Representation of skin carcinomas in public awareness - Awareness worldwide and in Germany.

BACKGROUND AND OBJECTIVES: In recent years, there has been an increase in skin cancer. The aim of this study was therefore to investigate the representation of skin cancer in public awareness worldwide and in Germany, and to determine whether Skin Cancer Awareness Month is represented in the search interests of the Internet-using population in the same way as Breast Cancer Awareness Month worldwide. DATA AND METHODS: In this study, Google Trends data were used to track levels of public awareness for different tumor entities and skin cancer types worldwide and for Germany. RESULTS: The results of this analysis clearly showed a high level of relative public search interest in breast cancer worldwide in the awareness month of October. Worldwide and in Germany, there was a certain increase in search interest and a certain seasonal effect around the May awareness month for skin cancer. For example, the analysis showed a search interest in May and during the summer months in Germany. CONCLUSIONS: It is likely that the population, for example in Germany, may benefit further from an even greater emphasis on the topic of skin cancer.

Effectiveness, Safety and Utilization of Vismodegib for Locally Advanced Basal Cell Carcinoma Under Real-world Conditions: Non-interventional Cohort Study JONAS.

Most patients with advanced basal cell carcinomas (BCCs) may not benefit sufficiently from standard treatment comprising surgery and radiation. Vismodegib, an oral selective hedgehog pathway inhibitor, is approved for treatment of patients with locally advanced BCC inappropriate for surgery or radiotherapy, or for patients with symptomatic metastatic BCC. In order to enhance understanding of the effectiveness, safety and utilization of vismodegib in clinical practice in Germany, a non-interventional study, JONAS, was conducted. A total of 53 patients with locally advanced BCC who initiated treatment with vismodegib between 2016 and 2018 were included in the study, which was embedded in the German ADOReg skin cancer registry. Duration of response, the primary endpoint, was 12.4 months, progression-free survival 32.2 months and overall response rate 77.4%. Most adverse events were mild to moderate. Overall, results confirmed previous findings, demonstrating favourable responses and manageable safety of vismodegib in patients with locally advanced BCC in clinical practice.

Cemiplimab in locally advanced basal cell carcinoma after hedgehog inhibitor therapy: an open-label, multi-centre, single-arm, phase 2 trial.

BACKGROUND: Before February, 2021, there was no standard treatment regimen for locally advanced basal cell carcinoma after first-line hedgehog inhibitor (HHI) therapy. Cemiplimab, a PD-1 antibody, is approved for treatment of advanced cutaneous squamous cell carcinoma and has shown clinical activity as monotherapy in first-line non-small-cell lung cancer. Here, we present the primary analysis data of cemiplimab in patients with locally advanced basal cell carcinoma after HHI therapy. METHODS: We did an open-label, multicentre, single-arm, phase 2 trial across 38 outpatient clinics, primarily at academic medical centres, in Canada, Europe, and the USA. Eligible patients (aged ≥18 years and with an Eastern Cooperative Oncology Group performance status of 0 or 1) with a histologically confirmed diagnosis of metastatic basal cell carcinoma (group 1) or locally advanced basal cell carcinoma (group 2) who had progressed on or were intolerant to previous HHI therapy were enrolled. Patients were not candidates for further HHI therapy due to progression of disease on or intolerance to previous HHI therapy or having no better than stable disease after 9 months on HHI therapy. Patients received cemiplimab 350 mg intravenously every 3 weeks for up to 93 weeks or until progression or unacceptable toxicity. The primary endpoint was objective response by independent central review. Analyses were done as per the intention-to-treat principle. The safety analysis comprised all patients who received at least one dose of cemiplimab. The primary analysis is reported only for group 2; group 1 data have not reached maturity and will be reported when the timepoint, according to the statistical analysis plan, has been reached. This study is registered with ClinicalTrials.gov, NCT03132636, and is no longer recruiting new participants. FINDINGS: Between Nov 16, 2017, and Jan 7, 2019, 84 patients were enrolled and treated with cemiplimab. At data cutoff on Feb 17, 2020, median duration of follow-up was 15 months (IQR 8-18). An objective response per independent central review was observed in 26 (31%; 95% CI 21-42) of 84 patients, including two partial responses that emerged at tumour assessments before the data cutoff and were confirmed by tumour assessments done subsequent to the data cutoff. The best overall response was five (6%) patients with a complete response and 21 (25%) with a partial response. Grade 3-4 treatment-emergent adverse events occurred in 40 (48%) of 84 patients; the most common were hypertension (four [5%] of 84 patients) and colitis (four [5%]). Serious treatment-emergent adverse events occurred in 29 (35%) of 84 patients. There were no treatment-related deaths. INTERPRETATION: Cemiplimab exhibited clinically meaningful antitumour activity and an acceptable safety profile in patients with locally advanced basal cell carcinoma after HHI therapy. FUNDING: Regeneron Pharmaceuticals and Sanofi.

