Stratified Cox Proportional Hazards Model Research Articles

Within-city spatial variations in PM2.5 magnetite nanoparticles and brain cancer incidence in Toronto and Montreal, Canada.

Magnetite nanoparticles are small, strongly magnetic iron oxide particles which are produced during high-temperature combustion and friction processes and form part of the outdoor air pollution mixture. These particles can translocate to the brain and have been found in human brain tissue. In this study, we estimated associations between within-city spatial variations in concentrations of magnetite nanoparticles in outdoor fine particulate matter (PM2.5) and brain cancer incidence. We performed a cohort study of 1.29 million participants in four cycles of the Canadian Census Health and Environment Cohort in Montreal and Toronto, Canada who were followed for malignant brain tumour (glioma) incidence. As a proxy for magnetite nanoparticle content, we measured the susceptibility of anhysteretic remanent magnetization (χARM) in PM2.5 samples (N = 124 in Montreal, N = 110 in Toronto), and values were assigned to residential locations. Stratified Cox proportional hazards models were used to estimate hazard ratios (per IQR change in volume-normalized χARM). ARM was not associated with brain tumour incidence (HR = 0.998, 95% CI 0.988, 1.009) after adjusting for relevant potential confounders. Although we found no evidence of an important relationship between within-city spatial variations in airborne magnetite nanoparticles and brain tumour incidence, further research is needed to evaluate this understudied exposure, and other measures of exposure to magnetite nanoparticles should be considered.

One-year freedom from arrhythmia following radiofrequency ablation using proactive oesophageal cooling

Abstract Background Proactive esophageal cooling is increasingly being utilized, and is now FDA cleared, to reduce the likelihood of ablation-related esophageal injury resulting from radiofrequency (RF) cardiac ablation of atrial fibrillation (AF). One-year follow-up from the largest randomized controlled study, the IMPACT trial, showed a trend towards improvement in long-term efficacy versus luminal esophageal temperature (LET) monitoring. With larger data sets now available for analysis, we sought to determine 1-year freedom from atrial arrhythmia associated with the use of proactive esophageal cooling. Methods Data from 2 trials comparing freedom from atrial arrhythmia after RF ablation using proactive esophageal cooling to LET monitoring were combined. Data were analyzed using a stratified Cox proportional hazards model to compare arrhythmia recurrence rates, with R statistical analysis software. Results Data from 631 patients across two studies comparing arrhythmia outcomes for proactive oesophageal cooling versus LET monitoring were analysed. Mean patient age was 66.4±9.8 years, and 37.4% were female. Arrhythmias were 56.3% paroxysmal AF and 43.7% persistent or long-standing persistent AF. Freedom from atrial arrhythmia at one year was 77.2% for patients receiving proactive oesophageal cooling and 64.4% for patients receiving LET monitoring (Figure 1), with a hazard ratio for cooling of 0.65 (95% CI 0.43 to 0.99, P = 0.044). Conclusions Proactive oesophageal cooling was associated with significantly greater freedom from atrial arrhythmia at one year when compared to LET monitoring during RF ablation.

Abstract PO2-19-09: INAVO122: a Phase III study of maintenance inavolisib or placebo + pertuzumab + trastuzumab following induction with pertuzumab + trastuzumab + a taxane in patients with PIK3CA-mutated, HER2-positive advanced breast cancer

Abstract Background The PI3K pathway plays a crucial role in HER2 signaling. Somatic mutations of PIK3CA, the gene that encodes the PI3K p110α subunit, may induce resistance to HER2-targeted therapies and are associated with poorer clinical outcomes (Swain SM, et al. SABCS 2022; P2-11-07). Inavolisib, a potent p110α-selective inhibitor that induces degradation of mutant p110α, has shown antitumor activity in PIK3CA-mutated HER2-positive breast cancer (HER2+ BC) and long-term tolerability with early intervention for common on-class toxicities, including hyperglycemia, diarrhea, and stomatitis (Bedard P, et al. ASCO 2022; 1052). The current study will assess the efficacy and safety of maintenance inavolisib + fixed-dose combination of pertuzumab + trastuzumab for subcutaneous injection (PH FDC SC) after first-line induction treatment in patients with PIK3CA-mutated, HER2+, advanced BC (aBC). Trial design INAVO122 is a multicenter, randomized, international, double-blind, placebo-controlled study. Patients will be enrolled for: first-line induction treatment if they are receiving/will receive PH + a taxane; or maintenance treatment completing induction treatment. In the maintenance phase, patients will be randomized 1:1 to receive inavolisib (9 mg orally once daily; Days 1–21 of 21-day cycles) + PH FDC SC (every 3 weeks), or placebo + PH FDC SC. Study treatment will continue until disease progression, unacceptable toxicity, death, consent withdrawal, or at the investigator’s discretion. ELIGIBILITY Enrolled patients must have centrally determined HER2+, PIK3CA-mutated tumors, with documented hormone receptor status per local assessment, and be disease-free for ≥ 6 months from completion of neoadjuvant/adjuvant systemic non-hormonal treatment. They must not have received any treatment for aBC prior to induction, and, at screening, fasting glucose must be < 126 mg/dL and HbA1c < 6.4%. To be randomized, patients must have completed induction therapy per standard of care without progression of disease and show left ventricular ejection fraction ≥ 50%. AIMS The primary endpoint is investigator-assessed progression-free survival. Secondary endpoints are overall survival; investigator-assessed objective response rate, duration of response, clinical benefit rate, and time to second disease progression; health-related quality of life; safety; and pharmacokinetics. STATISTICAL METHODS The primary endpoint analysis will utilize a two-sided stratified log-rank test at a two-sided significance level of 5%. A stratified Cox proportional hazards model will be used to estimate the hazard ratio between the two treatment arms and its 95% confidence intervals. ACCRUAL Target randomization is ~230 patients; recruitment began in July 2023. CONTACT INFORMATION For more information or to refer a patient, email global.rochegenentechtrials@roche.com or call 1-888-662-6728 (USA only). Clinicaltrials.gov number NCT05894239. Citation Format: Sandra Swain, Carlos Barrios, Reva Basho, Giuseppe Curigliano, Nadia Harbeck, Chiun-Shen Huang, Sherene Loi, Nicholas Turner, Jessica Chen, Volkmar Henschel, Simon Warburton, Fabiola Amair-Pinedo, Javier Cortés. INAVO122: a Phase III study of maintenance inavolisib or placebo + pertuzumab + trastuzumab following induction with pertuzumab + trastuzumab + a taxane in patients with PIK3CA-mutated, HER2-positive advanced breast cancer [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 PO2-19-09.

