Favorable Outcome In Patients Research Articles

A practical approach to nutritional intervention for people with chronic kidney disease in Vietnam.

A comprehensive nutritional management is necessary for favourable outcomes in patients with chronic kidney disease (CKD). We aimed to assess the changes in nutritional status and disease progression with nutritional management where renal replacement therapy (RRT) was not in place. A quasi-experiment intervention was conducted on 70 CKD patients at stages 3-5 from July to December 2022. Participants were excluded if they underwent RRT, including dialy-sis (hemodialysis or peritoneal dialysis), or kidney transplantation. The nutritional regimen covered nutrition-al counseling, samples of the dietary menu, and supplement products. We evaluated nutritional status using Subjective Global Assessment (SGA) scale and sub-clinical blood test at T0 (hospital admission) and T1 (two weeks after the admission or 24 hours before the discharge). After the intervention, the number of patients classified as malnutrition or at risk of malnourished reduced significantly (65.7% to 54.3% and 25.7% and 5.7%, respectively). The serum concentration of urea, creatinine and parathyroid hormone decreased remarkably, especially in patients receiving nutritional management. In the intervention group, the dietary pattern provided increased intakes of calcium and iron at T1, while phosphorus, sodium and potassium decreased after follow-up. Nausea/vomiting, loss of appetite, tiredness and sleep disorders were improved in the intervention compared to the control group. Nutritional therapy enhanced the nutritional sta-tus, and quality of dietary and renal function in CKD patients without RRT. Applying nutrition education and treatment at an early stage can slow CKD progression, which should be applicable elsewhere in Vietnam.

Loss of p14 diminishes immunogenicity in melanoma via non-canonical Wnt signaling by reducing the peptide surface density.

Immunotherapy has achieved tremendous success in melanoma. However, only around 50% of advanced melanoma patients benefit from immunotherapy. Cyclin-dependent kinase inhibitor 2A (CDKN2A), encoding the two tumor-suppressor proteins p14ARF and p16INK4a, belongs to the most frequently inactivated gene loci in melanoma and leads to decreased Tcell infiltration. While the role of p16INK4a has been extensively investigated, knowledge about p14ARF in melanoma is scarce. In this study, we elucidate the impact of reduced p14ARF expression on melanoma immunogenicity. Knockdown of p14ARF in melanoma cell lines diminished their recognition and killing by melanoma differentiation antigen (MDA)-specific Tcells. Resistance was caused by a reduction of the peptide surface density of presented MDAs. Immunopeptidomic analyses revealed that antigen presentation via human leukocyte antigen class I (HLA-I) molecules was enhanced upon p14ARF downregulation in general, but absolute and relative expression of cognate peptides was decreased. However, this phenotype is associated with a favorable outcome for melanoma patients. Limiting Wnt5a signaling reverted this phenotype, suggesting an involvement of non-canonical Wnt signaling. Taken together, our data indicate a new mechanism limiting MDA-specific Tcell responses by decreasing both absolute and relative MDA-peptide presentation in melanoma.

One-year outcome of wide-area pulmonary vein isolation using the third-generation visually guided laser balloon

Abstract Background The third-generation laser balloon (LB3) is equipped with an ultra-compliant balloon and a motor-driven laser generator, which contribute to durable and gapless isolated lesion creation. However, the efficacy of wide-area pulmonary vein (PV) isolation (PVI) using LB3 remains to be elucidated. Purpose This study aims to investigate efficacy of wide-area PVI using LB3. Methods This is a single-center retrospective study. Patients with atrial fibrillation (AF) who underwent LB3 ablation during the period from August 2021 to June 2022 were enrolled. All PVs were electrically isolated only by LB3. After initial circular ablation, LB3 was inflated to a larger size at each PV, and the isolation area was extended. After ablation, voltage maps of the left atrium were obtained by high-resolution mapping catheters to evaluate isolation areas (<0.1mV). Follow-up included a 12-lead electrocardiogram, Holter monitoring, and/or pacemaker/implantable cardioverter-defibrillator interrogation. The efficacy endpoint was defined as freedom from atrial tachyarrhythmia (ATa) between months 3 and 12. Results Forty-four patients with paroxysmal AF and 34 with persistent AF (mean arrhythmia duration 12.4 months, range 1–60 months) were included. First pass isolation was achieved in 90.6% (280/309) of PVs. The total laser application time was 24.1±6.4 minutes, and the total delivered energy was 15.3±3.2 kJ. The isolation area at the left- and right-sided PV antrum were 14.2±1.8 and 19.5±1.1 cm², respectively. At the end of the 12 months of follow-up, the freedom from ATa was 78.2% in patients with paroxysmal AF and 78.0% in persistent AF, which indicates ATa free survival at one year was similar in both groups (P=0.91). Conclusions Wide-area PVI using LB3 may lead to favorable outcomes in patients with AF.Fluoroscopic and endoscopic imageKaplan-Meier curves and voltage map

