Differences In Benefits Research Articles

Mechanism matters: Differential benefits of cold-stored whole blood for trauma resuscitation from a prospective multicenter study.

Resuscitation with cold-stored low-titre whole blood (LTOWB) has increased despite the paucity of robust civilian data. Most studies are in predominately blunt trauma and lack analysis of specific subgroups or mechanism of injury. We sought to compare outcomes between patients receiving LTOWB versus balanced component therapy (BCT) after blunt (BL) and penetrating (PN) trauma. Secondary analysis of a prospective multicenter study of patients receiving either LTWOB-containing or BCT resuscitation was performed. Patients were grouped by mechanism of injury (BL vs. PN). A generalized estimated equations model using inverse probability of treatment weighting was employed. Primary outcome was mortality and secondary outcomes were acute kidney injury, venous thromboembolism, pulmonary complications, and bleeding complications. Additional analyses were performed on no-traumatic brain injury (TBI), severe torso injury, and LTOWB-only resuscitation patients. There were 1,617 patients (BL 47% vs PN 54%) identified; 1,175 (73%) of which received LTOWB. PN trauma patients receiving LTOWB demonstrated improved survival compared to BCT (77% vs. 56%; p < 0.01). Interval survival was higher at 6 hours (95% vs. 88%), 12 hours (93% vs. 80%), and 24 hours (88% vs. 57%) (all p < 0.05). The survival benefit following LTOWB was also seen across PN non-TBI (83% vs. 52%), and severe torso injuries (75% vs. 43%) (all p < 0.05). After controlling for age, sex, injury severity, and trauma center, LTWOB was associated with decreased odds of death (odds ratio, 0.31, p < 0.05) in PN trauma. However, no difference in overall mortality was seen across the BL groups. Both PN and BL patients receiving LTOWB had more frequent acute kidney injury compared to BCT (19% vs. 7% and 12% vs 6%, respectively; p < 0.05). Low-titre whole blood resuscitation was independently associated with decreased mortality following PN trauma, but not BL trauma. Further analysis in BL trauma is required to identify subgroups that may demonstrate survival benefit. Therapeutic/Care Management; Level III.

Patient Characteristics, Management, and Outcomes in a Novel Cohort of Primary Hyperparathyroidism.

Primary hyperparathyroidism (PHPT) increases the risk of bone loss, debilitating fractures, kidney stones, impaired renal function, and neurocognitive symptoms. Studies describing the natural history of PHPT have been limited to small samples, single institutions, or specific populations. We assessed the natural history of PHPT through a large, diverse national cohort from an electronic health record dataset representing more than 100 million patients. The TriNetX database was queried for adult patients with PHPT. We extracted demographics, comorbidities, and longitudinal biochemistries. Primary outcomes included major osteoporotic fracture (MOF) and chronic kidney disease (CKD). Outcomes were stratified by treatment strategy (surgical parathyroidectomy [PTX] vs nonsurgical) and age. Among 50 958 patients with PHPT, 26.5% were treated surgically at a median of 0.3 years postdiagnosis. At diagnosis, median age was 65 years, 74.0% were female, and median calcium level was 10.9 mg/dL. Black and older patients underwent PTX less frequently than White and younger patients. MOF 10-year incidence was 5.20% (PTX) and 7.91% (nonsurgical), with median 1.7-year delay with PTX compared to nonsurgical. PTX-associated MOF absolute risk reduction was 0.83% (age < 65 years) and 3.33% (age ≥ 65 years). CKD 10-year incidence was 21.2% (PTX) and 33.6% (nonsurgical), with median 1.9-year delay with PTX. PTX-associated CKD absolute risk reduction was 12.2% (age < 65 years) and 9.5% (age ≥ 65 years). We report 1 of the largest, representative, population-based natural histories of PHPT with different management strategies. A minority of patients underwent PTX, especially in older age. Patients managed surgically had lower incidence of fracture and CKD, and older patients experienced differential benefit.

Abstract PO1-01-13: Clinical characterization, prognostic and predictive values of HER2-low in early breast cancer in the PALLAS trial