Abstract GS01-12: MONARCH 3: Final overall survival results of abemaciclib plus a nonsteroidal aromatase inhibitor as first-line therapy for HR+, HER2- advanced breast cancer

Abstract Background: Abemaciclib is approved both for high-risk early breast cancer as well as advanced breast cancer (ABC) in the first- and second-line setting. In MONARCH 2, the addition of abemaciclib to fulvestrant significantly improved both progression-free survival (PFS) and overall survival (OS) in patients with HR+, HER2- ABC with disease progression on prior endocrine therapy (ET). In MONARCH 3, the addition of abemaciclib to a nonsteroidal aromatase inhibitor (NSAI) significantly improved PFS (HR, 0.540; 95% CI, 0.418-0.698; p=0.000002) as initial therapy in HR+, HER2- ABC. At the last interim OS analysis (~252 events, at 5.8 years follow-up [FU]), a numerically favorable median OS difference (12.6 months) was observed (HR, 0.754; 95% CI, 0.584-0.974; p=0.0301, non-significant [NS]). Here, we present the final OS analysis of MONARCH 3 (NCT02246621). Methods: MONARCH 3 is a randomized, double-blind, Phase 3 study of abemaciclib + NSAI (anastrozole or letrozole) vs placebo + NSAI in postmenopausal women with HR+, HER2- ABC without prior systemic therapy in the advanced setting. OS was a gated secondary endpoint and chemotherapy-free survival (CFS) an exploratory endpoint. Final OS analysis was planned after approximately 315 OS events had occurred in the intent-to-treat (ITT) population with a split alpha between the ITT population and the subgroup with visceral disease (sVD) according to a prespecified graphical testing scheme. Kaplan-Meier method and stratified Cox proportional hazards models were used for time-to-event analyses. All reported p-values are two-sided. Results A total of 493 women were randomized 2:1 to receive abemaciclib + NSAI (n=328) or placebo + NSAI (n=165). After a median FU of 8.1 years, 7% of patients were still receiving treatment in the abemaciclib arm vs 3% in the placebo arm. In the ITT population, 314 OS events were observed (198 deaths among 328 patients [60%] in the abemaciclib arm and 116 among 165 [70%] in the placebo arm; HR, 0.804; 95% CI, 0.637-1.015; p=0.0664, NS). Median OS was 66.8 months in the abemaciclib arm and 53.7 months in the placebo arm, a numerical difference of 13.1 months in the ITT population. In the sVD, 178 events were observed (113 deaths among 173 patients [65%] in the abemaciclib arm and 65 among 90 [72%] in the placebo arm; HR, 0.758; 95% CI, 0.558-1.030; p=0.0757, NS). Median OS was 63.7 months in the abemaciclib arm and 48.8 months in the placebo arm, a numerical difference of 14.9 months in the sVD. Consistent OS differences were observed across prespecified subgroups. PFS benefit was sustained (median 29.0 vs 14.8 months; HR, 0.535; 95% CI, 0.429-0.668; nominal p<0.0001) with substantial difference in 6-year PFS rates (23.3% vs 4.3% for abemaciclib vs placebo). CFS was also improved with abemaciclib vs placebo (median 46.7 vs 30.6 months; HR, 0.693; 95% CI, 0.557-0.863; nominal p=0.0010). No new safety signals were observed with longer term use. Conclusion In patients with HR+, HER2- ABC, abemaciclib in combination with a NSAI resulted in numerically longer OS compared to NSAI alone; however, statistical significance was not reached after a median FU of 8.1 years. The clinically meaningful improvement in median OS (>13 months) combined with the sustained significant improvement in median PFS (>14 months) and substantial extension in median CFS (>16 months) continue to support the use of abemaciclib in combination with NSAI as first-line therapy in ABC. Citation Format: Matthew Goetz, Masakazu Toi, Jens Huober, Joo Hyuk Sohn, Olivier Trédan, Inhae Park, Mario Campone, Shin-Cheh Chen, Luis Manual Manso, Shani Paluch-Shimon, Orit C. Freedman, Valerie Andre, Abhijoy Saha, Gertjan van Hal, Ashwin Shahir, Hiroji Iwata, Stephen RD Johnston, Joyce O'Shaughnessy, Xavier Pivot, Sara Tolaney, Sara Hurvitz, Antonio Llombart. MONARCH 3: Final overall survival results of abemaciclib plus a nonsteroidal aromatase inhibitor as first-line therapy for HR+, HER2- advanced breast cancer [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 GS01-12.

