Implications of tumor-infiltrating lymphocytes in early-stage triple-negative breast cancer: clinical oncologist perspectives.

Breast cancer (BC) is the most common neoplasm in women worldwide and one of the leading causes of female death. The triple-negative subtype, characterized by the absence of hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2), tends to occur in younger patients, be more aggressive and less differentiated. Furthermore, this subtype is considered the most immunogenic and associated with higher levels of tumor cell infiltration, mainly lymphocytes. Tumor-infiltrating lymphocytes (TILs) play a crucial role in the interaction of the host's immune system and cancer cells. The microenvironment is critical in tumor development and progression. Assessment of infiltrating lymphocytes can provide valuable information about the immune response and, given the lack of biomarkers to guide treatment decisions and predict outcomes in triple-negative tumors and can be considered as a potential biomarker. Some evidence suggests that higher levels of these lymphocytes are associated with better responses to systemic treatment, longer progression-free survival and overall survival (OS). However, treatment escalation or de-escalation strategies for triple-negative BC (TNBC) currently do not consider the presence or density of TILs for therapeutic decisions. TILs appear to be useful predictive and prognostic indicators. Further clinical studies are needed to confirm these relationships and integrate TILs as a biomarker consistently into clinical practice. This article summarizes key concepts relating to the role of the immune infiltrate in BC, along with the current status and future prospects regarding TILs as a predictive and prognostic biomarker.

Improving access to cancer clinical research in Brazil: recent advances and new opportunities. Expert opinions from the 4th CURA meeting, São Paulo, 2023.

Clinical research is the cornerstone of improvements in cancer care. However, it has been conducted predominantly in high-income countries with few clinical trials available in Brazil and other low-and-middle-income countries (LMIC). Of note, less than one-third of registered clinical trials addressing some of the most commonly diagnosed cancers (breast, lung and cervical) recruited patients from LMIC in the last years. The Institute Project CURA promoted the fourth CURA meeting, discussing barriers to cancer clinical research and proposing potential solutions. A meeting was held in São Paulo, Brazil, in June 2023 with representatives from different sectors: Brazilian Health Regulatory Agency (Anvisa), National Commission of Ethics in Research (CONEP), non-governmental organisations, such as the Latin American Cooperative Oncology Group, the Brazilian Society of Clinical Oncology (SBOC), Contract Research Organisations, pharmaceutical companies and investigators. A total of 16 experts pointed out achievements as shortening the time of regulatory processes involving Anvisa and CONEP, development of staff training programs, maintenance of the National Program of Oncological Attention (PRONON), and the foundation of qualified centres in North and Northeast Brazilian regions. Participants also highlighted the need to be more competitive in the field, which requires optimising ongoing policies and implementing new strategies as decentralisation of clinical research centres, public awareness campaigns, community-centered approaches, collaborations and partnerships, expansion of physicians-directed policies, exploring the role of the steering committee. Active and consistent reporting of the initiatives might help to propagate ongoing advances, increasing Brazilian participation in clinical cancer research. Engagement of all players is crucial to maintain continuous progress with further improvements in critical points including regulatory timelines and increments in qualified human resources which aligned with new educational initiatives focused on physicians and the general population will expand access to cancer clinical trials in Brazil.

Focused ultrasound on the substantia nigra enables safe neurotensin-polyplex nanoparticle-mediated gene delivery to dopaminergic neurons intranasally and by blood circulation.

Neurotensin-polyplex nanoparticles provide efficient gene transfection of nigral dopaminergic neurons when intracerebrally injected in preclinical trials of Parkinson's disease because they do not cross the blood-brain barrier (BBB). Therefore, this study aimed to open BBB with focused ultrasound (FUS) on the substantia nigra to attain systemic and intranasal transfections and evaluate its detrimental effect in rats. Systemically injected Evans Blue showed that a two-pulse FUS opened the nigral BBB. Accordingly, 35 µL of neurotensin-polyplex nanoparticles encompassing the green fluorescent protein plasmid (79.6 nm mean size and + 1.3 mV Zeta-potential) caused its expression in tyrosine hydroxylase(+) cells (dopaminergic neurons) of both substantiae nigrae upon delivery via internal carotid artery, retro-orbital venous sinus, or nasal mucosa 30 min after FUS. The intracarotid delivery yielded the highest transgene expression, followed by intranasal and venous administration. However, FUS caused neuroinflammation displayed by infiltrated lymphocytes (positive to cluster of differentiation 45), activated microglia (positive to ionized calcium-binding adaptor molecule 1), neurotoxic A1 astrocytes (positive to glial fibrillary acidic protein and complement component 3), and neurotrophic A2 astrocytes (positive to glial fibrillary acidic protein and S100 calcium-binding protein A10), that ended 15 days after FUS. Dopaminergic neurons and axonal projections decreased but recuperated basal values on day 15 after transfection, correlating with a decrease and recovery of locomotor behavior. In conclusion, FUS caused transient neuroinflammation and reversible neuronal affection but allowed systemic and intranasal transfection of dopaminergic neurons in both substantiae nigrae. Therefore, FUS could advance neurotensin-polyplex nanotechnology to clinical trials for Parkinson's disease.

