Tarun Mehra

T-helper-1-cell cytokines drive cancer into senescence

Cancer control by adaptive immunity involves a number of defined death and clearance mechanisms. However, efficient inhibition of exponential cancer growth by T cells and interferon-γ (IFN-γ) requires additional undefined mechanisms that arrest cancer cell proliferation. Here we show that the combined action of the T-helper-1-cell cytokines IFN-γ and tumour necrosis factor (TNF) directly induces permanent growth arrest in cancers. To safely separate senescence induced by tumour immunity from oncogene-induced senescence, we used a mouse model in which the Simian virus 40 large T antigen (Tag) expressed under the control of the rat insulin promoter creates tumours by attenuating p53- and Rb-mediated cell cycle control. When combined, IFN-γ and TNF drive Tag-expressing cancers into senescence by inducing permanent growth arrest in G1/G0, activation of p16INK4a (also known as CDKN2A), and downstream Rb hypophosphorylation at serine 795. This cytokine-induced senescence strictly requires STAT1 and TNFR1 (also known as TNFRSF1A) signalling in addition to p16INK4a. In vivo, Tag-specific T-helper 1 cells permanently arrest Tag-expressing cancers by inducing IFN-γ- and TNFR1-dependent senescence. Conversely, Tnfr1−/− Tag-expressing cancers resist cytokine-induced senescence and grow aggressively, even in TNFR1-expressing hosts. Finally, as IFN-γ and TNF induce senescence in numerous murine and human cancers, this may be a general mechanism for arresting cancer progression.

Implementation of a patient blood management monitoring and feedback program significantly reduces transfusions and costs

Patient blood management (PBM) measures have been shown to be effective in reducing transfusions while maintaining patient outcome. The issuance of transfusion guidelines is seen as being key to the success of PBM programs. As the introduction of guidelines alone did not visibly reduce transfusions in our center, a monitoring and feedback program was established. The aim of our study was to show the effectiveness of such measures in reducing transfusions and cost.

Alternative approaches to antifungal therapies.

The expansive use of immunosuppressive medications in fields such as transplantational medicine and oncology, the higher frequency of invasive procedures in an ageing population and the HIV/AIDS pandemic have increased the frequency of systemic fungal infections. At the same time, increased resistance of pathogenic fungi to classical antifungal agents has led to sustained research efforts targeting alternative antifungal strategies. In this review, we focus on two promising approaches: cationic peptides and the targeting of fungal virulence factors. Cationic peptides are small, predominantly positively charged protein fragments that exert direct and indirect antifungal activities, one mechanism of action being the permeabilization of the fungal membrane. They include lysozyme, defensins and cathelicidins as well as novel synthetic peptides. Among fungal virulence factors, the targeting of candidal secreted aspartic proteinases seems to be a particularly promising approach.

Brentuximab as a treatment for CD30+ mycosis fungoides and Sézary syndrome.

IMPORTANCE The prognosis of advanced cutaneous T-cell lymphoma (CTCL), including Sézary syndrome and mycosis fungoides (MF), is poor. So far, no curative option apart from allogeneic stem cell transplantation is available. Large cell transformation often hallmarks cases with a more aggressive clinical course, and large tumor cells may express CD30. Recently, brentuximab vedotin, a conjugate of an anti-CD30 antibody and monomethylauristatin E, which inhibits the polymerization of microtubuli, has produced promising results in phase 2 trials in CD30+ Hodgkin lymphoma and anaplastic large cell lymphoma. OBSERVATIONS We describe 4 patients with advanced CTCL, 3 with MF and 1 with Sézary syndrome, who were treated with brentuximab. All patients had received multiple previous systemic therapies. In 2 cases of MF, a remission enabling subsequent allogeneic stem cell transplantation was achieved. CONCLUSIONS AND RELEVANCE Brentuximab is a well-tolerated, promising new treatment option for advanced CTCL that can be integrated in an allogeneic stem cell transplantation plan by selectively depleting malignant CD30+ cutaneous lymphoma cells.

Primary Localization and Tumor Thickness as Prognostic Factors of Survival in Patients with Mucosal Melanoma

Background Data on survival with mucosal melanoma and on prognostic factors of are scarce. It is still unclear if the disease course allows for mucosal melanoma to be treated as primary cutaneous melanoma or if differences in overall survival patterns require adapted therapeutic approaches. Furthermore, this investigation is the first to present 10-year survival rates for mucosal melanomas of different anatomical localizations. Methodology 116 cases from Sep 10 1984 until Feb 15 2011 retrieved from the Comprehensive Cancer Center and of the Central Register of the German Dermatologic Society databases in Tübingen were included in our analysis. We recorded anatomical location and tumor thickness, and estimated overall survival at 2, 5 and 10 years and the mean overall survival time. Survival times were analyzed with the Kaplan-Meier method. The log-rank test was used to compare survival times by localizations and by T-stages. Principal Findings We found a median overall survival time of 80.9 months, with an overall 2-year survival of 71.7%, 5-year survival of 55.8% and 10-year survival of 38.3%. The 10-year survival rates for patients with T1, T2, T3 or T4 stage tumors were 100.0%, 77.9%, 66.3% and 10.6% respectively. 10-year survival of patients with melanomas of the vulva was 64.5% in comparison to 22.3% of patients with non-vulva mucosal melanomas. Conclusion Survival times differed significantly between patients with melanomas of the vulva compared to the rest (p = 0.0006). It also depends on T-stage at the time of diagnosis (p<0.0001).