Mobile snapshot hyperspectral imaging device for skin evaluation using diffractive optical elements.

OBJECTIVE: A mobile handheld snapshot hyperspectral imaging device was developed and tested for in vivo skin evaluation using a new spectral imaging technology. METHODS: The device is equipped with four different LED light sources (VIS, 810 nm, 850 nm, and 940 nm) for illumination. Based on a diffractive optical element (DOE) combined with a CMOS sensor chip, a snapshot hyperspectral imager is achieved for the application on human skin. The diffractive optical element (DOE) consists of a two-dimensional array of identically repeated diffractive microstructures. One hyperspectral image for all wavelength regions is taken within a few seconds. Complex recalculation of the VIS spectral distribution and image information from the received DOE image requires several minutes, depending on computing performance. A risk assessment on the irradiation sources shows no risk of harm due to the LED radiation. RESULTS: Skin tone color patches experiments reproducibly deliver images and spectra of different skin tones. First in vivo use of the device identified pigmentation changes within the field of view. CONCLUSION: We present a working mobile snapshot hyperspectral imaging tool based on diffractive optical elements. This device or future developments thereof can be used for broad skin evaluation in vivo.

Multi-wavelength, handheld laser speckle imaging for skin evaluation.

OBJECTIVE: A handheld device was developed and qualified for in vivo human skin evaluation using laser speckle imaging technology. METHODS: Each laser speckle device prototype allows the choice of up to three different laser wavelengths in the range of 400 nm to 800 nm in total. Speckle pattern analysis gives various speckle parameters, for example, speckle contrast, speckle size, speckle modulation or fractal dimension. The developed laser speckle device prototypes were evaluated investigating three skin issues. RESULTS: We receive reproducible results from the speckle imaging device. For skin ageing, we found significant changes within three age groups. The effect of a methyl nicotinate treatment was clearly visible and quantifiable using a moorFLPI device as well as our speckle imaging device. In terms of basal cell carcinoma diagnosis, we found significant differences between normal and diseased skin, even though the number of samples was limited. CONCLUSION: As shown with first application examples, it was possible to demonstrate the potential of the method for skin evaluation in vivo.

Aprepitant in Anti-histamine-refractory Chronic Nodular Prurigo: A Multicentre, Randomized, Double-blind, Placebo-controlled, Cross-over, Phase-II trial (APREPRU).

The aim of this multicentre, randomized, double-blind, placebo-controlled, cross-over, phase-II study was to determine the antipruritic effect of aprepitant vs. placebo in 58 patients with anti-histamine-refractory chronic pruritus in chronic nodular prurigo. Patients were randomized to receive either first oral aprepitant 80 mg/day or placebo for 4 weeks. Following a 2-week wash-out phase, the patients were crossed-over to receive the other treatment for 4 weeks. Primary efficacy criterion was the intra-individual difference between mean itch intensity (visual analogue scale) at baseline compared with the end of treatment period. Prurigo lesions, pruritus course, quality of life, patient benefits, and safety were secondary parameters. No significant differences were found between aprepitant treatment and placebo for any of the parameters investigated. Under the experimental conditions of the study, aprepitant, 80 mg daily for 4 weeks, did not have an antipruritic effect in patients with chronic prurigo. (DRKS00005594; EudraCT Number: 2013-001601-85).