[Cytokine measurement using a multiplex technique with spectral flow cytometry: application in the study of the immunobiology of ascariasis]. / Medición de citoquinas mediante una técnica multiplex por citometría espectral: aplicación en el estudio de la inmunobiología de la ascariasis.

OBJECTIVE: To quantify the production of Th1/Th2/Th17 cytokines induced by Ascaris lumbricoides antigens in peripheral blood mononuclear cells (PBMCs) using a multiplex technique. METHODS: PBMCs were cultured from individuals with mild A. lumbricoides infection (n = 20) and uninfected individuals (n = 21) and stimulated with A. lumbricoides extract (ExtAscaris), a mix of anti-CD2/CD3/CD28 (CDmix) as a positive control, and only medium (negative control). Cytokines in the supernatants were measured using the BD™ Cytometric Bead Array Human Th1/Th2/Th17 kit, to identify IFN-γ, TNF, IL-10, IL-6, IL-4, IL-2, and IL-17A. Readings were taken on a spectral cytometer (Northern Lights, Cytek, USA), and analysis was performed using R software with packages "tidyverse," "beadplexr," "flowCore," and "arsenal." Cytokine concentrations were calculated using a 5-parameter logistic curve. The t-test was used to compare cases and controls, and statistical significance was set at p < 0.05. The study was approved by the Ethics Committee of the University of Cartagena and the participants provided informed consent. This study was financially supported by the Colombian Sistema General de Regalías under the BPIN2020000100405 - BPIN2020000100364. RESULTS: Efficient fluorescence intensity extraction for each cytokine was achieved using detection channel R8 and the "mclust" clustering model (Figure 1). No significant differences were found in the levels of the seven cytokines between cases and controls (Figure 2). Although the IFN-γ response to ExtAscaris was higher in cases than in controls (252.5 ng/mL vs. 173.1 ng/mL), the difference was not significant. IL-17A (detection limit: 18.9 pg/mL) was more detectable in cases than controls (5 cases, 23% vs. 2 controls, 9.5%). IL-4 was only detected in the supernatants from CDmix-stimulated cultures but not with the Ascaris extract (Figure 2). CONCLUSIONS: The multiplex technique using spectral flow cytometry combined with open-source software analysis proved applicable for quantifying cytokines induced by A. lumbricoides antigens in PBMCs. However, a more sensitive method is needed to evaluate IL-4 response in the context of ascariasis. The results did not reveal significant differences in cytokine production between cases and controls for the evaluated stimuli.

OBJETIVOS: Cuantificar la producción de citoquinas Th1/Th2/Th17, inducida por antígenos de Ascaris lumbricoides en PBMCs, utilizando una técnica de multiplex. MÉTODOS: Se realizaron cultivos de PBMCs de personas con infección leve por A. lumbricoides (n = 20), y no infectadas (n = 21), y se estimularon con extracto de A. lumbricoides (ExtAscaris), un mix de anti-CD2/CD3/CD28 (CDmix), como control positivo, y solo medio (control negativo). Las citoquinas en los sobrenadantes, se midieron usando el estuche BD™ Cytometric Bead Array Human Th1/Th2/Th17, para identificar IFN-γ, TNF, IL-10, IL-6, IL-4, IL-2 e IL-17A. La lectura se realizó en un citómetro espectral (Northern Lights, Cytek, USA), y el análisis en software R, usando los paquetes tidyverse, beadplexr, flowCore y arsenal. Se calculó la concentración de citoquinas mediante ajuste de curva logística de cinco parámetros. Se empleó la prueba t para comparar casos y controles y una p < 0,05, se consideró como significativa. Se contó con autorización del Comité de Ética de la Universidad de Cartagena para hacer la investigación y con el consentimiento informado por parte de los participantes. Este trabajo fue financiado por el Sistema General de Regalías de Colombia, bajo el BPIN2020000100405 - BPIN2020000100364. RESULTADOS: Al utilizar el canal de detección R8 para identificar las citoquinas y el modelo de agrupamiento mclust, se extrajo eficientemente la intensidad de fluorescencia para cada citoquina (Figura 1). No se encontraron diferencias significativas en los niveles de las siete citoquinas entre casos y controles (Figura 2). Aunque la respuesta de IFN-, γ hacia ExtAscaris fue más alta en los casos de controles (252,5 ng/mL vs 173,1 ng/mL), la diferencia no fue significativa. La IL-17A (límite de detección: 18,9 pg/mL) fue más detectable en casos que en controles (cinco casos, 23% vs dos controles, 9,5%). La IL-4 solo se detectó en los sobrenadantes de cultivos estimulados con CDmix, pero no con el extracto de Ascaris (Figura 2). CONCLUSIONES: La técnica multiplex por citometría espectral, combinada con el análisis en software de licencia libre, se mostró aplicable para cuantificar citoquinas inducidas por antígenos de A. lumbricoides en PBMCs. Sin embargo, se requiere de un método más sensible para evaluar la respuesta de IL-4 en el contexto de la ascariasis. Los resultados no revelaron diferencias significativas en la producción de citoquinas entre casos y controles para los estímulos evaluados.

