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Targeting FGFR3 alterations with adjuvant infigratinib in invasive urothelial carcinoma: the phase III PROOF 302 trial.
No full textPROOF 302 is an ongoing randomized, double-blind, placebo-controlled, adjuvant phase III trial (NCT04197986) in approximately 218 patients from 120 centers worldwide. Eligibility criteria include post-surgical high-risk muscle-invasive upper tract urothelial cancer (85% of patients) or urothelial bladder cancer (15%), susceptible FGFR3 alterations (activating mutations, gene fusions or rearrangements), ≤120 days following radical surgery and ineligible for/or refusing cisplatin-based (neo)adjuvant chemotherapy. Patients receive either oral infigratinib 125 mg or placebo daily on days 1-21 of a 28-day cycle for up to 52 weeks or until recurrence, unacceptable toxicity or death. Primary end point: centrally determined disease-free survival (DFS); secondary end points: investigator-assessed DFS, metastasis-free survival, overall survival and safety/tolerability; exploratory end points: correlative biomarker analysis, quality-of-life and infigratinib pharmacokinetics
Transcultural adaptation and validation of the Spanish version of the Global Pain Scale.
No full textThe aim of this study was to perform a cross-cultural adaption and validation of the Global Pain Scale (GPS) to produce a Spanish-language version (GPS-Sp) and to determine the psychometric properties of this instrument. The GPS was cross-culturally translated into Spanish following the guidelines of the International Society for Pharmacoeconomics and Outcomes Research. The initial study population was composed of 384 patients recruited from February to May 2021. All participants were aged at least 18 years and were currently experiencing pain. All gave signed informed consent to take part and completed the Brief Inventory-Sp and GPS-Spain questionnaires. Cronbach's ɑ and test/retest reliability values were calculated and floor/ceiling effects analyzed. Construct validity was assessed by confirmatory factor analysis (CFA). The 370 patients included in the final analysis presented the following characteristics: 36.2% were male and 63.8% were female; mean age 42.6 (19-88) years; mean body mass index 24.99. Internal consistency was good. The Cronbach's ɑ for GPS-Sp was 0.86 and the intraclass correlation coefficient was 0.94 (95% CI; 0.87-0.97). Five main explanatory factors were identified by CFA, which produced the following values: RMSEA = 0.057; CFI = 0.807; GFI = 0.809; NFI = 0.763. No floor/ceiling effect was observed. The GPS-Sp is a valid, reliable and sensitive instrument for assessing pain in a Spanish-speaking population and could facilitate pain relief in this population
Tofacitinib for Treatment of Alopecia Areata: Real-world Evidence and Factors Associated with Therapeutic Response.
No full textLaboratory Cross-Comparison and Ring Test Trial for Tumor BRCA Testing in a Multicenter Epithelial Ovarian Cancer Series: The BORNEO GEICO 60-0 Study
No full textGermline and tumor BRCA testing constitutes a valuable tool for clinical decision-making in the management of epithelial ovarian cancer (EOC) patients. Tissue testing is able to identify both germline (g) and somatic (s) BRCA variants, but tissue preservation methods and the widespread implementation of NGS represent pre-analytical and analytical challenges that need to be managed. This study was carried out on a multicenter prospective GEICO cohort of EOC patients with known gBRCA status in order to determine the inter-laboratory reproducibility of tissue sBRCA testing. The study consisted of two independent experimental approaches, a bilateral comparison between two reference laboratories (RLs) testing 82 formalin-paraffin-embedded (FFPE) EOC samples each, and a Ring Test Trial (RTT) with five participating clinical laboratories (CLs) evaluating the performance of tissue BRCA testing in a total of nine samples. Importantly, labs employed their own locally adopted next-generation sequencing (NGS) analytical approach. BRCA mutation frequency in the RL sub-study cohort was 23.17%: 12 (63.1%) germline and 6 (31.6%) somatic. Concordance between the two RLs with respect to BRCA status was 84.2% (gBRCA 100%). The RTT study distributed a total of nine samples (three commercial synthetic human FFPE references, three FFPE, and three OC DNA) among five CLs. The median concordance detection rate among them was 64.7% (range: 35.3-70.6%). Analytical discrepancies were mainly due to the minimum variant allele frequency thresholds, bioinformatic pipeline filters, and downstream variant interpretation, some of them with consequences of clinical relevance. Our study demonstrates a wide range of concordance in the identification and interpretation of BRCA sequencing data, highlighting the relevance of establishing standard criteria for detecting, interpreting, and reporting BRCA variants.S
Myeloid-derived suppressor cells and vaccination against pathogens.
No full textIt is widely accepted that the immune system includes molecular and cellular components that play a role in regulating and suppressing the effector immune response in almost any process in which the immune system is involved. Myeloid-derived suppressor cells (MDSCs) are described as a heterogeneous population of myeloid origin, immature state, with a strong capacity to suppress T cells and other immune populations. Although the initial characterization of these cells was strongly associated with pathological conditions such as cancer and then with chronic and acute infections, extensive evidence supports that MDSCs are also involved in physiological/non-pathological settings, including pregnancy, neonatal period, aging, and vaccination. Vaccination is one of the greatest public health achievements and has reduced mortality and morbidity caused by many pathogens. The primary goal of prophylactic vaccination is to induce protection against a potential pathogen by mimicking, at least in a part, the events that take place during its natural interaction with the host. This strategy allows the immune system to prepare humoral and cellular effector components to cope with the real infection. This approach has been successful in developing vaccines against many pathogens. However, when the infectious agents can evade and subvert the host immune system, inducing cells with regulatory/suppressive capacity, the development of vaccines may not be straightforward. Notably, there is a long list of complex pathogens that can expand MDSCs, for which a vaccine is still not available. Moreover, vaccination against numerous bacteria, viruses, parasites, and fungi has also been shown to cause MDSC expansion. Increases are not due to a particular adjuvant or immunization route; indeed, numerous adjuvants and immunization routes have been reported to cause an accumulation of this immunosuppressive population. Most of the reports describe that, according to their suppressive nature, MDSCs may limit vaccine efficacy. Taking into account the accumulated evidence supporting the involvement of MDSCs in vaccination, this review aims to compile the studies that highlight the role of MDSCs during the assessment of vaccines against pathogens
Facilitators and Barriers of Medication Adherence Based on Beliefs of Persons with Bipolar Disorder: A Qualitative Study.
