Combined HR Research Articles

P0748 Characterisation of Remission Levels in Patients with Ulcerative Colitis Treated with 5-Aminosalicylates: Results of the CARUC-ASA Prospective Multicentre Study

Abstract Background The treatment goals for chronic inflammatory bowel diseases are increasingly ambitious, targeting steroid-free remission, mucosal healing, and biomarker normalisation. In ulcerative colitis (UC), histological remission lowers risks of hospitalisation, cancer, and relapse. This study aims to describe remission levels in UC patients in symptomatic remission on first-line 5-aminosalicylic acid (5-ASA) and factors associated with remission. Methods This national, multicentre, prospective, phase 4 interventional study (ClinicalTrials.gov: NCT05992142) included UC patients in symptomatic remission, defined by a stool frequency score ≤ 1 and no rectal bleeding, on 5-ASA monotherapy (oral and/or rectal) for at least 6 months. Patients on corticosteroids, immunomodulators, biologics, or small molecules were excluded. Assessments included stool frequency, rectal bleeding, urgency, rectosigmoidoscopy (Mayo score, UCEIS), biopsies with the Geboes score assessed by central reading, faecal calprotectin (FCP), and MARS (Medication Adherence Report Scale) questionnaire. The different levels of remission were defined as followed: Complete Symptomatic Remission (CSR: PRO-2 = 0, no urgency), Endoscopic Remission (ER: Mayo 0–1, UCEIS 0–1), Complete Endoscopic Remission (CER: Mayo 0, UCEIS 0–1), Histological Remission (HR: Geboes 0–1), and FCP <150 μg/g; and Deep Remission as combined CCR, CER, and HR. In the absence of CER, physicians completed a questionnaire to investigate the reasons for not altering therapy. Results From December 2022 to February 2024, 198 UC patients (median age 50, 41% female) were enrolled from 14 centres. Montreal classifications were E1 (37%), E2 (44%), and E3 (18%). Treatment included oral 5-ASA (n=134, 68%), rectal 5-ASA (n=19, 9%), and a combination (n=45, 23%) with a median duration of 2.0 years (1.0 - 4.0). The median MARS-5 score was 24. ER was observed in 172/198 patients (87%), CER in 138/198 (70%), and HR in 156/196 (80%). Among those in ER and CER, 151/172 (88%) and 127/137 (93%) also had HR, respectively. Normal FCP was seen in 152/194 (78%) and in 128/153 (83%) of the HR subgroup. Deep remission was achieved in 47/197 (24%) of patients. The main reason for absence of deep remission was the absence of CSR (63%). The main reason for not altering treatment, despite the absence of CER, was physician reluctance in 37% of cases. 5-ASA administration form was significantly associated with ER (p=0.5, OR=2.9, 95%CI 1.1-7.3) for oral against combined. Conclusion In UC patients in clinical remission on 5-ASA, the majority achieved endoscopic and/or histological remission, suggesting that higher remission levels beyond clinical remission alone are attainable in selected, highly adherent patients on first-line therapy.

Predicted indirectly recognizable HLA epitopes scores and clinical outcomes after haploidentical stem cell transplantation in pediatric patients with relapsed neuroblastoma