Electrophysiologic characteristics and outcomes of atrial tachycardia ablation after mitral valve surgery

Abstract Background Atrial tachycardia (AT) is a commonly encountered rhythm disorder in patients with mitral valvular (MV) surgery. Radiofrequency (RF) ablation is the preferred therapeutic option in symptomatic patients. Purpose We aimed to evaluate the characteristics and ablation outcomes of AT in patients with previous mitral valve (MV) surgery. Methods A total of 100 symptomatic patients [mean age: 56 ±12, gender: 56 (56%) female] with documented AT were enrolled. Activation mapping was performed during tachycardia in all patients as well as entrainment mapping when needed. Voltage mapping was performed in sinus rhythm in the related atrium. Low voltage areas and signals with continuous-fragmented morphology were also tagged. Results In 127 procedures, a total of 158 ATs were documented [59 (37.3%) ATs were right-sided, 95 (60.1%) ATs were left-sided and 4(2.5%) AT was biatrial]. Mean number of ATs per procedure was 1.2±0.6. Macroreentry was the primary mechanism in right and left atrium (83.1% and 63.1%, respectively). Cavo-tricuspid isthmus (CTI) dependent macroreentry was the most frequent mechanism in right ATs whereas perimitral reentry was the most common mechanism in left ATs. Atrial low voltage zones comprised 45.5±25.1 % of total left atrium. The acute procedural success was 95.2%. Freedom from ATa after index procedure was 80% at 12 months and 65.6 % at 24 months. After multiple procedures, freedom from ATa was 77% during the mean follow-up duration of 39.7 ± 27.2 months. Conclusion Left ATs are more common compared to the right ATs and macroreentry is the major mechanism in both right & left ATs. RF ablation of ATs has favourable long-term outcomes in patients with MV surgery.

Clinical and electrophysiological characteristics and long term outcomes of catheter ablation for right and left atrial tachycardias

Abstract Background Atrial tachycardias (AT) are complex supraventricular tachycardias which are refractory to antiarrhythmic drugs that require catheter ablation. Purpose In this trial, we aimed to evaulate the outcomes of catheter ablation in patients with symptomatic atrial tachycardia, define the acute procedural success and the recurrence rates in long-term follow-up and determine the clinical and electrophysiological features that affect these outcomes. Methods A total of 666 [mean age: 55 ±16, gender: 344 (51.7%) female] symptomatic patients with AT were enrolled. Prior catheter or surgical ablation history for ATa was present in 199 (29.9%) and 18 (2.7%) of these patients, respectively. Activation mapping was performed during tachycardia in all patients as well as entrainment mapping when needed. Voltage mapping were performed in sinus rhythm in both atriums, late potential mapping was also performed in some patients. Low voltage areas and signals with continuous-fragmented morphology were tagged. Results Macroreentry was the primary mechanism in right and left atrium (70.2% and 52.8%, respectively). Cavotricuspid isthmus (CTI) dependent macroreentry was the most frequent mechanism in right ATs and perimitral reentry and roof-dependent macroreentry were the most common mechanisms in left ATs. A total of 59 (7.5%) complications were observed in 780 procedures.(2.1% major and 5.5% minor) Acute procedural success was 95.9%. Freedom from ATa was 72.8 % during a mean follow-up of 39±23 months. Freedom from ATa after index procedure was 82.3% at 12 months and 75.9 % at 24 months. After multiple procedures, freedom from ATa was 90% at 12 months and 86% at 24 months during the follow-up. In multivariate Cox regression analysis, atrial fibrillation (AF) [(HR) 2.43, 95% c(CI) 1.78-3.30; p<0.001] , history of cardiac surgery [(HR) 1.68, 95% c(CI) 1.22-2.30; p=0.001] and moderate to severe tricuspid regurgitation [(HR) 1.47, 95% c(CI) 1.08-2.01; p=0.014] were significant predictors of ATa recurrence. Conclusion Our findings demonstrated that tailored catheter ablation of ATs especially guided by high density mapping has a high acute success rate and favourable long-term outcomes in patients with symptomatic AT episodes.

Arthroscopic debridement, synovectomy and thermal shrinkage for basal joint arthritis.

