Treatment Status Research Articles

A comparison of time-varying propensity score vs sequential stratification approaches to longitudinal matching with a time-varying treatment.

Methods for matching in longitudinal cohort studies, such as sequential stratification and time-varying propensity scores, facilitate causal inferences in the context of time-dependent treatments that are not randomized where patient eligibility or treatment status changes over time. The tradeoffs in available approaches have not been compared previously, so we compare two methods using simulations based on a retrospective cohort of patients eligible for weight loss surgery, some of whom received it. This study compares matching completeness, bias, coverage, and precision among three approaches to longitudinal matching: (1) time-varying propensity scores (tvPS), (2) sequential stratification that matches exactly on all covariates used in tvPS (SS-Full) and (3) sequential stratification that exact matches on a subset of covariates (SS-Selected). These comparisons are made in the context of a deep sampling frame (50:1) and a shallow sampling frame (5:1) of eligible comparators. A simulation study was employed to estimate the relative performance of these approaches. In 1,000 simulations each, tvPS retained more than 99.9% of treated patients in both the deep and shallow sampling frames, while a smaller proportion of treated patients were retained for SS-Full (91.6%) and SS-Selected (98.2%) in the deep sampling frame. In the shallow sampling frame, sequential stratification retained many fewer treated patients (73.9% SS-Full, 92.0% SS-Selected) than tvPS yet coverage, precision and bias were comparable for tvPS, SS-Full and SS-Selected in the deep and shallow sampling frames. Time-varying propensity scores have comparable performance to sequential stratification in terms of coverage, bias, and precision, with superior match completeness. While performance was generally comparable across methods, greater match completeness makes tvPS an attractive option for longitudinal matching studies where external validity is highly valued.

Designing a Measure of Body Image: Cognitive Interview Findings from an Adolescent and Young Adult Cancer Sample.

Purpose: A cancer diagnosis in adolescence and young adulthood significantly impacts a person's quality of life, particularly concerning identity, self-esteem, and subsequently, body image. This study aims to develop a psychometrically-sound patient-reported outcome measure of body image for adolescent and young adult (AYA) oncology patients that was guided by the National Institutes of Health's Patient-Reported Outcomes Measurement Information System® (PROMIS) Scientific Standards and our past concept elicitation interviews with AYAs. Methods: We conducted a multi-step approach involving item identification, refinement, generation; translatability and reading level review; and cognitive interviews. A purposive sample of 25 AYA patients participated, ensuring representation across educational levels, gender, treatment status, and cancer type. Results: Translatability and reading level reviews facilitated language adjustments. Cognitive interviews revealed that 76% of AYAs found the 50 candidate items assessing body image concerns to be easy to answer. AYAs reported that the body image items captured their lived experiences. Three items were excluded due to comprehension difficulties. Conclusion: This study addresses the critical gap in validated measures for assessing body image in AYA oncology patients. Interview findings provided evidence for the content validity and comprehensibility for 47 items assessing body image. The next steps involve large-scale psychometric testing to evaluate the reliability and validity of the body image items to form an item bank allowing the design of short forms or use of computerized-adaptive testing. Ultimately, this work lays the foundation for developing interventions to mitigate the impact of cancer on AYAs' body image during diagnosis, treatment, and recovery.

EPCO-40. TRANSCRIPTIONAL TRAJECTORY INFERENCE OF IMAGE-LOCALIZED, MULTI-REGIONAL HIGH-GRADE GLIOMA BIOPSIES REVEALS DISTINCT POPULATION ECOLOGIES AND SEX-ASSOCIATED ENRICHED PATHWAYS

Abstract The intra- and inter-patient heterogeneity in high-grade glioma (HGG) continues to contribute to its poor prognosis. Clinical biopsies are often harvested from limited regions and typically are not image localized. Thus, they fail to capture the diversity within tumor regions, immune expression or normal cell abundances that play key roles in tumor development. It is important to gain an understanding of these subpopulation ecologies, their spatial resolution, and interactions between them that may then be exploited for future therapeutic benefit. Further, these may differ by patient characteristics such as sex, age at diagnosis and treatment status. Using an ongoing image-localized biopsy collection protocol, we have so far evaluated the bulk transcriptomics of 202 multi-regional biopsies from 58 patients to characterize HGG heterogeneity. These samples were processed through Monocle, a reverse graph embedding algorithm that groups samples into states and orders them along developmental trajectories. Deconvolution methods were previously used to predict relative abundances of 7 normal, 6 glioma, and 5 immune cell subpopulations for each sample, which we have now overlaid on the Monocle graph. Monocle classified HGG into 4 main states along a three-pronged trajectory. These states reveal distinct population ecologies with associated enriched gene pathways. We also note significant immune pathway enrichments that differ between state and patient-reported sex. Together, these algorithms reveal a simple transcriptomic trajectory that helps us understand the development and evolution of HGG. Characterizing the in vivo diversity within and between high grade gliomas is important for understanding prognosis, stratifying future treatments and ultimately improving patient outcome.