A realistic combined exposure scenario: effect of microplastics and atrazine on Piaractus mesopotamicus.

Microplastics, considered emerging environmental contaminants resulting from plastic degradation, are discovered in diverse aquatic ecosystems and can be unintentionally ingested by fish. Therefore, it is essential to characterize their interaction with other contaminants, such as agrochemicals, in aquatic environments. This study aimed to assess histological, enzymatic, and genotoxic biomarkers in juvenile pacú (Piaractus mesopotamicus) exposed to polyethylene (PE) microplastic particles and the herbicide atrazine, individually or combined, for 15 days. Four treatments were used: a negative control (CON), PE in the fish diet (0.1% w/w, FPE), atrazine through water (100 µg L-1, ATZ), and the mixture (ATZ+FPE). Results confirmed histological alterations in gills (edema and lamellar fusion) and liver (necrotic areas and congestion) of fish exposed to ATZ and ATZ+FPE. The number of goblet cells increased in the posterior intestine of fish under ATZ+FPE compared to CON and FPE. Enzyme activities (CAT, GST, AChE, and BChE) significantly increased in ATZ+FPE compared to CON. However, no genotoxic effect was demonstrated. These findings provide insights into the complex impacts of simultaneous exposure to atrazine and microplastics, emphasizing the need for continued research to guide effective environmental management strategies against these contaminants that represent a risk to aquatic organisms.

Novel implant design for comminuted posterior wall acetabular fractures.

BACKGROUND: In recent years, the medical community has witnessed a notable increase in high-energy traumatic injuries, leading to a surge in complex fracture patterns that challenge existing treatment methodologies. Among these, the posterior approach to acetabular fractures stands out for offering direct visualization of the retro-acetabular surface, with current fixation methods relying on 3.5 mm low-profile reconstruction plates and various other implants. Despite the effectiveness of these methods, there is a burgeoning demand for a singular, adaptable implant that not only streamlines the surgical process but also optimizes patient outcomes. METHODS: In an innovative approach to address this need, three-dimensional (3D) models of the posterior acetabular wall were meticulously crafted using AutoCAD® software. The chosen material for the implant was 316L surgical steel for its durability and strength. The design of the implant featured a low-profile mesh structure, which was instrumental in facilitating osteosynthesis. This design allowed for the placement of screws of varying lengths in multiple directions, ensuring the initial reconstruction of the joint in an anatomical position without hindering the placement of the definitive implant. The primary objective was to secure the fixation and stabilization of the fracture by specifically targeting the smaller bone fragments. A comparative analysis was then conducted between this novel plate and a conventional 316L surgical steel, seven-hole, 3.5 mm reconstruction plate through finite element analysis. RESULTS: The comparative analysis unveiled that both plates demonstrated comparable deformation capacities, with no significant differences in load-bearing capabilities observed. This finding suggests that the innovative plate can match the performance of traditional plates used in such surgeries. CONCLUSIONS: The finite element analysis revealed that the newly developed anatomical plate for posterior wall acetabular fractures meets the necessary physical and mechanical criteria for permanent implementation in patients with these fractures. This breakthrough represents a promising advancement that could simplify surgical procedures and potentially elevate patient outcomes. LEVEL OF EVIDENCE II: This study is classified as a Level II, diagnostic study.

Predictive Factors of Functional Outcomes and Quality of Life in Patients with Ankle Fractures: A Systematic Review.