Abstract PO1-18-12: Trial in progress: Open-label, randomized, multicenter, phase 3, ELAINE 3 study of the efficacy and safety of lasofoxifene plus abemaciclib for treating locally advanced or ER+/HER2- metastatic breast cancer with an ESR1 mutation

Abstract Background: Patients with estrogen receptor-positive (ER+) metastatic breast cancer (BC) may develop resistance to endocrine therapy (ET), particularly following treatment with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i), potentially driven by a mutation in the ERa-coding gene, ESR1. Lasofoxifene, an oral, next-generation ET and ER breast antagonist, had potent activity in mBC xenograft models expressing ESR1 mutations, either as a single agent or combined with a CDK4/6i. Subsequently, two phase 2 studies evaluated lasofoxifene in women with ER+/HER2- metastatic BC and an ESR1 mutation who had disease progression on previous ET and CDK4/6i. The ELAINE 1 trial showed numerically greater progression-free survival (PFS, median ~6 vs 4 months; P=0.138), objective response rate (ORR, 13% vs 3%; P=0.124), and clinical benefit rate (CBR, 37% vs 22%; P=0.117) with lasofoxifene monotherapy versus the ER degrader fulvestrant, with a favorable safety profile (Goetz MP, et al. Ann Oncol. 2022;33:S1387). The single-arm, ELAINE 2 trial demonstrated that lasofoxifene combined with abemaciclib was well tolerated with a median PFS of ~13 months, ORR of 56%, and CBR of 66% (Damodaran S, et al. J Clin Oncol. 2023;41:suppl 16; abstr 1057). Based on these data, the phase 3, registrational, ELAINE 3 trial was initiated. Methods: ELAINE 3 (NCT05696626) is an open-label, phase 3, multicenter study evaluating the efficacy, safety, and tolerability of lasofoxifene plus abemaciclib versus fulvestrant plus abemaciclib. Key inclusion criteria are pre- and postmenopausal women and men aged ≥18 years; ER+/HER2-, locally advanced and/or metastatic BC (measurable and/or non-measurable disease); ≥1 acquired ESR1 mutation; progression on an aromatase inhibitor plus palbociclib or ribociclib as their first hormonal treatment for advanced/metastatic BC; and ≤1 line of chemotherapy in the advanced/metastatic setting. Patients will be randomized 1:1 to receive lasofoxifene 5 mg/day plus abemaciclib 150 mg BID, or fulvestrant 500 mg IM on days 1, 15, and 29, then 4 weekly plus abemaciclib 150 mg BID. Treatment will continue until progression, death, unacceptable toxicity, or withdrawal from the study. The primary endpoint is PFS; key secondary endpoints are ORR, overall survival, CBR, duration of response, and time to response. Time to cytotoxic chemotherapy, quality of life, and safety will also be evaluated. Blood samples for circulating tumor DNA (ctDNA) will be collected at screening, at weeks 4 and 8 and every 8 weeks thereafter, and at the final visit for genomic analyses. Outcomes with lasofoxifene/abemaciclib and fulvestrant/abemaciclib will be compared using a stratified Cox proportional hazards model and stratified logrank test. Expected PFS is ≥10.3 months for lasofoxifene/abemaciclib and 7 months for fulvestrant/abemaciclib (PFS hazard ratio of 0.68 at final analysis). The target sample size is 400, to achieve 90% power with a one-sided type I error rate of 0.025 after 285 PFS events. Full recruitment is expected to occur over 18 months at 125 global sites. Citation Format: Matthew Goetz, Seth Wander, Thomas Bachelot, Gerald Batist, Javier Cortés, Massimo Cristofanilli, Giuseppe Curigliano, Alexandre de Nonneville, Einav Nili-Gal Yam, Komal Jhaveri, Cynthia Ma, Heather Parsons, Hope Rugo, Sarah Sammons, Daniel Stover, Chris Twelves, Aditya Bardia, Paul V. Plourde, David J Portman, Senthil Damodaran. Trial in progress: Open-label, randomized, multicenter, phase 3, ELAINE 3 study of the efficacy and safety of lasofoxifene plus abemaciclib for treating locally advanced or ER+/HER2- metastatic breast cancer with an ESR1 mutation [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 PO1-18-12.

Intentional self-harm and death by suicide in body dysmorphic disorder:A nationwide cohort study

Body dysmorphic disorder (BDD) is thought to be associated with considerable suicide risk. This nationwide cohort study quantified the risks of intentional self-harm - including non-suicidal self-injuries and suicide attempts - and death by suicide in BDD. Individuals with a validated ICD-10 diagnosis of BDD in the Swedish National Patient Register, registered between January 1, 1997 and December 31, 2020, were matched with 10 unexposed individuals from the general population on birth year, sex, and county of residence. Conditional Poisson regression models estimated incidence rate ratios (IRR) and 95% confidence intervals (CIs) for intentional self-harm and stratified Cox proportional hazards models estimated hazard ratios (HRs) and 95% CIs for death by suicide. Models adjusted for sociodemographic variables and lifetime psychiatric comorbidities. Among 2,833 individuals with BDD and 28,330 unexposed matched individuals, 466 (16.45%) and 1,071 (3.78%) had at least one record of intentional self-harm during the study period, respectively (IRR=3.37; 95% CI, 3.02-3.76). In the BDD cohort, about two thirds (n=314; 67%) had their first recorded self-harm event before their first BDD diagnosis. A total of 17 (0.60%) individuals with BDD and 27 (0.10%) unexposed individuals died by suicide (HR=3.47; 95% CI, 1.76-6.85). All results remained robust to additional adjustment for lifetime psychiatric comorbidities. A higher proportion of individuals with BDD who died by suicide had at least one previous record of intentional self-harm, compared to unexposed individuals (52.94% vs. 22.22%; p=0.0363). BDD was associated with a three-fold increased risk of intentional self-harm and death by suicide.