Ligamentous laxity, cartilage wear, and diffuse synovitis are frequently seen in thumb basal joint arthritis. Although these degenerative changes may be mild for the majority, they have the potential to cause discomfort during movement and compromised hand function. This study assesses the long-term outcomes of arthroscopic debridement, synovectomy, and thermal shrinkage in managing early-stage basal joint arthritis. We retrospectively reviewed patients with basal joint arthritis who underwent arthroscopic debridement, synovectomy, and thermal shrinkage between November 2010 and January 2021 by a single surgeon at our medical institute. We assessed functional outcomes, thumb range of motion, perioperative nonsteroidal anti-inflammatory drug (NSAID) use, return to work and satisfaction level. A total of 12 patients (13 hands), with a mean follow-up of 72 months, were included in this study. Significant improvements were observed in pain scores and functional outcomes, along with a reduction in postoperative NSAID use. Patients also reported a relatively quick return to work and a high satisfaction level. The study highlights the benefits of arthroscopic intervention, providing a minimally invasive approach with favorable long-term outcomes for patients with symptomatic basal joint arthritis.

Integration of Complex Mathematical Approaches and Statistical Methodologies in Machine Learning for Design of Robust Prediction Models

The disease known as breast cancer continues to be one of the most common and potentially fatal diseases that affect women all over the world. In order to provide effective therapy and more favorable outcomes for patients, early detection and correct diagnosis are absolutely necessary. This research explores the integration of operational research (OR) methodologies and advanced statistical methods within machine learning frameworks to enhance the prediction accuracy of breast cancer outcomes. By harnessing the power of nonlinear optimization and statistical techniques, including regression analysis and probability distribution models, we aim to refine the predictive capabilities of existing algorithms. The research employs a comprehensive dataset derived from clinical trials and patient records, analyzed through a series of machine learning models that incorporate elements of combinatorial optimization, decision analysis, and stochastic modeling. Key performance metrics, such as accuracy, sensitivity, and specificity, are evaluated against standard benchmarks to determine the efficacy of the integrated approaches. Preliminary results indicate that incorporating OR and statistical methods significantly improves model robustness and predictive accuracy. The study not only demonstrates the potential of applied mathematics in medical diagnostics but also provides a framework for future research in enhancing machine learning models for health outcomes prediction through mathematical innovations. This investigation contributes to the field of mathematical oncology by demonstrating how applied nonlinear analysis can bridge the gap between theoretical mathematical approaches and practical clinical applications, offering new pathways for early and more accurate detection of breast cancer.

THE ENIGMA OF THE ‘SMOKER‘S PARADOX‘ : RESULTS FROM A SINGLE–CENTER REGISTRY OF PATIENTS WITH STEMI UNDERGOING PRIMARY PERCUTANEOUS CORONARY INTERVENTION

Abstract Background Smoker’s paradox usually refers to the common observation of a favourable outcome of smoker patients in acute myocardial infarction. The interpretation of this phenomenon is still controversial and not fully explained. We aimed at assessing whether smoking could be associated with mortality in a large cohort of prospectively enrolled patients with ST segment elevation myocardial infarction (STEMI) referred to primary percutaneous coronary intervention (PCI). Methods From April 2006 to December 2018 a population of 2456 STEMI patients treated with primary PCI were prospectively enrolled in the MATRIX registry. Ischemic time, clinical, demographics, angiographic data and 1–year follow–up were collected. Results Among 2546 patients admitted with STEMI 1007 (41%) were current smokers. Smokers were 10 years younger and had lower crude in–hospital and 1–year mortality (1.5% vs 6%, p<0.0001 and 5% vs 11%, p<0.0001), shorter ischemic time (203 [147–299] vs 220 [154–334] minutes, p=0.002) and shorter decision time (60 [30–135] vs 70 [36–170] minutes, p=0.0063). After propensity–matching, age, cardiogenic shock and low TIMI score were associated with in–hospital mortality, while smoking habit was still associated with reduced mortality. Smoking was also associated with reduced death rate at 1–year follow–up (HR 0.54, 95% CI [0.37 – 0.78]; p<0.001). Conclusions Our data show a protective link between smoking status and mortality in patients with STEMI, the so called “smoker’s paradox”. This could be explained not only by the shorter ischemic time and younger age of the smoking population but also by a specific pathogenetic effect of smoking underlying the onset of STEMI and response to therapies.

Leaflet modification before transcatheter aortic valve implantation in patients at risk for coronary obstruction: the ShortCut study.

