Sacituzumab Govitecan in patients with breast cancer brain metastases and recurrent glioblastoma: a phase 0 window-of-opportunity trial.

Sacituzumab Govitecan (SG) is an antibody-drug conjugate that has demonstrated efficacy in patients with TROP-2 expressing epithelial cancers. In a xenograft model of intracranial breast cancer, SG inhibited tumor growth and increased mouse survival. We conducted a prospective window-of-opportunity trial (NCT03995706) at the University of Texas Health Science Center at San Antonio to examine the intra-tumoral concentrations and intracranial activity of SG in patients undergoing craniotomy for breast cancer with brain metastases (BCBM) or recurrent glioblastoma (rGBM). We enrolled 25 patients aged ≥18 years diagnosed with BCBM and rGBM to receive a single intravenous dose of SG at 10 mg/kg given one day before resection and continued on days 1 and 8 of 21-day cycles following recovery. The PFS was 8 months and 2 months for BCBM and rGBM cohorts, respectively. The OS was 35.2 months and 9.5 months, respectively. Grade≥3 AE included neutropenia (28%), hypokalemia (8%), seizure (8%), thromboembolic event (8%), urinary tract infection (8%) and muscle weakness of the lower limb (8%). In post-surgical tissue, the median total SN-38 was 249.8 ng/g for BCBM and 104.5 ng/g for rGBM, thus fulfilling the primary endpoint. Biomarker analysis suggests delivery of payload by direct release at target site and that hypoxic changes do not drive indirect release. Secondary endpoint of OS was 35.2 months for the BCBM cohort and 9.5 months for rGBM. Non-planned exploratory endpoint of ORR was 38% for BCBM and 29%, respectively. Exploratory endpoint of Trop-2 expression was observed in 100% of BCBM and 78% of rGBM tumors. In conclusion, SG was found to be well tolerated with adequate penetration into intracranial tumors and promising preliminary activity within the CNS. Trial Registration: Trial (NCT03995706) enrolled at Clinical Trials.gov as Neuro/Sacituzumab Govitecan/Breast Brain Metastasis/Glioblastoma/Ph 0: https://clinicaltrials.gov/study/NCT03995706?cond=NCT03995706 .

Corrigendum to "Addressing docking pose selection with structure-based deep learning: Recent advances, challenges and opportunities" [Comput Struct Biotechnol J vol. 23 (2024) 2141-2151].

[This corrects the article DOI: 10.1016/j.csbj.2024.05.024.].

Penicillin concentrations in bone and subcutaneous tissue: A porcine microdialysis study comparing oral and intravenous treatment.

Penicillin is available in both an oral (penicillin V) and intravenous formulation (penicillin G), theoretically allowing for a safe transition between the two. However, the use of oral penicillin remains a topic of debate due to low and variable bioavailability. This study aimed to assess the time for which the free penicillin concentration exceeded targeted minimum inhibitory concentrations for Staphylococcus aureus and Streptococcus species (0.125, 0.25, and 0.5 mg/L) in cancellous bone and subcutaneous tissue after intravenous penicillin and oral penicillin administration. 12 female pigs (68-75 kg) were assigned, according to local standard clinical regimes, to either intravenous penicillin (1.2 g) or oral penicillin (0.8 g) treatment every 6 h over an 18 h period. Microdialysis catheters were placed for sampling in tibial cancellous bone and adjacent subcutaneous tissue. Data was dynamic/continually collected in the first dosing interval (0-6 h), simulating a prophylactic situation, and the third dosing interval (12-18 h), simulating a therapeutic setting. Plasma samples were collected for reference. For all investigated targets, intravenous treatment resulted in a longer mean time above relevant minimum inhibitory concentrations in cancellous bone during the first dosing interval, and in both cancellous bone and subcutaneous tissue during the third dosing interval compared to oral treatment. With clinically relevant dosing, intravenous penicillin provides superior exposure compared to oral penicillin in both a prophylactic and therapeutic setting.

Neuroendocrine mechanisms of mood disorders during menopause transition: A narrative review and future perspectives.