Low levels of classical BSE infectivity in rendered fat tissue.

BSE infectivity in mesentery fat is most likely associated with embedded nervous tissue. To prove this mesentery containing celiac ganglion was taken from oral BSE infected cattle in different stages of the disease and from one control animal. Fat was rendered according to standard tallow production methods and the prion infectivity therein analysed in transgenic mouse bioassay. Rendered fat of the clinical animal revealed low infectivity levels, whereas preclinical and control animals remained negative. This study, although not representative, provides a proof of principle, indicating the potential contamination of melted mesenteric fat by embedded nervous structures during standard tallow production.

Complete lymph node dissection versus no dissection in patients with sentinel lymph node biopsy positive melanoma (DeCOG-SLT): a multicentre, randomised, phase 3 trial.

BACKGROUND: Complete lymph node dissection is recommended in patients with positive sentinel lymph node biopsy results. To date, the effect of complete lymph node dissection on prognosis is controversial. In the DeCOG-SLT trial, we assessed whether complete lymph node dissection resulted in increased survival compared with observation. METHODS: In this multicentre, randomised, phase 3 trial, we enrolled patients with cutaneous melanoma of the torso, arms, or legs from 41 German skin cancer centres. Patients with positive sentinel lymph node biopsy results were eligible. Patients were randomly assigned (1:1) to undergo complete lymph node dissection or observation with permuted blocks of variable size and stratified by primary tumour thickness, ulceration of primary tumour, and intended adjuvant interferon therapy. Treatment assignment was not masked. The primary endpoint was distant metastasis-free survival and analysed by intention to treat. All patients in the intention-to-treat population of the complete lymph node dissection group were included in the safety analysis. This trial is registered with ClinicalTrials.gov, number NCT02434107. Follow-up is ongoing, but the trial no longer recruiting patients. FINDINGS: Between Jan 1, 2006, and Dec 1, 2014, 5547 patients were screened with sentinel lymph node biopsy and 1269 (23%) patients were positive for micrometastasis. Of these, 483 (39%) agreed to randomisation into the clinical trial; due to difficulties enrolling and a low event rate the trial closed early on Dec 1, 2014. 241 patients were randomly assigned to the observation group and 242 to the complete lymph node dissection group. Ten patients did not meet the inclusion criteria, so 233 patients were analysed in the observation group and 240 patients were analysed in the complete lymph node dissection group, as the intention-to-treat population. 311 (66%) patients (158 in the observation group and 153 in the dissection group) had sentinel lymph node metastases of 1 mm or less. Median follow-up was 35 months (IQR 20-54). Distant metastasis-free survival at 3 years was 77·0% (90% CI 71·9-82·1; 55 events) in the observation group and 74·9% (69·5-80·3; 54 events) in the complete lymph node dissection group. In the complete lymph node dissection group, grade 3 and 4 events occurred in 15 patients (6%) and 19 patients (8%) patients, respectively. Adverse events included lymph oedema (grade 3 in seven patients, grade 4 in 13 patients), lymph fistula (grade 3 in one patient, grade 4 in two patients), seroma (grade 3 in three patients, no grade 4), infection (grade 3 in three patients, no grade 4), and delayed wound healing (grade 3 in one patient, grade 4 in four patients); no serious adverse events were reported. INTERPRETATION: Although we did not achieve the required number of events, leading to the trial being underpowered, our results showed no difference in survival in patients treated with complete lymph node dissection compared with observation only. Consequently, complete lymph node dissection should not be recommended in patients with melanoma with lymph node micrometastases of at least a diameter of 1 mm or smaller. FUNDING: German Cancer Aid.

Genetic, histochemical and biochemical studies on goat TSE cases from Cyprus.