Background: Evaluating the predictors of unfavorable outcomes in patients with ankle fractures is crucial for identifying high-risk patients and implementing personalized treatment strategies. This study aimed to analyze factors that influence quality of life in patients with ankle fractures. Methods: Four databases were consulted. The main outcomes were functionality and quality of life scales combined using the standard mean difference (SMD) (Review Manager 5.4). Results: Eight studies with 2486 patients were included. A significant correlation was found between female sex and worse functionality scores (beta 4.15, 95% CI 1.84-6.46). Additionally, older age was correlated with worse functionality scores (beta -0.24, 95% CI -0.29 to -0.19). Patients with diabetes or metabolic syndrome also had worse outcomes (SMD 0.27, 95% CI 0.18-0.36). High BMI and obesity were also associated with worse quality of life scores (beta 2.62, 95% CI 0.77-4.48). Smokers had greater disability in the analyzed scales (SMD 0.22, 95% CI 0.05-0.39). No significant differences were observed with respect to syndesmotic involvement. Conclusions: Age, sex, diabetes, high BMI, and smoking negatively impact functional outcomes and quality of life in patients with ankle fractures.

Disease-free survival as a surrogate for overall survival in HR+/HER2- early breast cancer: A correlation analysis.

BACKGROUND: Overall survival (OS) is a universally accepted measure of clinical benefit; however, prolonged follow-up is needed to observe sufficient events. Disease-free survival (DFS) has been widely adopted as a primary endpoint for early breast cancer (EBC) trials, as follow-up is comparatively shorter. Here, we present an analysis evaluating DFS as a surrogate for OS for adjuvant treatment of hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) EBC. METHODS: A systematic literature review which included randomized controlled trials (RCTs) with ≥80% of adult patients with HR+/HER2- EBC was conducted. The RCTs evaluated various systemic therapeutic categories; key inclusion criteria included reporting of DFS and OS hazard ratios (HRs) and mature OS data. Spearman rank correlation and weighted linear regression analyses evaluated DFS and OS HR correlation. A scenario analysis tested base-case analysis robustness, and a parallel analysis using patient-level data was conducted. RESULTS: The base case (N = 14 RCTs) showed an unweighted Spearman coefficient of 0.81 between OS and DFS (weighted: 0.81), with 84% of the variability in OS explained by DFS differences (R2 from weighted regression). The surrogate threshold effect (Burzykowski T, Buyse M. Pharm Stat. 2006;5:173-186) was 0.82 for DFS/OS HR. Scenario analysis (n = 9 RCTs), which excluded chemotherapy trials, and patient-level analysis using FACE trial data were consistent with the base-case analysis. CONCLUSIONS: These analyses support DFS as a reliable surrogate endpoint for OS in adjuvant HR+/HER2- EBC trials. Using DFS as a surrogate measure will permit timelier access to novel treatments for patients with HR+/HER2- EBC.

Assessing Knowledge, Competence, and Performance Following Web-Based Education on Early Breast Cancer Management: Health Care Professional Questionnaire Study and Anonymized Patient Records Analysis.

BACKGROUND: Web-based learning activities are key components of continuing medical education (CME) for health care professionals (HCPs). However, the published outcomes of web-based educational interventions for early breast cancer (EBC) are limited. OBJECTIVE: This study aims to objectively assess knowledge, competence, and performance among HCPs following participation in 2 EBC-focused CME activities and to identify the remaining educational gaps. METHODS: We developed 2 CME-accredited web-based educational activities addressing high-risk EBC, including integration of shared decision-making to optimize patient care (touchMDT) and stratification for early identification of high-risk patients and novel treatment strategies (touchPANEL DISCUSSION). Knowledge, competence, and performance were assessed before and after the activities against an expanded outcomes framework (levels 1-5) using self-reported questionnaires and an analysis of anonymized data extracted from patient records. RESULTS: Six months after the launch of the activity, 7047 and 8989 HCP participants engaged with touchMDT and touchPANEL DISCUSSION, respectively. The overall satisfaction was 82% (a total score of 20.6 out of 25) for the touchMDT and 88% (a total score of 21.9 out of 25) for the touchPANEL DISCUSSION. For the evaluation of knowledge and competence (50 respondents before the activity and 50 learners after the activity), there was a significant increase in the mean number of correctly answered questions from pre- to postactivity (touchMDT: median 4.0, IQR 3.0-5.0 to median 5.5, IQR 4.0-7.0; mean 4.00, SD 1.39 to mean 5.30, SD 1.56 and touchPANEL DISCUSSION: median 4.0, IQR 4.0-5.0 to median 6.0, IQR 5.0-7.0; mean 4.32, SD 1.30 to mean 5.88, SD 1.49; both P<.001). A significant improvement in self-reported performance (50 respondents before the activity and 50 learners after the activity) was observed in a combined analysis of both activities (median 3.0, IQR 2.0-3.0 to median 4.0, IQR 3.0-5.0; mean 2.82, SD 1.08 to mean 4.16, SD 1.45; P<.001). Patient record analysis (50 respondents before the activity and 50 learners after the activity) showed that the HCPs used a range of measures to determine EBC recurrence risk and revealed no significant differences in adjuvant therapies used before and after the activity (P=.97 and P>.99 for Ki-67 <20% and Ki-67 ≥20% tumors, respectively). The remaining educational gaps included strategies for implementing shared decision-making in clinical practice and the use of genetic and biomarker testing to guide treatment selection. CONCLUSIONS: Brief, web-based CME activities on EBC were associated with an improvement in HCP knowledge, competence, and self-reported performance and can help identify unmet needs to inform the design of future CME activities.