Time to benefit of colchicine in patients with cardiovascular disease: A pooled analysis of randomized controlled trials

BackgroundLow-dose colchicine has been shown to lower major adverse cardiovascular events (MACE) among those with cardiovascular disease (CVD). It remains unclear how long a CVD patient needs to live to potentially benefit from colchicine. Our study aimed to determine the time to benefit (TTB) of colchicine in individuals with CVD. MethodsLiterature searches were performed in PubMed for the cardiovascular outcome trial of colchicine in patients with CVD until October 12, 2023. The primary outcome measured was MACE. Reconstructed individual participant data (IPD) and the stratified Cox proportional hazards model were used to calculate the hazard ratio (HR) and 95 % confidence interval (CI) to estimate the efficacy of colchicine, and Weibull survival curves were fitted to estimate TTB for specific absolute risk reduction (ARR) thresholds (0.002, 0.005, and 0.01). ResultsFour trials randomizing 11,594 adults aged between 59.8 and 66.5 years were included (follow-up duration: 12–28.6 months). Compared with placebo, colchicine reduced the risk of MACE (HR 0.68, 95 % CI: 0.60 to 0.78) but had no impact on cardiovascular and all-cause mortality. A TTB of 11.0 months (95 % CI: 0.59 to 21.3) was estimated to be needed to prevent 1 MACE in 100-colchicine-treated patients. The TTB for acute coronary syndrome was similar compared to stable coronary artery disease (10.7 vs. 11.2 months for ARR = 0.010). ConclusionsBy using reconstructed IPD, this pooled analysis demonstrated that colchicine was associated with reduced nonfatal MACE, and the TTB was approximately 11.0 months to prevent 1 MACE per 100 patients.

Effect modification of diet and vitamins on the association between air pollution particles of different diameters and hypertension: A 12-year longitudinal cohort study in densely populated areas of China

IntroductionParticulate matter (PM) is identified as one of the exacerbating and triggering factors for hypertension. Diet intake and the consumption of vitamins may potentially moderate the impact of PM on hypertension. MethodsA 12-year longitudinal cohort study was conducted on a population in densely populated areas of China. Residual balancing with weighted methods was employed to control for time-varying and no time-varying confounding factors. Stratified Cox proportional hazards models were conducted to examine the moderating effects of diet and vitamins on the risk of hypertension with PM. ResultsThere was a significant positive association between long-term exposure to different diameter PM and the risk of developing hypertension. The hazard ratios (HRs) for hypertension were 1.0200 (95 % CIs: 1.0147, 1.0253) for PM1, 1.0120 (95 % CIs: 1.0085, 1.0155) for PM2.5, and 1.0074 (95 % CIs, 1.0056, 1.0092) for PM10. The diet and vitamins moderated these associations, the intake of healthy foods and vitamins exhibited a significant positive moderating effect on the relationship between PM exposure and hypertension risk. Among all participants, the high intake of fruit (PM1 (HRs: 1.0102, 95 % CIs: 1.0024, 1.0179), PM2.5 (HRs: 1.0060, 95 % CIs: 1.0011, 1.0109), and PM10 (HRs: 1.0044, 95 % CIs: 1.0018, 1.0070)) and vitamin E (PM1 (HRs: 1.0143, 95 % CIs: 1.0063, 1.0223), PM2.5 (HRs:1.0179, 95 % CIs: 1.0003, 1.0166), and PM10 (HRs: 1.0042, 95 % CIs: 1.0008, 1.0075)) with lower risk of hypertension than the overall level and low intake of related foods and vitamins, exhibited a strong positive moderating effect on the relationship between PM and hypertension. Similar trends were observed for the intake of fish, root food, whole grains, eggs, fungus food, vitamin B2, B3. However, Na, meat, sugary and alcoholic exhibited opposite trends. The moderating effect of vitamin E intake was stronger than vitamin B and C. ConclusionsDiet and vitamins intake may moderate the association between PM exposure and the risk of hypertension in adults.

Respiratory morbidity among offspring misclassified as growth restricted.

An ultrasound-based diagnosis implies that some fetuses suspected to be growth-restricted (FGR) are discovered at birth to be appropriately grown (appropriate for gestational age [AGA] birth weight, between the 10th and 90th percentile). These fetuses may thus be exposed to unnecessary medical interventions, including early labor induction. In this study, we have evaluated the long-term respiratory health of offspring misclassified as FGR. A population-based cohort analysis was conducted, including deliveries of AGA singletons between 1991 and 2021 at a tertiary referral hospital. Incidence of morbidity due to various respiratory conditions was compared between AGA offspring with prenatal diagnosis of FGR, and those without a false diagnosis of FGR. The Kaplan-Meier approach was used to estimate cumulative morbidity incidence. The stratified Cox proportional-hazards model was used to control for confounders. A total of 324,620 deliveries of AGA newborns were included in the analyses; 3249 of them (1.0%) were misclassified prenatally as FGR. The FGR subgroup delivered at an earlier gestational age (36.7 vs. 39.1 weeks, p < .001) and had more than 25% higher incidence of respiratory-related morbidity during childhood (33.2% vs. 26.5%), specifically related to asthma and obstructive sleep apnea (p < .001 for all). A higher cumulative morbidity rate due to respiratory conditions was observed in the Kaplan-Meier survival curve (log-rank p value < .001). This association between FGR and respiratory morbidity was independent of preterm delivery, maternal age, cesarean delivery, and child's birth year (adjusted hazard ratio = 1.14, 95% confidence interval: 1.07-1.21, p < .001), using a Cox proportional hazards model. AGA newborns misclassified as FGR, are at an increased risk for long-term respiratory morbidity during childhood and adolescence.

Development of preoperative and postoperative models to predict recurrence in postoperative glioma patients: a longitudinal cohort study