Abstract Background: Low levels of HER2 expression (HER2-low) have recently emerged as a therapeutic target in patients (pts) with breast cancer (BC). The aim of this study was to evaluate clinical and demographic variables associated with HER2 expression, as well as the value of HER2-low as a prognostic and predictive biomarker for palbociclib benefit in pts enrolled in the PALLAS trial. Methods: The phase III PALLAS trial investigated the addition of palbociclib to adjuvant endocrine therapy (ET) in pts with stage II-III hormone receptor-positive BC. The aims of this analysis are (1) to assess the association between the presence of low levels of HER2 expression with demographic and clinicopathological parameters, (2) to test the prognostic value of HER2-low status on invasive disease-free survival (IDFS), distant relapse-free survival (DRFS), and overall survival (OS) and (3) to assess the value of HER2 expression as a predictive biomarker of response to palbociclib. HER2-low was defined as HER2 immunohistochemistry (IHC) 1+ or IHC 2+ with negative in situ hybridization; all pathologic evaluation was performed locally. Pts with HER2-0 and Her2-low BC were included in this analysis; those with HER2-positive BC or missing HER2 status were excluded. Association of HER2 with other baseline covariates were tested with Chi-squared tests. Prognostic and predictive power of HER2 were assessed with Cox Models. Multivariable models included age, T-stage, N-stage, grade and progesterone receptor (PR) expression. Hazard ratios (HR) and 95% Confidence intervals (CI) are reported. Results: From the original PALLAS intention-to-treat population (N = 5,753), 5304 pts (92.2%) were included in this analysis. Among these, 2,254 pts (42.5%) were classified as HER2 IHC 0 (HER2-0) and 3,050 (57.5%) as HER2-low (1,838 with IHC 1+ and 1,212 with IHC 2+). For this analysis, median follow-up was 59.8 months. Compared to HER2-0, pts with HER2-low tumors had statistically higher estrogen receptor expression levels (mean expression 89.2% vs 88.2%, p = 0.019), lower PR expression levels (65.9% vs 68.2%, p = 0.007). Importantly, HER2-low status varied significantly across 21 participating countries (range 16.7% to 75.6%; p&amp;lt; 0.001) and was more frequent in pts enrolled in North America (63.1%) than in Europe (53.4%) and other regions (53.4%) (p &amp;lt; 0.001). No differences in HER2 expression were observed according to anatomic stage, T-stage, N-stage, histological grade, age, menopausal status, primary surgery type, prior radiation, prior chemotherapy, or baseline performance status. There were no statistically significant differences in IDFS, DRFS or OS according to HER2 status in univariate or multivariable Cox models (prognostic value, HR provided in the Table). There was no significant interaction between the HER2 status and the benefit to palbociclib in IDFS, DRFS or OS (Table). Similar results were obtained when HER2-0 was compared to HER2 1+ and HER2 2+ separately. Conclusions: In this large, prospective and international cohort, no differences were observed in clinical parameters, prognosis, or differential benefit from palbociclib (predictive value) between HER2-0 and HER2-low tumors. Significant geographic variability was observed in the prevalence of HER2-low status, suggesting a high degree of variation in pathologic assessment of HER2 expression without impact on outcomes. Support: AFT, Abbvie Pfizer; Clinicaltrials.gov: NCT02513394 https://acknowledgments.alliancefound.org Citation Format: Guilherme Nader-Marta, Christian F. Singer, Dominik Hlauschek, Angela DeMichele, Paolo Tarantino, Georg Pfeiler, Miguel Martín, Justin Balko, Zbigniew Nowecki, Marija Balic, Adam Brufsky, Arlene Chan, Patrick G. Morris, Tufia Haddad, Sibylle Loibl, Yuan Liu, Lidija Sölkner, Christian Fesl, Erica Mayer, Michael Gnant. Clinical characterization, prognostic and predictive values of HER2-low in early breast cancer in the PALLAS trial [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 PO1-01-13.

Tu1645 DIFFERENTIAL PATTERNS AND BENEFIT OF IBS-D MEDICATION USE IN SURGICALLY NAIVE PATIENTS WITH CROHN'S DISEASE AND ULCERATIVE COLITIS

Tu1645 DIFFERENTIAL PATTERNS AND BENEFIT OF IBS-D MEDICATION USE IN SURGICALLY NAIVE PATIENTS WITH CROHN'S DISEASE AND ULCERATIVE COLITIS

Intermittent energy restriction inhibits tumor growth and enhances paclitaxel response in a transgenic mouse model of endometrial cancer