Expression of CD164 on Malignant T Cells in Sézary Syndrome

Sézary syndrome is a primary cutaneous T-cell lymphoma characterized by pruritic erythroderma, peripheral lymphadenopathy and the presence of malignant T cells in the blood. Unequivocal detection of malignant cells in patients with Sézary syndrome is of important diagnostic, prognostic and therapeutic value. However, no single Sézary syndrome specific cell surface marker has been identified. In a cohort of patients with Sézary syndrome, CD164 expression on total CD4+ lymphocytes was significantly upregulated compared with healthy controls. CD164 expression was in most cases limited to CD4+CD26- malignant T lymphocytes, unequivocally identified using flow-cytometry by the expression of a specific Vβ clone for each patient. Increased expression of CD164 may be a promising diagnostic parameter and a potential target for a CD164-linked therapeutic approach in Sézary syndrome.

Treatment of severe acne with low-dose isotretinoin.

1/M Acne conglobata 8 to 0 0.25 60.5 8.1 None None Elevated serum cholesterol, creatinine kinase at last visit, mild cheilitis 2/M Acne fulminans 8 to 2 0.18 55.5 10.0 Oral methylpred nisolone Adapalene gel Transient elevation of serum TG, mild cheilitis 3/F Acne fulminans 8 to 4 0.15 34.8 7.4 Oral prednisolone Clindamycin/ benzoyl-peroxide Transient elevation of serum cholesterol, γ-GT, TG, mild cheilitis 4/M Acne conglobata 8 to 2 0.16 112.3 16.2 Oral prednisolone Erythromycin cream Transient elevation of cholesterol, TG, alkaline phosphatase, mild cheilitis

Toxic epidermal necrolysis

Toxic epidermal necrolysis (TEN) is a rare, life-threatening drug-induced skin disease with a mortality rate of approximately 30%. The clinical hallmark of TEN is a marked skin detachment caused by extensive keratinocyte cell death associated with mucosal involvement. The exact pathogenic mechanism of TEN is still uncertain. Recent advances in this field have led to the identification of several factors that might contribute to the induction of excessive apoptosis of keratinocytes. In addition, specific human leukocyte antigen types seem to be associated with certain drugs and the development of TEN. As well-controlled studies are lacking, patients are treated with various immunomodulators (e.g. intravenous immunoglobulin) in addition to the best supportive care.

Predictors of High Profit and High Deficit Outliers under SwissDRG of a Tertiary Care Center

Principles Case weights of Diagnosis Related Groups (DRGs) are determined by the average cost of cases from a previous billing period. However, a significant amount of cases are largely over- or underfunded. We therefore decided to analyze earning outliers of our hospital as to search for predictors enabling a better grouping under SwissDRG. Methods 28,893 inpatient cases without additional private insurance discharged from our hospital in 2012 were included in our analysis. Outliers were defined by the interquartile range method. Predictors for deficit and profit outliers were determined with logistic regressions. Predictors were shortlisted with the LASSO regularized logistic regression method and compared to results of Random forest analysis. 10 of these parameters were selected for quantile regression analysis as to quantify their impact on earnings. Results Psychiatric diagnosis and admission as an emergency case were significant predictors for higher deficit with negative regression coefficients for all analyzed quantiles (p<0.001). Admission from an external health care provider was a significant predictor for a higher deficit in all but the 90% quantile (p<0.001 for Q10, Q20, Q50, Q80 and p = 0.0017 for Q90). Burns predicted higher earnings for cases which were favorably remunerated (p<0.001 for the 90% quantile). Osteoporosis predicted a higher deficit in the most underfunded cases, but did not predict differences in earnings for balanced or profitable cases (Q10 and Q20: p<0.00, Q50: p = 0.10, Q80: p = 0.88 and Q90: p = 0.52). ICU stay, mechanical and patient clinical complexity level score (PCCL) predicted higher losses at the 10% quantile but also higher profits at the 90% quantile (p<0.001). Conclusion We suggest considering psychiatric diagnosis, admission as an emergencay case and admission from an external health care provider as DRG split criteria as they predict large, consistent and significant losses.

Diagnostic relevance of direct immunofluorescence in ocular mucous membrane pemphigoid

The objective was to determine the diagnostic value of direct immunofluorescence (DIF) in ocular mucous membrane pemphigoid (ocular MMP), taking into account immunofluorescence patterns and biopsy sites.