No full textOne of the big challenges in treating individuals with bipolar disorder (BD) is nonadherence to medication. This is the principal factor associated with a worse prognosis or outcome of the disease. This study aimed to explore and analyze the individual perceptions that people with BD have about the positive and negative aspects when taking medication. A descriptive and interpretative study was carried out using the qualitative research paradigm with the use of the analytical technique of discourse analysis, extracting the data through the completion of focus groups. Participants' speech was digitally audio-recorded in digital format. In order to complete the codification of the participants' speech content, we relied on the qualitative data analysis (using the QRS NVivo 10 computer software). Thirty-six participants diagnosed with bipolar disorder took part in our study. In the participants' speech concerning the main barriers to pharmacological treatment, three key topics were identified. Perceived facilitators were summarized in four factors. The main facilitators regarding the use of pharmacological treatment in individuals with BD were the ones related with the perceived need for treatment in the acute phase, the recognition of the illness, the shared clinical decision, and the causal biological attribution in the chronic phase. In terms of perceived barriers, social control was identified in both phases, adverse effects in the acute phase, and the absence of effective treatment in the chronic state.S
PET ASSESSMENT OF THE EFFECTIVENESS OF TOCILIZUMAB IN GIANT CELL ARTERITIS. STUDY OF 101 PATIENTS FROM CLINICAL PRACTICE
No full textBlood pressure variability and cognitive dysfunction: What is the cause and what is the consequence?
No full textWe read with great interest the paper entitled “Blood pressure variability and cognitive dysfunction: A systematic review and meta-analysis of longitudinal cohort studies” recently published in the Journal of Clinical Hypertension.1 The authors concluded that high variability of systolic blood pressure was associated with an increased risk of all-cause dementia but not an increased incidence of cognitive decline on neuropsychological examinations. Their results also showed significant positive correlations with all-cause dementia risk but not when Alzheimer's disease-related dementia and vascular dementia were considered separately.S
Editorial: Tumor Microenvironment and Cancer Cell Interactions in Solid Tumor Growth and Therapy Resistance.
No full textSolid tumour tissues contain a tumour microenvironment (TME) which influences tumour progression and therapy resistance (Romano et al., 2021). TME is a network including non-cancer stromal cells, extracellular matrix (ECM), growth factors, nutrients, blood and lymphatic vessels (Avagliano et al., 2020b), and its structure and components, depending on the type and location of the tumour, make each solid tumour unique (Granato et al., 2017; Avagliano et al., 2020a). Moreover, the TME plasticity leads to its evolution with disease and adaptation to cancer cell and environmental alterations. The components of TME by interacting with each other and with tumour cells generate a cancer niche that sustains immunosuppressive processes, drug resistance, cancer recurrence and dissemination that represent the main causes of cancer related deaths.S
PARP1 inhibition by Olaparib reduces the lethality of pancreatic cancer cells and increases their sensitivity to Gemcitabine.
No full textPancreatic cancer (PC) is one of the tumors with the lowest survival rates due to the poor efficacy of the treatments currently used. Gemcitabine (GMZ), one of the chemotherapeutic agents employed when the tumor is unresectable, frequently fails due to the development of drug resistance. PARP1 is a relevant protein in this phenomenon and appears to be related to cancer progression in several types of tumors, including PC. To determine the relevance of PARP1 in the development and treatment of PC, we used the Panc02 cell line to generate modified PC cells with stably inhibited PARP1 expression (Panc02-L) and used GMZ, Olaparib (OLA) and GMZ+OLA as therapeutic strategies. Viability, radiosensitization, angiogenesis, migration, colony formation, TUNEL, cell cycle, multicellular tumorsphere induction and in vivo assays were performed to test the influence of PARP1 inhibition on resistance phenomena and tumor progression. We demonstrated that stable inhibition or pharmacological blockade of PARP1 using OLA-sensitized Panc02 cells against GMZ significantly decreased their IC50, reducing colony formation capacity, cell migration and vessel formation (angiogenesis) in vitro. Furthermore, in vivo analyses revealed that Panc02-L-derived (PARP1-inhibited) tumors showed less growth and lethality, and that GMZ+OLA treatment significantly reduced tumor growth. In conclusion, PARP1 inhibition, both alone and in combination with GMZ, enhances the effectiveness of this chemotherapeutic agent and represents a promising strategy for the treatment of PC.This work was supported by the Project Innbio INB-009 (Granada University and ibs. GRANADA), Project DTS17/00081 (Instituto de Salud Carlos III) and by the CTS-107 Group and Projects A-CTS-666-UGR20 and B-CTS-122-UGR20 of the Junta de Andalucía (FEDER) (Spain). FQ acknowledges the FPU2018 grant from the Ministerio de Educación, Ciencia y Deporte y Competitividad (Spain). We thank Instrumentation Scientific Center (CIC) from University of Granada for technical assistance.S