Treatment of sunitinib-induced hypertension in solid tumor by nitric oxide donors

[Abstract] Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) are overexpressed in the majority of renal cell carcinomas. This characteristic has supported the rationale of targeting VEGF-driven tumour vascularization, especially in clear cell RCC. VEGF-inhibiting strategies include the use of tyrosine kinase inhibitors (sunitinib, axitinib, pazopanib, and sorafenib) and neutralizing antibodies such as bevacizumab. Hypertension (HTN) is one of the most common adverse effects of angiogenesis inhibitors. HTN observed in clinical trials appears to correlate with the potency of VEGF kinase inhibitor against VEGFR-2: agents with higher potency are associated with a higher incidence of HTN. Although the exact mechanism by tyrosine kinase inhibitors induce HTN has not yet been completely clarified, two key hypotheses have been postulated. First, some studies have pointed to a VEGF inhibitors-induced decrease in nitric oxide synthase (NOS) and nitric oxide (NO) production, that can result in vasoconstriction and increased blood pressure. VEGF, mediated by PI3K/Akt and MAPK pathway, upregulates the endothelial nitric oxide synthase enzyme leading to up-regulation of NO production. So inhibition of signaling through the VEGF pathway would lead to a decrease in NO production, resulting in an increase in vascular resistance and blood pressure. Secondly a decrease in the number of microvascular endothelial cells and subsequent depletion of normal microvessel density (rarefaction) occurs upon VEGF signaling inhibition. NO donors could be successfully used not only for the treatment of developed angiogenesis-inhibitor-induced hypertension but also for preventive effects

Wideband Epidermal Antenna for Medical Radiometry

Microwave thermometry is a noninvasive and passive technique for measuring internal body temperature. Wearable compact antennas, matched to the specific body area, are required for this method. We present a new epidermal wideband antenna for medical radiometry. The double asymmetric H-shaped slot antenna was designed to be matched to different parts of the body without fat layers. The slots are fed by a short-circuited microstrip line in order to decrease size and back radiation, thus reducing potential interferences. In this way, contribution to radiometric temperature due to back radiation is lower than 4%, versus the 20% of the volume under investigation, over the whole operating frequency band. The designed prototype was manufactured on a flexible substrate. The antenna is a very small size, to make it comfortable and suitable for being used by patients with different body mass indexes. The double H-shaped antenna shows good wideband matching results from around 1.5 GHz up to 5 GHz, in different body locations such as the neck, foot instep and foot sole

Enzalutamide: a new prostate cancer targeted therapy against the androgen receptor

[Abstract] Enzalutamide (MDV3100), an androgen receptor-signalling inhibitor, represents the most recent compound added to the therapeutic armamentarium for the treatment of metastatic castration-resistant prostate cancer (mCRPC) who progressed to docetaxel. The anti-tumour activity and safety of enzalutamide has been demonstrated in a phase III clinical trial, showing a benefit in overall survival, which was the primary endpoint. There are no head-to-head studies comparing the different treatment options in this subset of patients. In this article, most relevant data published in the literature have been reviewed, with special attention to the therapeutic alternatives currently available for postdocexatel mCRPC patients, emphasising the mechanisms of action of the different drugs, efficacy and quality of life-related aspects

Metastases of renal cell carcinoma to the thyroid gland with synchronous benign and malignant follicular cell-derived neoplasms

Clear cell renal cell carcinoma (CCRCC) is the most common origin for metastasis in the thyroid. A 51-year-old woman was referred to our hospital for a subcarinal lesion. Ten years before, the patient had undergone a nephrectomy for CCRCC. Whole-body fluorodeoxyglucose positron emission tomography revealed elevated values in the thyroid gland, while the mediastinum was normal. An endoscopic ultrasonography-guided fine-needle aspiration biopsy of the mediastinal mass was consistent with CCRCC, and this was confirmed after resection. The thyroidectomy specimen also revealed lymphocytic thyroiditis, nodular hyperplasia, one follicular adenoma, two papillary microcarcinomas, and six foci of metastatic CCRCC involving both thyroid lobes. Curiously two of the six metastatic foci were located inside two adenomatoid nodules (tumor-in-tumor). The metastatic cells were positive for cytokeratins, CD10, epidermal growth factor receptor, and vascular endothelial growth factor receptor 2. No BRAF gene mutations were found in any of the primary and metastatic lesions. The patient was treated with sunitinib and finally died due to CCRCC distant metastases 6 years after the thyroidectomy. In CCRCC patients, a particularly prolonged survival rate may be achieved with the appropriate therapy, in contrast to the ominous prognosis typically found in patients with thyroid metastases from other origins

Radium-223 dichloride: a new paradigm in the treatment of prostate cancer

Review[Abstract] Radionuclides have been widely used for cancer treatment. Recently, new research about radium-223 dichloride has been conducted in prostate cancer, which reveals that it is the first radiopharmaceutical to demonstrate an improvement in overall survival and time to first symptomatic skeletal event in patients with castration resistant prostate cancer with symptomatic bone metastases. This fact has created a new paradigm in the treatment of prostate cancer landscape, where only chemotherapy and hormone therapy had a role, while β-emitters had been confined exclusively to the role of pain relief with no impact on survival. The aim of this review is to outline current treatment approaches for advanced prostate cancer with a focus on the role of radium-223 dichloride, reviewing patients' profile that make them suitable to therapy and chances for further studies