The menopause transition is an important period in a woman's life, during which she is at an increased risk of mood disorders. Estrogen and progesterone fluctuations during the menopausal transition and very low levels of estradiol after menopause have a profound effect on the central nervous system (CNS), causing an imbalance between excitatory and inhibitory inputs. Changes in neurotransmission and neuronal interactions that occur with estradiol withdrawal disrupt the normal neurological balance and may be associated with menopausal symptoms. Hot flushes, depressed mood and anxiety are all symptoms of menopause that are a consequence of the complex changes that occur in the CNS, involving many signaling pathways and neurotransmitters (i.e. γ-aminobutyric acid, serotonin, dopamine), neurosteroids (i.e. allopregnanolone), and neuropeptides (i.e. kisspeptin, neurokinin B). All these pathways are closely linked, and the complex interactions that exist are not yet fully understood. This review summarizes the neuroendocrine changes in the CNS during the menopausal transition, with particular emphasis on those that underlie mood changes.

Play it again, but more sadly: Influence of timbre, mode, and musical experience in melody processing.

The emotional properties of music are influenced by a host of factors, such as timbre, mode, harmony, and tempo. In this paper, we consider how two of these factors, mode (major vs. minor) and timbre interact to influence ratings of perceived valence, reaction time, and recognition memory. More specifically, we considered the notion of congruence-that is, we used a set of melodies that crossed modes typically perceived as happy and sad (i.e., major and minor) in Western cultures with instruments typically perceived as happy and sad (i.e., marimba and viola). In a reaction-time experiment, participants were asked to classify melodies as happy or sad as quickly as possible. There was a clear congruency effect-that is, when the mode and timbre were congruent (major/marimba or minor/viola), reaction times were shorter than when the mode and timbre were incongruent (major/viola or minor/marimba). In Experiment 2, participants first rated the melodies for valence, before completing a recognition task. Melodies that were initially presented in incongruent conditions in the rating task were subsequently recognized better in the recognition task. The recognition advantage for melodies presented in incongruent conditions is discussed in the context of desirable difficulty.

Parkinson's Disease and Other Alzheimer's Disease and Related Dementia Pathologies and the Progression of Parkinsonism in Older Adults.

Background: The interrelationship of parkinsonism, Parkinson's disease (PD) and other Alzheimer's disease (AD) and Alzheimer's disease and related dementias (ADRD) pathologies is unclear. Objective: We examined the progression of parkinsonian signs in adults with and without parkinsonism, and their underlying brain pathologies. Methods: Annual parkinsonian signs were based on a modified Unified Parkinson's Disease Rating Scale. We used linear mixed effects models to compare the progression of parkinsonian signs in 3 groups categorized based on all available clinical evaluations: Group1 (never parkinsonism or clinical PD), Group2 (ever parkinsonism, but never clinical PD), Group3 (ever clinical PD). In decedents, we examined the progression of parkinsonian signs with PD and eight other AD/ADRD pathologies. Results: During average follow-up of 8 years, parkinsonian signs on average increased by 7.3% SD/year (N = 3,807). The progression of parkinsonian signs was slowest in Group1 (never parkinsonism or clinical PD), intermediate in Group2, and fastest in Group3. In decedents (n = 1,717) pathologic PD and cerebrovascular (CVD) pathologies were associated with a faster rate of progressive parkinsonian signs (all p values <0.05). However, pathologic PD was rare in adults without clinical PD (Group1, 5%; Group2, 7% versus Group3, 55%). Yet, 70% of adults in Group2 without pathologic PD showed one or more CVD pathologies. In Group2, adults with pathologic PD showed faster progression of parkinsonian signs compared with those without evidence of pathologic PD and their rate of progression was indistinguishable from adults with clinical PD. Conclusions: Parkinsonism in old age is more commonly related to cerebrovascular pathologies relative to pathologic PD and only a minority manifest prodromal PD.

Feco-prevalence, endoscopic pattern and associated factors of Helicobacter Pylori infection among symptomatic adult patients in Northern Tanzania.