ObjectiveOverweight/obesity is the strongest risk factor for endometrial cancer (EC), and weight management can reduce that risk and improve survival. We aimed to establish the differential benefits of intermittent energy restriction (IER) and low-fat diet (LFD), alone and in combination with paclitaxel, to reverse the procancer effects of high-fat diet (HFD)-induced obesity in a mouse model of EC. MethodsLkb1fl/flp53fl/fl mice were fed HFD or LFD to generate obese and lean phenotypes, respectively. Obese mice were maintained on a HFD or switched to a LFD (HFD-LFD) or IER (HFD-IER). Ten weeks after induction of endometrial cancer, mice in each group received paclitaxel or placebo for 4 weeks. Body and tumor weights; tumoral transcriptomic, metabolomic and oxylipin profiles; and serum metabolic hormones and chemocytokines were assessed. ResultsHFD-IER and HFD-LFD, relative to HFD, reduced body weight; reversed obesity-induced alterations in serum insulin, leptin and inflammatory factors; and decreased tumor incidence and mass, often to levels emulating those associated with continuous LFD. Concurrent paclitaxel, versus placebo, enhanced tumor suppression in each group, with greatest benefit in HFD-IER. The diets produced distinct tumoral gene expression and metabolic profiles, with HFD-IER associated with a more favorable (antitumor) metabolic and inflammatory environment. ConclusionIn Lkb1fl/flp53fl/fl mice, IER is generally more effective than LFD in promoting weight loss, inhibiting obesity-related endometrial tumor growth (particularly in combination with paclitaxel), and reversing detrimental obesity-related metabolic effects. These findings lay the foundation for further investigations of IER as an EC prevention and treatment strategies in overweight/obesity women.

Differential Experiences of Intimate Partner Violence during COVID-19: A Cross-Regional Study in Mexico.

The COVID-19 pandemic brought on a marked increase in intimate partner violence (IPV) worldwide, Mexico being no exception. Factors that exacerbated gender-based violence (GBV) in the household during the pandemic include gendered loss of income, regression in access to social and legal justice resources, reversal to more traditional gender norms and roles, and increased alcoholism. While there are studies about the prevalence and determinants of IPV in rural and urban Mexico, there appears to be a lack of information regarding how these realities differed as they interacted with the compounding pressures of the COVID-19 pandemic. Stemming from 10 ethnographic interviews with women across rural and urban localities of Oaxaca, Mexico City, and Mexico State, who were recruited from NGOs providing psychological and legal services against GBV, we analyze some factors associated with the prevalence of IPV during confinement. We conclude that all women in our study experienced IPV both before and during the pandemic, with variations in IPV patterns influenced by their rural or urban residence, socio-economic status, ethnic-racial identity, and proximity to the abuser's network. We also found that not all impacts were negative, rather COVID-19 measures had a paradoxical effect for some women where restrictions on geographical mobility and decrease in access to alcohol became pivotal protective factors. We recommend that public policymakers and civil society organizations alike pay attention to these differential challenges and benefits in their crisis responses.

Prevalence of menthol cigarette use among adults who smoke from the United States by census division and demographic subgroup, 2002–2020: findings from the International Tobacco Control (ITC) project

BackgroundTargeted marketing of menthol cigarettes in the US influences disparities in the prevalence of menthol smoking. There has been no analysis of sub-national data documenting differences in use across demographic subgroups. This study estimated trends in the prevalence of menthol use among adults who smoke in the nine US census divisions by sex, age, and race/ethnicity from 2002 to 2020.MethodsData from 12 waves of the US ITC Survey were used to estimate the prevalence of menthol cigarette use across census divisions and demographic subgroups using multilevel regression and post-stratification (n = 12,020). Multilevel logistic regression was used to predict the prevalence of menthol cigarette use in 72 cross-classified groups of adults who smoke defined by sex, age, race/ethnicity, and socioeconomic status; division-level effects were fit with a random intercept. Predicted prevalence was weighted by the total number of adults who smoke in each cross-classified group and aggregated to divisions within demographic subgroup. Estimates were validated against the Tobacco Use Supplement to the Current Population Survey (TUS-CPS).ResultsOverall modeled prevalence of menthol cigarette use was similar to TUS-CPS estimates. Prevalence among adults who smoke increased in each division from 2002 to 2020. By 2020, prevalence was highest in the Middle (46.3%) and South Atlantic (42.7%) and lowest in the Pacific (25.9%) and Mountain (24.2%) divisions. Prevalence was higher among adults aged 18–29 (vs. 50+) and females (vs. males). Prevalence among non-Hispanic Black people exceeded 80% in the Middle Atlantic, East North Central, West North Central, and South Atlantic in all years and varied most among Hispanic people in 2020 (Pacific: 26.5%, New England: 55.1%).ConclusionsSignificant geographic variation in the prevalence of menthol cigarette use among adults who smoke suggests the proposed US Food and Drug Administration (FDA) menthol cigarette ban will exert differential public health benefits and challenges across geographic and demographic subgroups.