Ribociclib plus Endocrine Therapy in Early Breast Cancer.

BACKGROUND: Ribociclib has been shown to have a significant overall survival benefit in patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. Whether this benefit in advanced breast cancer extends to early breast cancer is unclear. METHODS: In this international, open-label, randomized, phase 3 trial, we randomly assigned patients with HR-positive, HER2-negative early breast cancer in a 1:1 ratio to receive ribociclib (at a dose of 400 mg per day for 3 weeks, followed by 1 week off, for 3 years) plus a nonsteroidal aromatase inhibitor (NSAI; letrozole at a dose of 2.5 mg per day or anastrozole at a dose of 1 mg per day for ≥5 years) or an NSAI alone. Premenopausal women and men also received goserelin every 28 days. Eligible patients had anatomical stage II or III breast cancer. Here we report the results of a prespecified interim analysis of invasive disease-free survival, the primary end point; other efficacy and safety results are also reported. Invasive disease-free survival was evaluated with the use of the Kaplan-Meier method. The statistical comparison was made with the use of a stratified log-rank test, with a protocol-specified stopping boundary of a one-sided P-value threshold of 0.0128 for superior efficacy. RESULTS: As of the data-cutoff date for this prespecified interim analysis (January 11, 2023), a total of 426 patients had had invasive disease, recurrence, or death. A significant invasive disease-free survival benefit was seen with ribociclib plus an NSAI as compared with an NSAI alone. At 3 years, invasive disease-free survival was 90.4% with ribociclib plus an NSAI and 87.1% with an NSAI alone (hazard ratio for invasive disease, recurrence, or death, 0.75; 95% confidence interval, 0.62 to 0.91; P = 0.003). Secondary end points - distant disease-free survival and recurrence-free survival - also favored ribociclib plus an NSAI. The 3-year regimen of ribociclib at a 400-mg starting dose plus an NSAI was not associated with any new safety signals. CONCLUSIONS: Ribociclib plus an NSAI significantly improved invasive disease-free survival among patients with HR-positive, HER2-negative stage II or III early breast cancer. (Funded by Novartis; NATALEE ClinicalTrials.gov number, NCT03701334.).

Elevated blood metal ion levels in patients undergoing instrumented spinal surgery: a systematic review and meta-analysis.

BACKGROUND CONTEXT: Elevated blood metal levels have been reported in patients after spinal surgery using metallic implants. Although some studies have suggested an association between heightened blood metal concentrations and potential adverse effects, estimates of the incidence of abnormal metal levels after spinal surgery have been inconsistent. PURPOSE: The aims of this systematic review and meta-analysis were to assess: (1) mean differences in blood metal ion levels between patients undergoing spinal fusion surgery and healthy controls, (2) odds of elevated blood metal ion levels after surgery compared to presurgery levels, and (3) pooled incidence of elevated blood metal ions overall and by metal type. STUDY DESIGN: Systematic review and meta-analysis. PATIENTS SAMPLE: The patient sample included 613 patients from 11 studies who underwent spinal surgery instrumentation. OUTCOME MEASURES: Blood metal ion concentrations and the incidence of patients with elevated metal levels compared with in those the control group. METHODS: A comprehensive search was conducted in PubMed, EMBASE, Scopus, and Cochrane Library to identify studies reporting blood metal ion levels after spinal fusion surgery. Mean differences (MD), odds ratios (OR), and incidence rates were pooled using random effects models. Heterogeneity was assessed using I2 statistics, and fixed-effects models were used if no heterogeneity was detected. Detailed statistical analysis was performed using the Review Manager version 5.4 software. RESULTS: The analysis included 11 studies, with a total of 613 patients. Mean blood metal ion levels were significantly higher after spinal fusion surgery (MD 0.56, 95% CI 0.17-0.96; I2=86%). Specifically, titanium levels were significantly elevated (MD 0.81, 95% CI 0.32-1.30; I2=47%). The odds of elevated blood metal ions were higher after surgery (OR 8.17, 95% CI 3.38-19.72; I2=41%), primarily driven by chromium (OR 23.50, 95% CI 5.56-99.31; I2=30%). The incidence of elevated chromium levels was found to be 66.98% (95% CI 42.31-91.65). CONCLUSION: In conclusion, blood metal ion levels, particularly titanium and chromium, were significantly increased after spinal fusion surgery compared to presurgery levels and healthy controls. Approximately 70% of the patients exhibited elevated blood levels of chromium and titanium.

