Claudia Pföhler

Merkel cell polyomavirus status is not associated with clinical course of Merkel cell carcinoma.

The majority of Merkel cell carcinomas (MCCs) are associated with the recently identified Merkel cell polyomavirus (MCV). However, as it is still unclear to which extent the presence of MCV impacts tumor characteristics or clinical outcome, we correlated the MCV status of tumor lesions obtained from 174 MCC patients including 38 MCC patients from Australia and 138 MCC patients from Germany with clinical characteristics, histomorphology, immunohistochemistry, and course of the disease. MCV DNA was present in 86% of MCCs and, in contrast to previous reports, no significant difference in MCV prevalence was present between Australian and German MCC cases. When patients were stratified according to their MCV status, only tumor localization (P=0.001), gender (P=0.024), and co-morbidity, i.e., frequency of patients with previous skin tumors (P=0.024), were significantly different factors. In contrast, year of birth and diagnosis, age at diagnosis, or histological type and features representing the oncogenic phenotype such as mitotic rate or expression of p16, p53, RB1, and Ki67 were not significantly different between MCV-positive and MCV-negative MCCs. MCV status also did not influence recurrence-free, overall, and MCC-specific survival significantly. In summary, although MCV-positive and MCV-negative MCCs may have different etiologies, these tumors have comparable clinical behaviors and prognosis.

Symptom profile and risk factors of anaphylaxis in Central Europe

Anaphylaxis is the most severe manifestation of an IgE‐dependent allergy. Standardized acquired clinical data from large cohorts of well‐defined cases are not available. The aim of this study was to analyse the symptom profile and risk factors of anaphylaxis in a large Central European cohort.

High Response Rate After Intratumoral Treatment With Interleukin-2: Results From a Phase 2 Study in 51 Patients With Metastasized Melanoma

Systemic high‐dose interleukin‐2 (IL‐2) achieved long‐term survival in a subset of patients with advanced melanoma. The authors reported previously that intratumorally applied IL‐2 induced complete local responses of all metastases in >60% of patients. The objectives of the current study were to confirm those results in a larger cohort and to identify patient or regimen characteristics associated with response.

In vitro Drug Sensitivity Predicts Response and Survival after Individualized Sensitivity-Directed Chemotherapy in Metastatic Melanoma: A Multicenter Phase II Trial of the Dermatologic Cooperative Oncology Group

Purpose:In vitro sensitivity assays are promising tools to predict the individual outcome of different chemotherapy regimens. However, a direct association between in vitro and in vivo chemosensitivity has to be shown by clinical studies. This multicenter phase II trial was aimed to investigate the efficacy of a sensitivity-directed, first-line chemotherapy in metastasized melanoma patients, and to prove an association between in vitro sensitivity and therapy outcome. Patients and Methods: The primary study end point was objective response; secondary end points were safety, overall survival, and progression-free survival. Viable tumor cells obtained from metastatic lesions were tested for chemosensitivity to seven single drugs and five drug combinations using an ATP-based luminescence viability assay. Results: Out of 82 recruited patients (intention-to-treat), 57 received assay-directed chemotherapy and 53 were evaluable for all study end points (per protocol). The drug combinations used were gemcitabine + treosulfan, paclitaxel + cisplatin, paclitaxel + doxorubicin, and gemcitabine + cisplatin. The per protocol population could be divided into 22 (42%) chemosensitive and 31 (58%) chemoresistant patients by an arbitrary chemosensitivity index. Objective response was 36.4% in chemosensitive patients compared with 16.1% in chemoresistant patients (P = 0.114); progression arrest (complete response + partial response + stable disease) was 59.1% versus 22.6% (P = 0.01). Chemosensitive patients showed an increased overall survival of 14.6 months compared with 7.4 months in chemoresistant patients (P = 0.041). Conclusion:In vitro chemosensitivity testing may be worthy of further exploration to see if it could be a useful tool to predict the outcome of melanoma patients treated with a sensitivity-directed chemotherapy. Therefore, these preliminary results will be evaluated by a planned phase III trial using a randomized, standard-regimen controlled setting.

Triggers and treatment of anaphylaxis: an analysis of 4,000 cases from Germany, Austria and Switzerland.