Abstract CT231: Identification of a novel agnostic predictive multiomic signature via Elastic Net/Machine Learning in TALAPRO-2 (TP-2), a phase 3 study of talazoparib (TALA) + enzalutamide (ENZA) vs placebo (PBO) + ENZA as first-line (1L) treatment in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC)

Abstract Background: TP-2 (NCT03395197) demonstrated significantly improved radiologic progression-free survival (rPFS) regardless of homologous recombination repair (HRR) gene alteration status for pts with mCRPC who received 1L TALA + ENZA (n=402) vs PBO + ENZA (n=403; Agarwal et al. Lancet. 2023. PMID: 37285865). We explore potential associations of ctDNA genomics and tumor gene expression with efficacy in TP-2. Methods: The analysis was based on the safety population (n=799). Two data sets were used: a FoundationOne®Liquid CDx data set (Azad et al. ASCO 2023, #5056) of prospectively collected/retrospectively analyzed plasma samples (n=681); and a tumor transcriptomic data set generated via HTG’s Oncology Biomarker Panel (with 10 additional genes implicated in PARP inhibitor sensitivity; n=304). Correlations between baseline molecular biomarkers and rPFS were assessed via a Cox proportional hazards model. Multivariate elastic net regression analysis incorporated 151 pts in the TALA + ENZA arm with 2,868 molecular features (ctDNA: 309 genes [only short variant alterations incorporated]; HTG: 2,559 tumor transcripts). Results: Positively predictive candidate tumor biomarkers for TALA + ENZA included androgen response signature and individual androgen receptor (AR) target genes such as PSA, ALDH1A3, and CAMKK2. These expression signatures/transcripts had no/minimal predictive value for PBO + ENZA. A 33-feature (3 genes, 30 transcripts) elastic net signature was identified that was predictive of rPFS with TALA + ENZA: TP53 and AR short variant alteration status were each prognostic and associated with worse rPFS. Expression of multiple AR target genes, including ALDH1A3 (top selected feature) and CAMKK2, was positively associated with rPFS. For TALA + ENZA, this multiomic signature was predictive of rPFS in pts regardless of HRR gene alteration status, and to a lesser extent for PBO + ENZA. None of the 12 HRR genes used for stratification in TP-2 were included in the signature. Conclusions: Our exploratory analysis identified candidate gene expression signatures, including AR pathway elements, potentially associated with differential benefit from TALA + ENZA, reinforcing the potential for exploitable crosstalk between AR and DNA repair pathways. Though validation is necessary, a predictive multiomic signature for benefit from TALA + ENZA regardless of HRR alteration status was identified that included alterations in genes previously implicated in prognosis and expression of multiple AR target transcripts. Strikingly, it did not include any of the 12 HRR genes used in prospective stratification for TP-2, reinforcing the potential benefit for TALA + ENZA beyond HRR-deficient tumors. Citation Format: Glenn Liu, Xinmeng Jasmine Mu, Karim Fizazi, A. Douglas Laird, Nobuaki Matsubara, Steven M. Yip, Jie Pu, Joan Carles, Andre P. Fay, Robert J. Jones, Stefanie Zschäbitz, Josep M. Piulats, Jae Young Joung, Whijae Roh, Jijumon Chelliserry, Nicola Di Santo, Michelle Saul, Arun A. Azad, Neeraj Agarwal. Identification of a novel agnostic predictive multiomic signature via Elastic Net/Machine Learning in TALAPRO-2 (TP-2), a phase 3 study of talazoparib (TALA) + enzalutamide (ENZA) vs placebo (PBO) + ENZA as first-line (1L) treatment in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT231.

Cardiac MRI-Enriched Phenomapping Classification and Differential Treatment Outcomes in Patients With Ischemic Cardiomyopathy.

Significant controversy continues to confound patient selection and referral for revascularization and mitral valve intervention in patients with ischemic cardiomyopathy (ICM). Cardiac magnetic resonance (CMR) enables comprehensive phenotyping with gold-standard tissue characterization and volumetric/functional measures. Therefore, we sought to determine the impact of CMR-enriched phenomapping patients with ICM to identify differential outcomes following surgical revascularization and surgical mitral valve intervention (sMVi). Consecutive patients with ICM referred for CMR between 2002 and 2017 were evaluated. Latent class analysis was performed to identify phenotypes enriched by comprehensive CMR assessment. The primary end point was death, heart transplant, or left ventricular assist device implantation. A multivariable Cox survival model was developed to determine the association of phenogroups with overall survival. Subgroup analysis was performed to assess the presence of differential response to post-magnetic resonance imaging procedural interventions. A total of 787 patients were evaluated (63.0±11.2 years, 24.8% women), with 464 primary events. Subsequent surgical revascularization and sMVi occurred in 380 (48.3%) and 157 (19.9%) patients, respectively. Latent class analysis identified 3 distinct clusters of patients, which demonstrated significant differences in overall outcome (P<0.001). Latent class analysis identified differential survival benefit of revascularization in patients as well as patients who underwent revascularization with sMVi, based on phenogroup classification, with phenogroup 3 deriving the most survival benefit from revascularization and revascularization with sMVi (hazard ratio, 0.61 [0.43-0.88]; P=0.0081). CMR-enriched unsupervised phenomapping identified distinct phenogroups, which were associated with significant differential survival benefit following surgical revascularization and sMVi in patients with ICM. Phenomapping provides a novel approach for patient selection, which may enable personalized therapeutic decision-making for patients with ICM.