Global Gene Expression Characterization of Circulating Tumor Cells in Metastasic Castration-Resistant Prostate Cancer Patients

Background: Current therapeutic options in the course of metastatic castration-resistant prostate cancers (mCRPC) reinforce the need for reliable tools to characterize the tumor in a dynamic way. Circulating tumor cells (CTCs) have emerged as a viable solution to the problem, whereby patients with a variety of solid tumors, including PC, often do not have recent tumor tissue available for analysis. The biomarker characterization in CTCs could provide insights into the current state of the disease and an overall picture of the intra-tumor heterogeneity. Methods: in the present study, we applied a global gene expression characterization of the CTC population from mCRPC (n = 9), with the goal to better understand the biology of these cells and identify the relevant molecules favoring this tumor progression. Results: This analysis allowed the identification of 50 genes specifically expressed in CTCs from patients. Six of these markers (HOXB13, QKI, MAOA, MOSPD1, SDK1, and FGD4), were validated in a cohort of 28 mCRPC, showing clinical interest for the management of these patients. Of note, the activity of this CTC signature was related to the regulation of MYC, a gene strongly implicated in the biology of mCRPC. Conclusions: Overall, our results represent new evidence on the great value of CTCs as a non-invasive biopsy to characterize PCThis work was partially financed with the “liquid Biopsy crowdfunding, 2017”. L.M-L. is supported by AECCS

Persistent HIV-controllers are more prone to spontaneously clear HCV: a retrospective cohort study.

HIV-controllers have the ability to spontaneously maintain viraemia at low or undetectable levels in the absence of antiretroviral treatment. Furthermore, HIV-controllers seem to have a superior capacity to spontaneously clear hepatitis C virus (HCV) compared to non HIV-controllers. Some of these subjects eventually lose HIV-controller status (transient controllers), whereas some HIV-controllers show a persistent natural HIV control (persistent controllers). We aimed to analyse whether persistent controllers have superior capacity to spontaneously clear HCV compared to transient controllers. We recruited HIV-controllers from January 1981 up to October 2016 with available antibodies to HCV (anti-HCV) data (n = 744). Factors associated with HIV spontaneous control in relation to HCV status were analysed in persistent and transient HIV-controllers with anti-HCV positive (n = 202 and n = 138 respectively) in comparison with 1700 HCV positive non HIV-controllers recruited from January 1981 up to March 2018, bivariate and multivariate analyses, following a logistic regression model, were applied. In addition, the factors related to the loss and time to lose HIV-controller status were explored (n = 744) using Log rank test and Kaplan-Meier curves, in this case the multivariate analysis consisted in a Cox regression model. A higher frequency of HCV spontaneous clearance was found in persistent HIV-controllers (25.5%) compared to non-controllers (10.2%). After adjusting for potential confounders, as sex, age, HIV transmission risk, CD4+ T-cell nadir and time of follow-up, HCV clearance was independently associated with persistent HIV spontaneous control (p = 0.002; OR (95% CI) = 2.573 (1.428 to 4.633)), but not with transient spontaneous control (p = 0.119; 1.589 (0.888 to 2.845)). Furthermore, persistent HIV-controllers were more likely to spontaneously clear the HCV in comparison with transient controllers (p = 0.027; 0.377 (0.159 to 0.893). Finally, not to lose or lengthen the time of losing this control was independently associated with HCV spontaneous clearance (p = 0.010; 0.503 (0.297 to 0.850). This study shows an association between spontaneous persistent HIV-control and HCV spontaneous clearance. The study findings support the idea of preserved immune mechanisms in persistent HIV control implicated in HCV spontaneous clearance. These results highlight persistent HIV-controllers but not transient controllers as a good model of functional HIV cure.This work was supported by the Instituto de Salud Carlos III (research contracts CPII014/00025 to E.R.‐M., and FI14/00431 to L.T.‐D. and research projects PI12/02283, PI16/00684, PI19/01127 to E.R.‐M.) and Red Temática de Investigación Cooperativa en SIDA (Projects RD12/0017/0029, RD12/0017/0031, and RD16/0025/0020 and RD16/0025/0013), which is included in the Acción Estratégica en Salud, Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica 2008 to 2011 and 2013 to 2016, Instituto de Salud Carlos III, Fondos FEDER. E.R.‐M. was supported by Consejería de Salud y Bienestar Social of Junta de Andalucía through the Nicolás Monardes program (C‐0032/17), N Rallón is a Miguel Servet investigator from the Spanish Carlos III Institute of Health (ISCIII), grant CP14/00198, Madrid, Spain and B.D.M. received a grant from The Spanish Ministry of Education (FPU13/02451). Work in CL‐G’s laboratory was supported by grants SAF (2010 to 17226) and (2016‐77894‐R) from MINECO (Spain) and FIS (PI 13/02269, ISCIII) and in part by the RIS‐RETIC grants RD06/006/0036 and RD12/0017/0028 funded by the ISC III‐FEDER. MP has a contract of RIS‐RETIC RD12/0017/0036.S

PrediCTC, liquid biopsy in precision oncology: a technology transfer experience in the Spanish health system.