IntroductionThe Predicted Indirectly ReCognizable HLA Epitopes (PIRCHE) model is a recently developed algorithm that predicts indirect T-cell recognition by calculating the number of such epitopes in donor-recipient pairs.MethodsIn this study, the clinical significance of PIRCHE was evaluated in pediatric patients with relapsed/progressed neuroblastoma undergoing haploidentical stem cell transplantation (haplo-SCT).ResultsA higher PIRCHE-I score was associated with faster platelet recovery (P = 0.007) and lower incidence of hemorrhagic cystitis (13% vs. 41%, P = 0.028) and invasive fungal infections (0% vs. 18%, P = 0.045). Additionally, a higher PIRCHE-I score was significantly associated with better overall survival (OS) (HR 0.57, 95% CI 0.34-0.97, P = 0.038). A higher PIRCHE-II score was associated with better OS (HR 0.57, 95% CI 0.34-0.94, P = 0.028) and reduced progression (HR 0.48, 95% CI 0.30-0.77, P = 0.002). When combined, the PIRCHE-I and PIRCHE-II scores demonstrated an even stronger association with improved OS (HR 0.35, 95% CI 0.15-0.82, P = 0.016). Multivariable analysis confirmed that a higher combined PIRCHE-I and PIRCHE-II score was independently associated with improved OS (combined PIRCHE score HR 0.22, 95% CI 0.06-0.79, P = 0.021), and a higher PIRCHE-II score was significantly associated with reduced progression (HR 0.42, 95% CI 0.25-0.70, P < 0.001).ConclusionIn conclusion, higher PIRCHE-I and PIRCHE-II scores are linked to better survival outcomes and reduced complications in pediatric haplo-SCT neuroblastoma patients. Incorporating PIRCHE scores into donor selection is expected to optimize transplant outcomes.

Obesity and the development of Parkinson’s disease within the Framingham Heart study cohort

ObjectiveTo determine the role of obesity in the development of Parkinson’s disease (PD). BackgroundObesity has been reported to be both a risk factor for PD, as well as potentially protective. The Framingham Heart Study (FHS) is a multigenerational longitudinal cohort study that was started in 1948, which is well-known for its cardiovascular health studies. In this study, we utilized the extensive cardiovascular and neurological data to determine if obesity contributes to the risk of the development of PD. MethodsParticipants in the FHS Original and Offspring cohorts were included in this study. Controls were selected based on sex and age at baseline examination, 1:10. Cox proportional hazard regression models were used, adjusting for age and sex. PD case status was determined utilizing prior medical and neurological examination data, Framingham Heart Study examinations, and self-report data by a panel of movement disorders neurologists using the UK Brain Bank Criteria (UKBB) and other supporting clinical details after being flagged for review by FHS neurologists. We used p < 0.05 for significance. ResultsAccounting for missing covariate data, this study included 117 participants with PD, with 1170 controls. We found that higher BMI was associated with lower PD risk, with participants with BMI 25 kg/m2 to 30 kg/m2 having HR of 0.66 (CI 0.44–0.98; p = 0.04) and BMI >= 30 kg/m2 having HR 0.47 (CI 0.27–0.84; p = 0.01). When the overweight and obese BMI groups were combined, we noted a more robust association, with combined HR of 0.67 (0.41–0.86; p = 0.01). ConclusionsObesity during mid-life potentially reduces the risk of developing PD; however, additional studies are needed to further explore this association.

Prognostic factors for intraductal papillary neoplasm of the bile duct following surgical resection: a systematic review and meta-analysis.

Intraductal papillary neoplasm of the bile duct (IPNB) is a biliary neoplasm characterized by intraductal papillary growth and varying degrees of malignant transformation. This study aimed to identify effective prognostic factors (PFs) for predicting the prognosis of IPNB after surgical resection, addressing the gap in the higher level evidence. We systematically searched databases from their inception to October 10, 2023. Data on 12 predetermined PFs were collected and subjected to a meta-analysis. Forest plots were used to summarize the findings. Fifteen studies with a total of 2311 patients were included. Among the PFs examined, extrahepatic tumor location (HR, 2.97; 95% CI 1.68-5.23), subclassification type 2 (HR, 2.62; 95% CI 1.45-4.76), R1 resection (HR, 2.47; 95% CI 1.73-3.51), elevated CA19-9 level (HR, 3.25; 95% CI 1.91-5.54), tumor multiplicity (HR, 2.65; 95% CI 1.40-5.02), and adjacent organ invasion (HR, 3.17; 95% CI 2.01-5.00) were associated with a poorer prognosis. Additionally, the combined HR values indicated that lymph node metastasis and poor tumor differentiation were linked to a worse prognosis, although both exhibited significant heterogeneity. Our study offers valuable insights for enhancing postoperative prognostication and treatment decision-making for IPNB patients with IPNB. These findings warrant further validation in future prospective studies.

