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Prostate cancer is one of the most frequent cancers in men and is a common cause of cancer-related death. Despite significant progress in the diagnosis and treatment of this tumor, patients who relapse after radical treatments inevitably develop metastatic disease. Patient stratification is therefore key in this type of cancer, and there is an urgent need for prognostic biomarkers that can define patients’ risk of cancer-related death. In the last 10 years, multiple prognostic factors have been identified and studied. Here, we review the literature available and discuss the most common aberrant genomic pathways in metastatic castration-resistant prostate cancer shown to have a prognostic relevance in this setting.

Background Cabazitaxel improves overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC) patients progressing after docetaxel. In this prospective study, we evaluated the prognostic role of CTC gene expression on cabazitaxel-treated patients and its association with plasma androgen receptor ( AR ) copy number (CN). Methods Patients receiving cabazitaxel 20 or 25 mg/sqm for mCRPC were enrolled. Digital PCR was performed to assess plasma AR CN status. CTC enrichment was assessed using the AdnaTest EMT-2/StemCell kit. CTC expression analyses were performed for 17 genes. Data are expressed as hazard ratio (HR) or odds ratio (OR) and 95% CI. Results Seventy-four patients were fully evaluable. CTC expression of AR-V7 (HR=2.52, 1.24–5.12, p =0.011), AKR1C3 (HR=2.01, 1.06–3.81, p =0.031), AR (HR=2.70, 1.46–5.01, p =0.002), EPCAM (HR=3.75, 2.10–6.71, p < 0.0001), PSMA (HR=2.09, 1.19–3.66, p =0.01), MDK (HR=3.35, 1.83–6.13, p < 0.0001), and HPRT1 (HR=2.46, 1.44–4.18, p =0.0009) was significantly associated with OS. ALDH1 (OR=5.50, 0.97–31.22, p =0.05), AR (OR=8.71, 2.32–32.25, p =0.001), EPCAM (OR=7.26, 1.47–35.73, p =0.015), PSMA (OR=3.86, 1.10–13.50, p =0.035), MDK (OR=6.84, 1.87–24.98, p =0.004), and HPRT1 (OR=7.41, 1.82–30.19, p =0.005) expression was associated with early PD. AR CN status was significantly correlated with AR-V7 ( p =0.05), EPCAM ( p =0.02), and MDK ( p =0.002) expression. In multivariable model, EPCAM and HPRT1 CTC expression, plasma AR CN gain, ECOG PS=2, and liver metastases and PSA were independently associated with poorer OS. In patients treated with cabazitaxel 20 mg/sqm, median OS was shorter in AR-V7 positive than negative patients (6.6 versus 14 months, HR=3.46, 1.47–8.17], p =0.004). Conclusions Baseline CTC biomarkers may be prognosticators for cabazitaxel-treated mCRPC patients. Cabazitaxel at lower (20 mg/sqm) dose was associated with poorer outcomes in AR-V7 positive patients compared to AR-V7 negative patients in a post hoc subgroup analysis. Trial registration Clinicaltrials.gov NCT03381326 . Retrospectively registered on 18 December 2017.

Alzheimer's disease (AD) is a fatal dementing neurodegenerative disease, currently lacking an efficacious disease-modifying therapy. In the last years, there has been some interest in the use of homotaurine as a potential therapeutic compound for AD, but more work is still needed to prove its efficacy as disease modifier in dementia. Since inflammation is believed to play a key role in AD development, we sought to investigate here the homotaurine effect on inflammatory response in patients at the earliest stages of AD, i.e., suffering from amnestic mild cognitive impairment (aMCI). Thus, the present study aims to evaluate the effects of homotaurine supplementation on cytokine serum levels and memory performances in MCI patients. Neuropsychological, clinical and cytokine assessment was performed at baseline (T0) and after 1 year (T12) of homotaurine supplementation in 20 patients categorized as carriers ( = 9) or no carriers ( = 11) of the ε4 allele of the apolipoprotein E (APOE) gene, the strongest genetic risk factor for AD. The serum levels of the pro-inflammatory mediators Interleukin (IL) 1β, Tumor necrosis factor-alpha (TNFα), IL-6 and IL-18, contextually with the anti-inflammatory molecules IL-18 binding protein (IL-18BP) and Transforming growth factor-beta (TGFβ), were analyzed to explore significant differences in the inflammatory status between T0 and T12 in the two APOE variant carrier groups. No significant differences over time were observed in patients as for most cytokines, except for IL-18. Following homotaurine supplementation, patients carrying the APOEε4 allele showed a significant decrease in IL-18 (both in its total and IL-18BP unbound forms), in turn associated with improved short-term episodic memory performance as measured by the recency effect of the Rey 15-word list learning test immediate recall. Thus, homotaurine supplementation in individuals with aMCI may have a positive consequence on episodic memory loss due, at least in part, to homotaurine anti-inflammatory effects. This study strongly suggests that future research should focus on exploring the mechanisms by which homotaurine controls brain inflammation during AD progression.