NCOG-24. CHARACTERIZING NEUROTOXICITY ASSOCIATED WITH SYSTEMIC CHEMOTHERAPY IN PATIENTS WITH BREAST CANCER USING DOMAIN-SPECIFIC INTRA-INDIVIDUAL NEUROCOGNITIVE VARIABILITY

Abstract BACKGROUND Systemic chemotherapy is associated with neurotoxicity and neurocognitive functioning (NCF) changes. Intra-individual neurocognitive variability (IIV) is an index of NCF spread/dispersion across neuropsychological tests and can be elevated in patients with breast cancer (BC) after systemic chemotherapy. This study investigated longitudinal IIV changes within NCF domains after chemotherapy to determine whether: (1) IIV for NCF domains are more sensitive to changes than traditional mean-based metrics, and (2) whether changes in domain-specific IIV are associated with changes in mood disturbance or quality of life (QOL). METHODS Prior to and during/shortly after chemotherapy, 37 women with BC were administered a standardized NCF battery including tests within domains of attention/speed of information processing (A/SoP), learning/memory (L/M), and executive functions (EF). Within each domain, the coefficient of variation (CoV) was computed using the standard deviation of normatively-adjusted T-scores while adjusting for intra-individual mean. Patients were assessed for QOL using Functional Assessment of Cancer Therapy-Breast and mood using the STAI and BDI. RESULTS Paired samples t-tests revealed that mean NCF performances declined for L/M (t[36])=-4.44,p<.001,Hedge’s g=.70) and improved for A/SoP (t[36]=3.21,p=.003,g=.29), while CoV increased/worsened for L/M (t[36]=3.82,p<.001,g=.76) but did not change for A/SoP (t[36]=-0.05,p=.959,g=.01). There was no change in EF mean or CoV (ps >.10). No domain mean or IIV change was associated with mood changes (ps>.10). Mean NCF changes were not associated with QOL (ps >.10). Increased/worsened L/M CoV was associated with improved FACT-Breast scale QOL (ρ=.40,p=.020). CONCLUSIONS Both mean- and IIV-based NCF worsened for learning/memory. Discrepancies between mean and IIV change for attention/speed of information processing may be due to differential susceptibility to practice effects. Unexpected associations between learning/memory IIV changes and QOL require further investigation. Future studies are needed to examine NCF dispersion changes across treatment status and in other cancer populations.

RADT-27. REPORT OF 9 CASES OF EMBRYONAL TUMORS OF THE CENTRAL NERVOUS SYSTEM WITH MULTILAYERED ROSETTES (ETMR)

Abstract OBJECTIVE Embryonal Tumors of the Central Nervous System with Multilayered Rosettes (ETMR) are rare, and there’s no standard treatment protocol. This article reports on the current treatment status and prognosis of ETMR in our hospital. METHODS We retrospectively collected patients with ETMR who received treatment in the Oncology Department of Guangdong sanjiu Brain Hospital from January 2017 to January 2021, analyzed their clinical data. RESULTS Among 31 cases of central nervous system embryonic tumors (excluding medulloblastoma and ATRT), 9 (29.03%) were ETMR. The median age at diagnosis was 3 years old (1-15), and the male to female ratio was 4:5. Among them, 5 cases were accompanied by C19MC gene variation. Tumor location:6 was in supratentorial, 1 in the pineal region, 1 in the pons, 1 in the cerebellopontine. Eight patients underwent surgical resection at the first diagnosis, with 6 cases of total resection, 1 case of partial resection, and 1 case of biopsy. One case was misdiagnosed as a germinoma in the pineal region at the initial. After recurrence, surgical resection was performed to confirm the pathology as ETMR. One case was misdiagnosed as glioblastoma during the first surgery. The initial treatment for 4 patients after surgery was radiotherapy combined with concurrent chemotherapy. Recurrence patterns: 2 cases were intracranial dissemination, 2 cases were local recurrence, 1 was spinal cord dissemination. One patient did not receive treatment after surgery and tumor recurrence 3 months later. Survival analysis: The median survival time was 20 months. The 1-year progression-free survival rate (PFS) and overall survival rate (OS) were 22% and 61%, and the 2-year overall survival rate (OS) was 31%. CONCLUSION ETMR has a low incidence and poor prognosis. It is easy to misdiagnose and NGS is necessary to assist diagnosis when needed. More effective treatment methods need to be explored.