Predicting effects of a digital stress intervention for patients with depressive symptoms: Development and validation of meta-analytic prognostic models using individual participant data.

Digital stress interventions could be helpful as an "indirect" treatment for depression, but it remains unclear for whom this is a viable option. In this study, we developed models predicting individualized benefits of a digital stress intervention on depressive symptoms at 6-month follow-up. Data of N = 1,525 patients with depressive symptoms (Center for Epidemiological Studies' Depression Scale, CES-D ≥ 16) from k = 6 randomized trials (digital stress intervention vs. waitlist) were collected. Prognostic models were developed using multilevel least absolute shrinkage and selection operator and boosting algorithms, and were validated using bootstrap bias correction and internal-external cross-validation. Subsequently, expected effects among those with and without a treatment recommendation were estimated based on clinically derived treatment assignment cut points. Performances ranged from R² = 21.0%-23.4%, decreasing only slightly after model optimism correction (R² = 17.0%-19.6%). Predictions were greatly improved by including an interim assessment of depressive symptoms (optimism-corrected R2 = 32.6%-35.6%). Using a minimally important difference of d = -0.24 as assignment cut point, approximately 84.6%-93.3% of patients are helped by this type of intervention, while the remaining 6.7%-15.4% would experience clinically negligible benefits (δ^ = -0.02 to -0.19). Using reliable change as cut point, a smaller subset (39.3%-46.2%) with substantial expected benefits (δ^ = -0.68) receives a treatment recommendation. Meta-analytic prognostic models applied to individual participant data can be used to predict differential benefits of a digital stress intervention as an indirect treatment for depression. While most patients seem to benefit, the developed models could be helpful as a screening tool to identify those for whom a more intensive depression treatment is needed. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Molecular ontogeny underlies the benefit of adding venetoclax to hypomethylating agents in newly diagnosed AML patients

The clinical impact of molecular ontogeny in acute myeloid leukemia (AML) was defined in patients treated with intensive chemotherapy. In a cohort of 314 newly diagnosed AML patients, we evaluated whether molecular ontogeny subgroups have differential benefit of venetoclax (VEN) added to hypomethylating agents (HMA). In secondary ontogeny (n = 115), median overall survival (OS)(14.1 vs. 6.9 months, P = 0.0054), composite complete remission (cCR 61% vs. 18%, P < 0.001) and allogeneic hematopoietic stem cell transplant (alloHCT) (24% vs. 6%, P = 0.02) rates were better in patients treated with HMA + VEN vs. HMA. In contrast, in TP53 AML(n = 111) median OS (5.7 vs. 6.1, P = 0.93), cCR (33% vs. 37%, P = 0.82) and alloHCT rates (15% vs. 8%, P = 0.38) did not differ between HMA + VEN vs. HMA. The benefit of VEN addition in the secondary group was preserved after adjustment for significant clinicopathologic variables (HR 0.59 [95% CI 0.38–0.94], P = 0.025). The OS benefit of HMA + VEN in secondary ontogeny was similar in those with vs. without splicing mutations (P = 0.92). Secondary ontogeny AML highlights a group of patients whose disease is selectively responsive to VEN added to HMA and that the addition of VEN has no clinical benefit in TP53-mutated AML.

Building cooperative and high-performance organizations with high-performance work systems: the role of firm age and industry dynamism

Although numerous empirical studies have linked human resource (HR) management systems, including systematic HR practices, such as high-performance work systems (HPWS), to superior organizational performance, our understanding of how these benefits vary among firms operating under different levels of environmental uncertainty is limited. By integrating insights from organizational theory, strategy, and strategic human resource management (SHRM), I theorize that an organization’s internal and external environments—specifically firm age and industry dynamism—modulate the benefits derived from HPWS. Utilizing longitudinal data encompassing 1,585 firm-year observations across five waves from 2009 to 2017, I demonstrate that the positive impact of HPWS on organizational performance is most pronounced for younger firms in highly dynamic industries. Conversely, for older firms, this positive effect weakens as industry dynamism increases. Additionally, I discovered that cooperative norms serve as a crucial mediating mechanism. My findings mark a significant advance in our understanding of when and how firms, amidst varying degrees of environmental uncertainty, reap differential benefits from HPWS—especially through the mediation of cooperative norms.