BACKGROUND: Africa has consistently had the highest prevalence (70.1%) of H. pylori, and this has led to significant cases of dyspepsia, gastric cancers, and upper gastrointestinal bleeding. However, most studies have used sero-prevalence, which might not give the current state of the infection. Among the tests, the stool antigen test is simple, quick, and effective. The study aimed to determine the feco-prevalence, endoscopic pattern, and associated factors of H. pylori infection among symptomatic adult patients in Northern Tanzania. MATERIALS AND METHODS: A hospital-based, cross-sectional study was conducted from October 2022 to April 2023 among adults attending the gastroenterology clinic at Kilimanjaro Chistian Medical Centre. A systematic random sampling was used to select the participants with indications of undergoing esophagogastroduodenoscopy. Questionnaires, stool and blood samples, and endoscopy were used to collect variable data. Numerical and categorical variables were summarized into narrations and tables. Logistic regression was used to assess the factors associated with H. pylori. RESULTS: The feco-prevalence of H. pylori was 43.4%. Chronic gastritis (51.1%) was the most common endoscopic pattern, whereas duodenal ulcers and gastric ulcers were significantly associated with H. pylori infection. Increasing in age (p <0.001) and blood group (p <0.001) were significantly associated with H. pylori infection in the adjusted analysis. CONCLUSION: The feco-prevalence of H. pylori is high in this setting. H. pylori stool antigen can be used as the initial workup for symptomatic patients before the initiation of proton pump inhibitors. Additionally, due to other causes of dyspepsia, it is advised that H. pylori stool antigen testing be part of the initial evaluation and esophagogastroduodenoscopy be considered in the absence of other alarm symptoms if symptoms persist despite an appropriate trial of medical therapy.

Variability in self-reported and biomarker-derived tobacco smoke exposure patterns among individuals who do not smoke by poverty income ratio in the USA.

INTRODUCTION: Tobacco smoke exposure (TSE) among individuals who do not smoke has declined in the USA, however, gaps remain in understanding how TSE patterns across indoor venues-including in homes, cars, workplaces, hospitality venues, and other areas-contribute to TSE disparities by income level. METHODS: We obtained data on adults (ages 18+, N=9909) and adolescents (ages 12-17, N=2065) who do not smoke from the National Health and Nutrition Examination Survey, 2013-2018. We examined the prevalence of self-reported, venue-specific TSE in each sample, stratified by poverty income ratio (PIR) quartile. We used linear regression models with a log-transformed outcome variable to explore associations between self-reported TSE and serum cotinine. We further explored the probability of detectable cotinine among individuals who reported no recent TSE, stratified by PIR. RESULTS: Self-reported TSE was highest in cars (prevalence=6.2% among adults, 14.2% among adolescents). TSE in own homes was the most strongly associated with differences in log cotinine levels (ß for adults=1.92, 95% CI=1.52 to 2.31; ß for adolescents=2.37 95% CI=2.07 to 2.66), and the association between home exposure and cotinine among adults was most pronounced in the lowest PIR quartile. There was an income gradient with regard to the probability of detectable cotinine among both adults and adolescents who did not report recent TSE. CONCLUSIONS: Homes and vehicles remain priority venues for addressing persistent TSE among individuals who do not smoke in the USA. TSE survey measures may have differential validity across population subgroups.

MDT-BRIDGE: Neoadjuvant Durvalumab Plus Chemotherapy Followed by Either Surgery and Adjuvant Durvalumab or Chemoradiotherapy and Consolidation Durvalumab in Resectable or Borderline-resectable Stage IIB-IIIB NSCLC.

