Preoperative Staging With 11C-Choline PET/CT Is Adequately Accurate in Patients With Very High-Risk Prostate Cancer

Purpose

To evaluate the accuracy of ¹¹C-choline positron emission tomography (PET)/computed tomography (CT) for nodal staging of prostate cancer (PCa) in different populations of high-risk patients.

Treatment of Advanced Merkel Cell Carcinoma: Current Therapeutic Options and Novel Immunotherapy Approaches

Advanced Merkel cell carcinoma (MCC) is a very aggressive, rare neuroendocrine tumor of the skin with a high frequency of locoregional recurrence and metastasis, and a high mortality rate. Surgical resection, sentinel lymph node biopsy, and radiotherapy represent the gold standard of treatment in patients with localized disease, while chemotherapy has a significant role in the treatment of advanced disease. However, no definitive evidence on the survival impact of radiotherapy in the advanced stages has been provided to date, and response to chemotherapy remains brief in the majority of cases, indicating an urgent need for alternative approaches. Biological and genome sequencing studies have implicated multiple molecular pathways in MCC, thus leading to the development of new agents that target angiogenic factors, anti-apoptosis molecules, poly-ADP ribose polymerase, intracellular signal proteins such as the PI3K/AKT/mTOR pathway, and peptide receptors such as somatostatin receptors. More recently, immunotherapy agents such as avelumab, pembrolizumab, and nivolumab, which act by blocking the programmed cell-death (PD)-1/PD-L1 immune checkpoint, have shown promising results, especially in the advanced setting, and should now be considered standard of care for metastatic MCC. Current research is focusing on developing new immunotherapeutic strategies, identifying predictive biomarker to aid in the selection of patients responsive to immunotherapy, and defining combination approaches to increase efficacy in refractory patients.     

Semi-structured physical activity intervention in daily life: a good compromise between effectiveness and feasibility

Background

As older-aged population is continuously increasing, it is essential to promote physical activity (PA) to preserve health and autonomy in daily living. Although several methods have been proposed, combining sustainability and efficacy at the same time is still a challenge.

Aims

To evaluate the effects of a semi-structured PA (SSPA) intervention including aerobic as well as strength and flexibility exercise in comparison to generic PA advice (PAAdv) in healthy older adults.

Methods

86 sedentary older adults were divided in two groups, SSPA (n?=?56) and PAAdv (n?=?30). Body weight (BW) and circumferences, blood pressure (BP), submaximal exercise heart rate (HR), as well as Chair Stand Test (CST), Arm Curl Test (ACT), Chair Sit-and-Reach Test (CSRT) and Back Scratch Test (BST) were performed before and after 16 weeks of intervention. SSPA group was further divided in SSPA?>?500 and SSPA?<?500 according to the total amount of PA performed (cut-off level of 500 MET min/week).

Results

Overall, SSPA groups improved more than the PAAdv group on WC, HC, BP, CST, ACT, CSRT and BST. SSPA?>?500 improved more than SSPA?<?500 and PAAdv on CST (+?20.2, +?11.3, +?4.5% respectively), ACT (+?21.5, +?14.9, ??1.3%, respectively), and CSRT (+?3.7, +?0.80, +?0.75 cm, respectively), and similarly to SSPA?<?500 on BST. Submaximal HR values significantly decreased for the SSPA?>?500 and PAAdv groups.

Conclusions

An SSPA program represents an ecological way to enhance fitness in older adults. A greater amount of SSPA (>?500 versus <?500 MET min/week) is associated with higher cardiovascular and muscular fitness benefits.

