Infliximab is an effective option in patients with ulcerative colitis previously exposed to full subcutaneous anti-TNF agent: Results from a real-world multicenter study.

BACKGROUND: Data on infliximab efficacy in bio-exposed patients with ulcerative colitis (UC) are limited. AIMS: To evaluate infliximab effectiveness and its predictors in UC patients with prior exposure to subcutaneous (SC) anti-TNF agent. METHODS: In this multicenter retrospective study (8 centers), we included all consecutive UC patients with prior exposure to subcutaneous anti-TNF, starting infliximab for symptomatic UC, excluding acute severe colitis. Corticosteroid-free clinical remission (CFREM) was assessed at week 14 (W14) and W52 while endoscopic improvement (CFREM + endoscopic Mayo score≤1) was evaluated at W14. RESULTS: Overall, 104 patients were included (pancolitis=54.8%, primary failure to subcutaneous anti-TNF=57.4%, concomitant immunosuppressant=53.8%, median partial Mayo score at baseline=7[5-8]). The rate of CFREM was 33.6% (35/104) at W14 and 40.4% (42/104) at W52. At W14, endoscopic improvement was achieved in 29.8%(31/104). In multivariable analysis, concomitant immunosuppressant was associated with higher rate of CFREM at W14(OR=2.83[1.06-7.54], p = 0.037) and W52(OR=2.68[1.16-6.22];p = 0.021), while primary failure to a previous subcutaneous anti-TNF agent led to lower rate of CFREM at W14 (OR=0.37[0.14-0.98], p = 0.046). After a median follow-up of 20.9 months[11.7-33.7]), 50.0%(52/104) patients had discontinued infliximab. CONCLUSION: Infliximab is an effective option in UC patients previously exposed to prior subcutaneous anti-TNF agent and should be used with concomitant immunosuppressant.

[Reports of prostate needle biopsies-what pathologists provide and urologists want]. / Befundbericht zu Prostatastanzbiopsien ­ was Pathologen liefern und Urologen wollen.

BACKGROUND: The prostate biopsy report is key for risk stratification of prostate cancer patients and subsequent therapeutic decision-making. However, due to the inclusion of a multitude of additional parameters its interpretation is becoming more challenging. OBJECTIVES: We aimed to determine how urologists currently interpret prostate biopsy reports, in particular how they consider different histopathological parameters for therapy decision-making. MATERIALS AND METHODS: A survey was sent to all urology practices in Germany with the help of the BDU (Berufsverband der Deutschen Urologen e. V.). In total, there were 106 complete responses that could be included for further analyses. RESULTS: Most urologists consider the number of positive cores and relative tumor burden (%) per core as crucial for the assessment of tumor extension. In case of targeted biopsies, the majority of urologists prefers a separate statement of positive cores per random biopsy scheme and per region of interest, respectively. The core with the highest Gleason score is mostly the basis for therapy decision-making (versus the overall Gleason score). Proportion of Gleason 4 pattern also seems to be critical for prostate cancer management. Only half of the urologists demand reporting of the new ISUP/WHO (International Society of Urological Pathology/World Health Organization) grade groups. Additional parameters claimed are Ki67, prostate-specific membrane antigen status, presence of intraductal or neuroendocrine component of the tumor. CONCLUSIONS: Our survey shows that there is no standardized reporting for prostate biopsies and that the interpretation of prostate biopsy reports varies among urologists. Further studies and guideline recommendations are necessary to establish a standardized reporting scheme for prostate biopsies.

The new ISUP 2014/WHO 2016 prostate cancer grade group system: first résumé 5 years after introduction and systemic review of the literature.

PURPOSE: To systematically and comprehensively review and summarize the most recent literature assessing the value of the new grading system introduced by the International Society of Urological Pathology (ISUP) in 2014 and accepted by the World Health Organization (WHO) in 2016. METHODS: A systematic literature search in the PubMed database was performed up to November 2018. Overall, 15 studies in the period from 2016 to 2018 evaluating the new grading system have been selected for evidence synthesis. RESULTS: The main goals of the new ISUP 2014/WHO 2016 grading system were to establish (I) a more accurate and simplified grade stratification, (II) less overtreatment of indolent prostate cancer as well as (III) an improved patient communication. The majority of the studies chose biochemical recurrence as an endpoint for evaluation and statistically assigns the new ISUP 2014/WHO 2016 grading system a higher prognostic accuracy than the former Gleason grading. However, in only a subset of studies it was clearly evident that the historical samples were not only re-grouped according to the new grade groups but also re-graded according to the new histomorphological 2014 ISUP criteria. CONCLUSIONS: The vast majority of the studies support an improved prognostic accuracy of the ISUP 2014/WHO 2016 grade groups and endorse its worldwide application.