BackgroundGlioma recurrence, subsequent to maximal safe resection, remains a pivotal challenge. This study aimed to identify key clinical predictors influencing recurrence and develop predictive models to enhance neurological diagnostics and therapeutic strategies.MethodsThis longitudinal cohort study with a substantial sample size (n = 2825) included patients with non-recurrent glioma who were pathologically diagnosed and had undergone initial surgical resection between 2010 and 2018. Logistic regression models and stratified Cox proportional hazards models were established with the top 15 clinical variables significantly influencing outcomes screened by the least absolute shrinkage and selection operator (LASSO) method. Preoperative and postoperative models predicting short-term (within 6 months) postoperative recurrence in glioma patients were developed to explore the risk factors associated with short- and long-term recurrence in glioma patients.ResultsPreoperative and postoperative logistic models predicting short-term recurrence had accuracies of 0.78 and 0.87, respectively. A range of biological and early symptomatic characteristics linked to short- and long-term recurrence have been pinpointed. Age, headache, muscle weakness, tumor location and Karnofsky score represented significant odd ratios (t > 2.65, p < 0.01) in the preoperative model, while age, WHO grade 4 and chemotherapy or radiotherapy treatments (t > 4.12, p < 0.0001) were most significant in the postoperative period. Postoperative predictive models specifically targeting the glioblastoma and IDH wildtype subgroups were also performed, with an AUC of 0.76 and 0.80, respectively. The 50 combinations of distinct risk factors accommodate diverse recurrence risks among glioma patients, and the nomograms visualizes the results for clinical practice. A stratified Cox model identified many prognostic factors for long-term recurrence, thereby facilitating the enhanced formulation of perioperative care plans for patients, and glioblastoma patients displayed a median progression-free survival (PFS) of only 11 months.ConclusionThe constructed preoperative and postoperative models reliably predicted short-term postoperative glioma recurrence in a substantial patient cohort. The combinations risk factors and nomograms enhance the operability of personalized therapeutic strategies and care regimens. Particular emphasis should be placed on patients with recurrence within six months post-surgery, and the corresponding treatment strategies require comprehensive clinical investigation.

Adverse Events Associated With Disease-Modifying Drugs for Multiple Sclerosis: A Multiregional Population-Based Study

It is not possible to fully establish the safety of a disease-modifying drug (DMD) for multiple sclerosis (MS) from randomized controlled trials as only very common adverse events occurring over the short-term can be captured, and the quality of reporting has been variable. We examined the relationship between the DMDs for MS and potential adverse events in a multiregion population-based study. We identified people with MS using linked administrative health data from 4 Canadian provinces. MS cases were followed from the most recent of first MS or related demyelinating disease event on January 1, 1996, until the earliest of emigration, death, or December 31, 2017. DMD exposure primarily comprised β-interferon, glatiramer acetate, natalizumab, fingolimod, dimethyl fumarate, teriflunomide, and alemtuzumab. We examined associations between DMD exposure and infection-related hospitalizations and physician visits using recurrent events proportional means models and between DMD exposure and 15 broad categories of incident adverse events using stratified multivariate Cox proportional hazard models. We identified 35,894 people with MS. While virtually all DMDs were associated with a 42%-61% lower risk of infection-related hospitalizations, there was a modest increase in infection-related physician visits by 10%-33% for select DMDs. For incident adverse events, most elevated risks involved a second-generation DMD, with alemtuzumab's hazard of thyroid disorders being 19.42 (95% CI 9.29-36.51), hypertension 4.96 (95% CI 1.78-13.84), and cardiovascular disease 3.72 (95% CI 2.12-6.53). Natalizumab's highest risk was for cardiovascular disease (adjusted hazard ratio [aHR] 1.61; 95% CI 1.24-2.10). For the oral DMDs, fingolimod was associated with higher hazards of cerebrovascular (aHR 2.04; 95% CI 1.27-3.30) and ischemic heart diseases (aHR 1.64; 95% CI 1.10-2.44) and hypertension (aHR 1.73; 95% CI 1.30-2.31); teriflunomide with higher hazards of thyroid disorders (aHR 2.30; 95% CI 1.11-4.74), chronic liver disease (aHR 1.94; 95% CI 1.19-3.18), hypertension (aHR 1.76; 95% CI 1.32-2.37), and hyperlipidemia (aHR 1.61; 95% CI 1.07-2.44); and from complementary analyses (in 1 province), dimethyl fumarate with acute liver injury (aHR 6.55; 95% CI 1.96-21.87). Our study provides an extensive safety profile of several different DMDs used to treat MS in the real-world setting. Our findings not only complement those observed in short-term clinical trials but also provide new insights that help inform the risk-benefit profile of the DMDs used to treat MS in clinical practice. The results of this study highlight the continued need for long-term, independent safety studies of the DMDs used to treat MS. This study provides Class III evidence that for patients with MS, while DMD exposure reduces the risk of infection-related hospitalizations, there are increased risks of infection-related physician visits and incident adverse events for select DMDs.

Disparities in the incidence of next-generation sequencing (NGS) among patients (pts) with advanced or metastatic prostate cancer (mPC) and urothelial carcinoma (mUC).

542 Background: Based on availability of approved agents targeting tumor somatic mutations, current guidelines recommend NGS for Pts with mPC and mUC. However, large cohort studies in mPC and mUC evaluating disparities in NGS testing have not been reported. Herein, we investigated the effect of social determinant of health (SDOH) on disparities in NGS testing in a large real-world dataset of pts with mPC and mUC. Methods: Pts data were extracted from the nationwide Flatiron Electronic Health Record (EHR)-derived de-identified database. Inclusion: new diagnosis of advanced or metastatic (adv/met) PCa and UCa between March 2015 to December 2022 and receipt of cancer therapy (to include only treatment eligible pts). Disparities in incidence of NGS testing after adv/met diagnosis by SES, R/E, region, and insurance were assessed using Fine and Grey’s (FG) modified stratified Cox proportional hazard (PH) model. FG model considered death as a competing risk. Stratification was done by year of adv/met diagnosis (accounting heterogeneity) and R/E (an effect modifier for SES, region, and insurance), assuming different baseline hazards in each stratum. All analysis done using R v.4.2.3. Results: Analytic cohorts comprised 11,936 pts with mPC and 6,490 pts with mUC. Hazard ratios (HR) and 95% confidence intervals (CI) from FG Cox PH models are reported in the table. For both cancer types, pts were more likely to get NGS testing when they were White, non-Hispanic (compared to Black, non-Hispanic), had higher SES, and had commercial insurance. Conclusions: Our data suggest an association between incidence of NGS testing and several SDOH in mPC and mUC. Further studies are needed to elucidate the reasons for these disparities and ways to mitigate them. [Table: see text]

All cause and cause specific mortality in obsessive-compulsive disorder: nationwide matched cohort and sibling cohort study

ObjectiveTo estimate the risk of all cause and cause specific mortality in people with obsessive-compulsive disorder (OCD) compared with matched unaffected people from the general population and with their unaffected...