INTRODUCTION: In the AEGEAN trial, neoadjuvant durvalumab plus platinum-based chemotherapy (D+CT) followed by adjuvant durvalumab, versus neoadjuvant chemotherapy alone, significantly improved pathological complete response (pCR) rate and event-free survival (EFS) in patients with resectable NSCLC. In the PACIFIC trial, consolidation durvalumab significantly improved progression-free (PFS) and overall survival (OS) for patients with unresectable stage III NSCLC after chemoradiotherapy. Strong pathological and clinical outcomes with chemoimmunotherapy have generated interest in its use to enable patients with borderline-resectable NSCLC to undergo surgery. Additionally, for patients initially deemed resectable but who later become unresectable/inoperable during neoadjuvant treatment, consolidation immunotherapy after chemoradiotherapy should be explored. PATIENTS AND METHODS: MDT-BRIDGE (NCT05925530) is a multicenter, phase II, non-randomized study in ∼140 patients with EGFR/ALK wild-type, stage IIB-IIIB (N2) NSCLC. Following baseline multidisciplinary team (MDT) assessment to determine resectable/borderline-resectable status, all patients receive 2 cycles of neoadjuvant D+CT every 3 weeks, followed by MDT reassessment of resectability. Patients deemed resectable receive 1-2 additional cycles of D+CT followed by surgery (Cohort 1). Patients deemed unresectable receive standard-of-care chemoradiotherapy (Cohort 2). Cohort 1 patients who become ineligible for surgery can enter Cohort 2. Following surgery or chemoradiotherapy, patients receive adjuvant or consolidation durvalumab for 1 year. The primary endpoint is resection rate in all patients. Additional endpoints include resection rates by baseline resectable/borderline-resectable status, resection outcomes, EFS/PFS, OS, pCR rate, circulating tumor DNA dynamics pre- and post-surgery (including correlation with clinical outcomes), and safety. CONCLUSION: Enrollment began in February 2024; primary completion is anticipated in April 2026.

Genomic Exploration of Essential Hypertension in African-Brazilian Quilombo Populations: A Comprehensive Approach with Pedigree Analysis and Family-Based Association Studies.

Essential Hypertension (EH) is a major global health concern, causing about 9.4 million deaths annually. Its prevalence varies across different regions, affecting 17% of the population in the Americas, 19.2% in the Western Pacific, 23.2% in Europe, 25.1% in Southeast Asia, 26.3% in the Eastern Mediterranean, and 27.2% in Africa. EH is a multifactorial disease influenced by both genetic and environmental factors. While genetic factors contribute 30-60% to blood pressure variation, the genetic complexity of EH remains largely unexplained due to limited knowledge of candidate genes and population-specific differences. Various methods, including candidate gene studies, genome-wide linkage analysis (GWLA), and genome-wide association studies (GWAS), have been employed to identify genetic factors, yet much of the heritability of EH is still unknown. This study aimed to investigate the genetic basis of EH by mapping regions of interest (ROIs) and identifying candidate genes and variants influencing EH in African-derived individuals from partially isolated populations of quilombo remnants in Vale do Ribeira, São Paulo, Brazil. Samples from 431 individuals (167 affected, 261 unaffected, 3 with unknown phenotype) from eight quilombo remnant populations were genotyped using a 650k SNP array. The global ancestry proportions were estimated at 47% African, 36% European, and 16% Native American. Genealogical information from 673 individuals was used to construct six pedigrees comprising 1104 individuals. The mapping strategy consisted of a multi-level computational approach. We constructed pedigrees based on interviews and kinship coefficient, pruned the dataset to obtain three non-overlapping markers subpanels, phased the haplotype and performed local ancestry to account for admixture. We performed GWLA and dense linkage analyses using markers subpanels and performed fine-mapping using family-based association studies (FBAS) based on population and pedigree imputed data, investigating EH-related genes and variants. The linkage analysis identified 22 ROIs with LOD scores 1.45-3.03, containing markers co-segregating with the phenotype. These ROIs encompassed 2363 genes. Fine-mapping identified 60 EH-related candidate genes and 118 suggestive or significant variants (FBAS). Among these, 14 genes, including PHGDH, S100A10, MFN2, and RYR2, were highlighted with strong evidence of association with hypertension. These genes, harboring 29 SNPs, were implicated in regulating blood pressure, sodium and potassium levels, and the aldosterone pathway. This study revealed, through a complementary approach - combining admixture-adjusted genome-wide linkage analysis based on Markov chain Monte Carlo (MCMC) methods, association studies on imputed data, and in silico investigations - genetic regions, variants and candidate genes that shed light on the genetic basis of essential hypertension, with significant potential to explain the genetic etiology in quilombo remnant populations.

Admixture Mapping of Chronic Kidney Disease and Risk Factors in Hispanic/Latino Individuals From Central America Country of Origin.