[Molecular tumor board-urothelial cancer]. / Molekulares Tumorboard ­ Urothelkarzinom.

BACKGROUND: Molecular tumor boards (MTB) are becoming more common. There are several molecular alterations in urothelial cancer a molecular tumor board can potentially rely on. OBJECTIVES: The aim is to specify molecular alterations and their correlations with different clinical endpoints and to highlight potential questions addressed to a MTB for urothelial cancer. MATERIALS AND METHODS: Descriptive review of the literature based on PubMed. RESULTS: The landscape of molecular alterations in urothelial cancer is heterogeneous. Thus, recent biomarker research has been focusing on biomarker panels and classifiers instead of single biomarkers. Recently, molecular subtypes of urothelial cancer have been identified and correlated with different clinical endpoints. Furthermore, circulating tumor cells and tumor DNA are under investigation as potential biomarkers. In addition to treatment response and prognosis, molecular markers are also needed to improve clinical staging prior to radical cystectomy or for proper patient selection for neoadjuvant chemotherapy. Erdafitinib is the first targeted therapy (fibroblast growth factor receptor [FGFR] alteration) in urothelial cancer that was recently approved (in the USA). CONCLUSIONS: Due to the lack of external validation, none of the identified biomarkers is currently established in clinical routine. In addition, there is no single driver mutation in urothelial cancer that facilitates the development of biomarkers and targeted therapies.

[Inhibitors of the androgen receptor N­terminal domain : Therapies targeting the Achilles' heel of various androgen receptor molecules in advanced prostate cancer]. / Inhibitoren des Androgenrezeptor-N-Terminus' : Zielgerichtete Therapien gegen die Achillesferse verschiedener Androgenrezeptormoleküle im fortgeschrittenen Prostatakarzinom.

Although prostate cancer responds well to primary endocrine therapies, tumor progression with castration resistant tumor cells almost invariably occurs within a few years. Unfortunately, some CRPC patients do not respond to second-line therapies with abiraterone or enzalutamide. Moreover, patients who initially responded well to second-line hormone therapy develop resistance to abiraterone and/or enzalutamide within a short period of time. Besides an increase of intracellular androgen receptor (AR) levels, the predominant resistance mechanisms include AR aberrations (point mutations, AR splice variants) occurring predominantly at the androgen or ligand binding domain of the AR. The following review delineates recent progress in the development of AR inhibitors that do not depend on androgen binding and represent a putative third generation of AR inhibitors.

[Neoadjuvant or Adjuvant Chemotherapy for Bladder Cancer?]. / Neo- oder adjuvante Chemotherapie beim Harnblasenkarzinom?

Advanced urothelial carcinoma of the bladder is associated with a high metastatic potential. Life expectancy for metastatic patients is poor and rarely exceeds more than one year without further therapy. Neoadjuvant chemotherapy can decrease the tumour burden while reducing the risk of death. Adjuvant chemotherapy has been discussed controversially. Patients with lymph node-positive metastases seem to benefit the most from adjuvant chemotherapy. In selected patients, metastasectomy can prolong survival. In metastastic patients, the combination of gemcitabine and cisplatin has become the new standard regimen due to a lower toxicity in comparison to the combination of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC). For second-line treatment, vinflunine is the only approved therapeutic agent.

Endoplasmic reticulum Ca2+ depletion activates XBP1 and controls terminal differentiation in keratinocytes and epidermis.