This trial sought to assess the safety and efficacy of ShortCut, the first dedicated leaflet modification device, prior to transcatheter aortic valve implantation (TAVI) in patients at risk for coronary artery obstruction. This pivotal prospective study enrolled patients with failed bioprosthetic aortic valves scheduled to undergo TAVI and were at risk for coronary artery obstruction. The primary safety endpoint was procedure-related mortality or stroke at discharge or 7 days, and the primary efficacy endpoint was per-patient leaflet splitting success. Independent angiographic, echocardiographic, and computed tomography core laboratories assessed all images. Safety events were adjudicated by a clinical events committee and data safety monitoring board. Sixty eligible patients were treated (77.0 ± 9.6 years, 70% female, 96.7% failed surgical bioprosthetic valves, 63.3% single splitting and 36.7% dual splitting) at 22 clinical sites. Successful leaflet splitting was achieved in all (100%; 95% confidence interval [CI] 94-100.0%, p<0.001) patients. Procedure time, including imaging confirmation of leaflet splitting, was 30.6 ± 17.9 min. Freedom from the primary safety endpoint was achieved in 59 (98.3%; 95% CI [91.1-100%]) patients, with no mortality and one (1.7%) disabling stroke. At 30 days, freedom from coronary obstruction was 95% (95% CI 86.1-99.0%). Within 90 days, freedom from mortality was 95% (95% CI 86.1-99.0%]), without any cardiovascular deaths. Modification of failed bioprosthetic aortic valve leaflets using ShortCut was safe, achieved successful leaflet splitting in all patients, and was associated with favorable clinical outcomes in patients at risk for coronary obstruction undergoing TAVI.

Surgical Risk in Elderly Patients with Meningiomas in Japan.

Background/Objective: No guidelines indicate surgical risk factors for the elderly because of the lack of data from general neurosurgeons. To better understand the management of surgical risk in elderly patients with meningiomas based on a national database in Japan. Methods: Results of surgically treated meningiomas were explored in 8138 patients registered in the Diagnosis Procedure Combination database in Japan during 2010-2015. Age (<65, 65-74, and ≥75 years), sex, Barthel index (BI), medical history, tumor location, oral medication prescriptions on admission, and stroke complications were evaluated. Multivariate logistic regression analysis identified risk factors for stroke complications, BI deterioration between admission and discharge, and in-hospital mortality. Results: Advanced age was the prominent risk factor for BI deterioration (odds ratio: 3.26; 95% confidence interval: 2.69-3.95) but not for in-hospital mortality. Lower BI (60-80) on admission increased the risk of BI deterioration in all age groups; however, BI < 60 demonstrated a significant inverse risk (0.47; 0.32-0.69) in the elderly (≥75 years). Location (falx, parasagittal, and deep) and anticoagulants were not significant risk factors for BI deterioration in patients aged ≥ 75 years, despite being significant risk factors in patients aged <65 and/or 65-74 years. Conclusions: Although advanced age could lead to postoperative functional decline at discharge, it was not sufficiently significant enough to be associated with in-hospital mortality. Because of the possibility of recovery even in elderly patients with severe disabilities, appropriate surgical selection and optimal management may lead to favorable functional outcomes in elderly patients with meningiomas.

Differences in quality of anticoagulation care delivery according to ethnoracial group in the United States: A scoping review.

Anticoagulation therapy is standard for conditions like atrial fibrillation, venous thromboembolism, and valvular heart disease, yet it is unclear if there are ethnoracial disparities in its quality and delivery in the United States. For this scoping review, electronic databases were searched for publications between January 1, 2011 - March 30, 2022. Eligible studies included all study designs, any setting within the United States, patients prescribed anticoagulation for any indication, outcomes reported for ≥ 2 distinct ethnoracial groups. The following four research questions were explored: Do ethnoracial differences exist in 1) access to guideline-based anticoagulation therapy, 2) quality of anticoagulation therapy management, 3) clinical outcomes related to anticoagulation care, 4) humanistic/educational outcomes related to anticoagulation therapy. A total of 5374 studies were screened, 570 studies received full-text review, and 96 studies were analyzed. The largest mapped focus was patients' access to guideline-based anticoagulation therapy (88/96 articles, 91.7%). Seventy-eight articles made statistical outcomes comparisons among ethnoracial groups. Across all four research questions, 79 articles demonstrated favorable outcomes for White patients compared to non-White patients, 38 articles showed no difference between White and non-White groups, and 8 favored non-White groups (the total exceeds the 78 articles with statistical outcomes as many articles reported multiple outcomes). Disparities disadvantaging non-White patients were most pronounced in access to guideline-based anticoagulation therapy (43/66 articles analyzed) and quality of anticoagulation management (19/21 articles analyzed). Although treatment guidelines do not differentiate anticoagulant therapy by ethnoracial group, this scoping review found consistently favorable outcomes for White patients over non-White patients in the domains of access to anticoagulation therapy for guideline-based indications and quality of anticoagulation therapy management. No differences among groups were noted in clinical outcomes, and very few studies assessed humanistic or educational outcomes.