PATH-51. CENTRAL NERVOUS SYSTEM METASTASES ARE GENOMICALLY DIVERGENT FROM THEIR RESPECTIVE EXTRACRANIAL SITES

Abstract INTRODUCTION Next-generation sequencing (NGS) has become standard of care in establishing the diagnosis and guiding treatment of cancers. Our understanding of genomic evolution of brain metastases (BM) and leptomeningeal disease (LMD) from solid tumor malignancies remains limited. Here we present updated data from our pilot study. METHODS We prospectively collected clinical data and NGS of seventeen patients undergoing craniotomy for symptomatic BM from solid tumor malignancies or cerebrospinal fluid (CSF) sampling for LMD. Matched systemic and CNS analyses were performed using a research-based NGS assay. When extracranial disease tissue was unavailable, liquid NGS served as a surrogate. RESULTS CNS metastases were present at initial diagnosis in 10/17 and 11/17 patients had not received systemic therapy prior to CNS tissue sampling. The predominant cancer type was NSCLC (n=11), followed by breast cancer (n=3), ovarian high grade serous carcinoma (n=1), GEJ adenocarcinoma (n=1), and basosquamous carcinoma of skin (n=1). The mean tumor mutational burden in extracranial samples was 3.65 (SD 3.34; SEM 0.97), in contrast to CNS samples 21.63 (SD 26.47; SEM 7.64). Concordant mutations in matched sampling had an increase in CNS variant allele frequency (VAF) (27.8% vs 17.3%; arithmetic difference = 10.5, p=0.054) and CNS gene copy number alterations (CNA) (2.4 copies vs 0.8 copies; arithmetic difference = 1.6, p=0.171). Known driver alterations in EGFR, KRAS and PIK3CA were retained. LMD was present in 4/17 patients, with two present at enrollment and two developing during the study. CONCLUSIONS Matched sequencing reveals CNS metastases to harbor a significantly higher TMB, retention of primary driver alterations with a trend towards higher VAF and CNA of concordant mutations. While limited by small sample size, these data indicate genetic evolution in CNS metastases regardless of prior treatment status.

Long-Term Follow-Up of Neuropsychiatric Symptoms After Sustained Virological Response to Interferon-Free and Interferon-Based Hepatitis C Virus Treatment.

Chronic hepatitis C virus (HCV) infection can be associated with neuropsychiatric symptoms like fatigue and cognitive impairment, independent of the liver status. The present study aims to assess changes in the pattern and extent of neuropsychological symptoms after successful treatment with interferon (IFN)-based and IFN-free therapy. HCV-infected patients who underwent neuropsychological assessment in previous studies were invited to a follow-up examination. Patients were grouped according to the treatment status: Sustained virological response (SVR) after IFN treatment (IFN SVR, n = 14) or after therapy with direct acting antivirals (DAA SVR, n = 28) or ongoing HCV infection (HCV RNA+, n = 11). A group of 33 healthy controls served as reference. Patients completed self-report questionnaires addressing health-related quality of life (HRQoL), mood and sleep quality and a neuropsychological test battery including tests of memory and attention (Luria's list of words, PSE test, cancelling "d" test, Word-Figure-Memory Test and computer-based test battery for the assessment of attention [TAP]). At baseline, all three patient groups had worse fatigue, depression, anxiety and HRQoL scores compared to healthy controls. Longitudinal analysis revealed that fatigue and mood slightly improved in all patient groups over time, while HRQoL improved in SVR patients but not in HCV RNA+ patients. Memory test results improved significantly in all patient groups, irrespective of their virological status. In contrast, the attention test results showed no clear change from baseline to follow-up. Our data can be considered as a hint that HCV eradication-independent of therapy regimen-does not substantially ameliorate neuropsychiatric symptoms in HCV-afflicted patients.

Retinal Function in Advanced Multiple Sclerosis.

