Nivolumab for locally advanced and metastatic cutaneous squamous cell carcinoma (NIVOSQUACS study)-Phase II data covering impact of concomitant haematological malignancies.

BACKGROUND: Monoclonal antibodies, such as cemiplimab and pembrolizumab, against the programmed death receptor (PD)-1 have become the current standard of care and first-line treatment of advanced cutaneous squamous cell carcinoma (cSCC), proving remarkable clinical benefit and acceptable safety. OBJECTIVES: To assess efficacy and safety of the anti-PD-1 antibody nivolumab in patients with locally advanced and metastatic cSCC. METHODS: Patients received open-label nivolumab 240 mg intravenously every 2 weeks for up to 24 months. Patients with concomitant haematological malignancies (CHMs), either non-progressing or stable under active therapy, were eligible for inclusion. RESULTS: Of 31 patients with a median age of 80 years, 22.6% of patients achieved an investigator assessed complete response, resulting in an objective response rate (ORR) of 61.3% and a disease control rate (DCR) of 64.5%. Progression-free survival (PFS) was 11.1 months, and the median overall survival (OS) was not reached after 24 weeks of therapy. Median follow-up was 23.82 months. Subgroup analysis of the CHM cohort (n = 11; 35%) revealed an ORR of 45.5%, a DCR of 54.5%, a median PFS of 10.9 months, and median OS of 20.7 months. Treatment related adverse events were reported in 58.1% of all patients (19.4% grade 3, the remaining grade 1 or 2). PD-L1 expression and CD-8+ T-cell infiltration did not significantly correlate with clinical response, although a trend towards a shorter PFS of 5.6 months was observed with PD-L1 negativity and low CD8+ intratumoral infiltration. CONCLUSION: This study demonstrated robust clinical efficacy of nivolumab in patients with locally advanced and metastatic cSCCs and a tolerability comparable to data of other anti-PD-1 antibodies. Favourable outcomes were obtained despite involving the oldest hitherto reported study cohort for anti-PD-1 antibodies and a significant proportion of CHM patients prone to high risk tumours and an aggressive course otherwise typically excluded from clinical trials.

[Anesthesiological aspects in patients with epidermolysis bullosa]. / Anästhesiologische Aspekte bei Patienten mit Epidermolysis bullosa.

Epidermolysis bullosa causes blistering due to altered structural proteins of the dermoepidermal junction, resulting in scarring and strictures of the skin and mucous membranes. Affected individuals typically require frequent surgical interventions due to burdensome symptoms and complications of the disease. The anesthesiological management of these patients is inherently challenging. This review article summarizes the relevant features of this patient cohort and provides practical recommendations for care.

[What is the current state of the artificial pancreas in diabetes care?] / Wo steht das künstliche Pankreas in der Diabetestherapie?

The artificial pancreas (also referred to as closed-loop system) brings us one step closer to the decade-long dream of automated insulin delivery. The closed-loop system directs subcutaneous insulin delivery corresponding to the glucose concentration using a control algorithm. Evidence shows that closed-loop systems substantially improve glucose control and quality of life; however, fully automated closed-loop systems have not yet been accomplished. Active input from patients is required for mealtime insulin dosing and corrections. This article provides an overview on the current state of development of the artificial pancreas in the treatment of diabetes.

Extended surgical safety margins and ulceration are associated with an improved prognosis in pleomorphic dermal sarcomas.

BACKGROUND: Pleomorphic dermal sarcomas (PDS) are frequent UV-induced sarcomas of the skin of intermediate grade malignant potential. Despite the fact that PDS have a noteworthy potential to recur (up to 28%) as well as to metastasize (up to 20%), there are no specific clinical guidelines with respect to follow-up these patients. Moreover, little is known about clinical, histological or molecular prognostic factors in PDS. OBJECTIVE: The aim of the present study was to identify risk factors to predict relapse in a large multicentre sample cohort of PDS which could aid to optimize personalized treatment recommendations regarding surgical safety margins and adjuvant radiotherapy. METHODS: Patients with a diagnosis of PDS were selected from nine European institutions based on the histopathologic criteria described by Fletcher. Clinicopathologic and follow-up data were collected and statistically analysed calculating univariate hazard ratios with 95% confidence intervals by use of the Cox proportional-hazards model and a significance level of P < 0.05. Patients with an incomplete excision of the tumour were excluded. RESULTS: Univariate Cox regression analysis of possible prognostic factors for progression-free survival (PFS) performed in 92 patients revealed that an excision margin of <2 cm is significantly associated with relapse of PDS [hazard ratio 4.478 (95% CI 1.536-13.055), P = 0.006]. Ulceration of the tumour was associated with a significantly better prognosis [0.396 (0.174-0.904), P = 0.028] whereas adjuvant radiotherapy did not reach statistical significance to improve prognosis in patients with PDS [0.775 (0.231-2.593), P = 0.679]. Gender, age, immunosuppression, intratumoural necrosis, tumour location, vertical thickness or horizontal diameter did not significantly influence PFS in PDS. CONCLUSION: We identified surgical safety margins of <2 cm and absence of ulceration as risk factors for relapse in patients with PDS. These findings may be implemented into both the primary treatment as well as the further monitoring of patients with PDS.