Neutrophil Gelatinase-Associated Lipocalin for the Differentiation of Mucinous Pancreatic Cystic Lesions.

Undetermined pancreatic cystic lesion (PCL) differentiation benefits from endoscopic ultrasound (EUS) based on morphology and cyst fluid analysis, but room for new biomarkers exists. Our aim was to assess the intracystic and serum diagnostic value of neutrophil gelatinase-associated lipocalin (Ngal) and interleukin 1 beta (IL-1β) for differentiation of PCLs. This prospective study included patients from one tertiary hospital, evaluated between April 2018 and May 2020. EUS fine-needle aspiration or pancreatic pseudocysts drainage was the source of PCL intracystic liquid. The final diagnosis was based on surgery or EUS results (morphology, cytology, glucose, and CEA-carcinoembryogenic antigen). The intracystic samples were tested for Ngal, IL-1β, glucose, and CEA, and serum for Ngal and IL-1β. We evaluated 63 cysts, 33 pseudocysts, and 30 non-inflammatory cysts. The diagnostic sensitivity and specificity for mucinous PCL was 70.8% and 92.3% for intracystic Ngal (cut-off: 500-800 ng/dL), without correlation with serum Ngal, no matter the inclusion of infected pseudocysts. After exclusion of infected pseudocysts, the sensitivity and specificity for glucose were 87% and 75%, respectively, and for CEA, they were 87.1%, and 96.8%, respectively. Intracystic Ngal shows promise in differentiating mucinous PCLs, but researchers need to conduct further studies to confirm its effectiveness. Intracystic IL-1β and serum Ngal made no diagnostic contribution.

Impact of screening participation on modelled mortality benefits of a multi-cancer early detection test by socioeconomic group in England

BackgroundCancer burden is higher and cancer screening participation is lower among individuals living in more socioeconomically deprived areas of England, contributing to worse health outcomes and shorter life expectancy. Owing...

The regulation of social factors on anxiety and microglial activity in nucleus accumbens of adolescent male mice: Influence of social interaction strategy

BackgroundAdolescence is a period characterized by a high vulnerability to emotional disorders, which are modulated by biological, psychological, and social factors. However, the underlying mechanisms remain poorly understood. MethodsCombining physical or emotional social defeat stress (PS and ES) and pair or isolation rearing conditions, we investigated the effects of stress type and social support on emotional behavior and central immune molecules in adolescent mice, including anxiety, social fear, and social interaction strategies, as well as changes in microglia-specific molecules (ionized calcium-binding adaptor molecule 1 (Iba1) and a cluster of differentiation molecule 11b (CD11b)) in the medial prefrontal cortex (mPFC), hippocampus (HIP), amygdala (AMY), and nucleus accumbens (NAc). ResultsMice exposed to both physical stress and isolated rearing condition exhibited the highest levels of anxiety, social fear, and microglial CD11b expression in the NAc. In terms of social support, pair-housing with siblings ameliorated social fear and NAc molecular changes in ES mice, but not in PS mice. The reason for the differential benefit from social support was attributed to the fact that ES mice exhibited more active and less passive social strategies in social environment compared to PS mice. Further, the levels of stress-induced social fear were positively associated with the expression of microglial CD11b in the NAc. ConclusionThese findings offer extensive evidence regarding the intricate effects of multiple social factors on social anxiety and immune alteration in the NAc of adolescent mice. Additionally, they suggest potential behavioral and immune intervention strategies for anxiety-related disorders in adolescents.

The differential benefit of using Handgrip in patients with ischemiainduced ventricular arrhythmia

The differential benefit of using Handgrip in patients with ischemiainduced ventricular arrhythmia

Exploratory analyses of homologous recombination repair (HRR) gene subgroups and potential associations with secondary efficacy endpoints in the HRR-deficient population from TALAPRO-2.