People with multiple sclerosis (pwMS) experience autoimmunity-mediated inflammation and neurodegeneration throughout the central nervous system. There remains a need for clinically accessible, reliable functional markers of neurodegeneration in MS. Previous research has described changes to electroretinography (ERG)-derived measures of retinal bipolar cell function in pwMS early in the disease course. We, therefore, investigated ERG as a potential outcome measure in individuals with more advanced disease. This cross-sectional observational study included pwMS with Expanded Disability Status Scale (EDSS) scores of ≥3.0 and healthy control (HC) participants who underwent ERG, optical coherence tomography, high- and low-contrast visual acuity measurement, and an ophthalmological examination. ERG findings in MS eyes with and without previous optic neuritis (MS +ON; MS -ON) were compared with those in HC eyes. Effects of EDSS, disease duration, ON, and treatment status on selected ERG outcomes were measured. Additional exploratory analyses assessed potential influences of MS phenotype and disease status (clinically active, radiologically active, and disease progression). Delays to two ERG peak times (dark-adapted 3.0 b-wave; light-adapted flicker) were recorded in MS +ON and MS -ON eyes. No influences of EDSS score, disease duration, previous ON, or treatment status were observed. Exploratory analyses were consistent with no effects of MS phenotype or disease status. ERG findings are abnormal in individuals with moderate-severe disability caused by MS; however, these findings are not distinct from those observed earlier in the disease course. Although bipolar dysfunction appears to be common in pwMS throughout the disease course, ERG is likely not useful in monitoring or prognostication of MS.

Evolution of treatment strategies for solid tumors with RET rearrangement in China and real-world treatment status of Non-small Cell Lung Cancer (NSCLC)

ObjectiveThe present study endeavors to furnish an exhaustive review of the research advancements on solid tumors harboring RET rearrangement within the Chinese context, particularly emphasizing the examination of real-world therapeutic strategies and clinical outcomes observed in individuals diagnosed with advanced non-small cell lung cancer (NSCLC). The review delves into a critical assessment of the therapeutic efficacy of targeted RET inhibitors, while also scrutinizing the diverse array of treatment modalities employed in the Chinese patient population.MethodsThe study conducted a comprehensive review of the advancements made by Chinese scholars in the realm of RET driver genes. It delved into the analysis of the incidence of RET rearrangements in solid tumors, alongside an examination of the varied treatment paradigms and their current status within China. Utilizing the RECIST 1.1 criteria, the study evaluated the therapeutic efficacy achieved in RET-positive NSCLC patients undergoing diverse treatment modalities. Furthermore, treatment-related adverse events (TRAEs) were meticulously graded following the Common Terminology Criteria for Adverse Events (CTCAE).ResultsA retrospective, multi-center, real-world analysis was conducted, encompassing 64 patients diagnosed with pathologically confirmed RET rearrangement advanced non-small cell lung cancer (NSCLC) between December 2015 and November 2023. Notably, KIF5B-RET emerged as the most prevalent RET fusion partner, accounting for 59.4% of cases. Therapeutic interventions among these patients included specific targeted inhibitors such as Pralsetinib (48.4%), chemotherapy (34.3%), multi-target inhibitors (15.6%), and one case (1.6%) involving immunotherapy combined with anti-angiogenic therapy. In terms of progression-free survival (PFS), Pralsetinib monotherapy demonstrated a median PFS of 16.03 months, outperforming chemotherapy (2.87 months; p < 0.0001), chemotherapy combined with anti-angiogenic therapy (6.90 months; p = 0.048), and multi-target inhibitors (2.50 months; p < 0.0001). Furthermore, the one-year and two-year overall survival (OS) rates for Pralsetinib monotherapy were 64.3% and 46.4%, respectively. Regarding safety, 71.0% of patients receiving Pralsetinib experienced at least one adverse event, with 45.2% classified as grade 3–4 in severity. Notably, no fatalities were attributed to adverse events. Common adverse events included hemoglobin reduction (35.5%) and neutropenia (32.3%), indicative of an overall favorable safety profile for Pralsetinib in this patient population.ConclusionThis study encapsulates the research endeavors and treatment advancements of RET rearrangement solid tumors within the Chinese healthcare landscape, specifically highlighting the diverse real-world therapeutic approaches and their effectiveness in managing advanced RET rearrangement NSCLC among Chinese patients. Notably, targeted RET inhibitors like Pralsetinib have emerged as potent therapeutic agents, exhibiting remarkable efficacy and a manageable safety profile in this patient cohort. These findings underscore the potential of Pralsetinib and similar targeted therapies as novel treatment options for individuals with RET fusion-positive NSCLC.

Exploring geriatric assessment-driven rehabilitation referral patterns and its influence on functional outcomes and survival in older adults with advanced cancer.