Scrapie and bovine spongiform encephalopathy (BSE) are transmissible spongiform encephalopathies (TSE's) affecting sheep and goats. Susceptibility of goats to scrapie is influenced by polymorphisms of the prion protein gene (PRNP) of the host. Five polymorphisms are associated with reduced susceptibility to TSE's. In the study presented here caprine samples from a scrapie eradication program on Cyprus were genotyped and further characterized using BioRad TeSeE rapid test, histological, immunohistochemical and biochemical methods. In total 42 goats from 20 flocks were necropsied from which 25 goats showed a positive result in the rapid test, a spongiform encephalopathy and an accumulation of pathological prion protein (PrPSc) in the obex. PrPSc deposits were demonstrated in the placenta, peripheral nervous and lymphoreticular system. Two animals showed PrPSc-accumulations in peripheral tissues only. By discriminatory immunoblots a scrapie infection could be confirmed for all cases. Nevertheless, slight deviations in the glycosylation pattern might indicate the presence of different scrapie strains. Furthermore scrapie samples from goats in the current study demonstrated less long term resistance to proteinase K than ovine or caprine BSE control samples. Reduced scrapie susceptibility according to the PRNP genotype was demonstrated (Fishers Exact test, p < 0.05) for the goats with at least one polymorphism (p = 0.023) at the six codons examined and in particular for those with polymorphisms at codon 146 (p = 0.016). This work characterizes scrapie in goats having implications for breeding and surveillance strategies.

The 12-month analysis from Basal Cell Carcinoma Outcomes with LDE225 Treatment (BOLT): A phase II, randomized, double-blind study of sonidegib in patients with advanced basal cell carcinoma.

BACKGROUND: The hedgehog pathway inhibitor sonidegib demonstrated meaningful tumor shrinkage in more than 90% of patients with locally advanced basal cell carcinoma (BCC) or metastatic BCC in the BCC Outcomes with LDE225 Treatment study. OBJECTIVE: This report provides long-term follow-up data collected up to 12 months after the last patient was randomized. METHODS: In this multicenter, randomized, double-blind phase II study, patients were randomized 1:2 to sonidegib 200 or 800 mg. The primary end point was objective response rate assessed by central review. RESULTS: Objective response rates in the 200- and 800-mg arms were 57.6% and 43.8% in locally advanced BCC and 7.7% and 17.4% in metastatic BCC, respectively. Among the 94 patients with locally advanced BCC who responded, only 18 progressed or died and more than 50% had responses lasting longer than 6 months. In addition, 4 of 5 responders with metastatic BCC maintained an objective response. Grade 3/4 adverse events and those leading to discontinuation were less frequent with sonidegib 200 versus 800 mg (38.0% vs 59.3%; 27.8% vs 37.3%, respectively). LIMITATIONS: No placebo or comparator arms were used because sonidegib demonstrated efficacy in advanced BCC in a phase I study, and the hedgehog pathway inhibitor vismodegib was not yet approved. CONCLUSION: With longer follow-up, sonidegib demonstrated sustained tumor responses in patients with advanced BCC.

Retrospective chart analysis of incidental findings detected by (18) F-fluorodeoxyglucose-PET/CT in patients with cutaneous malignant melanoma.

BACKGROUND AND OBJECTIVES: (18) F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) frequently reveals incidental findings. The present study focused on incidental FDG-PET/CT findings in cutaneous melanoma patients, and verified their relevance with respect to further diagnostic measures and interventions. PATIENTS AND METHODS: Medical records of 181 consecutive melanoma patients were retrospectively evaluated to verify the management of incidental findings, with particular emphasis on histological findings. RESULTS: Thirty-three of 181 (18 %) patients showed 39 relevant incidental findings, located in the colorectal tract (n  =  15 patients), thyroid (n  =  8), prostate (n  =  2), locomotor system (n  =  2), lymph nodes (n  =  2), parotid gland (n  =  1), tonsils (n  =  1), kidneys (n  =  1), and gallbladder (n  =  1). Performed in 25 patients, additional diagnostic procedures revealed a clinical correlate in 21 cases. Sixteen of 21 patients had tumoral involvement, including five malignant lesions (four colorectal and one prostate carcinoma). The malignancies were diagnosed at an early stage, and successfully removed in the majority of cases. CONCLUSIONS: The diagnostic use of FDG-PET/CT is routinely recommended for stage IIC melanoma and higher, and is widely accepted as indication. This study effectively identified otherwise undetected cancers, especially colorectal malignancies. Early interventions were possible in most cases. Incidental findings on FDG-PET/CT should be worked up with appropriate diagnostic measures, considering the patient's condition and wishes.