     

Variability of Voriconazole Trough Levels in Haematological Patients: Influence of Comedications with cytochrome P450(CYP) Inhibitors and/or with CYP Inhibitors plus CYP Inducers

Voriconazole plasma exposure greatly varies among haematological patients. The purpose of this study was to identify the magnitude of influence of comedications with CYP inhibitors and/or with CYP inhibitors plus CYP inducers on voriconazole trough level (C_min). Voriconazole C_min was retrospectively assessed among haematological patients who underwent therapeutic drug monitoring (TDM). Univariate and multivariate linear mixed‐effect regression analyses were performed to identify the independent predictors of normalized C_min. Of the 83 included patients, 35 had comedications with CYP inhibitors (omeprazole or pantoprazole) and 21 with CYP inhibitors (omeprazole or pantoprazole) plus CYP inducers (methylprednisolone, dexamethasone, phenobarbital, rifampin or carbamazepine). Median C_min value (n = 199) was 2.4 mg/L with a wide range of distribution (<0.2–13.5 mg/L). Median (IQR) normalized voriconazole C_min value was significantly higher in the presence of CYP inhibitors (4.20 mg/L, 3.23–5.51 mg/L) than either in the absence of interacting cotreatments (2.55 mg/L, 1.54–3.47 mg/L) or in the presence of CYP inhibitors plus CYP inducers (2.16 mg/L, 1.19–3.09 mg/L). The presence of CYP inhibitors was highly significantly associated with C_min >5.5 mg/L (OR: 23.22, 95% CI: 3.01–179.09, p = 0.003). No significant association emerged when CYP inhibitors were coadministered with CYP inducers (OR: 3.53, 95% CI: 0.36–34.95, p = 0.280). The amount of expected C_min increase was significantly influenced by both the type and the dose of the administered proton pump inhibitor. The study highlights that the benefit from TDM of voriconazole may be maximal in those patients who are cotreated with CYP inhibitors and/or with CYP inhibitors plus CYP inducers, especially when receiving proton pump inhibitors (PPIs) at very high dosages intravenously.     

Empirical extensions of the lasso penalty to reduce the false discovery rate in high‐dimensional Cox regression models

Correct selection of prognostic biomarkers among multiple candidates is becoming increasingly challenging as the dimensionality of biological data becomes higher. Therefore, minimizing the false discovery rate (FDR) is of primary importance, while a low false negative rate (FNR) is a complementary measure. The lasso is a popular selection method in Cox regression, but its results depend heavily on the penalty parameter λ. Usually, λ is chosen using maximum cross‐validated log‐likelihood (max‐cvl). However, this method has often a very high FDR. We review methods for a more conservative choice of λ. We propose an empirical extension of the cvl by adding a penalization term, which trades off between the goodness‐of‐fit and the parsimony of the model, leading to the selection of fewer biomarkers and, as we show, to the reduction of the FDR without large increase in FNR. We conducted a simulation study considering null and moderately sparse alternative scenarios and compared our approach with the standard lasso and 10 other competitors: Akaike information criterion (AIC), corrected AIC, Bayesian information criterion (BIC), extended BIC, Hannan and Quinn information criterion (HQIC), risk information criterion (RIC), one‐standard‐error rule, adaptive lasso, stability selection, and percentile lasso. Our extension achieved the best compromise across all the scenarios between a reduction of the FDR and a limited raise of the FNR, followed by the AIC, the RIC, and the adaptive lasso, which performed well in some settings. We illustrate the methods using gene expression data of 523 breast cancer patients. In conclusion, we propose to apply our extension to the lasso whenever a stringent FDR with a limited FNR is targeted. Copyright © 2016 John Wiley & Sons, Ltd.     

Potential anti-tumor effects of FTY720 associated with PP2A activation: a brief review

FTY720 (Fingolimod, Gilenya^?) is an FDA-approved immunosuppressant currently used in the treatment of multiple sclerosis. However, a large number of studies over the last few years have shown that FTY720 shows potent antitumor properties that suggest its potential usefulness as a novel anticancer agent. Interestingly, the restoration of protein phosphatase 2A (PP2A) activity mediated by FTY720 could play a key role in its antitumor effects. Taking into account that PP2A inactivation is a common event that determines poor outcome in several tumor types, FTY720 could serve as an alternative therapeutic strategy for cancer patients with such alterations.