Vagal stimulation in heart failure

Vagal nerve stimulation (VNS) has a strong pathophysiological rationale as a potentially beneficial treatment for heart failure with reduced ejection fraction. Despite several promising preclinical studies and pilot clinical studies, the two large, controlled trials—NECTAR-HF and INOVATE-HF—failed to demonstrate the expected benefit. It is likely that clinical application of VNS in phase III studies was performed before a sufficient degree of understanding of the complex pathophysiology of autonomic electrical modulation had been achieved, therefore leading to an underestimation of its potential benefit. More knowledge on the complex dose–response issue of VNS (i.e., pulse amplitude, frequency, duration and duty cycle) has been gathered since these trials and a new randomized study is currently underway with an adaptive design and a refined approach in an attempt to deliver the proper dose to a more selected group of patients.

Magenkarzinom: Kombination aus Zolbetuximab und Chemotherapie bietet neuen therapeutischen Ansatz

<b>Background:</b> Claudin 18.2 (CLDN18.2) is contained within normal gastric mucosa epithelial tight junctions; upon malignant transformation, CLDN18.2 epitopes become exposed. Zolbetuximab, a chimeric monoclonal antibody, mediates specific killing of CLDN18.2-positive cells through immune effector mechanisms. <b>Patients and methods:</b> The FAST study enrolled advanced gastric/gastro-oesophageal junction and oesophageal adenocarcinoma patients (aged ≥18 years) with moderate-to-strong CLDN18.2 expression in ≥40% tumour cells. Patients received first-line epirubicin + oxaliplatin + capecitabine (EOX, arm 1, n = 84) every 3 weeks (Q3W), or zolbetuximab + EOX (loading dose, 800 mg/m² then 600 mg/m² Q3W) (arm 2, n = 77). Arm 3 (exploratory) was added after enrolment initiation (zolbetuximab + EOX 1000 mg/m² Q3W, n = 85). The primary endpoint was progression-free survival (PFS) and overall survival (OS) was a secondary endpoint. <b>Results:</b> In the overall population, both PFS [hazard ratio (HR) = 0.44; 95% confidence interval (CI), 0.29–0.67; P &#x3c; 0.0005] and OS (HR = 0.55; 95% CI, 0.39–0.77; P &#x3c; 0.0005) were significantly improved with zolbetuximab + EOX (arm 2) compared with EOX alone (arm 1). This significant PFS benefit was retained in patients with moderate-to-strong CLDN18.2 expression in ≥70% of tumour cells (HR = 0.38; 95% CI, 0.23–0.62; P &#x3c; 0.0005). Significant improvement in PFS was also reported in the overall population of arm 3 versus arm 1 (HR = 0.58; 95% CI, 0.39–0.85; P = 0.0114) but not in high CLDN18.2-expressing patients; no significant improvement in OS was observed in either population. Most adverse events (AEs) related to zolbetuximab + EOX (nausea, vomiting, neutropenia, anaemia) were grade 1–2. Grade ≥3 AEs showed no substantial increases overall (zolbetuximab + EOX versus EOX alone). <b>Conclusions:</b> In advanced gastric/gastro-oesophageal junction and oesophageal adenocarcinoma patients expressing CLDN18.2, adding zolbetuximab to first-line EOX provided longer PFS and OS versus EOX alone. Zolbetuximab + EOX was generally tolerated and AEs were manageable. Zolbetuximab 800/600 mg/m² is being evaluated in phase III studies based on clinical benefit observed in the overall population and in patients with moderate-to-strong CLDN18.2 expression in ≥70% of tumour cells.