178 Background: TALAPRO-2 demonstrated statistically significant improvement in radiographic PFS with 1L talazoparib (TALA) + enzalutamide (ENZA) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) with and without HRR gene alterations (HRRm). Tumors were prospectively determined to harbor HRRm. Pts were randomized 1:1 to TALA 0.5 mg (N=200) or placebo (PBO; N=199) + ENZA 160 mg QD. Exploratory biomarker analyses assessed HRR gene subgroups and potential associations with secondary efficacy endpoints in pts with HRRm tumors. Methods: Prospective testing used a 12-gene HRR panel (HRR12) of FoundationOne CDx/FoundationOne Liquid CDx.For single gene groups, only pts bearing alteration(s) in that gene and no other HRR12 genes were analyzed. Gene cluster alteration dominance hierarchy: any BRCA1/2 alteration ( BRCA cluster); any PALB2 ( PALB2 cluster); any CDK12 ( CDK12 cluster); any ATM ( ATM cluster); all other HRR12 genes (each pt counted once). Endpoints: ORR, time to progression or death on first subsequent antineoplastic therapy (PFS2), PSA response ≥50%, time to PSA progression (TTPP), and time to initiation of cytotoxic chemotherapy (TTCC). Results: TALA + ENZA demonstrated differential benefit for BRCA2 single gene group across endpoints: ORR, 78.9% vs 33.3% (odds ratio [OR], 0.13 [95% CI, 0.03–0.63]); PFS2, median not reached (NR) vs 26.1 mo (HR, 0.44 [0.20–0.97]); PSA response &gt;50%, 87.0% vs 58.3%; TTPP, NR vs 9.2 mo (HR, 0.20 [0.10–0.41]); TTCC, NR vs 17.0 mo (HR, 0.27 [0.13–0.57]). Similar broad benefit was seen for BRCA cluster and BRCA1 single gene groups and to a lesser extent PALB2 single gene and cluster groups (allowing for small n in the latter 3 groupings). Broad differential benefit was evident for CDK12 single gene group : ORR 70.0% vs 28.6% (OR 0.17 [0.01–2.03]); PFS2, 36.4 vs 18.8 mo (HR, 0.29 [0.11–0.75]); PSA response ≥50%, 85.7% vs 53.3%; TTPP, 13.8 vs 11.1 mo (HR 0.61 [0.29–1.26]); the exception was TTCC, NR vs NR (HR 1.32 [0.43–4.06]). Similar benefit was seen for CDK12 cluster. For ATM single gene group, differential numerical benefit was seen for ORR, 81.8% vs 20.0% (OR 0.06 [0.00–1.17]); TTPP, 26.8 vs 15.9 mo (HR, 0.61 [0.25–1.47]); TTCC, NR vs NR (HR 0.60 [0.18–1.96]); no differential benefit was seen in other endpoints (similar for ATM cluster). The CHEK2 single gene group showed numerically differential benefit for PSA endpoints and TTCC. The other HRR12 gene cluster typically showed comparable efficacy between arms with potential exception of TTPP, 28.6 vs 14.0 mo (HR 0.65 [0.33–1.31]), and TTCC, NR vs NR (HR 0.65 [0.26–1.62]). Conclusions: Broad differential efficacy benefit was evident for TALA + ENZA vs PBO + ENZA across multiple molecular subgroups and was most pronounced for the BRCA1- PALB2- BRCA2 axis and CDK12. Additional analyses are warranted. Clinical trial information: NCT03395197 .

Somatostatin receptor 1 (SSTR1) expression as a potential predictive biomarker for response to androgen receptor signaling inhibitor (ARSI) therapy in metastatic castration-resistant prostate cancer (mCRPC).

180 Background: Overcoming ARSI resistance is an unmet need for mCRPC patients. Known resistance mechanisms include genetic alterations augmenting androgen receptor (AR) function (e.g., amplifications of the AR gene and its enhancer and AR mutations) and treatment-emergent evolution from an AR-driven to an AR-indifferent phenotype such as small cell neuroendocrine prostate cancer. Other mechanisms remain unexplored. Methods: To phenotype ARSI-resistant prostate cancer, we compared the RNA-seq profiles of paired metastatic biopsies from 31 mCRPC patients obtained before the initiation of first-line abiraterone or enzalutamide, and upon radiographic progression. The patient samples were obtained from two independent cohorts, the Stand Up To Cancer/Prostate Cancer Foundation (SU2C/PCF) West Coast Prostate Cancer Dream Team (WCDT) and a multi-institutional cohort from the Netherlands sequenced through the Hartwig Medical Foundation. We first evaluated RNA-seq data to identify the most differentially expressed genes and then performed survival analysis in the retrospective WCDT cohort (n=115, including 54 ARSI-naïve and 61 ARSI-experienced tumors) to assess the association between gene expression and overall survival, defined as the time interval from biopsy to death from any cause. Results: In the analysis of paired RNA-seq data from 31 mCRPC patients, SSTR1 was identified as the most significantly altered gene; SSTR1 expression was consistently decreased in post-treatment, ARSI-resistant tumors (log2[fold change]=-2.5, p=1.08×10-16). SSTR1 encodes somatostatin receptor 1, a G-protein coupled receptor that, when activated by the endogenous peptide hormone somatostatin or exogenous somatostatin analogues, mediates anti-proliferative, anti-migratory, and anti-secretory effects on target cells. Retrospective analysis in the 115 WCDT patients demonstrated that low SSTR1 expression was associated with worse overall survival ( p=0.047); ARSI treatment improved survival for patients with SSTR1-high (≥ median) tumors (HR=0.29, p=0.0002) more significantly than those with SSTR1-low (&lt; median) tumors (HR=0.67, p=0.17), with an interaction ( SSTR1 expression * ARSI treatment) towards statistical significance ( p=0.0598). A differential survival benefit of ARSI therapy with respect to SSTR1 expression was observed only among the 61 ARSI-experienced patients. Conclusions: SSTR1 expression is a potential predictive biomarker for response to ARSI in mCRPC, with higher SSTR1 expression predicting better response. This observation could be explained by an anti-tumor effect of SSTR1 signaling. Further work is warranted to prospectively validate these findings and to investigate SSTR1 as an actionable drug target to overcome ARSI resistance.

