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ObjectiveThe addition of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) to endocrine therapy impressively improved the outcome of patients with hormone receptor-positive metastatic breast cancer. Despite their great efficacy, not all patients respond to treatment and many of them develop acquired resistance. The aim of this retrospective study was to assess the role of [18F]-FDG PET/CT in predicting PFS and OS in breast cancer patients treated with CDK4/6i.Methods114 patients who performed an [18F]-FDG PET/CT scan before (PET1) and 2-6 months (PET2) after starting treatment were retrospectively enrolled. Metabolic response was evaluated by EORTC, PERCIST and Deauville Score and correlated to PFS and OS.ResultsIn patients who did not progress at PET2 (n = 90), PFS rates were not significantly different between classes of response by EORTC and PERCIST. Conversely, patients showing a Deauville score ≤3 had a longer PFS (median PFS 42 vs 21.0 months; p = 0.008). A higher total metabolic tumor volume at PET1 (TMTV1) was also associated with a shorter PFS (median 18 vs 42 months; p = 0.0026). TMTV1 and Deauville score were the only independent prognostic factors for PFS at multivariate analysis and their combination stratified the population in four definite classes of relapse risk. Conversely, the above parameters did not affect OS which was only influenced by a progressive metabolic disease at PET2 (3-years survival rate 29.8 vs 84.9%; p

PurposeClinical trials have shown a significant increase in pathologic complete response (pCR) with the addition of pertuzumab to neoadjuvant chemotherapy for patients with early-stage HER-2 positive breast cancer. To date, limited studies have examined comparative outcomes of neoadjuvant pertuzumab in real-world setting. The Neopearl study aimed to assess comparative real-life efficacy and safety of neoadjuvant pertuzumab for these patients.MethodsWe conducted a nationwide retrospective analysis involving 17 oncology facilities with a certified multidisciplinary breast cancer treatment committee. We identified patients with HER-2 positive stage II-III breast cancer treated with neoadjuvant chemotherapy based on trastuzumab and taxanes with or without pertuzumab. All patients underwent breast surgery and received a comprehensive cardiologic evaluation at baseline and after neoadjuvant treatment. Patients who received the combination of pertuzumab, trastuzumab, and chemotherapy constituted case cohort (PTCT), whereas those treated with trastuzumab and chemotherapy accounted for control cohort (TCT). The pCR rate and 5-year event free survival (EFS) were the primary outcomes. Secondary end-points were rates of conversion from planned modified radical mastectomy (MRM) to breast conservation surgery (BCS) and cardiotoxicities.ResultsFrom March 2014 to April 2021, we included 271 patients, 134 (49%) and 137 (51%) in TCT and PTCT cohort, respectively. Positive axillary lymph nodes and stage III were more frequent in PTCT cohort. The pCR rate was significantly increased in patients who received pertuzumab (49% vs 62%; OR 1.74, 95%CI 1.04-2.89) and with HER-2 enriched subtypes (16% vs 85%; OR 2.94, 95%CI 1.60-5.41). After a median follow-up of 5 years, the 5-year EFS was significantly prolonged only in patients treated with pertuzumab (81% vs 93%; HR 2.22, 95%CI 1.03-4.79). The same analysis performed on propensity score matched population showed concordant results. On univariate analysis, only patients with positive lymph nodes were found to benefit from pertuzumab for both pCR and 5-year EFS. The rates of conversion from MRM to BCS and cardiologic toxicities did not differ between the cohorts.ConclusionOur findings support previous data on improved outcomes with the addition of pertuzumab to trastuzumab-based neoadjuvant chemotherapy. This benefit seems to be more significant in patients with clinically positive lymph nodes.

We analyze a sample of 244 ram-pressure-stripped candidate galaxy members within the virial radius of 62 nearby clusters to determine their velocity anisotropy profile β ( r ). We use previously determined mass profiles for the 62 clusters to build an ensemble cluster by stacking the 62 cluster samples in projected phase space. We solve the Jeans equation for dynamical equilibrium by two methods, MAMPOSSt and the Jeans inversion technique, and determine β ( r ) both in parametric form and nonparametrically. The two methods consistently indicate that the orbits of the ram-pressure-stripped candidates are increasingly radial with distance from the cluster center, from almost isotropic ( β ≃ 0) at the center, to very radial at the virial radius ( β ≃ 0.7). The orbits of cluster galaxies undergoing ram pressure stripping are similar to those of spiral cluster galaxies but more radially elongated at large radii.