Geographic differences in lung cancer: focus on carcinogens, genetic predisposition, and molecular epidemiology.

Lung cancer poses a global health challenge and stands as the leading cause of cancer-related deaths worldwide. However, its incidence, mortality, and characteristics are not uniform across all regions worldwide. Understanding the factors contributing to this diversity is crucial in a prevalent disease where most cases are diagnosed in advanced stages. Hence, prevention and early diagnosis emerge as the most efficient strategies to enhance outcomes. In Western societies, tobacco consumption constitutes the primary risk factor for lung cancer, accounting for up to 90% of cases. In other geographic locations, different significant factors play a fundamental role in disease development, such as individual genetic predisposition, or exposure to other carcinogens such as radon gas, environmental pollution, occupational exposures, or specific infectious diseases. Comprehensive clinical and molecular characterization of lung cancer in recent decades has enabled us to distinguish different subtypes of lung cancer with distinct phenotypes, genotypes, immunogenicity, treatment responses, and survival rates. The ultimate goal is to prevent and individualize lung cancer management in each community and improve patient outcomes.

Incidence and risk factors of distal adjacent disc degeneration in adolescent idiopathic scoliosis patients undergoing fusion surgery: a systematic review and meta-analysis.

PURPOSE: The objective of this meta-analysis was to determine the incidence of disc degeneration in patients with surgically treated adolescent idiopathic scoliosis (AIS) and identify the associated risk factors. METHODS: PubMed, EMBASE, Scopus, and Cochrane Collaboration Library databases were searched. The outcomes of interest were the incidence of disc degeneration, SRS-22, and radiological risk factors. The lower instrumented vertebra (LIV) was also evaluated. Fixed effects were used if there was no evidence of heterogeneity. Statistical analysis was performed using Review Manager. RESULTS: A meta-analysis was conducted including nine studies with a total of 565 patients. The analysis revealed that the global incidence of intervertebral disc degeneration in patients with surgically treated AIS patients was 24.78% (95% CI 16.59-32.98%) 10 years after surgery, which significantly increased to 32.32% (95% CI 21.16-43.47% at an average of 13.8 years after surgery. Among patients with significant degenerative disc changes, the SRS-22 functional, self-image, and satisfaction domains showed significantly worse results (MD - 0.25, 95% CI - 0.44 to - 0.05; MD - 0.50, 95% CI - 0.75 to - 0.25; and MD - 0.34, 95% CI - 0.66 to - 0.03, respectively). Furthermore, instrumentation at or above the L3 level was associated with a lower incidence of intervertebral disc degeneration compared to instrumentation below the L3 level (OR 0.25, 95% CI 0.10-0.64). It was also found that the preoperative and final follow-up lumbar curve magnitudes (MD 8.11, 95% CI 3.82-12.41) as well as preoperative and final follow-up lumbar lordosis (MD 0.42, 95% CI - 3.81 to 4.65) were associated with adjacent disc degeneration. CONCLUSIONS: This meta-analysis demonstrated that the incidence of intervertebral disc degeneration significantly increased with long-term follow-up using fusion techniques, reaching up to 32% when patients were 28 years of age. Incomplete correction of deformity and fusion of levels below L3, were identified as negative prognostic factors. Furthermore, patients with disc degeneration showed worse functional outcomes.

Adhesion and Contact Aging of Acrylic Pressure-Sensitive Adhesives to Swollen Elastomers.

Fluid-infused (or swollen) elastomers are known for their antiadhesive properties. The presence of excess fluid at their surface is the main contributor to limiting contact formation and minimizing adhesion. Despite their potential, the mechanisms for adhesion and contact aging to fluid-infused elastomers are poorly understood beyond contact with a few materials (ice, biofilms, glass). This study reports on adhesion to a model fluid-infused elastomer, poly(dimethylsiloxane) (PDMS), swollen with silicone oil. The effects of oil saturation, contact time, and the opposing surface are investigated. Specifically, adhesion to two different adherents with comparable surface energies but drastically different mechanical properties is investigated: a glass surface and a soft viscoelastic acrylic pressure-sensitive adhesive film (PSA, modulus ∼25 kPa). Adhesion between the PSA and swollen PDMS [with 23% (w/w) silicone oil] retains up to 60% of its value compared to contact with unswollen (dry) PDMS. In contrast, adhesion to glass nearly vanishes in contact with the same swollen elastomer. Adhesion to the PSA also displays stronger contact aging than adhesion to glass. Contact aging with the PSA is comparable for dry and unsaturated PDMS. Moreover, load relaxation when the PSA is in contact with the PDMS does not correlate with contact aging for contact with the dry or unsaturated elastomer, suggesting that contact aging is likely caused by chain interpenetration and polymer reorganization within the contact region. Closer to full saturation of the PDMS with oil, adhesion to the PSA decreases significantly and shows a delay in the onset of contact aging that is weakly correlated to the poroelastic relaxation of the elastomer. Additional confocal imaging suggests that the presence of a layer of fluid trapped at the interface between the two solids could explain the delayed (and limited) contact aging to the oil-saturated PDMS.