Influence of Cesarean Section on Postpartum Fertility and Dysmenorrhea: A Retrospective Cohort Study in Japan.

To investigate the association between cesarean section (CS) and postpartum fertility and dysmenorrhea using data from a Japanese insurance registry. This retrospective cohort study used a data set of patients registered between 2007 and 2021 in an insurance registry comprising specific employee-based health insurance companies in Japan. Of those data sets, we included data from participants who had their first recorded childbirth between 2014 and 2018. The exclusion criteria were any prior deliveries, dysmenorrhea, or complications that would affect the next pregnancy or postpartum dysmenorrhea since 2007. The occurrence of subsequent childbirth and postpartum dysmenorrhea until 2021 was compared between the CS and vaginal delivery (VD) groups using the log-rank test and Cox proportional hazards model with stratification according to age and age matching. This study included 25,984 (5,926 after age matching) and 5,926 participants in the VD and CS groups, respectively. After age matching, the rate of subsequent childbirth was 18.3% and 16.3%, and the rate of postpartum dysmenorrhea was 6.5% and 7.8% in the VD and CS groups, respectively. There were fewer subsequent childbirths in the CS group than in the VD group after age matching in the stratified Cox proportional hazards model (hazard ratio [HR] 95% confidence interval [CI]: 0.86 [0.79-0.94]). The CS group had a significantly higher risk of dysmenorrhea (HR [95% CI]: 1.18 [1.03-1.36]). Although confounding might be existing, our study suggests that CS might be associated with decreased postpartum fertility and increased dysmenorrhea. The medical indications for CS should be carefully determined; post-CS women should be meticulously followed up.

Increased Risk of Benign Prostate Hyperplasia (BPH) in Patients with Gout: A Longitudinal Follow-Up Study Using a National Health Screening Cohort.

A previous study reported a high risk of benign prostatic hyperplasia (BPH) in patients with gout. This study intended to evaluate the risk of BPH in gout patients. A total of 514,866 Korean National Health Insurance Service-Health Screening Cohorts were retrieved from 2002 to 2019. Among these individuals, 14,961 gout patients and 58,764 control participants were matched based on demographic factors. The incidence of BPH during the follow-up periods was collected for both the gout and control groups. The risk of BPH was analyzed using stratified Cox proportional hazard models, and hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated. Secondary analyses were conducted based on demographic factors and comorbidities. The incidence of BPH was 23.40% in gout patients and 20.70% in control participants. In the adjusted model, the HR of BPH was 1.13-fold higher in gout patients than in the control group (95% CI = 1.09-1.18). Compared with the ≥60-year-old group, the <60-year-old group demonstrated a higher HR for BPH in gout patients (1.19 [1.13-1.24] vs. 1.07 [1.01-1.13]). The risk of BPH in gout patients was consistent according to various comorbidities. Patients with gout demonstrated a greater risk of BPH than participants without gout. The young adult population had a higher risk of BPH related to gout.

Effect of multidisciplinary team care on patient survival in chronic hepatitis B or C hepatocellular carcinoma.

Multidisciplinary team care coordinates with medical teams to improve the quality of cancer care. This study explored multidisciplinary team care in hepatitis B or hepatitis C virus-related hepatocellular carcinoma patients from the time of diagnosis to the first-time treatment interval and investigated treatment outcomes and prognosis. This retrospective cohort study included data from a nationwide population from 2007 to 2016. Data were collected from the Taiwan Cancer Registry Database, linked to the Taiwan National Health Insurance Research Database. Propensity score matching was applied at a ratio of 1:2 to reduce the selection bias. A multiple regression model with generalized estimating equations was used to analyze whether multidisciplinary team care affected the diagnosis-to-treatment interval. The stratified Cox proportional hazards model examined whether involvement in multidisciplinary team care influenced survival status. A total of 10,928 and 21,856 patients with hepatocellular carcinoma received multidisciplinary and non-multidisciplinary care, respectively. Participants with multidisciplinary care had a longer diagnosis-to-treatment interval but a lower risk of cumulative cancer death (HR=0.88, 95% CI:0.84-0.92). In patients with intermediate- to advanced-stage hepatocellular carcinoma, multidisciplinary team care has obvious benefits for improving survival. Patients with hepatocellular carcinoma who participated in multidisciplinary team care had a longer diagnosis-to-treatment interval but a lower risk of cancer death. Patients with intermediate- to advanced-stage hepatocellular carcinoma who received multidisciplinary team care significantly benefited from this outcome. Hospitals should provide HCC patients with multidisciplinary team care to improve cancer care.

Association between Tonsillectomy and Cardiovascular Diseases in Adults.

This study aimed to evaluate the association between tonsillectomy and cardiovascular diseases (CVDs) in the Korean adult population. Using data from the 2002-2015 Korean National Health Insurance Service-Health Screening Cohort, a total of 1082 participants aged 40 years or older who had undergone tonsillectomy were matched with 4328 control individuals for age, sex, income, and region of residence. We evaluated the incidence of CVDs in both the tonsillectomy and control groups and calculated the hazard ratios (HRs) of stroke, ischemic heart disease (IHD), and heart failure (HF) for participants who underwent tonsillectomy using a stratified Cox proportional hazard model. The incidence rates of stroke (81.3 vs. 46.6 per 10,000 person-years) and IHD (112.3 vs. 64.9 per 10,000 person-years) were significantly higher in patients who had undergone tonsillectomy than in the control group. After adjustment, the tonsillectomy group exhibited a 1.78-fold and 1.60-fold higher occurrence of stroke (CI = 1.32-2.42, p < 0.001) and IHD (CI = 1.24-2.08, p < 0.001), respectively, compared to the control group. However, there was no significant difference in the incidence rate of tonsillectomy and control groups (11.1 vs. 6.1 per 10,000 person-years). The HR of HF did not differ significantly between the tonsillectomy and control groups in the adjusted model (p = 0.513). We identified a significant relationship between a history of tonsillectomy and occurrence of stroke/IHD in the Korean adult population.