Both the frequency of HbA1c testing and the frequency of self-monitoring of blood glucose predict metabolic control: A multicentre analysis of 15 199 adult type 1 diabetes patients from Germany and Austria.

BACKGROUND: The objective of this study was to examine the association between metabolic control and frequency of haemoglobin A1c (HbA1c ) measurements and of self-monitoring of blood glucose, as well as the interaction of both. METHODS: Data of 15 199 adult type 1 diabetes patients registered in a standardized electronic health record (DPV) were included. To model the association between metabolic control and frequency of HbA1c testing or of self-monitoring of blood glucose, multiple hierarchic regression models with adjustment for confounders were fitted. Tukey-Kramer test was used to adjust P values for multiple comparisons. Vuong test was used to compare non-nested models. RESULTS: The baseline variables of the study population were median age 19.9 [Q1; Q3: 18.4; 32.2] years and diabetes duration 10.4 [6.8; 15.7] years. Haemoglobin A1c was 60.4 [51.5; 72.5] mmol/mol. Frequency of HbA1c testing was 8.0 [5.0; 9.0] within 2 years, and daily self-monitoring of blood glucose frequency was 5.0 [4.0; 6.0]. After adjustment, a U-shaped association between metabolic control and frequency of HbA1c testing was observed with lowest HbA1c levels in the 3-monthly HbA1c testing group. There was an inverse relationship between self-monitoring of blood glucose and HbA1c with lower HbA1c associated with highest frequency of testing (>6 daily measurements). Quarterly HbA1c testing and frequent self-monitoring of blood glucose were associated with best metabolic control. The adjusted Vuong Z statistic suggests that metabolic control might be better explained by HbA1c testing compared to self-monitoring of blood glucose (P < .0001). CONCLUSION: This research reveals the importance of quarterly clinical HbA1c monitoring together with frequent self-monitoring of blood glucose in diabetes management to reach and maintain target HbA1c .

[Mucosal manifestations of epidermolysis bullosa : Clinical presentation and management]. / Schleimhautbeteiligung bei Epidermolysis bullosa : Klinik und Therapiemaßnahmen.

Mucosal lesions occur with different prevalence and severity in all subtypes of hereditary epidermolysis bullosa (EB), a group of rare genodermatoses. They are associated with increased morbidity and mortality, especially in severe junctional and dystrophic subtypes. Despite progress in clinical approaches to curative therapy, the management of these patients is still primarily symptom-oriented. Current recommendations mainly rely on expert opinion and experience from health care professionals of specialized centers, since the rarity of this disease largely limits the availability and feasibility of randomized controlled trials. Accurate preventive and supportive care measures, however, can significantly lessen symptoms, avoid/ameliorate complications, and enhance the quality of life of these patients.

Telomere length increase after weight loss induced by bariatric surgery: results from a 10 year prospective study.

BACKGROUND/OBJECTIVES: Obesity contributes to telomere attrition. Studies focusing on short-term effects of weight loss have been unable to identify protection of telomere length. This study investigates long-term effects of pronounced weight loss induced by bariatric surgery on telomere length. SUBJECTS/METHODS: One hundred forty-two patients were recruited in a prospective, controlled intervention study, follow-up investigations were done after 10.46±1.48 years. A control group of normal weight participants was recruited and followed from 1995 to 2005 in the Bruneck Study. A total of 110 participants from each study was matched by age and sex to compare changes in telomere length. Quantitative PCR was used to determine telomere length. RESULTS: Telomere length increased significantly by 0.024±0.14 (P=0.047) in 142 bariatric patients within 10 years after surgery. The increase was different from telomere attrition in an age- and sex-matched cohort population of the Bruneck Study (-0.057±0.18; ß=0.08; P=0.003). Significant changes in telomere length disappeared after adjusting for baseline body mass index (BMI) because of general differences in BMI and telomere length between the two study populations (ß=0.07; P=0.06). Age was proportional to telomere length in matched bariatric patients (r=0.188; P=0.049) but inversely correlated with telomere length in participants of the Bruneck Study (r=-0.197; P=0.039). There was no association between percent BMI/excess weight loss and telomere attrition in bariatric patients. Baseline telomere length in bariatric patients was inversely associated with baseline plasma cholesterol and triglyceride concentrations. Telomere shortening was associated with lower high-density lipoprotein cholesterol and higher fasting glucose concentration at baseline in bariatric patients. CONCLUSIONS: Increases in relative telomere length were found after bariatric surgery in the long term, presumably due to amelioration of metabolic traits. This may overrule the influence of age and baseline telomere length and facilitate telomere protection in patients experiencing pronounced weight loss.