BACKGROUND: Endoplasmic reticulum (ER) Ca(2+) depletion, previously shown to signal pathological stress responses, has more recently been found also to trigger homeostatic physiological processes such as differentiation. In keratinocytes and epidermis, terminal differentiation and barrier repair require physiological apoptosis and differentiation, as evidenced by protein synthesis, caspase 14 expression, lipid secretion and stratum corneum (SC) formation. OBJECTIVES: To investigate the role of Ca(2+) depletion-induced ER stress in keratinocyte differentiation and barrier repair in vivo and in cell culture. METHODS: The SERCA2 Ca(2+) pump inhibitor thapsigargin (TG) was used to deplete ER calcium both in cultured keratinocytes and in mice. Levels of the ER stress factor XBP1, loricrin, caspase 14, lipid synthesis and intracellular Ca(2+) were compared after both TG treatment and barrier abrogation. RESULTS: We showed that these components of terminal differentiation and barrier repair were signalled by physiological ER stress, via release of stratum granulosum (SG) ER Ca(2+) stores. We first found that keratinocyte and epidermal ER Ca(2+) depletion activated the ER-stress-induced transcription factor XBP1. Next, we demonstrated that external barrier perturbation resulted in both intracellular Ca(2+) emptying and XBP1 activation. Finally, we showed that TG treatment of intact skin did not perturb the permeability barrier, yet stimulated and mimicked the physiological processes of barrier recovery. CONCLUSIONS: This report is the first to quantify and localize ER Ca(2+) loss after barrier perturbation and show that homeostatic processes that restore barrier function in vivo can be reproduced solely by releasing ER Ca(2+), via induction of physiological ER stress.

Suppression of cFLIP is sufficient to sensitize human melanoma cells to TRAIL- and CD95L-mediated apoptosis.

Death ligands such as tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and certain forms of CD95L are attractive therapeutic options for metastatic melanoma. Since knowledge about the regulation of death receptor sensitivity in melanoma is sparse, we have analysed these signaling pathways in detail. The loss of CD95 or TRAIL-R1, but not of TRAIL-R2, surface expression correlated with apoptosis sensitivity in a panel of melanoma cell lines. In contrast, the expression of proteins of the apical apoptosis signaling cascade (FADD, initiator caspases-8 and cFLIP) did not predict apoptosis sensitivity. Since both TRAIL-R1 and -R2 transmit apoptotic signals, we asked whether cFLIP, highly expressed in several of the cell lines tested, is sufficient to maintain resistance to TRAIL-R2-mediated apoptosis. Downregulation of cFLIP in TRAIL-R2-positive, TRAIL-resistant IGR cells dramatically increased TRAIL sensitivity. Conversely ectopic expression of cFLIP in TRAIL-sensitive, TRAIL-R2-expressing RPM-EP melanoma cells inhibited TRAIL- and CD95L-mediated cell death. Thus, modulation of cFLIP is sufficient to sensitize TRAIL-R2-expressing cells for TRAIL. Taken together, albeit expressing all proteins necessary for death receptor-mediated apoptosis, TRAIL-R1 negative melanoma cells cannot undergo TRAIL- or CD95L-induced apoptosis due to expression of cFLIP. Hence, cFLIP represents an attractive therapeutic target for melanoma treatment, especially in combination with TRAIL receptor agonists.

Characterization of cigar tobaccos by gas chromatographic/mass spectrometric analysis of nonvolatile organic acids: application to the authentication of Cuban cigars.

A reliable method based on gas chromatographic/mass spectrometric (GC/MS) profiling of nonvolatile organic acids is described for the characterization of cigars. The method involves an aqueous extraction of ground tobacco and selective isolation of the acids by simply stirring strong anion exchange (SAX) disks in the aqueous tobacco extract. The acids are then directly silylated on the disk with N-methyl-N-trimethylsilyl-trifluroacetamide (MSTFA) in acetonitrile in an autosampler vial. Elution of the derivatized acids in situ allows the sample to be directly analyzed by GC/MS without further sample handling. Compared to the conventional disk-extraction technique using a vacuum manifold, this method is much less labor intensive, and is desirable for multiple sample analysis. Nicotinic acid, succinic acid, glyceric acid, malic acid, pyroglutamic acid, threonic acid, citric acid, uracil, and an unidentified acid were reproducibly quantified in tobacco samples. Principal component analysis (PCA) of the acid profiles of the filler tobaccos of 18 Cuban cigars and 31 non-Cuban cigars shows separation of the two groups, indicating that the acid profiles are potentially useful in the authentication of Cuban cigars.

Ion mobility spectrometry of drugs of abuse in customs scenarios: concentration and temperature study.

A custom-built ion mobility spectrometer has been used to obtain the IMS spectra of cocaine, heroin, amphetamine sulfate and LSD at different drug concentrations and desorption temperatures. Practical detection limits for these four drugs were obtained as a function of desorber temperature and for heroin as a function of analysis time. Spectral and ionization interferences for each of the four drugs of interest were determined. Spectral interferences by innocuous materials are few; ionization interferences occur only at very high ratios of the mass of innocuous material to that of the drug of interest.