Carfilzomib, Daratumumab, and Dexamethasone (KdD) Vs Carfilzomib and Dexamethasone (Kd) for Relapsed/Refractory Multiple Myeloma (RRMM) in the Phase 3 Candor Study: Subgroup Analysis According to Renal Functioning

Renal impairment frequently occurs in patients (pts) with multiple myeloma (MM) and is associated with poor survival outcomes. In the phase 3 CANDOR trial, carfilzomib, dexamethasone, and daratumumab (KdD) met its primary endpoint of prolonged progression-free survival (PFS) vs carfilzomib and dexamethasone (Kd) (28.4 vs 15.2 mo; hazard ratio [HR]: 0.64; 95% CI: 0.49-0.83) after 50 months (mo) follow-up (Usmani Blood Adv 2023). The study aim was to perform a prespecified subgroup analysis of efficacy and safety by baseline renal function in pts with relapsed/refractory MM (RRMM) receiving KdD vs Kd in the CANDOR trial. Adult pts with RRMM were randomized 2:1 to KdD or Kd in the open-label, phase 3 CANDOR trial (NCT03158688) (Dimopoulos Lancet 2020). RRMM pts with measurable disease who had received 1-3 prior lines of therapy, with partial response or better to ≥1 line of therapy were eligible. Dialysis was an exclusion criterion. All pts received carfilzomib (K) as a 30-min intravenous (IV) infusion on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle (20 mg/m 2 on days 1 and 2 during cycle 1 and 56 mg/m 2 thereafter). Daratumumab (8 mg/kg) was administered IV on days 1 and 2 of cycle 1 and at 16 mg/kg once weekly for the remaining doses of the first 2 cycles, then every 2 weeks (wks) for 4 cycles (cycles 3 to 6), and every 4 wks thereafter. All pts received 40 mg dexamethasone oral or IV weekly (20 mg for pts &amp;gt;75 years). Pts were grouped according to baseline renal function (creatinine clearance [CrCl] ≥15-&amp;lt;60 mL/min, ≥60-&amp;lt;90 mL/min, and ≥90 mL/min (Dimopoulous J Clin Onc 2016). The Cockcroft-Gault formula was used to calculate baseline and on study renal function. PFS and overall response rates (ORRs) were protocol-derived/investigator-assessed. Median PFS was estimated using the Kaplan-Meier method, with HRs and corresponding 95% CIs estimated using a stratified Cox proportional hazards model. Response rates were summarized descriptively, with odds ratios (ORs) and corresponding 95% CIs estimated by Mantel-Haenszel methods using stratified randomization. Renal response was defined as pt CrCl improvement to ≥60 mL/min in any 2 consecutive study visits in pts with baseline CrCl of &amp;lt;50 mL/min. A total of 466 pts were randomized; renal subgroups were CrCl ≥15-&amp;lt;60 mL/min (renal impairment), n=67 and n=36; ≥60-&amp;lt;90 mL/min, n=112 and n=57; and ≥90 mL/min, n=132 and n=61 for KdD and Kd, respectively. One pt in the KdD arm with missing baseline CrCl was excluded. Baseline characteristics were generally balanced between treatment arms and renal subgroups ( Table 1). After a median follow-up of ~50 mo (data cutoff: April 15, 2022), pts treated with KdD vs Kd had improved median PFS across all renal subgroups; median PFS was 24.9 mo vs 8.4 mo (HR, 0.61; 95% CI, 0.35-1.06), 31.6 mo vs 19.9 mo (0.63; 0.41-0.96), and 27.4 mo vs 15.3 mo (0.64; 0.43-0.95) for pts with CrCl ≥15-&amp;lt;60 mL/min, ≥60-&amp;lt;90 mL/min, and ≥90 mL/min, respectively ( Table 2). Median overall survival (OS) for KdD vs Kd was 44.6 mo vs 25.2 mo (HR, 0.58; 95% CI, 0.32-1.03), 48.0 mo vs 43.7 mo (0.91; 0.58-1.43), and NE vs NE (0.74; 0.46-1.20), respectively. ORRs were 87% vs 50% (OR, 8.02; 95% CI, 2.84-22.65); 85% vs 82% (1.26; 0.49-3.27); and 86% vs 80% (1.59; 0.69-3.68), respectively. Complete response rates were 36% vs 8% (7.43; 1.85-29.74); 44% vs 21% (3.17; 1.47-6.87); and 38% vs 21% (2.20; 1.08-4.49), respectively. Among 38 KdD pts and 27 Kd pts with baseline CrCl &amp;lt;50 mL/min, the renal response rate was 21% vs 11% (OR, 2.65; 95% CI, 0.63-11.11), respectively. In pts with renal impairment, most common grade ≥3 TEAEs were thrombocytopenia (38% [25/66] vs 23% [8/35]), hypertension (24% [16/66] vs 20% [7/35]), anemia (24% [16/66] vs 29% [10/35]), and pneumonia (23% [15/66] vs 9% [3/35]) in the KdD arm vs Kd arm. Most common grade ≥3 TEAEs of interest in pts with renal impairment were respiratory tract infections (32% vs 14%), hypertension (26% vs 20%), and infusion reaction on the same date of any carfilzomib dosing (14% vs 11%), respectively. Grade ≥3 acute renal failure occurred in 6% vs 11%, 4% vs 7%, and 2% vs 3% of pts with baseline CrCl ≥15-&amp;lt;60 mL/min, ≥60-&amp;lt;90 mL/min, and ≥90 mL/min, respectively. Overall, the safety profile in each subgroups was consistent with the established carfilzomib safety profile (Usmani Blood Adv 2023). KdD showed consistent clinical benefit vs Kd in median PFS, ORR and OS irrespective of the baseline renal function. Safety findings were consistent with the overall study population.