[Molecular diagnosis of methicillin-resistent Staphylococcus aureus: Methods and efficacy]. / Molekulare Diagnostik von Methicillin-resistentem Staphylococcus aureus : Methoden und Effektivität.

Methicillin-resistant Staphylococcus aureus (MRSA) isolates are a serious public health problem whose ever-increasing rate is commensurate with the pressure it is exerting on the healthcare system. At present, more than 20% of clinical S. aureus isolates in German hospitals are methicillin-resistant, in Austria less than 10%. Strategies from low-prevalence countries show that this development is not necessarily inevitable. In the Scandinavian countries and the Netherlands, thanks to a rigorous prevention programme, MRSA prevalence has been kept at an acceptably low level (< 1-3%). Central to these search-and-destroy control strategies is an admission screening using several MRSA swabs taken from mucocutaneous colonisation sites of high-risk patients (MRSA surveillance). It has also been reported that the speed with which MRSA carriage is detected has an important role, as it is a key component of any effective strategy to prevent the pathogen from spreading. Since MRSA culturing involves a 2-3 day delay before the final results are available, rapid detection techniques (commonly referred to as MRSA rapid tests) using polymerase chain reaction (PCR) methods and, most recently, rapid culturing methods have been developed. The implementation of rapid tests reduces the time of detection of MRSA carriers from 48-72 to 2-5 h. Clinical evaluation data have shown that MRSA can thus be detected with very high sensitivity. Specificity, however, is sometimes impaired due to false-positive PCR signals occurring in mixed flora specimens. In order to rule out false-positive PCR results, a culture screen must always be carried out simultaneously. The data provide preliminary evidence that a PCR assay can reduce nosocomial MRSA transmission in high-risk patients or high-risk areas, whereas an approach that screens all patients admitted to the hospital is probably not effective. Information concerning the cost effectiveness of rapid MRSA tests is still sparse and thus the issue remains debated.

[Molecular diagnostics in melanoma]. / Molekulare Diagnostik beim Melanom.

The molecular landscape of melanoma is changing more rapidly than ever since new molecular technology approaches have made it possible to examine human melanoma for genetic alterations underlying the disease. In recent years, these approaches have identified new familial melanoma susceptibility genes, most of them also conferring risk to other cancers. This has implications for clinical testing and surveillance. Furthermore, molecular testing of melanoma to determine therapeutic eligibility for targeted therapies is now standard of care and should be familiar to the dermatologist.

Long-term effects of weight loss after bariatric surgery on functional and structural markers of atherosclerosis.

OBJECTIVE: Pronounced weight loss after bariatric surgery was demonstrated to have significant beneficial effects on surrogates of early atherosclerosis. The aim of this prospective examination was to investigate whether these improvements of endothelial function and vascular structure are persistent in the long-term. DESIGN AND METHODS: A total of 52 obese adults were examined before and 5 years after bariatric surgery. Carotid intima media thickness (IMT), brachial flow-mediated dilation (FMD), abdominal fat distribution, and metabolic parameters were determined. Additional 18 months data were available from 27 patients. RESULTS: After 5 years, mean weight loss ± SD of 25% ± 12 in all subjects was accompanied by known improvements in metabolism. Change in IMT was -0.02 mm ± 0.007, whereas FMD improved by +1.5% ± 0.5. In the subgroup IMT decreased by 0.04 mm ± 0.06 within the first 18 months, whereas no significant change was observed between 18 month and 5 years. FMD improved by 3.8% ± 0.6 after 18 months followed by a nonsignificant decrease of -1.4% ± 0.9. CONCLUSIONS: These long-term results demonstrate that bariatric surgery-induced weight loss improves both functional and structural markers of early atherosclerosis providing further evidence for the beneficial effects of weight loss on obesity-associated alterations of the vasculature.

[Darier disease]. / Morbus Darier.

Darier disease (Darier-White disease, dyskeratosis follicularis) is a rare autosomal dominant genodermatosis with regional differences in prevalence. The responsible mutations have been identified on chromosome 12q23-24.1. The gene encodes a calcium-ATPase type 2 in the sarco-/endoplasmic reticulum (SERCA2), which belongs to the large family of P-type cation pumps. This pump couples ATP hydrolysis to the transport of cations across membranes and thus plays a significant role in intracellular calcium signaling. Neuropsychiatric disorders are often associated with Darier disease. However, these diseases are not due to mutations in the gene ATP2A2 but to a susceptibility locus in a 6.5 Mb region near this gene. Currently, the treatment is strictly limited to the relief of symptoms. In severe cases, oral retinoids (acitretin: initial 10-20 mg/Tag and isotretinoin: 0.5-1 mg/kg/day) lead to a response in 90% of cases. However, side effects often prevent long-term use of vitamin A derivatives.