstructions indicate that MLF evolved partly from pre-adapted taxa from the Mediterranean, Macaronesia and the tropics. According to the fossil record laurophyllous taxa existed in Macaronesia since the Plio- and Pleistocene. MLF are composed of species with a heterogeneous origin. The taxa dated to the Pleistocene are likely not 'Tertiary relicts'. Some species may be interpreted as relictual. In this case, the establishment of most species in the Plio-Pleistocene suggests that there was a massive species turnover before this time. Alternatively, MLF were largely newly assembled through global recruitment rather than surviving as relicts of a once more widespread vegetation. This process may have possibly been triggered by the intensification of the trade winds at the end of the Pliocene as indicated by proxy data.

Treatment of unresectable squamous cell carcinoma of the skin with epidermal growth factor receptor antibodies--a case series.

BACKGROUND: Non-melanoma skin cancer (NMSC), including squamous cell carcinoma (SCC) and basal cell carcinoma (BCC), is the most common malignancy. Unresectable or metatstatic SCC is rare and therapy can be difficult because of advanced age and comorbidities. Targeted therapy with monoclonal antibodies (mAbs) against EGFR is an option in these patients. OBJECTIVE: The aim of this presentation is to provide additional evidence on the safety of anti-EGFR mAbs in long-term palliation and adjuvant treatment of advanced SCC. MATERIALS AND METHODS: This is a retrospective analysis of 4 patients with locally advanced or metastatic SCC who received cetuximab and/or panitumumab. RESULTS: 3 patients (2 females, 1 male, ages 86 to 93) received cetuximab for the treatment of unresectable SCC. In 2 patients partial remissions were achieved and maintained with continuous treatment for 17 and 18 months. Another patient achieved complete remission after 16 cetuximab treatments and is still free of disease with ongoing therapy after an overall observation period of 16 months. In a fourth patient, with recurrent loco-regional metastatic disease of the scalp and neck, adjuvant cetuximab followed by panitumumab was introduced after extensive surgery. 2 patients had a grade II-III skin rash successfully treated with topical erythromycin, systemic doxycyclin and dose modification. CONCLUSION: Cetuximab is suitable for palliation in elderly patients, able to maintain remissions and prevent disease progression over extended periods of continuing treatment without significant toxicity. Furthermore, adjuvant anti-EGFR therapy may be a promising treatment strategy in patients with a high risk of recurrence.

A new COL3A1 mutation in Ehlers-Danlos syndrome type IV.

The vascular type of the Ehlers-Danlos syndrome (Ehlers-Danlos syndrome type IV, EDS IV; OMIM #130050) is a rare connective tissue disorder with autosomal dominant transmission caused by mutations in the COL3A1 gene resulting in increased fragility of connective tissue with arterial, intestinal, and uterine ruptures and premature death. We present a 28-year-old female who in addition to typical EDS IV symptoms had severe peripheral artery occlusive disease (PAOD) and subtotal stenosis of the abdominal aorta. COL3A1 sequencing resulted in detection of an as yet undescribed mutation in exon 36 at position 2465 leading to a nucleotide replacement (c.2465G>C; p.G822A). Ultrastructural analysis of a skin biopsy revealed abnormal morphology and distribution of dermal collagen fibres. We conclude that PAOD is a possible manifestation of EDS IV and that further research is required to define its true prevalence among patients with EDS IV and its molecular pathology including genotype-phenotype correlation.

Correlation of serum procalcitonin with the severity of skin and skin structure infections - a pilot study.

BACKGROUND: Procalcitonin (PCT) is a specific biomarker for early detection of bacterial infections. While the usefulness of procalcitonin in severe conditions such as sepsis is well established, its relevance in the diagnosis and prognosis of localized cutaneous bacterial infections is unknown. Our aim was to initially evaluate if PCT is a useful parameter for predicting the severity of skin and skin structure infections (SSSI). Furthermore, the correlation of PCT levels with C-reactive protein (CRP), leukocyte counts, erythrocyte sedimentation rate (ESR), and body temperature was investigated. PATIENTS AND METHODS: Serum PCT, routine laboratory parameters, and body temperature were regularly examined in 50 consecutive patients with SSSI requiring inpatient intravenous antibiotic treatment. Patients were classified into 2 groups according to the guidelines developed by the FDA (U.S. Food and Drug Administration) as having either an uncomplicated (SSSI) or a complicated skin and skin structure infection (cSSSI). RESULTS: No significant correlation could be detected between the length of inpatient antibiotic treatment and PCT on days 1, 2, 3, and the maximum value on these days. The same result was found when uncomplicated SSSI and complicated SSSI (cSSSI) were evaluated separately. However, PCT levels were significantly higher in the latter. Furthermore, PCT levels showed a significant correlation with CRP, leukocyte count, ESR, and body temperature. CONCLUSION: PCT might be a useful additional tool for initial diagnosis and monitoring of patients with SSSI.