Introdução: A Fitoterapia é uma prática estratégica para as ações em saúde, que amplia as possibilidades terapêuticas e contribui para a atenção integral aos usuários do Sistema Único de Saúde (SUS). Objetivo: O presente artigo apresenta um estudo descritivo do mapeamento dos fitoterápicos e das plantas medicinais oferta dos nas farmácias municipais no Rio Grande do Sul. Método: Foi utilizado um formulário semiestruturado o qual foi aplicado aos municípios do estado. Resultados: Foi verificado que trinta e sete porcento (37%) dos municípios que preencheram o formulário dispensam medicamentos fitoterápicos à população com predomínio dos medicamentos industrializados, visto que apenas três municípios manipulam fitoterápicos. Além disso, seis municípios ofertam chá medicinal e dezessete dispõem de horto de plantas medicinais, principalmente para uso educativo sobre a planta fresca e distribuição de espécies vegetais e/ou mudas para os usuários. Conclusão: A quase totalidade, noventa e três porcento (93%) dos entrevistados, considerou a fitoterapia importante, o que mostra a necessidade de maior estruturação desta abordagem terapêutica no âmbito do SUS.

BackgroundIn triple negative breast cancer patients treated with neoadjuvant chemotherapy, residual disease at surgery is the most relevant unfavorable prognostic factor. Current guidelines consider the use of adjuvant capecitabine, based on the results of the randomized CREATE-X study, carried out in Asian patients and including a small subset of triple negative tumors. Thus far, evidence on Caucasian patients is limited, and no real-world data are available.MethodsWe carried out a multicenter, observational study, involving 44 oncologic centres. Triple negative breast cancer patients with residual disease, treated with adjuvant capecitabine from January 2017 through June 2021, were recruited. We primarily focused on treatment tolerability, with toxicity being reported as potential cause of treatment discontinuation. Secondarily, we assessed effectiveness in the overall study population and in a subset having a minimum follow-up of 2 years.ResultsOverall, 270 patients were retrospectively identified. The 50.4% of the patients had residual node positive disease, 7.8% and 81.9% had large or G3 residual tumor, respectively, and 80.4% a Ki-67 >20%. Toxicity-related treatment discontinuation was observed only in 10.4% of the patients. In the whole population, at a median follow-up of 15 months, 2-year disease-free survival was 62%, 2 and 3-year overall survival 84.0% and 76.2%, respectively. In 129 patients with a median follow-up of 25 months, 2-year disease-free survival was 43.4%, 2 and 3-year overall survival 78.0% and 70.8%, respectively. Six or more cycles of capecitabine were associated with more favourable outcomes compared with less than six cycles.ConclusionThe CaRe study shows an unexpectedly good tolerance of adjuvant capecitabine in a real-world setting, although effectiveness appears to be lower than that observed in the CREATE-X study. Methodological differences between the two studies impose significant limits to comparability concerning effectiveness, and strongly invite further research.

Hypertrophic cardiomyopathy (HCM) is an autosomal dominant disease, characterized by the presence of unexplained left ventricular hypertrophy. This condition is often associated with electrocardiographic abnormalities including QTc prolongation occurring in 13% of patients. The main explanation for prolonged QTc in HCM is myocardial hypertrophy and the related structural damage. However, other mechanisms, including long QT syndrome (LQTS) genes mutations, may be involved. In the present study we explored the hypothesis of a distinct genetic basis underlying QTc prolongation in HCM by investigating the potential co-inheritance of pathogenic gene variants associated with LQTS and HCM. For this purpose, starting from a cohort of 150 HCM patients carrying pathogenic variants in sarcomere genes, we selected 25 patients carrying a QTc prolongation unexplained by any other cause. The QTc was considered prolonged if greater than 450 ms in males and greater than 470 ms in females. The NGS analysis was performed with Illumina TrueSight Cardio panel genes on Illumina MiniSeq platform. We identified pathogenic/likely pathogenic variants in the KCNQ1 in two patients (c.1781G > A, p. Arg594Gln; c.532G > A, p. Ala178Thr) (8%). Variants of uncertain significance were identified in SCN5A, KCNJ5, AKAP9 and ANK2 in four patients (16%). Although the results are limited by the small number of patients included in the study, they highlight a minor contribution of LQTS genes for QTc prolongation in HCM patients. The screening for ion channel genes mutations may be considered in HCM patients with prolonged QTc unexplained by any other cause. This in-depth molecular diagnosis may contribute to improve risk stratification and treatment planning.

