Scabies is one of the most common and, in terms of burden of disease, one of the most significant skin diseases worldwide. In Germany, an increase in cases is currently being discussed, for which ...reliable data have been lacking until now.
The goal is to clarify the prevalence and treatment of scabies in Germany.
Multisource analyses of treatment data from a nationwide statutory health insurance company, the Federal Statistical Office and company skin screenings.
In Germany, the number of cases of scabies has been rising since 2009 and especially since 2014. In the outpatient setting, there was an increase of 52.8% to around 128,000 treatment cases between 2010 and 2015. Currently, more than 11,000 inpatient cases are documented annually in Germany with scabies as the main diagnosis (ICD-10 B86). The increase between 2010 and 2016 was about 306%. The main outpatient specialist groups providing care are dermatologists and general practitioners, while in the inpatient sector treatment is provided by departments of dermatology, paediatrics and internal medicine.
Due to the aforementioned development of prevalence and incidence, the need for care will remain at a high level in the future, which suggests an increased need for education and early detection.
Postoperative myocardial revascularization atrial fibrillation (POAF) is a clinical complication that affects about 30% of patients and its mechanisms of origin are still poorly understood. This fact ...makes it difficult to identify the patient at greatest risk for this arrhythmia. This mission seems evident due to the complications it entails, including longer hospital stays, risk of stroke, heart failure, and death. There are reports of preoperative clinical aspects inherent to the patient's condition, such as gender and age, and discontinuation of beta-blockers as risk factors. In addition, additional information obtained by electrocardiogram, echocardiogram, and blood count data, for example, present only modest predictive results. The analysis of heart rate and heart rate variability obtained by the Stroke Risk Analysis System (SRA) is a technique used to predict ambulatory atrial fibrillation (AF), using recordings of only one hour showing good accuracy. This system, however, has not yet been used to predict the emergence of POAF. The rationale for its use is based on the suspicion that the emergence of POAF is strongly related to sympatho-vagal imbalance and the increase in atrial ectopia, that is, changes in heart rhythm, the main variables analyzed by the SRA algorithm.
To assess the accuracy of the SRA to identify patients at risk of having POAF after coronary artery bypass graft surgery (CABG).
114 consecutive patients with coronary artery disease underwent coronary artery bypass grafting between the years 2015 and 2018. Between the first and fifth postoperative days, they underwent continuous electrocardiographic monitoring using the Holter system for cardiac rhythm analysis. Patients were divided into two groups: Group I was formed of those with POAF and Group II included patients without POAF. The tracings obtained by Holter were reanalyzed using the CardioManager®/Cardios program, converted and divided into one-hour sections using the SRA®/Cardios and Geratherm Converter program and submitted to the SRA-Apoplex medical/Geratherm® analysis algorithm. The SRA identifies three possibilities for classifying patient risk: a) Risk 0: patient in sinus rhythm; b) Risk 1: patient at increased risk for paroxysmal AF; c) Risk 2: patient with AF already present. For Group I, SRA were considered positive when Risks 1 and 2 were identified. For Group II, those identified as Risk 0 were considered negative SRA.
POAF occurred in 33/114 patients (28%). The sensitivity, specificity, positive predictive value, and negative predictive value of the SRA to identify patients with POAF were 69%, 84%, 69%, and 82%, respectively; the positive and negative likelihood ratios, in addition to the accuracy of the SRA were, respectively, 4.3%, 0.36%, and 79%. A subanalysis of the results of the day on which AF occurred was performed on the records obtained in the first three hours of recording and up to three hours before the appearance of POAF. In the first period, the SRA was able to predict POAF in 57% of cases, while in the second period, the system identified the arrhythmia in 83% of cases.
a) The SRA presents good accuracy to predict POAF; b) its accuracy is moderate in the first three hours of recording; c) the accuracy increases significantly near the beginning of POAF; d) these findings indicate that electrophysiological changes that precede POAF are acute, occurring a few hours before the event and are identified by the SRA algorithm.
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.
Patients with melanoma who had a median of 12 injectable metastases received intratumoral IL-2 treatments 3 times weekly until they achieved clinical remission. The initial dose of 3 million international units was escalated, depending on the individual patient's tolerance.