PSMA-Targeted Therapy: Advancements in Detection and Treatment Modalities with Dr. Scott T. Tagawa.

Prostate cancer is one of the most challenging malignancies due to its high incidence and prevalence, as it is the most frequently diagnosed non-skin cancer in men. The timely identification of prostate cancer and its metastasis is paramount for ensuring favorable outcomes for patients. Prostate-specific membrane antigen (PSMA) emerges as a promising biomarker for its detection, due to its specificity. This makes it an ideal target for the early identification of a metastatic phenotype. Situated on the membrane of tumor cells, PSMA facilitates the attachment of PSMA-targeting particles, enabling their detection through positron emission tomography (PET) scans with relative ease. Utilizing these imaging agents in conjunction with PET scans enhances the accuracy of prostate cancer tumor detection compared to PET scans alone. The advancement in prostate cancer imaging has paved the way for innovative treatment modalities. Prostate-specific membrane antigen-targeted radionuclide therapies (PSMA-TRT) exploit PSMA imaging agents to target identified prostate cancer malignancies with precise radiation, thereby reducing or eliminating the tumor mass. PSMA-TRT exhibits significant promise in prostate cancer therapy, evident from the notable declines in prostate-specific antigen (PSA) levels post treatment. However, PSMA-TRT carries both beneficial and adverse effects. While it represents a substantial leap forward in tumor cell imaging, PSMA-based antigens, being larger particles than ligands, offer prolonged imaging capabilities. Yet, the long-term effects of PSMA-TRT remain unknown, with the short-term adverse ones including fatigue, nausea, pain flares, and potential radiation exposure to others.

KDM7A-DT induces genotoxic stress, tumorigenesis, and progression of p53 missense mutation-associated invasive breast cancer.

Stress-induced promoter-associated and antisense lncRNAs (si-paancRNAs) originate from a reservoir of oxidative stress (OS)-specific promoters via RNAPII pausing-mediated divergent antisense transcription. Several studies have shown that the KDM7A divergent transcript gene (KDM7A-DT), which encodes a si-paancRNA, is overexpressed in some cancer types. However, the mechanisms of this overexpression and its corresponding roles in oncogenesis and cancer progression are poorly understood. We found that KDM7A-DT expression is correlated with highly aggressive cancer types and specific inherently determined subtypes (such as ductal invasive breast carcinoma (BRCA) basal subtype). Its regulation is determined by missense TP53 mutations in a subtype-specific context. KDM7A-DT transcribes several intermediate-sized ncRNAs and a full-length transcript, exhibiting distinct expression and localization patterns. Overexpression of KDM7A-DT upregulates TP53 protein expression and H2AX phosphorylation in nonmalignant fibroblasts, while in semi-transformed fibroblasts, OS superinduces KDM7A-DT expression in a TP53-dependent manner. KDM7A-DT knockdown and gene expression profiling in TP53-missense mutated luminal A BRCA variant, where it is abundantly expressed, indicate its significant role in cancer pathways. Endogenous over-expression of KDM7A-DT inhibits DNA damage response/repair (DDR/R) via the TP53BP1-mediated pathway, reducing apoptosis and promoting G2/M checkpoint arrest. Higher KDM7A-DT expression in BRCA is associated with KDM7A-DT locus gain/amplification, higher histologic grade, aneuploidy, hypoxia, immune modulation scores, and activation of the c-myc pathway. Higher KDM7A-DT expression is associated with relatively poor survival outcomes in patients with luminal A or Basal subtypes. In contrast, it is associated with favorable outcomes in patients with HER2+ER- or luminal B subtypes. KDM7A-DT levels are coregulated with critical transcripts and proteins aberrantly expressed in BRCA, including those involved in DNA repair via non-homologous end joining and epithelial-to-mesenchymal transition pathway. In summary, KDM7A-DT and its si-lncRNA exhibit several intrinsic biological and clinical characteristics that suggest important roles in invasive BRCA and its subtypes. KDM7A-DT-defined mRNA and protein subnetworks offer resources for identifying clinically relevant RNA-based signatures and prospective targets for therapeutic intervention.