Effects of once-weekly semaglutide on major adverse cardiovascular events in patients with type 2 diabetes and polyvascular disease: a post hoc analysis of the SUSTAIN 6 trial

Abstract Background The presence of polyvascular disease (defined as atherosclerosis involving ≥2 distinct vascular territories) is a strong, independent predictor of subsequent cardiovascular (CV) events in patients with type 2 diabetes (T2D). In the SUSTAIN 6 trial, the glucagon-like peptide-1 receptor agonist once-weekly (OW) subcutaneous semaglutide reduced major adverse cardiovascular events (MACE; a composite of death from CV causes, non-fatal myocardial infarction and non-fatal stroke) in patients with T2D at high CV risk. Purpose This analysis of SUSTAIN 6 assessed the effect of OW semaglutide on MACE in patients with T2D, stratified by the number of atherosclerotic vascular territories at baseline. Methods Patients in SUSTAIN 6 were randomised to receive 0.5 or 1.0 mg OW subcutaneous semaglutide or placebo. The median follow-up was 2.1 years. In this post hoc analysis, the SUSTAIN 6 population was stratified according to documented atherosclerosis: polyvascular disease (≥2 vascular territories), single vascular disease (1 vascular territory) or no atherosclerotic cardiovascular disease (ASCVD). Time to first MACE was analysed using a stratified Cox proportional hazards model, with pooled treatment by vascular risk group as fixed factors. Results In SUSTAIN 6, 640 patients (19.4%) had polyvascular disease, 1821 patients (55.2%) had vascular disease in one arterial bed and 836 patients (25.4%) had no ASCVD at baseline. Demographic and clinical characteristics at baseline are presented in the Table. In the total population, the presence of polyvascular disease and single vascular disease was associated with a greater risk of MACE, compared with no ASCVD (hazard ratio [HR]: 2.25 [95% confidence interval – CI: 1.47;3.52] and HR: 1.64 [95% CI: 1.11;2.48], respectively). In the SUSTAIN 6 trial, OW semaglutide significantly reduced the risk of MACE vs placebo (HR: 0.74 [95% CI: 0.58;0.95]). In this analysis, the risk of MACE was consistently lower with OW semaglutide vs placebo across those with polyvascular disease, single vascular disease and no ASCVD (pinteraction=0.98) (Figure). The absolute risk reductions for OW semaglutide vs placebo at 2 years were 3.37% [95% CI: –1.28;8.02] (number needed to treat [NNT] 30) in patients with polyvascular disease, 2.02% [95% CI: –0.30;4.34] (NNT 50) in patients with single vascular disease and 0.78% [95% CI: –1.96;3.52] (NNT 128) in patients with no ASCVD. Conclusion Patients with polyvascular disease in the SUSTAIN 6 trial population are at over two times greater risk of MACE than those without ASCVD. The MACE risk reduction with OW semaglutide vs placebo is consistent across people with T2D and polyvascular disease, single vascular disease or no ASCVD. However, patients with T2D and polyvascular disease may derive greater absolute benefit from semaglutide treatment owing to their higher risk.

Life expectancy in women and men after STEMI: a comparison to a matched general population

Abstract Background/Introduction ST-elevation myocardial infarction (STEMI) is considered a risk factor for short- and long-term mortality. Further, studies indicate that female sex is associated with increased mortality among STEMI patients. Our aim was to assess the impact of female and male sex on short- and long-term excess mortality in comparison to matched general populations. Methods We identified all patients undergoing first-time percutaneous coronary intervention (PCI) who were treated with primary PCI (pPCI) for STEMI from 2003 to 2018 in the Western Denmark Heart Registry (covering approximately 3.3 million inhabitants). Each patient was matched in a 1:5 ratio by age and sex with individuals from the Western Denmark general population without prior myocardial infarction or coronary revascularization. To assess excess mortality after STEMI, we compared mortality in women and men to their matched general population using a stratified Cox proportional hazards model. Excess mortality was assessed in the periods from 0-30 days, 31-90 days, and 91 days – 4 years of follow-up. Results A total of 18,216 pPCI-treated STEMI patients were included, 4,833 (26.5%) women and 13,382 (73.5%) men. The matched general population cohort consisted of 91,075 individuals, 24,165 women and 66,910 men. Median age at STEMI diagnosis was 68 years (IQR 58-78) in women and 62 years (54-71) in men. Excess mortality was markedly higher in the first 30 days after STEMI with the relative risk being 35 times higher for both women (hazard ratio (HR) 34.63, 95% CI 26.11-45.95) and men (HR 35.18, 28.48-43.48) compared to their matched general populations. From 31-90 days, the excess mortality remained higher after STEMI for women (HR 3.58, 2.58-4.97) and men (HR 2.00, 1.58-2.55). However, in the 91 days - 4 years follow-up period there was only a marginal unadjusted 13% excess mortality in women (HR 1.13, 1.02-1.25) while an 8% lower mortality was observed in men (HR 0.92, 0.86-0.98; p for interaction&amp;lt;0.05). After adjusting for comorbidities in the 91 days - 4 years period, an excess mortality in women was no longer observed (HR 1.03, 0.93-1.14), while men with STEMI remained at lower risk than the general population (HR 0.87, 0.81-0.94). Conclusions In a large, contemporary STEMI cohort mortality within the first 30 days were 35 times higher in both women and men when compared to mortality in an age- and sex- matched general population. However, STEMI patients surviving the first 90 days were no longer at higher risk than their matched general population individuals; the latter most likely reflecting guideline-directed prophylactic interventions.Excess mortality in women with STEMIExcess mortality in men with STEMI