Forty-eight of 51 patients were evaluable. Only grade 1/2 toxicity was recorded. A complete response that lasted >/=6 months was documented in 70% of all injected metastases. A complete local response of all treated metastases was achieved in 33 patients (69%), including 11 patients who had between 20 and 100 metastases. Response rates were higher for patients who had stage III disease compared with patients who had stage IV disease. No objective responses of distant untreated metastases were observed. The 2-year survival rate was 77% for patients with stage IIIB/IIIC disease and 53% for patients with stage IV disease. Efficacy and survival did not differ between patients who had >/=20 lesions and patients who had <20 lesions.
Intratumoral IL-2 treatment elicited complete local responses in a high percentage of patients. Further studies will be required to investigate the mode of action of this treatment and its impact on survival.
Microsatellite instability (MSI) resulting from inactivation of the DNA mismatch repair system (MMR) characterizes a highly immunological subtype of colorectal carcinomas. Those tumors express ...multiple frameshift-mutated proteins which present a unique pool of tumor-specific antigens. The DNA MMR protein MSH3 is frequently mutated in MSI(+) colorectal tumors, thus making it an attractive candidate for T cell-based immunotherapies.
FSP-specific CD8(+) T cells were generated from a healthy donor using reverse immunology. Those T cells specifically recognized T2 cells sensitized with the respective peptides. Specific recognition and killing of MSI(+) colorectal carcinoma cells harbouring the mutated reading frame was observed. The results obtained with T cell bulk cultures could be reproduced with T cell clones obtained from the same cultures. Blocking experiments (using antibodies and cold target inhibition) confirmed peptide as well as HLA-A0201-specificity.
We identified two novel HLA-A0201-restricted cytotoxic T cell epitopes derived from a (-1) frameshift mutation of a coding A(8) tract within the MSH3 gene. These were (386)-FLLALWECSL (FSP18) and (387)-LLALWECSL (FSP19) as well as (403)-IVSRTLLLV (FSP23) and (402)-LIVSRTLLLV (FSP31), respectively. These results suggest that MSH3(-1) represents another promising MSI(+)-induced target antigen. By identifying two distinct epitopes within MSH3(-1), the sustained immunogenicity of the frameshift mutated sequence was confirmed. Our data therefore encourage further exploitation of MSH3 as a piece for peptide-based vaccines either for therapeutic or--even more important--preventive purposes.
The protein pattern of healthy human eccrine sweat was investigated and 10 major proteins were detected from which apolipoprotein D, lipophilin B, and cathepsin D (CatD) were identified for the first ...time in human eccrine sweat. We focused our studies on the function of the aspartate protease CatD in sweat. In vitro digestion experiments using a specific fluorescent CatD substrate showed that CatD is enzymatically active in human sweat. To identify potential substrates of CatD in human eccrine sweat LL-37 and DCD-1L, two antimicrobial peptides present in sweat, were digested in vitro with purified CatD. LL-37 was not significantly digested by CatD, whereas DCD-1L was cleaved between Leu44 and Asp45 and between Leu29 and Glu30 almost completely. The DCD-1L-derived peptides generated in vitro by CatD were also found in vivo in human sweat as determined by surface-enhanced laser desorption/ionization (SELDI) mass spectrometry. Furthermore, besides the CatD-processed peptides we identified additionally DCD-1L-derived peptides that are generated upon cleavage with a 1,10-phenanthroline-sensitive carboxypeptidase and an endoprotease. Taken together, proteolytic processing generates 12 DCD-1L-derived peptides. To elucidate the functional significance of postsecretory processing the antimicrobial activity of three CatD-processed DCD-1L peptides was tested. Whereas two of these peptides showed no activity against Gram-positive and Gram-negative bacteria, one DCD-1L-derived peptide showed an even higher activity against Escherichia coli than DCD-1L. Functional analysis indicated that proteolytic processing of DCD-1L by CatD in human sweat modulates the innate immune defense of human skin.