The specific characteristics of patients who are most likely to benefit from pazopanib therapy are still uncertain. We report on the results of an Italian multicenter, retrospective analysis investigating the factors associated with longer response to first-line pazopanib in patients with metastatic renal cell carcinoma. Adult patients were considered if they had received treatment with pazopanib (800 mg/day) for >12 months in the first-line setting. In total, 112 patients were evaluated. Median duration of pazopanib treatment was 22.6 months (IQR 17.8 months). Median PFS was 22.6 months (95%CI= 20.2-25.0). Eighty-three patients (74.1%) had a PFS ≥18 months. Median OS was 32.9 months (95%CI=30.2-35.6). At statistical analysis, only PS score (1+ vs. 0) was significantly associated with PFS (HR=1.76; 95%CI=1.02-3.05; p=0.04). Pazopanib therapy may be suitable for all patients with mRCC, and especially in those with PS 0.

Objectives. Aging is the major risk factor for Alzheimer Disease (AD) and Mild Cognitive Impairment (MCI). The aim of this study was to identify novel modifications of brain functional connectivity in MCI patients. MCI individuals were compared to healthy elderly subjects. Methods. We enrolled 37 subjects (age range 60-80 y.o.). Of these, 13 subjects were affected by MCI and 24 were age-matched healthy elderly control (HC). Subjects were evaluated with Mini Mental State Examination (MMSE), Frontal Assessment Battery (FAB), and prose memory (Babcock story) tests. In addition, with functional Magnetic Resonance Imaging (fMRI), we investigated resting state network (RSN) activities. Resting state (Rs) fMRI data were analyzed by means of Independent Component Analysis (ICA). Subjects were followed-up with neuropsychological evaluations for three years. Results. Rs-fMRI of MCI subjects showed increased intrinsic connectivity in the Default Mode Network (DMN) and in the Somatomotor Network (SMN). Analysis of the DMN showed statistically significant increased activation in the posterior cingulate cortex (PCC) and left inferior parietal lobule (lIPL). During the three years follow-up, 4 MCI subjects converted to AD. The subset of MCI AD-converted patients showed increased connectivity in the right Inferior Parietal Lobule (rIPL). As for SMN activity, MCI and MCI-AD converted groups showed increased level of connectivity in correspondence of the right Supramarginal Gyrus (rSG). Conclusions. Our findings indicate alterations of DMN and SMN activity in MCI subjects, thereby providing potential imaging-based markers that can be helpful for the early diagnosis and monitoring of these patients.

The risk for Alzheimer's disease (AD) is associated with the presence of the 𝜀4 allele of Apolipoprotein E ( ) gene and, recently, with a novel genetic variant of the gene. This study aimed at evaluating interactions between -𝜀4 and /G variants in the modulation of behavioral and cognitive features of two cohorts of patients suffering from mild cognitive impairment (MCI) or AD. We enrolled a total of 173 female MCI or AD patients (83 MCI; 90 AD). Subjects were screened with a comprehensive set of neuropsychological evaluations and genotyped for the and polymorphic variants. Analysis of covariance was performed to assess the main and interaction effects of and genotypes on the cognitive and behavioral scores. The analysis revealed that the simultaneous presence of -𝜀4 and /G variants results in significant effects on specific neuropsychiatric scores in MCI and AD patients. In MCI patients, and variants worked together to impact the levels of anxiety negatively. Similarly, in AD patients, the variants were found to be associated with increased anxiety levels. Our data indicate a novel synergistic activity and in the modulation of behavioral traits of female MCI and AD patients.

Impairment in real-world functioning remains one of the most problematic challenges that people with schizophrenia have to face. Various psychosocial interventions have proven to be effective in promoting recovery and improving functioning in schizophrenia; however, their implementation and their effectiveness in routine rehabilitation practice are still objects of study. The present pilot study aimed to assess the feasibility and effectiveness on clinical and real-world outcomes of an integrated treatment protocol composed of stable pharmacological treatment, computer-assisted cognitive remediation and social skills training provided in a rehabilitation center. Predictors of functional improvement were also assessed. Seventy-two patients diagnosed with schizophrenia participated in the study. A significant (p < 0.001) improvement in positive, negative and total symptoms, as well as in global clinical severity and real-world functioning outcomes was observed, with a large effect size in positive and total symptoms, global clinical severity and real-world functioning, and a moderate effect size on negative symptoms. Improvement in total symptoms (p < 0.001) and in global clinical severity (p = 0.007) emerged as individual predictors of functional improvement. These findings, although preliminary, suggest that an integrated, evidence-based treatment program is feasible and effective in a real-world rehabilitation context, and that similar interventions should be further implemented in everyday clinical practice.