Older adults with advanced cancer experience functional disability that warrants rehabilitation services; however, evidence indicates inconsistencies in referral. The purpose was to (1) identify predictors of geriatric assessment (GA)-driven referrals to rehabilitation services and (2) explore associations between referral and change in function, health-related quality of life (HRQoL), and overall survival among older adults with advanced cancer. This was a secondary analysis (NCT020107443, UG1CA189961) of a nationwide GA clinical trial. Patients were older adults with advanced cancer who had at least one GA-defined physical performance or functional status impairment. Primary outcomes were oncologist-initiated discussion about or referral to rehabilitation services after the GA (Aim 1) and decline in activities of daily living (ADL), Instrumental ADL (IADL), and HRQoL within 3 months, and overall survival at 1 year (Exploratory Aims). Analyses included multivariable logistic regression and Cox proportional hazards models. Demographic and clinical factors were controlled for by using 1:1 propensity score matching. In total 265 patients were analyzed. After adjustment, impaired cognition (odds ratio [OR] = 2.25, p = 0.01), Karnofsky score indicating disability (OR = 2.86, p < 0.01), and receipt of monoclonal antibodies (OR = 1.95, p = 0.04) were associated with higher odds of referral. In contrast, polypharmacy was associated with lower odds of referral (OR = 0.31, p < 0.01). Referred patients were less likely to decline in ADL (OR 0.30, p = 0.07) and IADL (OR 0.64, p = 0.35), but more likely to decline in HRQoL (OR 1.20, p = 0.67) and have worse survival (HR 1.18, p = 0.62). Cancer treatment, polypharmacy, cognition, and disability status likely influence oncologists' decision to refer for rehabilitation. Referral was not independently associated with change in functional disability, HRQoL, or survival. Future studies should evaluate patients' utilization of rehabilitation services post-referral and determine whether dose/timing of rehabilitation services influence clinical outcomes.

HERC5: a comprehensive in silico analysis of its diagnostic, prognostic, and therapeutic potential in cancer.

HERC5, a vital protein in the HERC family, plays crucial roles in immune response, cancer progression, and antiviral defense. This bioinformatic study comprehensively assessed HERC5's significance across various malignancies by analyzing its gene expression, immune and molecular subtype expressions, target proteins, biological functions, and prognostic and diagnostic values in pan-cancer. We further examined its correlation with clinical features, co-expressed and differentially expressed genes, and prognosis in clinical subgroups, focusing on endometrial cancer (UCEC). Our findings showed that HERC5 RNA is expressed at low levels in most cancers and significantly differs across immune and molecular subtypes. HERC5 accurately predicts cancer and correlates with most cancer prognoses. In UCEC, HERC5 was significantly associated with age, hormonal status, clinical stage, treatment status, and metastasis. Elevated HERC5 expression was linked to worse progression-free interval, disease-specific survival, and overall survival in UCEC, particularly in diverse clinical subgroups. Significant differences in HERC5 expression were also observed in various human cancer cell line validations. In summary, HERC5 may be a critical biomarker for pan-cancer prognosis, progression, and diagnosis, as well as a promising new target for cancer therapy.

Dynamic evolution of fibroblasts revealed by single cell RNA sequencing of human pancreatic cancer.

Cancer progression and response to therapy are inextricably reliant on the co-evolution of a supportive tissue microenvironment. This is particularly evident in pancreatic ductal adenocarcinoma (PDAC), a tumor type characterized by expansive and heterogeneous stroma. Herein, we employed single cell RNAseq and spatial transcriptomics of normal, inflamed, and malignant pancreatic tissues to contextualize stromal dynamics associated with disease and treatment status, identifying temporal and spatial trajectories of fibroblast differentiation. Using analytical tools to infer cellular communication, together with a newly developed assay to annotate genomic alterations in cancer cells, we additionally explored the complex intercellular networks underlying tissue circuitry, highlighting a fibroblast-centric interactome that grows in strength and complexity in the context of malignant transformation. Our study yields new insights on the stromal remodeling events favoring the development of a tumor-supportive microenvironment and provides a powerful resource for the exploration of novel points of therapeutic intervention in PDAC.