BACKGROUND: Chronic kidney disease (CKD) is highly prevalent in Central America, and genetic factors may contribute to CKD risk. To understand the influences of genetic admixture on CKD susceptibility, we conducted an admixture mapping screening of CKD traits and risk factors in US Hispanic and Latino individuals from Central America country of origin. METHODS: We analyzed 1023 participants of HCHS/SOL (Hispanic Community Health Study/Study of Latinos) who reported 4 grandparents originating from the same Central America country. Ancestry admixture findings were validated on 8191 African Americans from WHI (Women's Health Initiative), 3141 American Indians from SHS (Strong Heart Study), and over 1.1 million European individuals from a multistudy meta-analysis. RESULTS: We identified 3 novel genomic regions for albuminuria (chromosome 14q24.2), CKD (chromosome 6q25.3), and type 2 diabetes (chromosome 3q22.2). The 14q24.2 locus driven by a Native American ancestry had a protective effect on albuminuria and consisted of 2 nearby regions spanning the RGS6 gene. Variants at this locus were validated in American Indians. The 6q25.3 African ancestry-derived locus, encompassing the ARID1B gene, was associated with increased risk for CKD and replicated in African Americans through admixture mapping. The European ancestry type 2 diabetes locus at 3q22.2, encompassing the EPHB1 and KY genes, was validated in European individuals through variant association. CONCLUSIONS: US Hispanic/Latino populations are culturally and genetically diverse. This study focusing on Central America grandparent country of origin provides new loci discovery and insights into the ancestry-of-origin influences on CKD and risk factors in US Hispanic and Latino individuals.

A toolkit for a modern gynecologic oncology tissue bank.

OBJECTIVES: Tissue banking procedures have evolved to keep pace with precision medicine, technology, emerging understanding of racial disparities, and regulatory requirements. However, there is little published guidance regarding strategies to create and maintain a successful biorepository. Our objective is to describe the infrastructure and protocols used by our Gynecologic Oncology Tissue Bank. METHODS: Our Tissue Bank was founded in 1992. In August 2022, internal funding was used to modernize the Tissue Bank. We hired three full-time employees, implemented universal screening of patients treated by gynecologic oncology faculty, updated consenting protocols, and standardized communication with providers. Tumor tissue, blood derivatives, ascites, and pleural fluid were collected from eligible, consenting patients and processed. Patient-derived cell lines and organoids were generated. For quality control purposes, one formalin-fixed, paraffin-embedded (FFPE) sample per tissue site was analyzed by a board-certified pathologist. All samples were labeled and tracked in an OpenSpecimen collection protocol and clinically annotated in a secure database. RESULTS: From August 2022 to October 2023, 227 patients (83% white, 15% Black, 1% Asian) were enrolled and 4249 specimens were collected. Adherent cell lines were generated from 15 patients with ovarian cancer and cell suspensions for organoid generation were collected from 46 patients with ovarian cancer. A recharge center was established to self-sustain the Tissue Bank. Samples have been shared with academic and commercial collaborators. CONCLUSIONS: Our Tissue Bank has enrolled a large number of diverse patients, collected numerous specimen types, and collaborated widely. The procedures described here provide guidance for other institutions establishing similar resources.

Safety of topical sildenafil cream, 3.6% in a randomized, placebo-controlled trial for the treatment of female sexual arousal disorder.