Erdafitinib, a pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor, was shown to be clinically active and tolerable in patients with advanced urothelial carcinoma and prespecified FGFR alterations in the primary analysis of the BLC2001 study at median 11 months of follow-up. We aimed to assess the long-term efficacy and safety of the selected regimen of erdafitinib determined in the initial part of the study. The open-label, non-comparator, phase 2, BLC2001 study was done at 126 medical centres in 14 countries across Asia, Europe, and North America. Eligible patients were aged 18 years or older with locally advanced and unresectable or metastatic urothelial carcinoma, at least one prespecified FGFR alteration, an Eastern Cooperative Oncology Group performance status of 0–2, and progressive disease after receiving at least one systemic chemotherapy or within 12 months of neoadjuvant or adjuvant chemotherapy or were ineligible for cisplatin. The selected regimen determined in the initial part of the study was continuous once daily 8 mg/day oral erdafitinib in 28-day cycles, with provision for pharmacodynamically guided uptitration to 9 mg/day (8 mg/day UpT). The primary endpoint was investigator-assessed confirmed objective response rate according to Response Evaluation Criteria In Solid Tumors version 1.1. Efficacy and safety were analysed in all treated patients who received at least one dose of erdafitinib. This is the final analysis of this study. This study is registered with ClinicalTrials.gov, NCT02365597. Between May 25, 2015, and Aug 9, 2018, 2328 patients were screened, of whom 212 were enrolled and 101 were treated with the selected erdafitinib 8 mg/day UpT regimen. The data cutoff date for this analysis was Aug 9, 2019. Median efficacy follow-up was 24·0 months (IQR 22·7–26·6). The investigator-assessed objective response rate for patients treated with the selected erdafitinib regimen was 40 (40%; 95% CI 30–49) of 101 patients. The safety profile remained similar to that in the primary analysis, with no new safety signals reported with longer follow-up. Grade 3–4 treatment-emergent adverse events of any causality occurred in 72 (71%) of 101 patients. The most common grade 3–4 treatment-emergent adverse events of any cause were stomatitis (in 14 [14%] of 101 patients) and hyponatraemia (in 11 [11%]). There were no treatment-related deaths. With longer follow-up, treatment with the selected regimen of erdafitinib showed consistent activity and a manageable safety profile in patients with locally advanced or metastatic urothelial carcinoma and prespecified FGFR alterations. Janssen Research & Development.

Zinc (Zn 2+ ) is a pleiotropic modulator of the neuronal and brain activity. The disruption of intraneuronal Zn 2+ levels triggers neurotoxic processes and affects neuronal functioning. In this study, we investigated how the pharmacological modulation of brain Zn 2+ affects synaptic plasticity and cognition in wild-type mice. To manipulate brain Zn 2+ levels, we employed the Zn 2+ (and copper) chelator 5-chloro-7-iodo-8-hydroxyquinoline (clioquinol, CQ). CQ was administered for two weeks to 2.5-month-old (m.o.) mice, and effects studied on BDNF-related signaling, metalloproteinase activity as well as learning and memory performances. CQ treatment was found to negatively affect short- and long-term memory performances. The CQ-driven perturbation of brain Zn 2+ was found to reduce levels of BDNF, synaptic plasticity-related proteins and dendritic spine density in vivo . Our study highlights the importance of choosing “when”, “where”, and “how much” in the modulation of brain Zn 2+ levels. Our findings confirm the importance of targeting Zn 2+ as a therapeutic approach against neurodegenerative conditions but, at the same time, underscore the potential drawbacks of reducing brain Zn 2+ availability upon the early stages of development.

Abstract Background Novel androgen receptor signaling inhibitors for prostate cancer (PC) impose the burden of self-administration on older patients overwhelmed by the requirement of many other concomitant medications. Patients and Methods This study evaluated the proportion of non-adherence in a 12-month follow-up period and the first 3 months to abiraterone (ABI) or enzalutamide (ENZ). In a prospective multicenter observational cohort study, patients with metastatic castration-resistant PC (mCRPC) aged ≥70 years receiving ABI or ENZ pre- or post-docetaxel were enrolled. Treatment monitoring included pill counting, a self-assessment questionnaire, and clinical diaries at each clinical visit. Non-adherence rates were based on proportions of missed/prescribed pills ratios by pill counting. Results Overall, 234 patients were recruited with median age of 78 years (range, 73–82); 86 (37%) were treated with ABI, and 148 (63%) with ENZ. The median follow-up for adherence was seven monthly cycles (IQR: 4–12). The two cohorts were well balanced for baseline characteristics. The percentage of non-adherence by pill counting was slightly higher for ABI than ENZ (5.2% vs. 4.2%, P < .001). By self-reporting, patients on ENZ tended to report more frequently than those with ABI forgetfulness as the reason for missing events (42% vs. 17%, P < .001). A lower Geriatric G8 score correlated with non-adherence (P = .004). Overall survival (OS) was 48.8 months. Patients on ABI had radiographic progression-free survival (rPFS) of 28.4 [24.2–32.5], while for ENZ patients, we reported a median rPFS of 23.1 [18.2–28.1] months. Conclusion Physicians tend to treat older mCRPC patients with ENZ. Non-adherence rate is relatively low overall but can be higher with ABI than with ENZ and correlates with the Geriatric G8 score. Forgetfulness is a potential barrier for ENZ. Adherence to prescribed oral anticancer treatments is underestimated and difficult to measure in oncology and can affect treatment efficacy, safety, and costs, especially in frail and older patients. This article evaluates adherence to abiraterone and enzalutamide in an observational cohort study of older patients with metastatic castration-resistant prostate cancer.