Abstract PO2-16-05: ESR1 mutations (ESR1mut) in HR(+)HER2(-)patients with metastatic breast cancer (MBC): prevalence along treatment course and predictive value for endocrine therapy (ET) resistance in real-world practice

Abstract Background: ET combined with CDK4/6 inhibitors (CDKi) is the standard of care for HR(+)HER2(-) patients with MBC. ESR1mut is an acquired resistance mechanism to ET, especially aromatase inhibitors (AI). The prevalence and behavior of ESR1mut in patients receiving the selective estrogen receptor degrader (SERD) fulvestrant remains in question. This study aimed to characterize the prevalence of ESR1mut at start of successive lines of therapy and to evaluate clinical outcomes of ET by ESR1 status in 1st line therapy in real-world practice. Methods: This study included patients with HR(+)HER2(-) MBC who underwent genomic testing using Foundation Medicine tissue or liquid comprehensive genomic profiling (CGP) assays, with specimens collected within 60 days of therapy initiation. Patient clinical data was obtained by the nationwide (US-based) de-identified Flatiron Health and Foundation Medicine real-world clinicogenomic breast database (FH-FMI CGDB), originated from ~280 US cancer clinics (~800 sites of care) between 01/2011 and 04/2023. ESR1mut prevalence was calculated in tissue and liquid samples collected in the 1st, 2nd, and 3rd lines of therapy. Real-world progression free-survival (rwPFS), time to treatment discontinuation (rwTTD), and overall survival (rwOS) were compared between patients who received AI + CDKi and between patients receiving fulvestrant + CDKi 1st line therapy [ESR1mut vs. ESR1 wild-type (wt) by tissue CGP] by Cox models. Multivariable analyses adjusted for adjuvant therapy, age, ECOG, menopausal status, histology, stage at diagnosis, metastatic site, and specific ESR1mut (Y537S, D538G, E380W, or others) were performed. Results: The prevalence of ESR1mut in tissue samples collected in 1st, 2nd, and 3rd lines of therapy was 7.9% (n=159/2004), 26.4% (n=66/250), and 34.0% (n=68/200), respectively. The prevalence of ESR1mut in liquid samples collected in the 1st, 2nd, and 3rd lines of therapy was 11.6% (n=30/259) 34.4% (n=63/183), and 35.9% (n=42/117), respectively. Among patients receiving AI + CDKi 1st line therapy (n=485), those with ESR1mut vs. ESR1wt had less favorable rwPFS [median 6.1 vs. 20.8 months, hazard ratio (HR) 2.36, 95% CI 1.35-4.14, p=0.003]. rwTTD and rwOS assessments were consistent with the magnitude of effect of rwPFS. Among patients receiving fulvestrant + CDKi 1st line therapy (n=302), those with ESR1mut vs. ESR1wt had less favorable rwPFS (median 10.5 vs. 14.5 months, HR 1.5, 95% CI 1.05-2.15, p=0.025), but no difference was observed for rwTTD and rwOS (p &amp;gt;0.05). Notably, the multivariable analyses found the independent association of ESR1mut and less favorable rwPFS (HR 2.18, 95% CI 1.15-4.1, p=0.018), rwTTD (HR 3.34, 95% CI, 1.84-6.1, p&amp;lt; 0.001), and rwOS (HR 2.46, 95% CI 1.04-5.9, p=0.041) in patients receiving AI + CDKi. The multivariable analyses confirmed no association between ESR1mut and outcomes in patients receiving fulvestrant + CDKi (p &amp;gt;0.05). No substantial differential associations were observed between specific ESR1mut and clinical outcomes in the multivariable analyses. Conclusion: In our dataset, ESR1mut is prevalent in about 8-11% of baseline tissue and liquid samples of patients with HR(+)HER2(-) MBC. Baseline ESR1mut is associated with less favorable outcomes in patients receiving AI + CDKi 1st line therapy, but not in patients receiving fulvestrant + CDKi. Specific ESR1mut do not seem to be associated with different outcomes to ET. ESR1mut prevalence increased during treatment course. Further investigation is warranted to determine optimal endocrine partner with CDKi based upon ESR1 status, particularly with development of oral SERDs. Citation Format: Manali Bhave, Julia Quintanilha, Ryon Graf, Takara Scott, Hanna Tukachinsky, Gerald Li, Alexa Schrock, Geoffrey Oxnard, Mia Levy, Kevin Kalinsky. ESR1 mutations (ESR1mut) in HR(+)HER2(-)patients with metastatic breast cancer (MBC): prevalence along treatment course and predictive value for endocrine therapy (ET) resistance in real-world practice [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-16-05.