Efetividade do metronidazol tópico e/ou sistêmico no controle do mau odor de tumores malignos fétidos: revisão sistemática

Introduction: Fetid tumors are a devastating complication of cancer and cause much discomfort and patient isolation. They usually develop themselves in the last six months of life and they are very difficult to be successfully treated. The aim of this systematic review was to analyze the evidence on the effectiveness of topical and/or systemic metronidazole for the treatment of bad odor in malignant tumor wounds. Results: Sixty-two articles were initially found, and of these, only 4 articles met the inclusion criteria. Two of them were clinical trials, being 1 double-blind, randomized and 1 non-controlled phase III studies. One study was retrospective with a 10-years data collection period and 1 was a cohort prospective study. Of these, 3 analyzed the efficacy of treating malignant tumors with a bad odor using topical metronidazole and only 1 compared the use of topical and systemic metronidazole. Discussion: A factor that contributes to the bad odor not being properly controlled is the lack of standardized protocols. Over the years, studies have tried to find affordable and effective interventions to reduce serious recurrences of bad odor in necrotic wounds. Conclusion: Both topical and systemic routes have been shown to be effective in controlling bad odor. The results of this systematic review highlight the lack of research in this area with little evidence to guide clinical practice in the treatment of these injuries. Further studies are needed to establish more effective protocols to control this distressing condition, experienced by some cancer patients.

Masitinib for the treatment of Alzheimer's disease

The actual standard treatment for mild-to-moderately severe Alzheimer's disease only attacks its symptoms. Masitinib is a potent and selective phenylaminothiazole-type tyrosine kinase inhibitor which is currently in Phase III studies for the treatment of Alzheimer's disease (AD) with the aim of modifying its evolution and with multiple pharmacological targets such as inhibition of mast cells activity, inhibition of microglia activation, modulation of Aβ and Tau protein signaling pathway and prevention of synaptic damage. Here, we review the preclinical and clinical studies that investigated the administration of masitinib treatment in monotherapy in AD. All research studies revealed positive effects concerning the cognitive functions in AD and generally with good safety and tolerability.

Moderate Hypofractionated Radiotherapy for Localized Prostate Cancer: The Triumph of Radiobiology

Background: Radiotherapy represents one of the main therapeutic modalities for localized prostate cancer. In the last two decades, emerging data regarding the radiobiology of prostate cancer suggests a very low α/β value which has led the scientific community to evaluate the potential advantage of hypofractionation. Objective: The aim of this manuscript is to present the rationale of prostate radiobiology and the medical evidence of moderate hypofractionation for prostate cancer. Methods: Existing literature was reviewed, including data from prospective clinical trials dealing with the efficacy and toxicity of hypofractionated radiotherapy. Fifteen prospective phase II studies, nine randomized phase III studies, and ten meta-analyses were selected. For every study included, the equivalent dose was calculated for both biochemical control and late toxicity. Results: The efficacy of hypofractionated radiotherapy, compared to conventional radiotherapy, regarding biochemical control, was evaluated in five superiority and four non-inferiority randomized phase III studies. The majority of participants in these studies were patients with low- and intermediate-risk prostate cancer. Even though the superiority criterion of the hypofractionation was not met in all studies, the non-inferiority criterion was. Prospective phase II studies of hypofractionation reported a low rate of acute and late toxicity. In randomized phase III studies, acute and late toxicity grade 3 and higher for the bowel and bladder were comparable between hypofractionated and conventional radiotherapy. The included meta-analyses showed no difference in efficacy and toxicity. Conclusion: Moderate hypofractionation is feasible and safe and may be considered an alternative option in low- and intermediate-risk prostate cancer patients.

Efficacy and safety of ceftobiprole in patients aged 65 years or older: a post hoc analysis of three Phase III studies

Aim: To evaluate the efficacy and safety of ceftobiprole in patients aged ≥65 years. Materials & methods: We conducted a post hoc analysis of three randomized, double-blind, Phase III studies in patients with acute bacterial skin and skin structure infections, community-acquired pneumonia and hospital-acquired pneumonia. Results: Findings for patients aged ≥65 years (n = 633) were consistent with those for the overall study populations, although a trend toward improved outcomes was reported in some subgroups, for example, patients aged ≥75 years with community-acquired pneumonia were more likely to achieve an early clinical response with ceftobiprole than comparator (treatment difference 16.3% [95% CI:1.8–30.8]). The safety profile was similar between treatment groups in all studies. Conclusion: This analysis further supports the efficacy and safety of ceftobiprole in older patients with acute bacterial skin and skin structure infections or pneumonia. Clinicaltrials.gov trial identifiers: NCT03137173 , NCT00326287 , NCT00210964 , NCT00229008