Rational corticosteroids administration and antibiotic treatment is key to managing cutaneous anthrax

BackgroundAnthrax is a global health concern, with cutaneous anthrax accounting for over 95% of cases and generally promising outcomes. Nonetheless, the absence of timely intervention can result in mortality rates of 10–40%. This research aims to explore the clinical presentations and phenotypic characteristics of cutaneous anthrax patients and evaluate the efficacy of various therapeutic approaches.MethodsA retrospective study was performed on 76 cutaneous anthrax patients identified at three hospitals from 2017 to 2022. Patients were categorized based on their hospital stay into two groups: those hospitalized for at least seven days and those for shorter durations. We assessed their clinical and phenotypic profiles, including symptoms, general health status, and laboratory findings, alongside treatment outcomes, focusing on corticosteroids therapy and antibiotic regimens.ResultsThe study encompassed 76 diagnosed individuals, predominantly young adult males (78.9%). A significant gender disparity was noted. Hormonal treatment markedly improved edema regression in patients (P < 0.002), highlighting its therapeutic value. The impact of various antibiotic treatments on disease progression differed significantly based on corticosteroids treatment status, with specific combinations showing more effectiveness in non-corticosteroids-treated patients.ConclusionsThe predominance of young male adults among cutaneous anthrax cases was observed, with corticosteroids treatment significantly reducing edema duration. In cases where corticosteroids therapy is not utilized, employing piperacillin-tazobactam alone or in combination with quinolones effectively shortens the illness duration, suggesting a tailored approach to treatment can enhance patient outcomes.

Aortic valve replacement and mortality with left ventricular hypertrophy in setting of normal LVEF

Abstract Background Without symptoms, indications for aortic valve replacement (AVR) in severe aortic stenosis (AS) differ for individuals with normal vs. low/decreasing left ventricular ejection fraction (LVEF). Conceptually, the development of left ventricular hypertrophy (LVH) could also indicate ventricular injury and potential benefit with earlier AVR. However, little is known about the comparative effectiveness of AVR in individuals with LVH. As such, unlike low or dropping LVEF, development of LVH is not in itself an indication for AVR in clinical guidelines. Methods Initially, 1,232,492 echocardiography reports from 12 hospitals were identified from 1 January 2000 to 22 November 2022, and previously validated natural language processing modules were then applied to identify aortic gradients, LVEF, and presence of LVH. These reports were linked to mortality data, key comorbidities with a 2-year lookback covariate window, and date of any AVR. We then isolated echocardiograms demonstrating normal flow severe AS, LVEF ≥ 55% and LVH. Chart reviews were conducted to reduce missing data and outcomes were censored on the date of the chart review (October 4, 2023). To assess the association between AVR and mortality, Cox proportional hazards models considering treatment status (ie, AVR or not) were used with the index echocardiogram as time zero. Covariates used in risk-adjustment were chosen a priori based on conditions and laboratory values used in cardiac surgery mortality risk-adjustment, since those variables could plausibly confound the treatment decision. To address immortal time bias, AVR was considered a time-varying covariate. Multiple additional approaches with propensity scores were performed as sensitivity analyses. Results After application of inclusion and exclusion criteria, 4856 unique patients remained for analysis. Of those, 2043 (42.1%) received AVR with 841/2043 (41.2%) receiving surgical AVR and 1202/2043 (58.8%) receiving transcatheter AVR. Patients who received AVR had lower unadjusted mortality than those who did not receive AVR (33.6% vs. 47.1%, p &amp;lt; 0.001). After adjustment, and accounting for time-dependence of AVR, AVR was associated with reduced mortality (HR 0.81, 95% CI 0.73-0.89, p &amp;lt; 0.0001). The sensitivity analyses were all consistent with the primary analysis. Conclusions AVR was associated with reduced mortality for patients with severe AS, preserved LVEF, and LVH. This association persisted even after accounting for time-dependence, which tends to reduce the observed effectiveness of procedures in observational data. With over a million echocardiograms over more than 20 years, this is the largest known analysis of AVR outcomes in individuals with severe AS and LVH. Our findings suggest LVH may be a high-risk phenotype of individuals with AS, similar to dropping LVEF. As such, these results raise the potential of more proactive AVR clinical guidelines in individuals with LVH, even when LVEF is normal.Survival in AVR Vs No AVR

Defibrillation deactivation state and activation status in patients with implantable cardioverter-defibrillators at the end of life