Efficacy of oral anticoagulants in chronic kidney disease and hemodialysis patients with atrial fibrillation: a systematic review and meta-analysis.

This meta-analysis seeks to evaluate the efficacy of direct oral anticoagulants (DOACs) versus vitamin K antagonists (VKA) in individuals with chronic kidney disease (CKD), end-stage renal disease (ESRD), and undergoing hemodialysis (HD) who also have atrial fibrillation (AF). A comprehensive search of MEDLINE, clinicaltrials.gov, EMBASE, and Cochrane Database for relevant studies reporting the usefulness of OAC therapy for CKD, ESRD, and HD patients with AF was conducted from its inception until 1st May 2023. The studies that reported OR, RR, or HR for adult AF patients to investigate the efficacy of OAC in CKD, ESRD, and HD were included. Statistical analysis was completed using a generic inverse variance and random-effects model to calculate the combined HR and their corresponding 95% CIs for all outcomes. The meta-analysis included 33 studies with 178,956 patients. The analysis revealed that the DOACs, when compared to VKA, significantly lowered the risk of stroke or systemic embolism (HR: 0.81 [95% CI: 0.70, 0.93]; P=0.002; I2=62%), bleeding (HR: 0.77, [95% CI: 0.67, 0.89]; P=0.0003; I2=83%), and intracranial hemorrhage (HR: 0.56, [95% CI 0.47, 0.66]; P<0.00001; I2=0%). Similarly, the risks of cardiovascular death (HR: 0.88, [95% CI 0.78, 1.00]; P=0.05; I2=0%), all-cause mortality (HR: 0.88, [95% CI 0.70, 1.10]; P=0.25; I2=96%), and myocardial infarction (HR: 0.80, [95% CI 0.54, 1.17]; P= 0.25; I2= 0%) were lowered by DOAC, but the result was insignificant. No significant difference was seen in the risk of gastrointestinal bleeding between DOAC and VKA as well (HR: 0.95, [95% CI 0.75, 1.20]; P=0.65; I2=83%). Our meta-analysis confirms that DOACs are effective for managing AF in patients with kidney disease, with potential clinical implications for AF and CKD management. Further research should explore DOACs' reno-protective effects.

AMBULATORY AND HOME BLOOD PRESSURE MONITORING FOR CARDIOVASCULAR DISEASE RISK EVALUATION: A SYSTEMATIC REVIEW AND META-ANALYSIS OF PROSPECTIVE COHORT STUDIES

Objective: The aim of this work was to systematically review the level of evidence based on prospective cohort studies investigating the role of 24-hour ABPM and HBPM on cardiovascular disease (CVD) risk prediction. Design and method: Eight studies were included in the meta-analysis. The Der Simonian and Laird's random-effects model with standard error adjustment using the Knapp-Hartung method was used. Results: Systolic BP from ABPM and HBPM were significantly, positively associated with CVD risk (combined HR per 1-SD systolic BP, 95%CI; 1.32, 1.19-1.45, I2 = 35.8%, and 1.30, 95%CI;1.11-1.49, I2 = 79.1%, respectively), after adjusting for office BP levels and other potential confounders. Diastolic BP from both ABPM and HBPM were positively associated with CVD risk (combined HR per 1-SD diastolic BP, 95%CI; 1.15, 1.01-1.29, I2 = 73.1% and 1.21, 1.05-1.37, I2 = 84.5%, respectively). Conclusions: BP either from ABPM or HBPM could predict CVD risk. As so, at least one of out-of-office BP measurements has to be taken into account during the evaluation of the hypertensive population.

Survival after Trastuzumab Therapy in Patients with Locally Advanced or Metastatic HER2-Positive Gastric or Gastroesophageal Junction Cancer: A Meta-Analysis of Randomized Controlled Trials.