Novel FOXM1 inhibitor STL001 sensitizes human cancers to a broad-spectrum of cancer therapies

Forkhead box protein M1 (FOXM1) is often overexpressed in human cancers and strongly associated with therapy resistance and less good patient survival. The chemotherapy options for patients with the most aggressive types of solid cancers remain very limited because of the acquired drug resistance, making the therapy less effective. NPM1 mutation through the inactivation of FOXM1 via FOXM1 relocalization to the cytoplasm confers more favorable treatment outcomes for AML patients, confirming FOXM1 as a crucial target to overcome drug resistance. Pharmacological inhibition of FOXM1 could be a promising approach to sensitize therapy-resistant cancers. Here, we explore a novel FOXM1 inhibitor STL001, a first-generation modification drug of our previously reported FOXM1 inhibitor STL427944. STL001 preserves the mode of action of the STL427944; however, STL001 is up to 50 times more efficient in reducing FOXM1 activity in a variety of solid cancers. The most conventional cancer therapies studied here induce FOXM1 overexpression in solid cancers. The therapy-induced FOXM1 overexpression may explain the failure or reduced efficacy of these drugs in cancer patients. Interestingly, STL001 increased the sensitivity of cancer cells to conventional cancer therapies by suppressing both the high-endogenous and drug-induced FOXM1. Notably, STL001 does not provide further sensitization to FOXM1-KD cancer cells, suggesting that the sensitization effect is conveyed specifically through FOXM1 suppression. RNA-seq and gene set enrichment studies revealed prominent suppression of FOXM1-dependent pathways and gene ontologies. Also, gene regulation by STL001 showed extensive overlap with FOXM1-KD, suggesting a high selectivity of STL001 toward the FOXM1 regulatory network. A completely new activity of FOXM1, mediated through steroid/cholesterol biosynthetic process and protein secretion in cancer cells was also detected. Collectively, STL001 offers intriguing translational opportunities as combination therapies targeting FOXM1 activity in a variety of human cancers driven by FOXM1.

GATA6 identifies an immune-enriched phenotype linked to favorable outcomes in patients with pancreatic cancer undergoing upfront surgery

This study underscores GATA6's role in distinguishing classical and basal-like pancreatic ductal adenocarcinoma (PDAC) phenotypes. Retrospective studies associate GATA6 immunohistochemistry (IHC) expression with survival outcomes, warranting prospective validation. In a prospective treatment-naive cohort of patients with resected PDAC, GATA6 IHC proves a prognostic discriminator, associating high GATA6 expression with extended survival and the classical PDAC phenotype. However, GATA6's prognostic significance is numerically lower after gemcitabine-based neoadjuvant chemoradiotherapy compared to its significance in patients treated with upfront surgery. Furthermore, GATA6 is implicated in immunomodulation, although a comprehensive investigation of its immunological role is lacking. Treatment-naive PDAC tumors with varying GATA6 expression yield distinct immunological landscapes. Tumors highly expressing GATA6 show reduced infiltration of immunosuppressive regulatory Tcells and M2 macrophages but increased infiltration of immune-stimulating, antigen-presenting, and activated Tcells. Our findings caution against solely relying on GATA6 for molecular subtyping in clinical trials and open avenues for exploring immune-based combination therapies.

Tamarind Seeds in Tracheobronchial Tree: Challenges during Rigid Bronchoscopy

ABSTRACT Background: Tamarind seed aspiration is not frequent in children and is usually observed in kids from rural backgrounds, with easy access to tamarind fruits and their by-products. Materials and Methods: We report a retrospective review of five patients managed in the pediatric surgery department for tamarind seed aspiration into the tracheobronchial tree. The data were analyzed based on age, clinical presentation, bronchoscopic observations, and the challenges faced during the rigid bronchoscopic retrieval and postoperative course. Results: There were four boys and one girl with a median age of 10 years. High-resolution computed tomography thorax was done in all patients. The foreign body was identified in the right main bronchus in one and the left main bronchus in four patients. All five patients underwent rigid bronchoscopy and retrieval of the seed. Two patients had an early presentation (within a week) - they needed temporary tracheotomy as the swollen seed could not be negotiated through the narrow glottis. Two patients had a late presentation (around 15 days) - they required removal in piecemeal using crushing forceps and multiple insertions of bronchoscope prolonging surgical time. One patient presented at 22 days posttamarind aspiration. It was soft enough for easy disintegration with crocodile forceps and expeditiously removed in three to four pieces. All patients recovered uneventfully. Conclusion: Removal of tamarind seed foreign body from the tracheobronchial tree is challenging. Anticipating the difficulties and being prepared well, helps to reduce the intraoperative difficulty, and allow successful removal with favorable patient outcomes.