Retrospektive Analyse von Zufallsbefunden, die bei Patienten mit kutanem malignen Malignom durch (18) F-Fluordeoxyglucose-PET/CT erhoben wurden.

HINTERGRUND UND ZIELE: Bei der (18) F-Fluordeoxyglucose-Positronenemissionstomographie/Computertomographie (FDG-PET/CT) ergeben sich häufig Zufallsbefunde. In der vorliegenden Studie konzentrierten wir uns auf mittels FDG-PET/CT erhaltene Zufallsbefunde bei Patienten mit kutanem Melanom und überprüften deren Relevanz hinsichtlich weiterer diagnostischer Maßnahmen und Interventionen. PATIENTEN UND METHODEN: Die Krankenakten von 181 konsekutiven Melanom-Patienten wurden retrospektiv ausgewertet, um das Management von Zufallsbefunden zu dokumentieren. Der Schwerpunkt lag dabei auf den histologischen Befunden. ERGEBNISSE: Bei 33 von 181 (18 %) Patienten lagen 39 relevante Zufallsbefunde vor, und zwar im Kolorektalbereich (n = 15 Patienten), in der Schilddrüse (n = 8), der Prostata (n = 2), dem Bewegungsapparat (n = 2), in Lymphknoten (n = 2), der Parotis (n = 1), den Mandeln (n = 1), den Nieren (n = 1) und der Gallenblase (n = 1). Bei 25 Patienten schlossen sich weitere diagnostische Verfahren an, wobei in 21 Fällen ein klinisches Korrelat nachgewiesen wurde. Bei 16 von 21 Patienten ergab sich eine Neoplasie, darunter fünf maligne Läsionen (vier Kolonkarzinome und ein Prostatakarzinom). Die Malignome wurden frühzeitig diagnostiziert und in der Mehrzahl der Fälle erfolgreich entfernt. SCHLUSSFOLGERUNGEN: Der Einsatz der FDG-PET/CT als Routine-Diagnostik wird in den Leitlinien empfohlen und ist indiziert bei malignem Melanom ab Stadium IIC. In dieser Studie wurden auf effektive Weise ansonsten nicht erkannte Krebserkrankungen, insbesondere Kolonkarzinome, detektiert. In den meisten Fällen war eine frühe Intervention möglich. Zufallsbefunde durch FDG-PET/CT sollten, unter Berücksichtigung des Zustands und der Wünsche des Patienten, mit den geeigneten diagnostischen Maßnahmen abgeklärt werden.

Treatment with two different doses of sonidegib in patients with locally advanced or metastatic basal cell carcinoma (BOLT): a multicentre, randomised, double-blind phase 2 trial.