BACKGROUND: There are currently no Food and Drug Administration-approved treatments for female sexual arousal disorder (FSAD), which is physiologically analogous to male erectile dysfunction. AIMS: The study sought to test the systemic and local genital safety of topical sildenafil cream, 3.6% (sildenafil cream) among healthy premenopausal women with FSAD and their sexual partners over a 12-week treatment period. METHODS: This was a phase 2b, exploratory, randomized, placebo-controlled, double-blind study of sildenafil cream among healthy premenopausal women with FSAD. Safety was assessed by the frequency and incidence of treatment-emergent adverse events (TEAEs) among participants and their sexual partners. Participants recorded the incidence of TEAEs in a daily eDiary (electronic diary). Sexual partners were contacted within 72 hours of each sexual event in which investigational product was used. All participants used placebo cream for 1 month, during a single-blind run-in period, and then if eligible, were randomized 1:1 to sildenafil cream or placebo cream. Participants used their assigned investigational product over a 12-week double-blind dosing period. They attended monthly follow-up visits, in which their eDiary TEAE data were reviewed by the study staff and graded for severity and relationship to study product. OUTCOMES: The frequency and incidence of TEAEs among participants and their sexual partners. RESULTS: During the 12-week double-blind dosing period, there were 78 TEAEs reported by 29 of 99 sildenafil-assigned participants and 65 TEAEs reported by 28 of 94 placebo-assigned participants (P = .76). All TEAEs were mild or moderate in severity. The most common treatment-related TEAE among active and placebo-assigned participants was application site discomfort. There were no differences in the number of treatment-related TEAEs among sildenafil cream vs placebo cream users (P > .99). Four sildenafil cream participants and 3 placebo cream participants discontinued the study due to TEAEs involving application site discomfort (P > .99). There were 9 TEAEs reported by 7 of 91 sexual partners exposed to sildenafil cream vs 4 TEAEs reported by 4 of 84 sexual partners exposed to placebo cream (P = .54). CLINICAL IMPLICATIONS: These data support further clinical development of topical sildenafil cream for the treatment of FSAD. STRENGTHS AND LIMITATIONS: Safety was assessed among participants and their sexual partners after 1357 and 1160 sexual experiences in which sildenafil cream or placebo cream were used, respectively. The phase 2b study was powered for the primary objectives of efficacy, rather than safety. CONCLUSION: These data demonstrate that topically applied sildenafil cream was safe and well tolerated by exposed users and their sexual partners.

Bacterial diversity and specific taxa are associated with decolonization of carbapenemase-producing enterobacterales after fecal microbiota transplantation.

OBJECTIVES: We evaluated the effect of fecal microbiota transplantation (FMT) on the clearance of carbapenemase-producing Enterobacterales (CPE) carriage. METHODS: We performed a prospective, multi-center study, conducted among patients who received a single dose of FMT from one of four healthy donors. The primary endpoint was complete clearance of CPE carriage two weeks after FMT with a secondary endpoint at three months. Shotgun metagenomic sequencing was performed to assess gut microbiota composition of donors and recipients before and after FMT. RESULTS: Twenty CPE-colonized patients were included in the study, where post-FMT 20% (n = 4/20) of patients met the primary endpoint and 40% (n = 8/20) of patients met the secondary endpoint. Kaplan-Meier curves between patients with FMT intervention and the control group (n = 82) revealed a similar rate of decolonization between groups. Microbiota composition analyses revealed that response to FMT was not donor-dependent. Responders had a significantly lower relative abundance of CPE species pre-FMT than non-responders, and 14 days post-FMT responders had significantly higher bacterial species richness and alpha diversity compared to non-responders (p < 0.05). Responder fecal samples were also enriched in specific species, with significantly higher relative abundances of Faecalibacterium prausnitzii, Parabacteroides distasonis, Collinsella aerofaciens, Alistipes finegoldii and Blautia_A sp900066335 (q<0.01) compared to non-responders. CONCLUSION: FMT administration using the proposed regimen did not achieve statistical significance for complete CPE decolonization but was correlated with the relative abundance of specific bacterial taxa, including CPE species.

Toxoplasma gondii infection supports the infiltration of T cells into brain tumors.

Few T cells infiltrate into primary brain tumors, fundamentally hampering the effectiveness of immunotherapy. We hypothesized that Toxoplasma gondii, a microorganism that naturally elicits a Th1 response in the brain, can promote T cell infiltration into brain tumors despite their immune suppressive microenvironment. Using a mouse genetic model for medulloblastoma, we found that T. gondii infection induced the infiltration of activatable T cells into the tumor mass and led to myeloid cell reprogramming toward a T cell-supportive state, without causing severe health issues in mice. The study provides a concrete foundation for future studies to take advantage of the immune modulatory capacity of T. gondii to facilitate brain tumor immunotherapy.

Surface-Grafted Biocompatible Polymer Conductors for Stable and Compliant Electrodes for Brain Interfaces.