The Best Current Research on Patellar Tendinopathy: A Review of Published Meta-Analyses.

Patellar tendinopathy is a frequent overuse injury in sports that can cause significant pain and disability. It requires evidence-based guidelines on effective prevention and management. However, optimal treatments remain uncertain. We aimed to analyze available meta-analyses to summarize treatment recommendations, compare therapeutic modalities, examine included trials, and offer methodological suggestions to improve future systematic reviews. Meta-analyses were systematically searched for in PubMed (PROSPERO: CRD42023457963). A total of 21 meta-analyses were included. The AMSTAR-2 scale assessed study quality, which was low, with only 23.8% of the meta-analyses being of moderate quality, and none were considered to be of high quality. Heterogeneous outcomes are reported. Multiple platelet-rich plasma (PRP) injections appear superior to eccentric exercises and provide lasting improvements compared to eccentric exercises when conservative treatments fail. Extracorporeal shockwave therapy (ESWT) also seems superior to non-operative options and similar to surgery for patellar tendinopathy in the long term. However, evidence for eccentric exercise efficacy remains unclear due to inconclusive findings. Preliminary findings also emerged for genetic risk factors and diagnostic methods but require further confirmation. This review reveals a lack of high-quality evidence on optimal patellar tendinopathy treatments. While PRP and ESWT show promise, limitations persist. Further rigorous meta-analyses and trials are needed to strengthen the evidence base and guide clinical practice. Methodological enhancements are proposed to improve future meta-analyses.

Cadaveric biomechanical studies of ADDISC total lumbar disc prosthesis.

BACKGROUND: Most total disc replacements provide excessive mobility and not reproduce spinal kinematics, inducing zygapophyseal joint arthritic changes and chronic back pain. In cadaveric lumbosacral spines, we studied if a new lumbar disc prosthesis kinematics mimics the intact intervertebral disc. METHODS: In eight cold preserved cadaveric lumbosacral spines, we registered the movement ranges in flexion, extension, right and left lateral bending, and rotation in the intact status, post-discectomy, and after our prosthesis implantation, comparing them for each specimen. FINDINGS: Comparing the intact lumbosacral spine with the L4-L5 prosthesis implanted specimens, we saw statistically significant differences in lateral bending and right rotation but not in the full range of rotation. Analyzing segments, we also noticed statistically significant differences at L4-L5 in flexion-extension and rotation. On the other hand, the L4-L5 discectomy, compared to the baseline spine condition, showed a statistically significant mobility increase in flexion, extension, lateral bending, and axial rotation, with an abnormal instantaneous center of rotation, which destabilizes the segment partly due to anterior annulus surgical removal. Disc prosthesis implantation reversed these changes in instantaneous center of rotation, but the prosthesis failed to restore the initial range of motion due to the destabilization of the ligaments in the operated disc. INTERPRETATION: The ADDISC total disc replacement reproduces the intact disc kinematics and Instantaneous Center of Rotation, but the prosthesis fails to restore the initial range of motion due to ligament destabilization. More studies will be necessary to define a technique that restores the damaged ligaments when implanting the prosthesis.

Systemic Treatment of Patients With Metastatic Breast Cancer: ASCO Resource-Stratified Guideline.