TKIs long-term treatment in CML may lead to persistent adverse events (AEs) that can promote relevant morbidity and mortality. Consequently, TKIs dose reduction is often used to prevent AEs. However, data on its impact on successful treatment-free remission (TFR) are quite scarce. We conducted a retrospective study on the outcome of CML subjects who discontinued low-dose TKIs from 54 Italian hematology centers participating in the Campus CML network. Overall, 1.785 of 5.108 (35.0%) regularly followed CML patients were treated with low-dose TKIs, more frequently due to relevant comorbidities or AEs (1.288, 72.2%). TFR was attempted in 248 (13.9%) subjects, all but three while in deep molecular response (DMR). After a median follow-up of 24.9 months, 172 (69.4%) patients were still in TFR. TFR outcome was not influenced by gender, Sokal/ELTS risk scores, prior interferon, number and last type of TKI used prior to treatment cessation, DMR degree, reason for dose reduction or median TKIs duration. Conversely, TFR probability was significantly better in the absence of resistance to any prior TKI. In addition, patients with a longer DMR duration before TKI discontinuation (i.e., >6.8 years) and those with an e14a2 BCR::ABL1 transcript type showed a trend towards prolonged TFR. It should also be emphasized that only 30.6% of our cases suffered from molecular relapse, less than reported during full-dose TKI treatment. The use of low-dose TKIs does not appear to affect the likelihood of achieving a DMR and thus trying a treatment withdrawal, but might even promote the TFR rate.

Background: Platelet-rich plasma (PRP) is increasingly used for the injection treatment of knee osteoarthritis (OA). However, the role of leukocytes contained in PRP is controversial, with some preclinical studies suggesting detrimental effects and others emphasizing their contribution in secreting bioactive molecules. Purpose: To compare the safety and effectiveness of leukocyte-rich PRP (LR-PRP) and leukocyte-poor PRP (LP-PRP) for the treatment of knee OA. Hypothesis: That leukocytes could influence results both in terms of adverse events and clinical outcomes. Study Design: Randomized controlled trial; Level of evidence, 1. Methods: This double-blind randomized controlled trial included 132 patients with Kellgren-Lawrence grade 1-3 knee OA who were randomized to a 3-injection cycle of either LR-PRP or LP-PRP. Patients were prospectively assessed at baseline and at 2, 6, and 12 months with subjective evaluations comprising the International Knee Documentation Committee (IKDC) subjective score, the KOOS (Knee injury and Osteoarthritis Outcome Score), the WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index), the visual analog scale for pain, the EuroQol–visual analog scale, the EuroQol–5 dimensions, and the Tegner activity scale. Objective evaluations consisted of the IKDC objective score, active/passive range of motion, and circumference of the index and contralateral knees. Patient judgment of the treatment was recorded as well as adverse reactions and failures. Results: An overall improvement in subjective and objective outcomes was documented, with no differences between the 2 groups, except for the improvement in the IKDC subjective score at 2 months, which was greater for the LR-PRP group compared with the LP-PRP group (14.8 ± 14.8 vs 8.6 ± 13.3, respectively; P =.046), as well as for active (P =.021) and passive (P =.040) ROM of the index knee at 6 months, showing statistically significant higher values in the LP-PRP group; and for quadriceps circumference of the index (P =.042) and contralateral (P =.045) knees at 12 months, which were significantly greater in the LR-PRP group. The IKDC subjective score improved from 42.5 ± 17.6 at baseline to 55.6 ± 21.4 at 12 months for the LR-PRP group (P <.0005) and from 45.7 ± 16.4 to 55.3 ± 20.4 for the LP-PRP group (P =.001). No differences in terms of patient treatment judgment were observed at all follow-up time points. No severe adverse events related to the treatment were reported, but some mild adverse events related to the treatment were observed: 16 in the LR-PRP group and 17 in the LP-PRP group. Treatment failed in 5 patients in the LR-PRP group and 2 in the LP-PRP group. Conclusion: This double-blind randomized controlled trial demonstrated that leukocytes did not affect the safety and efficacy of intra-articular PRP injections for the treatment of patients with knee OA. Both LR-PRP and LP-PRP demonstrated comparable clinical outcomes at all follow-up time points, without showing differences in subjective and objective outcomes or in adverse events and treatment failures. Registration: NCT04187183 (ClinicalTrials.gov). [ABSTRACT FROM AUTHOR]