BACKGROUND Anaphylaxis is the most severe manifestation of a mast cell-dependent immediate reaction and may be fatal. According to data from the Berlin region, its incidence is 2-3 cases per 100 000 persons per year. METHOD We evaluated data from the anaphylaxis registry of the German-speaking countries for 2006-2013 and data from the protocols of the ADAC air rescue service for 2010-2011 to study the triggers, clinical manifestations, and treatment of anaphylaxis. RESULTS The registry contained data on 4141 patients, and the ADAC air rescue protocols concerned 1123 patients. In the registry, the most common triggers for anaphylaxis were insect venom (n = 2074; 50.1%), foods (n = 1039; 25.1%), and drugs (n = 627; 15.1%). Within these groups, the most common triggers were wasp (n = 1460) and bee stings (n = 412), legumes (n = 241), animal proteins (n = 225), and analgesic drugs (n = 277). Food anaphylaxis was most frequently induced by peanuts, cow milk, and hens egg in children and by wheat and shellfish in adults. An analysis of the medical emergency cases revealed that epinephrine was given for grade 3 or 4 anaphylaxis to 14.5% and 43.9% (respectively) of the patients in the anaphylaxis registry and to 19% and 78% of the patients in the air rescue protocols. CONCLUSION Wasp and bee venom, legumes, animal proteins, and analgesic drugs were the commonest triggers of anaphylaxis. Their relative frequency was age-dependent. Epinephrine was given too rarely, as it is recommended in the guidelines for all cases of grade 2 and above.

Implementation of Anaphylaxis Management Guidelines: A Register-Based Study

Background Anaphylaxis management guidelines recommend the use of intramuscular adrenaline in severe reactions, complemented by antihistamines and corticoids; secondary prevention includes allergen avoidance and provision of self-applicable first aid drugs. Gaps between recommendations and their implementation have been reported, but only in confined settings. Hence, we analysed nation-wide data on the management of anaphylaxis, evaluating the implementation of guidelines. Methods Within the anaphylaxis registry, allergy referral centres across Germany, Austria and Switzerland provided data on severe anaphylaxis cases. Based on patient records, details on reaction circumstances, diagnostic workup and treatment were collected via online questionnaire. Report of anaphylaxis through emergency physicians allowed for validation of registry data. Results 2114 severe anaphylaxis patients from 58 centres were included. 8% received adrenaline intravenously, 4% intramuscularly; 50% antihistamines, and 51% corticoids. Validation data indicated moderate underreporting of first aid drugs in the Registry. 20% received specific instructions at the time of the reaction; 81% were provided with prophylactic first aid drugs at any time. Conclusion There is a distinct discrepancy between current anaphylaxis management guidelines and their implementation. To improve patient care, a revised approach for medical education and training on the management of severe anaphylaxis is warranted.

Topical imiquimod eradicates skin metastases of malignant melanoma but fails to prevent rapid lymphogenous metastatic spread

SIR, The ichthyoses are a heterogeneous group of skin disorders of epidermal differentiation, with both inherited and acquired forms. This cornification disorder may be found isolated or in association with other genetic defects. In 1998, five siblings with congenital ichthyosis, follicular atrophoderma, hypotrichosis and hypohidrosis were described as a new genodermatosis by Lestringant et al. We report a 17-year-old Turkish patient with ichthyosis vulgaris, follicular atrophoderma, woolly hair and hypotrichosis as a second report on this syndrome. A 17-year-old-girl was admitted to our hospital because of woolly hair, sparse eyelashes and eyebrows, and a very dry skin. She was born at term after an uncomplicated pregnancy. Ichthyosis and baldness were present at birth, but there was no history of a collodion baby. She had almost no scalp hair until she was 4 months old. In the early childhood period, funnel-shaped round follicular depressions had appeared on the dorsal aspects of the hands. She stated that her scalp hair had improved and straightened with age. The patient was otherwise healthy and detailed ophthalmological, neurological and audiometric examinations were normal. There was no history of atopy. There was no family history of similar skin problems. Both her parents and paternal grandparents were first cousins. There was no maternal history of drug intake during pregnancy. On examination, there was diffuse ichthyosiform scaling sparing the major flexures and face as in ichthyosis vulgaris (Fig. 1). The ichthyotic skin was hypohydrotic but the axilla, palms and soles sweated normally. Follicular atrophoderma was observed on the backs of her hands (Fig. 2). She had diffuse and patchy non-scarring hypotrichosis with a receding frontal hairline. Her hair was normal in length, but was light brown in colour, coarse, curly and unruly, in contrast to the straight black hair of the rest of her family. Eyelashes and particularly eyebrows were sparse (Figs 3–4). Routine haematological, biochemical, immunological, thyroid and radiological investigations were normal. Osteopoikilosis was not present on the X-rays. Echocardiography and ECG were normal. Hair microscopy was normal apart from curling. Biopsy from ichthyotic skin showed orthokeratosis with focal hypogranulosis (Fig. 5). Electron microcopy showed normal tonofilaments. Based on clinical and laboratory findings a diagnosis of ichthyosis vulgaris associated with follicular atrophoderma, hypotrichosis and woolly hair was made. The patient was prescribed 10% urea cream and salicylic acid ointments. The ichthyotic lesions resolved within a few weeks. Ichthyosis is a feature of several genetic disorders. These are rare disorders and the associated ichthyosis may be mild. The following syndromes with ichthyosis may be considered

Neoadjuvant Imatinib in Advanced Primary or Locally Recurrent Dermatofibrosarcoma Protuberans: A Multicenter Phase II DeCOG Trial with Long-term Follow-up