BACKGROUND: Patients with advanced basal cell carcinoma have limited treatment options. Hedgehog pathway signalling is aberrantly activated in around 95% of tumours. We assessed the antitumour activity of sonidegib, a Hedgehog signalling inhibitor, in patients with advanced basal cell carcinoma. METHODS: BOLT is an ongoing multicentre, randomised, double-blind, phase 2 trial. Eligible patients had locally advanced basal cell carcinoma not amenable to curative surgery or radiation or metastatic basal cell carcinoma. Patients were randomised via an automated system in a 1:2 ratio to receive 200 mg or 800 mg oral sonidegib daily, stratified by disease, histological subtype, and geographical region. The primary endpoint was the proportion of patients who achieved an objective response, assessed in the primary efficacy analysis population (patients with fully assessable locally advanced disease and all those with metastatic disease) with data collected up to 6 months after randomisation of the last patient. This trial is registered with ClinicalTrials.gov, number NCT01327053. FINDINGS: Between July 20, 2011, and Jan 10, 2013, we enrolled 230 patients, 79 in the 200 mg sonidegib group, and 151 in the 800 mg sonidegib group. Median follow-up was 13·9 months (IQR 10·1-17·3). In the primary efficacy analysis population, 20 (36%, 95% CI 24-50) of 55 patients receiving 200 mg sonidegib and 39 (34%, 25-43) of 116 receiving 800 mg sonidegib achieved an objective response. In the 200 mg sonidegib group, 18 (43%, 95% CI 28-59) patients who achieved an objective response, as assessed by central review, were noted among the 42 with locally advanced basal cell carcinoma and two (15%, 2-45) among the 13 with metastatic disease. In the 800 mg group, 35 (38%, 95% CI 28-48) of 93 patients with locally advanced disease had an objective response, as assessed by central review, as did four (17%, 5-39) of 23 with metastatic disease. Fewer adverse events leading to dose interruptions or reductions (25 [32%] of 79 patients vs 90 [60%] of 150) or treatment discontinuation (17 [22%] vs 54 [36%]) occurred in patients in the 200 mg group than in the 800 mg group. The most common grade 3-4 adverse events were raised creatine kinase (five [6%] in the 200 mg group vs 19 [13%] in the 800 mg group) and lipase concentration (four [5%] vs eight [5%]). Serious adverse events occurred in 11 (14%) of 79 patients in the 200 mg group and 45 (30%) of 150 patients in the 800 mg group. INTERPRETATION: The benefit-to-risk profile of 200 mg sonidegib might offer a new treatment option for patients with advanced basal cell carcinoma, a population that is difficult to treat. FUNDING: Novartis Pharmaceuticals Corporation.

Effectiveness, safety and utilization of cobimetinib and vemurafenib in patients with BRAF V600 mutant melanoma with and without cerebral metastasis under real-world conditions in Germany: the non-interventional study coveNIS.

Cobimetinib/vemurafenib combination therapy is approved for treatment of adults with unresectable or metastatic BRAF V600 mutated malignant melanoma (mM). The non-interventional post-authorisation safety study coveNIS collected real-world data on cobimetinib/vemurafenib treatment focussing on overall survival (OS), safety and utilization. MM patients with brain metastases are usually excluded from clinical studies. coveNIS observed 2 cohorts: mM patients without (Cohort A) and with cerebral metastases (Cohort B), aiming to close the data gap for the latter population. A direct comparison of the 2 cohorts was not intended. The primary effectiveness objective was OS; the safety objective was the incidence of all and of serious adverse events (AEs). Secondary objectives included progression-free survival (PFS), time to development of cerebral metastasis (Cohort A) and time to central nervous system relapse (Cohort B). All statistical analyses were descriptive. Between 2017 and 2021, 95 patients were included (Cohort A: 54, Cohort B: 41 patients) at 32 sites in Germany. Median OS was 21.6 months in Cohort A, 7.4 months in Cohort B. Median PFS was 6.9 months in Cohort A, 5.2 months in Cohort B. The proportion of patients experiencing any AEs was 83.3% (Cohort A) and 87.8% (Cohort B). The two most common AEs in Cohort A were 'diarrhoea' (37%), 'vomiting' (20.4%) and 'pyrexia' (20.4%); in Cohort B 'diarrhoea' (36.6%) and 'fatigue' (22%). In conclusion, the OS rates in Cohort A and Cohort B of coveNIS are in line with the OS data from other trials with BRAF/MEK inhibitors for mM. No new safety signals were observed.

Icatibant, a new bradykinin-receptor antagonist, in hereditary angioedema.