Tooth development, or odontogenesis, is a complex process in which several molecular pathways play a key role. Recently, microRNAs, a class of approximately 20-nucleotide small RNA molecules that regulate gene expression, have been implicated in the odontogenesis process. This study aimed to assess the role of miRNAs in odontogenesis anomalies, specifically agenesis and impaction. We analyzed a manually curated list of 82 miRNAs associated with human odontogenesis, sourced from literature data. Employing two different approaches to validate findings, we conducted functional enrichment analysis to evaluate the cell pathways, diseases, and phenotypes enriched for those miRNAs. Our findings indicate that the analyzed miRNAs regulate pathways linked to tooth anomalies, including the TGFꞵ and Wnt signaling pathways, and those governing the pluripotency of stem cells, known to mediate various cellular processes, and interconnected with odontogenesis-related pathways. Furthermore, the analysis disclosed several pathways associated with tumors, including small cell lung and gastric cancer. These results were confirmed also by diseases and phenotypes enrichment evaluation. Moreover, cell network analysis disclosed that miRNAs are embedded and interconnected in networks associated with dental diseases and cancer development, thus confirming the functional enrichment analyses. In summary, our results offer a quantitative measure of the potential involvement of miRNAs in regulating pathways crucial for developmental processes, notably odontogenesis, and provide results suggesting potential association with oncogenesis processes as well. [ABSTRACT FROM AUTHOR]

Hereditary cardiomyopathies (CMPs), including arrhythmogenic cardiomyopathy (ACM), dilated cardiomyopathy (DCM), and hypertrophic cardiomyopathy (HCM), represent a group of heart disorders that significantly contribute to cardiovascular morbidity and mortality and are often driven by genetic factors. Recent advances in next-generation sequencing (NGS) technology have enabled the identification of rare variants in both well-established and minor genes associated with CMPs. Nowadays, a set of core genes is included in diagnostic panels for ACM, DCM, and HCM. On the other hand, despite their lesser-known status, variants in the minor genes may contribute to disease mechanisms and influence prognosis. This review evaluates the current evidence supporting the involvement of the minor genes in CMPs, considering their potential pathogenicity and clinical significance. A comprehensive analysis of databases, such as ClinGen, ClinVar, and GeneReviews, along with recent literature and diagnostic guidelines provides a thorough overview of the genetic landscape of minor genes in CMPs and offers guidance in clinical practice, evaluating each case individually based on the clinical referral, and insights for future research. Given the increasing knowledge on these less understood genetic factors, future studies are essential to clearly assess their roles, ultimately leading to improved diagnostic precision and therapeutic strategies in hereditary CMPs. [ABSTRACT FROM AUTHOR]

Acute pyelonephritis (APN) is a relatively common community-acquired infection, particularly in women. The early appropriate antibiotic treatment of this potentially life-threatening infection is associated with improved outcomes. The international management guidelines for complicated urinary tract infections and APN recommend using oral antibiotics with Escherichia coli and other Enterobacterales to fluoroquinolones, trimethoprim-sulfamethoxazole (TMP-SMX), and beta-lactams has left patients without reliable oral antibiotic treatment options for APN. This narrative review proposes using precision medicine concepts to improve empirical antibiotic therapy for APN in ambulatory settings. Whereas resistance rates to a particular antibiotic class may exceed 10% at the population-based level, the predicted antibiotic resistance rates based on patient-specific risk factors fall under 10% in many patients with APN on the individual level. The utilization of clinical tools for the prediction of fluoroquinolones, TMP-SMX, and third-generation cephalosporin resistance improves the ambulatory antibiotic management of APN. It may also reduce the need to switch antibiotic therapy later based on the in vitro antibiotic susceptibility testing results of bacterial isolates in urinary cultures. This approach may mitigate the burden of increasing antibiotic resistance in the community by ensuring that the initial antibiotic prescribed has the highest likelihood of treating APN appropriately.

Pacing strategy refers to the distribution of effort and speed throughout the race to achieve optimal performance. This study aims to understand whether the choice of pacing strategy in swimming depends on the length of competitions and how sex, age, and performance level influence this strategy. Participants were the finalists of the 800 m and 1500 m freestyle events at the elite and junior world championships in 2022–2023. Race outcomes and pacing parameters were compared between the two distances and across different groups of swimmers. Swimmers in both distances did not break world records. Pacing strategy generally followed a U-shape with significant differences in the frequency and duration of speed changes between the two distances. The 800 m exhibited more frequent changes in acceleration, while the 1500 m events generally followed a more consistent time-series pattern. There were differences in pacing strategies between males and females and between junior and elite swimmers. Swimmers closer to world records showed more consistent pacing patterns compared to those farther from records. This study suggests that pacing strategies are influenced by race distance, sex, age, and performance level. The research highlights the complex interplay between physiological and psychological factors that shape a swimmer’s decision-making during a race.