Abstract Background Implantable cardioverter-defibrillators (ICDs) are effective in preventing sudden cardiac death due to lethal arrhythmias. Defibrillation is also known to cause physical and emotional distress to patients, and guidelines on palliative care for cardiovascular disease recommend that when patients with ICDs reach the end of life, the benefits and burdens of ICDs should be fully explained to patients and a policy regarding the cessation of defibrillation discussed. However, there are few reports on the treatment status and defibrillation deactivation in patients with ICDs in the terminal phase. Aim To investigate defibrillation activation and defibrillation deactivation in terminally ill patients with ICDs. Results Death was confirmed in 146 patients in the medical record, and a DNAR policy was decided in 46 patients. The decision to deactivate defibrillation was informed to 24 patients (16%), and 15 patients (10%) were deactivated (11 patients in terminal heart failure and 4 patients in others). Four of the nine patients (6%) who did not deactivate defibrillation had a shock before death.Of the 22 patients (14 cardiovascular deaths and 8 others) who were not explained about the deactivation of defibrillation, 4 had shock activation before death.Of the 24 patients who received explanation about defibrillation deactivation, 6 (25%) had the policy decided by the patient and family, and 18 (75%) had the policy decided by the family because the patient's will could not be confirmed due to deterioration of end-stage condition. Discussion This study showed that defibrillation was deactivated in only 10% of Japanese patients with end-stage ICDs.ICD patients do not always reach the end of life due to heart failure. It is important for physicians, clinical engineers, and device nurses involved in device care to provide information and to confirm the wishes of patients and their families regarding the deactivation of defibrillation so that they can be supported in their decision-making regarding defibrillation no matter under what circumstances they reach the end of life. Conclusion Discussion of ICD deactivation in palliative care is needed to reduce the risk of painful shock and distress at the end of life.

Endoscopic surgery for squamous cell carcinoma in the nasal cavity and ethmoid sinus: A retrospective observational study

ObjectiveReports of endoscopic surgery for squamous cell carcinoma of the nasal cavity and ethmoid sinus are limited. Herein, we present a comprehensive account of the results obtained from performing endoscopic surgery based on the concept of en bloc resection. MethodsThis was a retrospective observational study of patients who underwent nasal endoscopic surgery for squamous cell carcinoma of the nasal cavity and ethmoid sinus at a hospital between July 2018 and December 2021. Primary endpoints were overall survival, relapse-free survival, and local recurrence-free survival. Data on tumor stage, tumor site of origin, postoperative treatment, and papilloma-related status were reviewed. Statistical analyses included the Kaplan–Meier method, Cox regression analysis, and Fisher's exact test. ResultsTwenty-two patients with a median age of 62 (range 27–84) years, comprising 15 male and 7 female, were included in this study, and the median duration of observation was 2.1 (range 0.6–4.3) years. The 2-year overall survival, relapse-free survival, and recurrence-free survival rates were 91.0%, 69.9%, and 79.0%, respectively. Cancer of the nasal cavity was significantly superior to that of the ethmoid sinus in terms of local recurrence-free survival (p = 0.03). The patients who underwent postoperative treatment had significantly worse recurrence-free survival rates than those who did not receive postoperative treatment (p = 0.03). ConclusionsThis study examined the results of the endoscopic treatment for squamous cell carcinoma of the nasal cavity and ethmoid sinus with the concept of en bloc resection. Patients with ethmoid sinus carcinoma had a greater risk for local recurrence, and the prognosis for patients requiring postoperative treatment was poor.

Factors influencing the discontinuation of biologic therapies in patients with ulcerative colitis

BackgroundThe therapeutic landscape for ulcerative colitis (UC) has recently broadened to include anti-TNFα, anti-integrin, and anti-IL-12/23p40 antibody agents. These biological agents are tailored to individual patient profiles. However, some patients cease biological treatment. This study investigates factors influencing the discontinuation of biological treatment in UC patients.MethodsThis retrospective single-cohort study encompasses UC patients who commenced treatment with biological agents like infliximab, adalimumab, golimumab, vedolizumab, and ustekinumab from April 2019 to March 2022. Patients were categorized into continuation and discontinuation groups based on their one-year treatment status. Baseline characteristics were compared between the groups.ResultsOf the 116 UC patients, 102 were included in the study. Among these, 74 (72.5%) continued and 28 (27.5%) discontinued biological therapy. Discontinuation rates for infliximab, adalimumab, golimumab, vedolizumab, and ustekinumab were 33.3%, 25.0%, 50.0%, 30.2%, and 15.6%, respectively. The primary discontinuation reason was lack of efficacy (85.7%), followed by adverse events (7.1%), pregnancy (3.6%), and death (3.6%). The discontinuation group had a significantly lower rate of concomitant thiopurine compared to the continuation group (28.6% vs. 56.8%, p = 0.0132). Multivariable analysis revealed that concomitant thiopurine was independently associated with therapy continuation (p = 0.0075).ConclusionThe study indicates that concomitant thiopurine significantly correlates with the continuation of biological therapies in UC patients, underscoring the importance of concomitant thiopurine in sustaining biological therapy. Further studies are warranted to assess the efficacy of combination therapy.