PURPOSE: To guide clinicians and policymakers in three global resource-constrained settings on treating patients with metastatic breast cancer (MBC) when Maximal setting-guideline recommended treatment is unavailable. METHODS: A multidisciplinary, multinational panel reviewed existing ASCO guidelines and conducted modified ADAPTE and formal consensus processes. RESULTS: Four published resource-agnostic guidelines were adapted for resource-constrained settings; informing two rounds of formal consensus; recommendations received ≥75% agreement. RECOMMENDATIONS: Clinicians should recommend treatment according to menopausal status, pathological and biomarker features when quality results are available. In first-line, for hormone receptor (HR)-positive MBC, when a non-steroidal aromatase inhibitor and CDK 4/6 inhibitor combination is unavailable, use hormonal therapy alone. For life-threatening disease, use single-agent chemotherapy or surgery for local control. For premenopausal patients, use ovarian suppression or ablation plus hormone therapy in Basic settings. For human epidermal growth factor receptor 2 (HER2)-positive MBC, if trastuzumab, pertuzumab, and chemotherapy are unavailable, use trastuzumab and chemotherapy; if unavailable, use chemotherapy. For HER2-positive, HR-positive MBC, use standard first-line therapy, or endocrine therapy if contraindications. For triple-negative MBC with unknown PD-L1 status, or if PD-L1-positive and immunotherapy unavailable, use single-agent chemotherapy. For germline BRCA1/2 mutation-positive MBC, if poly(ADP-ribose) polymerase inhibitor is unavailable, use hormonal therapy (HR-positive MBC) and chemotherapy (HR-negative MBC). In second-line, for HR-positive MBC, Enhanced setting recommendations depend on prior treatment; for Limited, use tamoxifen or chemotherapy. For HER2-positive MBC, if trastuzumab deruxtecan is unavailable, use trastuzumab emtansine; if unavailable, capecitabine and lapatinib; if unavailable, trastuzumab and/or chemotherapy (hormonal therapy alone for HR-positive MBC).Additional information is available at www.asco.org/resource-stratified-guidelines. It is ASCO's view that healthcare providers and system decision-makers should be guided by the recommendations for the highest stratum of resources available. The guideline is intended to complement but not replace local guidelines.

Assessing Biomechanical and Clinical Outcomes of an Elbow Orthosis Intervention in Youth Baseball: Preliminary Results.

Proper orthosis design may help youth baseball players develop safer pitching mechanics to prevent elbow injuries. This study evaluated the impact of a custom elbow orthosis on pitching biomechanics and adverse events. Ten 11-12-year-old players (mean age 11.5 years) from a regional league team were recruited. The inclusion criteria were at least two years of baseball experience. Six players were randomly assigned to the orthosis group, with four in the control group. Anthropometric data and baseline characteristics were recorded. A video analysis assessed elbow flexion angle during pitching at baseline and at 2 months. The frequency of orthosis wear was also tracked. Adverse events during twice-weekly practices were documented. Post-study surveys evaluated orthosis comfort, stability, and safety perceptions. In the orthosis group (n = 6), four participants showed improved elbow flexion angle, and two of the six participants showed almost no change. The overall median difference was 23.5°. In the control group (n = 4), three participants showed improvement, with a median improvement of 5.5°. Twelve adverse events, including pain, were reported by players not wearing orthoses, whereas no events occurred with orthosis use. Individual players in the control group or who did not wear the orthosis correctly experienced multiple episodes of pain from pitching over the study period. This preliminary study indicates a custom elbow orthosis can optimize pitching biomechanics and prevent adverse events in youth baseball players over the course of two months.

Long-term patient-reported outcomes from monarchE: Abemaciclib plus endocrine therapy as adjuvant therapy for HR+, HER2-, node-positive, high-risk, early breast cancer.

BACKGROUND: In monarchE, abemaciclib demonstrated a sustained benefit in invasive disease-free survival and a tolerable safety profile at 42-months median follow-up. With no expected disease-related symptoms, therapies in the adjuvant setting should preserve quality of life (QoL). With all patients off abemaciclib, we report updated patient-reported outcomes (PROs) for the full 2-year treatment period and follow-up. METHODS: Patients completed PROs including FACT-B, FACT-ES, and FACIT-Fatigue at baseline, 3, 6, 12, 18, and 24 months during treatment, and 1, 6, and 12 months after treatment discontinuation. Mixed effects repeated measures model estimated changes from baseline within and between arms for QoL scales and individual items. Meaningful changes were prespecified and no statistical testing was performed. Frequencies of responses to items associated with relevant adverse events and treatment bother were summarized. RESULTS: At baseline, completion rates for PRO instruments were >96 %. Mean changes from baseline for all QoL scales were numerically similar within and between arms (ie, less than prespecified thresholds). The same was observed for all individual items, except diarrhea. Within abemaciclib arm, meaningful differences for diarrhea were observed at 3 and 6 months (mean increases of 1.19 and 1.03 points on 5-point scale, respectively). During treatment, most patients in both arms (69-78 %) reported being bothered "a little bit" or "not at all" by side effects. Overall, patterns for fatigue were similar between arms. During post-treatment follow-up, PROs in both arms were similar to baseline. CONCLUSION: PRO findings confirm a tolerable and reversible toxicity profile for abemaciclib. QoL was preserved with the addition of adjuvant abemaciclib to endocrine therapy, supporting its use in patients with HR+, HER2-, high-risk early breast cancer.