Durable and conductive interfaces that enable chronic and high-resolution recording of neural activity are essential for understanding and treating neurodegenerative disorders. These chronic implants require long-term stability and small contact areas. Consequently, they are often coated with a blend of conductive polymers and are crosslinked to enhance durability despite the potentially deleterious effect of crosslinking on the mechanical and electrical properties. Here the grafting of the poly(3,4 ethylenedioxythiophene) scaffold, poly(styrenesulfonate)-b-poly(poly(ethylene glycol) methyl ether methacrylate block copolymer brush to gold, in a controlled and tunable manner, by surface-initiated atom-transfer radical polymerization (SI-ATRP) is described. This "block-brush" provides high volumetric capacitance (120 F cm─3), strong adhesion to the metal (4 h ultrasonication), improved surface hydrophilicity, and stability against 10 000 charge-discharge voltage sweeps on a multiarray neural electrode. In addition, the block-brush film showed 33% improved stability against current pulsing. This approach can open numerous avenues for exploring specialized polymer brushes for bioelectronics research and application.

Utility of the 70-Gene MammaPrint Assay for Prediction of Benefit From Extended Letrozole Therapy in the NRG Oncology/NSABP B-42 Trial.

PURPOSE: MammaPrint (MP) determines distant metastatic risk and may improve patient selection for extended endocrine therapy (EET). This study examined MP in predicting extended letrozole therapy (ELT) benefit in patients with early-stage breast cancer (BC) from the NSABP B-42 trial. PATIENTS AND METHODS: MP was tested in 1,866 patients randomly assigned to receive ELT or placebo. The primary end point was distant recurrence (DR). Secondary end points were disease-free survival (DFS) and BC-free interval (BCFI). Tumors were classified as MP high risk (MP-HR) or low risk (MP-LR). MP-LR tumors were further classified as ultralow risk (MP-UL) or low non-ultralow risk (MP-LNUL). RESULTS: There was no statistically significant difference in ELT benefit on DR between MP-HR and MP-LR (interaction P = .38). MP-LR tumors (n = 1,160) exhibited a statistically significant 10-year benefit of 3.7% for DR (hazard ratio [HR], 0.43 [95% CI, 0.25 to 0.74]; P = .002), whereas MP-HR tumors (n = 706) exhibited a nonsignificant 2.4% benefit (HR, 0.65 [95% CI, 0.34 to 1.24]; P = .19). The 10-year ELT benefit was significant for DFS (7.8%) and BCFI (7.0%) for MP-LR tumors, whereas MP-HR tumors did not significantly benefit (interaction DFS: P = .015, BCFI: P = .006). In exploratory analysis, the 10-year ELT benefit was significant and more pronounced in MP-LNUL (n = 908) tumors: 4.0% for DR, 9.5% for DFS, and 7.9% for BCFI; the benefit in MP-UL (n = 252) tumors was not significant: 3% for DR, 1.8% for DFS, and 4.1% for BCFI. CONCLUSION: The primary hypothesis of predictive ability of MP on DR was not confirmed. However, the secondary outcomes demonstrated MP was predictive of ELT response and identified a subset of patients with early-stage hormone receptor-positive BC (MP-LR) with improved outcomes from ELT. These data could have important clinical implications in patient selection beyond clinical risk assessment for EET.

[Contemporary diagnosis and treatment of tricuspid regurgitation: from neglected valve to primetime]. / Diagnosi e trattamento contemporaneo dell'insufficienza tricuspidale: da valvola dimenticata a primetime.

Tricuspid insufficiency has long been considered an entity with low prognostic importance and associated with symptoms and signs only secondarily to left heart pathology. Scientific research in recent years has debunked this myth, demonstrating a key role in determining symptoms and signs of right heart failure, even in advanced stages. In parallel, advances in transcatheter technologies have opened up treatment options even for patients with increased surgical risk, who were previously excluded from traditional surgical options, with increasingly convincing results in reducing symptoms and improving the quality of life of our patients. The contemporary challenge is to translate these messages into everyday clinical practice and to encourage the centralization of patients in centers that currently have the expertise for feasibility evaluation and subsequent treatment. In this Review, we will analyze the most recent evidence on the pathophysiology and diagnosis of tricuspid insufficiency, the latest recommendations from European guidelines, and we will try to illustrate the most common technologies for percutaneous treatment and the abundant evidence supporting them.