Inference in Experiments with Matched Pairs and Imperfect Compliance

This paper studies inference for the local average treatment effect in randomized controlled trials with imperfect compliance where treatment status is determined according to “matched pairs.” By “matched pairs,” we mean that units are sampled i.i.d. from the population of interest, paired according to observed, baseline covariates and finally, within each pair, one unit is selected at random for treatment. Under weak assumptions governing the quality of the pairings, we first derive the limit distribution of the usual Wald (i.e., two-stage least squares) estimator of the local average treatment effect. We show further that conventional heteroskedasticity-robust estimators of the Wald estimator’s limiting variance are generally conservative, in that their probability limits are (typically strictly) larger than the limiting variance. We therefore provide an alternative estimator of the limiting variance that is consistent. Finally, we consider the use of additional observed, baseline covariates not used in pairing units to increase the precision with which we can estimate the local average treatment effect. To this end, we derive the limiting behavior of a two-stage least squares estimator of the local average treatment effect which includes both the additional covariates in addition to pair fixed effects, and show that its limiting variance is always less than or equal to that of the Wald estimator. To complete our analysis, we provide a consistent estimator of this limiting variance. A simulation study confirms the practical relevance of our theoretical results. Finally, we apply our results to revisit a prominent experiment studying the effect of macroinsurance on microenterprise in Egypt.

Benefit of dual bronchodilator therapy on exacerbations in former and current smokers with chronic obstructive pulmonary disease in real-world clinical practice: a multicenter validation study (TOReTO)

BackgroundDual bronchodilator therapy, consisting of a long-acting beta-agonist (LABA) and a long-acting muscarinic antagonist (LAMA), has proven effective for patients with chronic obstructive pulmonary disease (COPD). However, it remains uncertain whether there are efficacy differences between current and former smokers with COPD. This study aims to explore the effectiveness of LABA/LAMA therapies in both these groups.MethodsThe TOReTO trial assessed lung function, symptoms, health status, the occurrence of exacerbations, clinically significant exacerbations, and the use of LABA/LAMA therapies. These therapies include Tio/Olo, umeclidinium/vilanterol (Umec/Vi), and umeclidinium/vilanterol (Umec/Vi) are used in patients with COPD. The study examined the differences in outcomes between current and former smokers. To balance the baseline characteristics, propensity score matching (PSM) was employed.ResultsData from 967 patients were collected. After PSM, the time to the first acute exacerbation in current smokers was analyzed separately for the three treatment groups and was significantly different between them (p = 0.0457). Among, there are differences in the occurrence of acute exacerbation between treatment and smoking status in Umec/Vi (p = 0.0114). There is no significant difference in the treatment of former smokers among the three different groups of LABA/LAMA fixed-dose combinations (p = 0.3079). COPD-related symptoms remained stable throughout the treatment period. There were no significant differences in symptom scores, including CAT and mMRC, among the three groups at the end of the study.ConclusionsThe three fixed-dose combinations of LABA/LAMA showed no difference in reducing exacerbations in former smokers but did show differences in current smokers. This trend has clinical significance, and future research will be conducted to control influencing variables to validate this point. However, due to the non-randomized study design, these findings should be interpreted with caution.

Oral functions in adult persons with spinal muscular atrophy compared to a healthy control group: a prospective cross-sectional study with a multimodal approach

BackgroundOral function tests have been shown to reliably detect impaired bulbar function in adults with spinal muscular atrophy (SMA). Although not routinely recorded, it is known that persons with SMA are affected to varying degrees. Detecting differences in bite and tongue force, endurance, and maximum mouth opening has become particularly promising since the introduction of causal therapy for SMA. This study aimed to compare oral function among adult persons with SMA with different SMA types, walking abilities, and treatment status to a healthy control group.MethodsData from oral function tests conducted on 58 persons with SMA and 45 healthy individuals were analyzed. Differences in oral function between SMA subgroups were pairwise tested and compared to the healthy control group using Wilcoxon rank sum tests.ResultsIn an overall comparison, three out of five oral function tests revealed lower values for the SMA group compared to the control group. Subgroup analyses indicated lower scores for most oral function tests in non-ambulatory, untreated patients with SMA type 2 compared to controls. Ambulatory, treated patients with SMA type 3 achieved strength and endurance values comparable to those of healthy individuals.ConclusionsThe impairment of oral function varies across persons with SMA. Routine measurement of oral function is warranted to determine individual bulbar involvement stages. Further evaluation should be scheduled if indicators such as restricted maximum mouth opening arise.Trial registration DRKS, DRKS00015842. Registered 30 July 2019, https://drks.de/register/de/trial/DRKS00015842/preview.