Searching for Preclinical Models of Acute Decompensated Heart Failure: a Concise Narrative Overview and a Novel Swine Model

Cardiovascular Drugs and Therapy - Available animal models of acute heart failure (AHF) and their limitations are discussed herein. A novel and preclinically relevant porcine model of decompensated...     

EAU-EANM-ESTRO-ESUR-SIOG Guidelines on Prostate Cancer—2020 Update. Part 1: Screening,Diagnosis, and Local Treatment with Curative Intent

ObjectiveTo present a summary of the 2020 version of the European Association of Urology (EAU)-European Association of Nuclear Medicine (EANM)-European Society for Radiotherapy and Oncology (ESTRO)-European Society of Urogenital Radiology (ESUR)-International Society of Geriatric Oncology (SIOG) guidelines on screening, diagnosis, and local treatment of clinically localised prostate cancer (PCa).Evidence acquisitionThe panel performed a literature review of new data, covering the time frame between 2016 and 2020. The guidelines were updated and a strength rating for each recommendation was added based on a systematic review of the evidence.Evidence synthesisA risk-adapted strategy for identifying men who may develop PCa is advised, generally commencing at 50 yr of age and based on individualised life expectancy. Risk-adapted screening should be offered to men at increased risk from the age of 45 yr and to breast cancer susceptibility gene (BRCA) mutation carriers, who have been confirmed to be at risk of early and aggressive disease (mainly BRAC2), from around 40 yr of age. The use of multiparametric magnetic resonance imaging in order to avoid unnecessary biopsies is recommended. When a biopsy is performed, a combination of targeted and systematic biopsies must be offered. There is currently no place for the routine use of tissue-based biomarkers. Whilst prostate-specific membrane antigen positron emission tomography computed tomography is the most sensitive staging procedure, the lack of outcome benefit remains a major limitation. Active surveillance (AS) should always be discussed with low-risk patients, as well as with selected intermediate-risk patients with favourable International Society of Urological Pathology (ISUP) 2 lesions. Local therapies are addressed, as well as the AS journey and the management of persistent prostate-specific antigen after surgery. A strong recommendation to consider moderate hypofractionation in intermediate-risk patients is provided. Patients with cN1 PCa should be offered a local treatment combined with long-term hormonal treatment.ConclusionsThe evidence in the field of diagnosis, staging, and treatment of localised PCa is evolving rapidly. The 2020 EAU-EANM-ESTRO-ESUR-SIOG guidelines on PCa summarise the most recent findings and advice for their use in clinical practice. These PCa guidelines reflect the multidisciplinary nature of PCa management.Patient summaryUpdated prostate cancer guidelines are presented, addressing screening, diagnosis, and local treatment with curative intent. These guidelines rely on the available scientific evidence, and new insights will need to be considered and included on a regular basis. In some cases, the supporting evidence for new treatment options is not yet strong enough to provide a recommendation, which is why continuous updating is important. Patients must be fully informed of all relevant options and, together with their treating physicians, decide on the most optimal management for them.     

A multidisciplinary expert opinion on CINV and RINV,unmet needs and practical real-life approaches

ABSTRACT

Introduction: A range of combination chemotherapy regimens are currently used in clinical practice. However, international antiemetic guidelines often only categorize the emetogenic potential of single agents rather than the emetogenicity of combination chemotherapy regimens. To manage the nausea and vomiting induced by antineoplastic combinations, guidelines suggest antiemetics that are appropriate for the component drug with the highest emetogenic potential. Furthermore, antiemetic guidelines generally do not consider the influence of other factors, including individual patient characteristics, on the emetic effects of cancer treatments. Similarly, the emetogenic potential of radiotherapy is stratified only according to the site of radiation, while other factors contributing to emetic risk are overlooked.

Areas covered: An Expert Panel was convened to examine unresolved issues and summarize the current clinical research on managing nausea and vomiting associated with combination chemotherapy and radiotherapy.

Expert opinion: The panel identified the incidence of nausea and vomiting induced by multi-drug combination therapies currently used to treat cancer at different anatomic sites and by radiotherapy in the presence of other risk factors. Based on these data and the clinical experience of panel members, several suggestions are made for a practical approach to prevent or manage nausea and vomiting due to chemotherapy regimens and radiation therapy.     