Purpose: Dermatofibrosarcoma protuberans (DFSP) is a rare cutaneous tumor. COL1A1–PDGFB gene fusion is frequent in DFSP, rendering tumor cell proliferation and survival dependent on PDGFRβ (platelet-derived growth factor receptor β) signaling. This trial investigated imatinib as neoadjuvant treatment of DFSP, including long-term follow-up. Experimental Design: The primary endpoint of this multicenter phase II trial was response; secondary endpoints were safety, tumor relapse, and response biomarkers. Patients with advanced primary or locally recurrent DFSP and measurable disease by RECIST (response evaluation criteria in solid tumors) were eligible and received imatinib 600 mg/d until definitive surgery with histopathologic proof of tumor-free margins. Results: Sixteen patients received imatinib, and 14 patients were evaluable for all endpoints. Median treatment duration was 3.1 months; median tumor shrinkage was 31.5%. Best overall response was 7.1% complete response (CR), 50.0% partial response (PR), 35.7% stable disease, and 7.1% progressive disease (PD). Toxicity was moderate with 25.0% grade 3 and 4 events. During a median follow-up of 6.4 years, one patient developed secondary resistance to imatinib but responded to second-line sunitinib. This patient also presented local recurrence, distant metastasis, and death from DFSP. Exploratory analysis showed that response to imatinib was associated with decreased tumor cellularity and formation of strong hyalinic fibrosis. Weak PDGFRB phosphorylation and pigmented-type DFSP were associated with nonresponse. Additional to PDGFRB, the kinases EGFR and insulin receptor were found activated in a high percentage of DFSPs. Conclusion: The neoadjuvant use of imatinib 600 mg/d in DFSP is efficacious and well tolerated. Long-term follow-up results do not definitely support smaller surgical margins after successful imatinib pretreatment, and presume that secondary resistance to imatinib might promote accelerated disease progression. Clin Cancer Res; 20(2); 499–510. ©2013 AACR.

Comparable expression and phosphorylation of the retinoblastoma protein in Merkel cell polyoma virus-positive and negative Merkel cell carcinoma.

Dear Editor, It has been demonstrated, that DNA from the Merkel cell polyoma virus (MCV) is monoclonally integrated in the genome of Merkel cell carcinoma (MCC) cells in the majority of tumors. In this respect, Bathia et al. recently reported an observation in THE JOURNAL which suggests that two subgroups of MCC can be distinguished on the basis of the abundance of MCV; moreover, these subgroups differed in their expression of cancer related proteins, i.e. the Retinoblastoma protein (RB). The authors report that MCV DNA load was less then one copy per 300 cells in 14 of 23 MCC tumors (60%), and that these tumors were characterized also by loss of RB expression. In the remaining samples, which were characterized by high levels of RB expression, the estimated viral load was always higher than 1 copy per 20 cells. Noteworthy, only in two cases viral load was higher than 1 copy per 2 cells. In consequence, the authors speculate on a possible mechanism in MCC with a minority of infected cells contributing to transformation of uninfected neighbouring cells by paracrine mechanisms. However, the results of Bathia and colleagues are in contrast to another recently published paper describing the viral load in MCVþ MCCs to be generally >1 copy per tumor cell as measured by quantitative PCR. Moreover, immunohistological analyses of MCVþ MCCs demonstrated that nearly every tumor cell expressed the MCV large T-antigen (LTA) protein. Confirming this latter report, our own immunohistochemical analysis of MCC tissues confirms this pattern of LTA expression, i.e. virtually every tumor cell of MCVþ MCCs is expressing LTA protein (Fig. 1a). Moreover, we analyzed genomic DNA purified from 50 MCC tissue samples for the presence of MCV by Real time PCR. Relative quantification of the samples was calculated by the DDCt method normalized to the repetitive DNA elements LINE1; genomic DNA of a MCC cell line that harbours at least two concatemerized copies of the MCV genome in every cell served as calibrator which allowed to approximate the minimal copy number per cell in the tissues. To this end, MCV DNA was undetectable in only 7 of the 50 samples (14%). In those samples with detectable MCV DNA the median of the estimated minimal copy numbers is approximately 1 copy per cell (Fig. 1b). Indeed, 63% of the MCV positive cases (27 samples) demonstrate minimal copy numbers higher than 0.5 copies/cell. Even some of the values below 0.5 may still be in accordance with 1 MCV copy per Figure 1. Presence of MCV in MCC tissues. (a) Immunohistochemical

Melanoma-associated retinopathy: high frequency of subclinical findings in patients with melanoma.

Summary Background Melanoma‐associated retinopathy (MAR) is a paraneoplastic syndrome with symptoms of night blindness, light sensations, visual loss, defect in visual fields, and reduced b‐waves in the electroretinogram. Patients with MAR often suffer from a sudden onset of ocular symptoms that are believed to result from antibody production against melanoma‐associated antigens that cross‐react with corresponding epitopes on retinal depolarizing bipolar cells.