BACKGROUND: Hereditary angioedema is characterized by recurrent attacks of angioedema of the skin, larynx, and gastrointestinal tract. Bradykinin is the key mediator of symptoms. Icatibant is a selective bradykinin B2 receptor antagonist. METHODS: In two double-blind, randomized, multicenter trials, we evaluated the effect of icatibant in patients with hereditary angioedema presenting with cutaneous or abdominal attacks. In the For Angioedema Subcutaneous Treatment (FAST) 1 trial, patients received either icatibant or placebo; in FAST-2, patients received either icatibant or oral tranexamic acid, at a dose of 3 g daily for 2 days. Icatibant was given once, subcutaneously, at a dose of 30 mg. The primary end point was the median time to clinically significant relief of symptoms. RESULTS: A total of 56 and 74 patients underwent randomization in the FAST-1 and FAST-2 trials, respectively. The primary end point was reached in 2.5 hours with icatibant versus 4.6 hours with placebo in the FAST-1 trial (P=0.14) and in 2.0 hours with icatibant versus 12.0 hours with tranexamic acid in the FAST-2 trial (P<0.001). In the FAST-1 study, 3 recipients of icatibant and 13 recipients of placebo needed treatment with rescue medication. The median time to first improvement of symptoms, as assessed by patients and by investigators, was significantly shorter with icatibant in both trials. No icatibant-related serious adverse events were reported. CONCLUSIONS: In patients with hereditary angioedema having acute attacks, we found a significant benefit of icatibant as compared with tranexamic acid in one trial and a nonsignificant benefit of icatibant as compared with placebo in the other trial with regard to the primary end point. The early use of rescue medication may have obscured the benefit of icatibant in the placebo trial. (Funded by Jerini; ClinicalTrials.gov numbers, NCT00097695 and NCT00500656.)

Spread of classic BSE prions from the gut via the peripheral nervous system to the brain.

An experimental oral bovine spongiform encephalopathy (BSE) challenge study was performed to elucidate the route of infectious prions from the gut to the central nervous system in preclinical and clinical infected animals. Tissue samples collected from the gut and the central and autonomic nervous system from animals sacrificed between 16 and 44 months post infection (mpi) were examined for the presence of the pathological prion protein (PrP(Sc)) by IHC. Moreover, parts of these samples were also bioassayed using bovine cellular prion protein (PrP(C)) overexpressing transgenic mice (Tgbov XV) that lack the species barrier for bovine prions. A distinct accumulation of PrP(Sc) was observed in the distal ileum, confined to follicles and/or the enteric nervous system, in almost all animals. BSE prions were found in the sympathetic nervous system starting at 16 mpi, and in the parasympathetic nervous system from 20 mpi. A clear dissociation between prion infectivity and detectable PrP(Sc) deposition became obvious. The earliest presence of infectivity in the brain stem was detected at 24 mpi, whereas PrP(Sc) accumulation was first detected after 28 mpi. In summary, our results decipher the centripetal spread of BSE prions along the autonomic nervous system to the central nervous system, starting already halfway in the incubation time.

Malignant melanoma S3-guideline "diagnosis, therapy and follow-up of melanoma".

This first German evidence-based guideline for cutaneous melanoma was developed under the auspices of the German Dermatological Society (DDG) and the Dermatologic Cooperative Oncology Group (DeCOG) and funded by the German Guideline Program in Oncology. The recommendations are based on a systematic literature search, and on the consensus of 32 medical societies, working groups and patient representatives. This guideline contains recommendations concerning diagnosis, therapy and follow-up of melanoma. The diagnosis of primary melanoma based on clinical features and dermoscopic criteria. It is confirmed by histopathologic examination after complete excision with a small margin. For the staging of melanoma, the AJCC classification of 2009 is used. The definitive excision margins are 0.5 cm for in situ melanomas, 1 cm for melanomas with up to 2 mm tumor thickness and 2 cm for thicker melanomas, they are reached in a secondary excision. From 1 mm tumor thickness, sentinel lymph node biopsy is recommended. For stages II and III, adjuvant therapy with interferon-alpha should be considered after careful analysis of the benefits and possible risks. In the stage of locoregional metastasis surgical treatment with complete lymphadenectomy is the treatment of choice. In the presence of distant metastasis mutational screening should be performed for BRAF mutation, and eventually for CKIT and NRAS mutations. In the presence of mutations in case of inoperable metastases targeted therapies should be applied. Furthermore, in addition to standard chemotherapies, new immunotherapies such as the CTLA-4 antibody ipilimumab are available. Regular follow-up examinations are recommended for a period of 10 years, with an intensified schedule for the first three years.