Cortical Mechanisms of Single-Pulse Transcranial Magnetic Stimulation in Migraine

Single-pulse transcranial magnetic stimulation (sTMS) of the occipital cortex is an effective migraine treatment. However, its mechanism of action and cortical effects of sTMS in migraine are yet to be elucidated. Using calcium imaging and GCaMP-expressing mice, sTMS did not depolarise neurons and had no effect on vascular tone. Pre-treatment with sTMS, however, significantly affected some characteristics of the cortical spreading depression (CSD) wave, the correlate of migraine aura. sTMS inhibited spontaneous neuronal firing in the visual cortex in a dose-dependent manner and attenuated l-glutamate-evoked firing, but not in the presence of GABA_A/B antagonists. In the CSD model, sTMS increased the CSD electrical threshold, but not in the presence of GABA_A/B antagonists. We first report here that sTMS at intensities similar to those used in the treatment of migraine, unlike traditional sTMS applied in other neurological fields, does not excite cortical neurons but it reduces spontaneous cortical neuronal activity and suppresses the migraine aura biological substrate, potentially by interacting with GABAergic circuits.Electronic supplementary materialThe online version of this article (10.1007/s13311-020-00879-6) contains supplementary material, which is available to authorized users.Key Words: Migraine, transcranial magnetic stimulation, GABA, glutamate, cortex     

Silicosi severa da terre di diatomee nella produzione di alginato ad uso odontoiatrico: uno studio necroscopico

«Severe silicosis due to diatomaceous earth in dental alginate: a necropsy study»Background:Severe silicosis from occupational exposure to calcined diatomaceous earth has been observed in the past, due to the high-temperature transformation of amorphous silica in crystalline phases, mainly cristobalite. In dental alginate production and use a silica exposure may be underestimated. Objectives: To describe the clinical picture, the scenario and pattern of occupational exposure to silica and the corresponding necroscopic findings of a case of silicosis in a worker engaged in the production of alginates for dental use.Methods:A commercial sample of calcinated diatomaceous earth and necroscopic lung samples were analysed by scanning electron microscopy (SEM-EDS) and X-ray diffraction (XRD) for the quali-quantitative determination of crystalline silica. Material safety data sheets (MSDSs) of diatomaceous earth produced in 2002 and 2018 were examined to assess the information content on silicosis risk. Clinical findings and post-mortem examinations of the worker are evaluated.Results:A cristobalite concentration of 36% (wt/wt) was determined in the diatomaceous earth sample and a large amount of diatom fragments were observed in lung samples. The DRX spectra indicated the presence of cristobalite either in the bulk sample or in the lung tissues. The MSDS dated 2002 reported the presence of SLC up to 63% with cristobalite concentrations <60%, and the resulting risk of silicosis, while the MSDS dated 2018 and referred to a commercial product currently on the market indicated a concentration of cristobalite <1% and no risk of silicosis. The worker was suffering from a severe silicosis, histologically confirmed by necropsy.Conclusion:The present case-study revealed that the risk of silicosis from calcined diatomaceous earths used to produce dental alginates has been ignored. The lack of engineering controls and personal protection measures led to a high cristobalite lung burden, consistent with the development of a severe silicosis that were a contributing factor of death. A MSDS of a commercial product currently on the market does not report this serious hazard.Key words: Silicosis, diatomaceous earth, dental alginate     

Blockade of CCR5 in melanoma: An alternative immune checkpoint modulator

Melanoma is a deadly tumor, which in recent years has been successfully treated with immune checkpoint inhibitors as PD-1/PD-L1 and CTLA-4 inhibitors and targeted therapy as BRAF and MEK inhibitors. However, immunotherapy poses deleterious side effects and pursuit of new therapeutic targets is warranted. As knowledge of tumor immunology advances, such targets are being recognized. C-motif chemokine receptor-5 (CCR5) is a receptor found on immune cells whose effects impact the immune response both to induce inflammation and to activate suppressor cells causing an anti-inflammatory effect. CCR5 is well known as a target for HIV therapy where its blockade is efficient and safe, it is also known that its mutation CCR5delta32 is for the most part non-pathological to its carriers. In oncology, activation of the CCR5 receptor has been observed in high-stage disease and CCR5 blockade has been associated with an increased immune response. In this letter, we build up the rationale to utilize CCR5 as a therapeutic target for metastatic melanoma.