BackgroundNivolumab combined with ipilimumab have shown activity in melanoma brain metastasis (MBM). However, in most of the clinical trials investigating immunotherapy in this subgroup, patients ...with symptomatic MBM and/or prior local brain radiotherapy were excluded. We studied the efficacy of nivolumab plus ipilimumab alone or in combination with local therapies regardless of treatment line in patients with asymptomatic and symptomatic MBM.MethodsPatients with MBM treated with nivolumab plus ipilimumab in 23 German Skin Cancer Centers between April 2015 and October 2018 were investigated. Overall survival (OS) was evaluated by Kaplan-Meier estimator and univariate and multivariate Cox proportional hazard analyses were performed to determine prognostic factors associated with OS.ResultsThree hundred and eighty patients were included in this study and 31% had symptomatic MBM (60/193 with data available) at the time of start nivolumab plus ipilimumab. The median follow-up was 18 months and the 2 years and 3 years OS rates were 41% and 30%, respectively. We identified the following independently significant prognostic factors for OS: elevated serum lactate dehydrogenase and protein S100B levels, number of MBM and Eastern Cooperative Oncology Group performance status. In these patients treated with checkpoint inhibition first-line or later, in the subgroup of patients with BRAFV600-mutated melanoma we found no differences in terms of OS when receiving first-line either BRAF and MEK inhibitors or nivolumab plus ipilimumab (p=0.085). In BRAF wild-type patients treated with nivolumab plus ipilimumab in first-line or later there was also no difference in OS (p=0.996). Local therapy with stereotactic radiosurgery or surgery led to an improvement in OS compared with not receiving local therapy (p=0.009), regardless of the timepoint of the local therapy. Receiving combined immunotherapy for MBM in first-line or at a later time point made no difference in terms of OS in this study population (p=0.119).ConclusionImmunotherapy with nivolumab plus ipilimumab, particularly in combination with stereotactic radiosurgery or surgery improves OS in asymptomatic and symptomatic MBM.
BackgroundSkin cancers are known for their strong immunogenicity, which may contribute to a high treatment efficacy of immune checkpoint inhibition (ICI). However, a considerable proportion of ...patients with skin cancer is immuno-compromised by concomitant diseases. Due to their previous exclusion from clinical trials, the ICI treatment efficacy is poorly investigated in these patients. The present study analyzed the ICI treatment outcome in advanced patients with skin cancer with a concomitant hematological malignancy.MethodsThis retrospective multicenter study included patients who were treated with ICI for locally advanced or metastatic melanoma (MM), cutaneous squamous cell carcinoma (cSCC), or Merkel cell carcinoma (MCC), and had a previous diagnosis of a hematological malignancy irrespective of disease activity or need of therapy at ICI treatment start. Comparator patient cohorts without concomitant hematological malignancy were extracted from the prospective multicenter skin cancer registry ADOREG. Treatment outcome was measured as best overall response, progression-free (PFS), and overall survival (OS).Results84 patients (MM, n=52; cSCC, n=15; MCC, n=17) with concomitant hematological malignancy were identified at 20 skin cancer centers. The most frequent concomitant hematological malignancies were non-Hodgkin’s lymphoma (n=70), with chronic lymphocytic leukemia (n=32) being the largest entity. While 9 patients received ICI in an adjuvant setting, 75 patients were treated for advanced non-resectable disease (55 anti-PD-1; 8 anti-PD-L1; 5 anti-CTLA-4; 7 combinations). In the latter 75 patients, best objective response (complete response+partial response) was 28.0%, disease stabilization was 25.3%, and 38.6% showed progressive disease (PD). Subdivided by skin cancer entity, best objective response was 31.1% (MM), 26.7% (cSCC), and 18.8% (MCC). Median PFS was 8.4 months (MM), 4.0 months (cSCC), and 5.7 months (MCC). 1-year OS rates were 78.4% (MM), 65.8% (cSCC), and 47.4% (MCC). Comparison with respective ADOREG patient cohorts without hematological malignancy (n=392) revealed no relevant differences in ICI therapy outcome for MM and MCC, but a significantly reduced PFS for cSCC (p=0.002).ConclusionsICI therapy showed efficacy in advanced patients with skin cancer with a concomitant hematological malignancy. Compared with patients without hematological malignancy, the observed ICI therapy outcome was impaired in cSCC, but not in MM or MCC patients.
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