Vinflunine in the treatment of relapsed metastatic urothelial cancer: A systematic review and meta-analysis of real-world series

Background. Vinflunine (VFL) is approved in Europe as second-line treatment of metastatic urothelial cancer after failure of platinum-containing therapy. We performed a systematic review and meta-analysis of real-world data (RWD) to assess utilization, efficacy and safety of VFL. Methods. We performed a MEDLINE search for the period of 1/1/2000-31/8/2017. Full-length articles providing post-marketing RWD on VFL in patients failing previous chemotherapy were eligible. Interventional clinical trials were excluded. Results: Ten studies with 797 patients were identified. According to pooled REs analysis, overall response rate was 19%, most frequent, all-grade toxicities were fatigue (41%), constipation (39%), nausea/vomiting (25%), and most prevalent Grade 3–4 toxicities were neutropenia (13%), anaemia (9%), fatigue (8%). Median OS was comparable to results reported in recent randomized studies. Conclusion. Our findings confirm the efficacy and safety of VFL in an unselected population and support the use of VFL in the changing treatment paradigm of relapsed mUC

Associations between reaction time measures and white matter hyperintensities in very old age.

In old age, a relationship has been reported between intraindividual variability (IIV) in reaction time and white matter integrity as evidenced by white matter hyperintensities (WMH). However, it is unclear how far such associations are due to incipient neurodegenerative pathology in the samples investigated. The present study examined the relationship between IIV and WMH in older individuals (N=526) drawn from the Sydney Memory and Ageing Study. Using a complex reaction time (RT) task, greater IIV and mean-RT were related to a higher WMH burden in the frontal lobe. Critically, significant associations remained having taken future dementia into account suggesting that they were not explained by incipient dementia. Additionally, independent measures of executive function accounted for the association between RT metrics and WHM. The results are consistent with the view that frontally-supported cognitive processes are involved in IIV-WMH relations, and that RT measures are sensitive to compromise in white matter structures in non-demented older individuals

Targeting of distinct signaling cascades and cancer-associated fibroblasts define the efficacy of Sorafenib against prostate cancer cells

Sorafenib, a multi-tyrosine kinase inhibitor, kills more effectively the non-metastatic prostate cancer cell line 22Rv1 than the highly metastatic prostate cancer cell line PC3. In 22Rv1 cells, constitutively active STAT3 and ERK are targeted by sorafenib, contrasting with PC3 cells, in which these kinases are not active. Notably, overexpression of a constitutively active MEK construct in 22Rv1 cells stimulates the sustained phosphorylation of Bad and protects from sorafenib-induced cell death. In PC3 cells, Src and AKT are constitutively activated and targeted by sorafenib, leading to an increase in Bim protein levels. Overexpression of constitutively active AKT or knockdown of Bim protects PC3 cells from sorafenib-induced killing. In both PC3 and 22Rv1 cells, Mcl-1 depletion is required for the induction of cell death by sorafenib as transient overexpression of Mcl-1 is protective. Interestingly, co-culturing of primary cancer-associated fibroblasts (CAFs) with 22Rv1 or PC3 cells protected the cancer cells from sorafenib-induced cell death, and this protection was largely overcome by co-administration of the Bcl-2 antagonist, ABT737. In summary, the differential tyrosine kinase profile of prostate cancer cells defines the cytotoxic efficacy of sorafenib and this profile is modulated by CAFs to promote resistance. The combination of sorafenib with Bcl-2 antagonists, such as ABT737, may constitute a promising therapeutic strategy against prostate cancer

The node of Ranvier in CNS pathology.

Healthy nodes of Ranvier are crucial for action potential propagation along myelinated axons, both in the central and in the peripheral nervous system. Surprisingly, the node of Ranvier has often been neglected when describing CNS disorders, with most pathologies classified simply as being due to neuronal defects in the grey matter or due to oligodendrocyte damage in the white matter. However, recent studies have highlighted changes that occur in pathological conditions at the node of Ranvier, and at the associated paranodal and juxtaparanodal regions where neurons and myelinating glial cells interact. Lengthening of the node of Ranvier, failure of the electrically resistive seal between the myelin and the axon at the paranode, and retraction of myelin to expose voltage-gated K(+) channels in the juxtaparanode, may contribute to altering the function of myelinated axons in a wide range of diseases, including stroke, spinal cord injury and multiple sclerosis. Here, we review the principles by which the node of Ranvier operates and its molecular structure, and thus explain how defects at the node and paranode contribute to neurological disorders

Vinflunine in the treatment of relapsed metastatic urothelial cancer: A systematic review and meta-analysis of real-world series

Background: Vinflunine (VFL) is approved in Europe as second-line treatment of metastatic urothelial cancer after failure of platinum-containing therapy. We performed a systematic review and meta-analysis of real-world data (RWD) to assess utilization, efficacy and safety of VFL. Methods: We performed a MEDLINE search for the period of 1/1/2000-31/8/2017. Full-length articles providing post-marketing RWD on VFL in patients failing previous chemotherapy were eligible. Interventional clinical trials were excluded. Results: Ten studies with 797 patients were identified. According to pooled REs analysis, overall response rate was 19%, most frequent, all-grade toxicities were fatigue (41%), constipation (39%), nausea/vomiting (25%), and most prevalent Grade 3–4 toxicities were neutropenia (13%), anaemia (9%), fatigue (8%). Median OS was comparable to results reported in recent randomized studies. Conclusion: Our findings confirm the efficacy and safety of VFL in an unselected population and support the use of VFL in the changing treatment paradigm of relapsed mUC. © 2019 Elsevier B.V