Purpose: Management of metastatic disease in oncology includes monitoring of therapy response principally by imaging techniques like CT-Scan. In addition to some limitations, the irruption of liquid biopsy and its application in personalized medicine has encouraged the development of more efficient technologies for prognosis and follow-up of patients in advanced disease. Methods: PrediCTC constitutes a panel of genes for the assessment of Circulating Tumor Cells (CTC) in metastatic colorectal cancer patients, with demonstrated improved efficiency compared to CT-Scan for the evaluation of early therapy response in a multicenter prospective study. In this work, we designed and developed a technology transfer strategy to define the market opportunity for an eventual implementation of PrediCTC in the clinical practice. Results: This included the definition of the regulatory framework, the analysis of the regulatory roadmap needed for CE mark, a benchmarking study, the design of a product development strategy, a revision of intellectual property, a cost-effectiveness study and an expert panel consultation. Conclusion: The definition and analysis of an appropriate technology transfer strategy and the correct balance among regulatory, financial and technical determinants are critical for the transformation of a promising technology into a viable technology, and for the decision of implementing liquid biopsy in the monitoring of therapy response in advanced disease.pre-print533 K

Electrophysiological resting‐state hyperconnectivity and poorer behavioural regulation as predisposing profiles of adolescent binge drinking

Adolescent Binge Drinking (BD) has become an increasing health and social concern, with detrimental consequences for brain development and functional integrity. However, research on neurophysiological and neuropsychological traits predisposing to BD are limited at this time. In this work, we conducted a 2-year longitudinal magnetoencephalography (MEG) study over a cohort of initially alcohol-naïve adolescents with the purpose of exploring anomalies in resting-state electrophysiological networks, impulsivity, sensation-seeking, and dysexecutive behaviour able to predict future BD patterns. In a sample of 67 alcohol-naïve adolescents (age = 14.5 ± 0.9), we measured resting-state activity using MEG. Additionally, we evaluated their neuropsychological traits using self-report ecological scales (BIS-11, SSS-V, BDEFS, BRIEF-SR and DEX). In a second evaluation, 2 years later, we measured participant's alcohol consumption, sub-dividing the original sample in two groups: future binge drinkers (22 individuals, age 14.6 ± 0.8; eight females) and future light/no drinkers (17 individuals, age 14.5 ± 0.8; eight females). Then, we searched for differences predating alcohol BD intake. We found abnormalities in MEG resting state, in a form of gamma band hyperconnectivity, in those adolescents who transitioned into BD years later. Furthermore, they showed higher impulsivity, dysexecutive behaviours and sensation seeking, positively correlated with functional connectivity (FC). Sensation seeking and impulsivity mainly predicted BD severity in the future, while the relationship between dysexecutive trait and FC with future BD was mediated by sensation seeking. These findings shed light to electrophysiological and neuropsychological traits of vulnerability towards alcohol consumption. We hypothesise that these differences may rely on divergent neurobiological development of inhibitory neurotransmission pathways and executive prefrontal circuits

Detection of MET Alterations Using Cell Free DNA and Circulating Tumor Cells from Cancer Patients

MET alterations may provide a potential biomarker to evaluate patients who will benefit from treatment with MET inhibitors. Therefore, the purpose of the present study is to investigate the utility of a liquid biopsy-based strategy to assess MET alterations in cancer patients. We analyzed MET amplification in circulating free DNA (cfDNA) from 174 patients with cancer and 49 healthy controls and demonstrated the accuracy of the analysis to detect its alteration in patients. Importantly, a significant correlation between cfDNA concentration and MET copy number (CN) in cancer patients (r = 0.57, p <10−10) was determined. Furthermore, we evaluated two approaches to detect the presence of MET on circulating tumor cells (CTCs), using the CellSearch® and Parsortix systems and monitored patients under anti-EGFR treatment (n = 30) combining both cfDNA and CTCs analyses. This follow-up provides evidence for the potential of MET CN assessment when patients develop resistance to anti-EGFR therapy and a significant association between the presence of CTCs MET+ and the Overall Survival (OS) in head and neck cancer patients (P = 0.05; HR = 6.66). In conclusion, we develop specific and noninvasive assays to monitor MET status in cfDNA/CTCs and demonstrate the utility of plasma MET CN determination as a biomarker for monitoring the appearance of resistance to anti-EGFR therapyThis study was financed by all the donors who participated in the Liquid Biopsy Crowdfunding campaign in 2017. LMR is supported by Asociación Española Contra el Cancer (AECC). ADL is funded by a “Juan Rodés” contract (JR17/00016) from ISCIIIS