CD20highCD138low tumor-infiltrating lymphocytes predominantly related to cytokine‒cytokine receptor interactions are associated with favorable outcomes in neuroblastoma patients

Recent advances have revealed that the role of the immune system is prominent in the antitumor response. In the present study, it is aimed to provide an expression profile of tumor-infiltrating lymphocytes (TILs), including mature B cells, plasma cells, and their clinical relevance in neuroblastoma. The expression of CD20 and CD138 was analyzed in the Cangelosi786 dataset (n = 769) as a training dataset and in our cohort (n = 120) as a validation cohort. CD20 high expression was positively associated with favorable overall survival (OS) and event-free survival (EFS) (OS: P < 0.001; EFS: P < 0.001) in the training dataset, whereas CD138 high expression was associated with poor OS and EFS (OS: P < 0.001; EFS: P < 0.001) in both the training and validation datasets. Accordingly, a combined pattern of CD20 and CD138 expression was developed, whereby neuroblastoma patients with CD20highCD138low expression had a consistently favorable OS and EFS compared with those with CD20lowCD138high expression in both the training and validation cohorts (P < 0.0001 and P < 0.01, respectively). Examination of potential molecular functions revealed that signaling pathways, including cytokine‒cytokine receptor interactions, chemokine, and the NF-kappa B signaling pathways, were involved. Differentially expressed genes, such as BMP7, IL7R, BIRC3, CCR7, CXCR5, CCL21, and CCL19, predominantly play important roles in predicting the survival of neuroblastoma patients. Our study proposes that a new combination of CD20 and CD138 signatures is associated with neuroblastoma patient survival. The related signaling pathways reflect the close associations among the number of TILs, cytokine abundance and patient outcomes and provide therapeutic insights into neuroblastoma.

ANGPTL3 diminishes the resistance of ovarian cancer to paclitaxel by blocking the PI3K-AKT-mTOR signaling pathway

Angiopoietin-like protein 3 (ANGPTL3) is key in ovarian cancer (OC) cell growth and metastasis, notably by enhancing natural killer cells' capacity for inducing cell toxicity and apoptosis. However, its role in influencing chemotherapy resistance in OC remains ambiguous. In this study, we discovered a correlation between reduced ANGPTL3 levels and a less favorable outcome in OC patients using the Kaplan-Meier Plotter database. Lower levels of ANGPTL3 were detected in paclitaxel (PTX)-resistant OC tissues and cell lines via western blotting and immunohistochemistry. To investigate ANGPTL3's effects, we established SKOV3/PTX and 2780/PTX as PTX-resistant OC cell lines by incrementally increasing PTX exposure and then transfecting them with overexpress ANGPTL3 (OE-ANGPTL3) lentivirus. We conducted various assays such as CCK-8, colony formation, Edu staining, flow cytometry, and transwell to investigate the impact of ANGPTL3 on PTX resistance. Additionally, this effect was examined in a mouse subcutaneous xenograft model. Both in vitro and in vivo experiments demonstrated that ANGPTL3 overexpression mitigated PTX resistance in OC cells by inactivating the PI3K-AKT-mTOR pathway. In summary, our research reveals that ANGPTL3 enhances PTX sensitivity in OC by downregulating the PI3K-AKT-mTOR pathway. The study of this study suggest that ANGPTL3 could serve as a valuable therapeutic target for OC, signifying its clinical relevance in OC management.

Transapical beating-heart septal myectomy for hypertrophic cardiomyopathy patients with midventricular obstruction

BackgroundWe developed a novel minimally invasive transapical beating-heart septal myectomy (TA-BSM) procedure for patients with midventricular obstruction (MVO), without the aid of cardiopulmonary bypass. This study aims to describe the TA-BSM procedure for the relief of MVO and to detail the clinical outcomes in these patients. MethodsSixty-one patients receiving TA-BSM for MVO were included: isolated MVO (n = 12) and combined MVO and subaortic obstruction (n = 49). We reviewed the electronic medical record to collect information on preoperative, intraoperative, and postoperative parameters. ResultsThe intraventricular pressure gradient after the resection was largely attenuated. On the catheter measurement, the median resting and provoked gradient decreased by 29.0 and 71.0 mm Hg, respectively. Likewise, the resting intraventricular gradient was successfully reduced from 58.0 to 11.0 mm Hg, and the maximal intraventricular gradient was reduced from 88.0 to 20.0 mm Hg at 6 months follow-up. In addition, all patients showed significantly improved MR and 37 of 42 patients with preoperative MR grade ≥ 2+ showed MR grade ≤ 1+ after TA-BSM. During the follow-up, no death was observed and no one had HCM-related rehospitalization. All patients reported improvement in symptoms and the mean New York Heart Association class improved from 3.0 (IQR, 3.0-3.0) preoperatively to 1.0 (IQR, 1.0-1.0) at 6 months follow-up. ConclusionsThe TA-BSM procedure is a valuable therapy to relieve MVO, improving hemodynamics and providing satisfactory clinical outcomes. The procedure can also preserve favorable outcomes for patients with MVO and concomitant subaortic obstruction.