Does theta burst stimulation have differential benefit for those with melancholic or non-melancholic depression?

BackgroundTo determine if theta burst stimulation (TBS) is of preferential benefit to those with melancholic or non-melancholic depression as an adjunctive treatment for treatment resistant depression (TRD). MethodsFifty-two patients receiving TBS at a private psychiatric hospital participated in a naturalistic study. Four diagnostic strategies were used to assign melancholic versus non-melancholic depression subtype status. Depression symptoms were assessed at baseline, mid-treatment, and end of treatment using the Montgomery-Ǻsberg Depression Rating Scale – Self-Assessment (MADRS-S). Forty-one participants also completed the MADR-S at a six-week follow-up assessment. ResultsWe quantified poor correlations between the four study measures of melancholia; a finding suggesting that valid measurement of melancholia is likely to remain problematic. TBS led to significant reductions in depression symptoms from baseline to end of treatment, with this effect maintained at follow up. Response rates for the whole sample were 61.5 % at end of treatment and 53.7 % at follow-up, while remission rates were 34.6 % at end of treatment and 31.7 % at follow-up. Improvement rates as well as responder and remission rates were comparable for the melancholic and non-melancholic groups, irrespective of the diagnostic strategy used. LimitationsThe study was naturalistic (i.e., there being no control group, and concomitant medication changes were allowed), depression severity was assessed only by use of self-report measures, and the sample size was relatively small. ConclusionTBS appears to be non-specific, in that we failed to quantify any statistically significant differential benefit for those with melancholic compared to those with non-melancholic depression.

Network meta-analysis of second line and beyond treatment options in metastatic clear cell renal cell carcinoma

IntroductionDeciding on the optimal second-line (2L) treatment for metastatic clear-cell renal cell carcinoma (ccRCC) remains challenging due to the limited information comparing each of the available options and the influence of the newly expanding first-line (1L) agents. Patients and MethodsWe identified phase II/III randomized controlled trials (RCTs) evaluating 2L treatments in metastatic ccRCC. This Network Meta-analysis (NMA) evaluates the overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and severe adverse events (SAE). We used normal likelihood model to incorporate log hazard ratios (HRs), odds ratios (OR), and 95%-confidence-intervals (CI). Treatment p-scores were used for ranking. Data was analyzed in a fixed-effects model using the netmeta package in R v.1.5-0. ResultsAll therapies demonstrated some benefits over placebo. Lenvatinib + everolimus ranked first for OS (HR = 0.44; 95%CI = 0.24–0.82; p-score = 0.92), PFS (HR = 0.13; 95%CI = 0.07–0.24, p-score = 0.98), and ORR (OR = 35.95; 95%CI = 11.55–111.87; p-score = 0.93) compared to placebo, though with a higher SAE (OR = 5.27; p-score = 0.23). Cabozantinib ranked second for OS (HR = 0.57, p-score = 0.80), PFS (HR = 0.19; p-score = 0.86), and ORR (OR = 27.24, p-score = 0.84). Nivolumab was third for ORR (p-score = 0.79), fourth for OS (p-score = 0.69), fifth for PFS (p-score = 0.61), and last for SAE (p-score = 0.83). Lenvatinib monotherapy ranked worst SAE (OR = 5.89, p-score = 0.17) and third for OS and PFS. The latest drug, tivozanib, was sixth for PFS, OS, and ORR. The NMA matrix revealed no differential OS benefit between cabozantinib, lenvatinib + everolimus, and nivolumab. Other regimens had no significant OS benefit when compared to placebo. ConclusionBased on OS and PFS, the lenvtatinib + everolimus combination yielded superior, followed by cabozantinib and Lenvatinib monotherapies; all were limited by a worse SAE profile. Nivolumab and pazopanib had the lowest odds of SAEs.