In the Trastuzumab for Gastric Cancer study, it was found that trastuzumab combined with doublet chemotherapy (fluoropyrimidine and platinum) was the gold-standard treatment for gastroesophageal adenocarcinoma (GEA) that was locally advanced, unresectable, or metastatic (HER2+). We performed a meta-analysis of randomized phase II/III studies testing trastuzumab in combination or alone. This meta-analysis's findings involved 2048 patients in total. The treatment arm and hormone receptor status were used to stratify the combined HR. Overall, the PFS (Random model) HR [0.80] and 95% confidence intervals (CI) [0.68-0.95] were significantly higher for regimens containing trastuzumab, fluoropyrimidine, and platinum compared to regimens containing fluoropyrimidine and platinum. The results of this meta-analysis provide additional support for trastuzumab's use in treating HER2-positive GEA, particularly in cases where the disease lacks a HER2+ receptor.

Abstract 66: Clonal Hematopoiesis of Indeterminate Potential and Incident Type 2 Diabetes Risk

Introduction: Clonal hematopoiesis of indeterminate potential (CHIP) is an aging-related accumulation of somatic mutations in hematopoietic stem cells, leading to clonal expansion. CHIP presence has been implicated in elevated risks for coronary heart disease (CHD) and death, but its association with incident type 2 diabetes (T2D) is unknown. Hypothesis: We hypothesized that CHIP is associated with elevated risk of incident T2D. Methods: CHIP was derived from whole genome sequencing of blood DNA in NHLBI Trans-omics for Precision Medicine (TOPMed) cohorts. We analyzed 17,637 participants without prior T2D, cardiovascular disease, or cancer at blood draw, with prospective follow-up for incident T2D. We evaluated baseline prevalence of CHIP vs. no CHIP with incident T2D risk using Cox regression. We also investigated CHIP variants previously related to CHD: DNMT3A , TET2 , ASXL1 , JAK2 , and TP53 . We estimated multivariable-adjusted hazard ratios and 95% confidence intervals (HR [CI]) adjusted for age, sex, body mass index, smoking, alcohol, and education. We combined cohort estimates via fixed effects meta-analysis. Results: On average, participants were age 63.4 years (SD=11.5) and 76% female. Prevalence of CHIP was 6.0% (1,055) at baseline. There were 2,467 incident T2D cases over mean=9.8 years follow-up. Compared to those without a mutation, having CHIP was associated with a 23% higher T2D risk, both overall (combined HR=1.23; 95% CI=1.04, 1.45), and among those with CHD-related CHIP mutations (87% of total CHIP): HR=1.23 (1.03, 1.46). Although those with CHIP mutations of TET2 (HR=1.48; 1.05, 2.08) and ASXL1 (HR=1.76; 1.03, 2.99) had larger elevations in T2D risk, and DNMT3A was suggestive of increased T2D risk (HR=1.15; 0.93, 1.43), statistical power was limited for JAK2 and TP53 mutation analyses. Conclusions: CHIP was associated with higher incidence of T2D. CHIP mutations located on loci previously implicated in aging and CHD were also related to T2D, suggesting shared pathology of atherosclerosis and T2D.

HBsAg (-)/HBsAb (-)/HBeAg (-)/HBeAb (+)/HBcAb (+) predicts a high risk of hepatitis B reactivation in patients with B-cell lymphoma receiving rituximab based immunochemotherapy.

Patterns of hepatitis B virus reactivation (HBV-R) in HBsAg (-)/HBcAb (+) patients with B-cell non-Hodgkin lymphoma (NHL) receiving rituximab based immunochemotherapy have not been well described. The retrospective study included 222 HBsAg (-)/HBcAb (+) NHL patients as training cohort and 127 cases as validation cohort. The incidence of HBV-R in HBsAg (-)/HBcAb (+) B-cell NHL patients was 6.3% (14/222), of which that in HBsAg (-)/HBsAb (-)/HBeAg (-)/HBeAb (+)/HBcAb (+) population was 23.7% (9/38). Multivariate analysis showed that HBsAg (-)/HBsAb (-)/HBeAg (-)/HBeAb (+)/HBcAb (+) correlated with a high risk of HBV-R in B-cell lymphoma patients (training phase hazard ratio[HR], 10.123; 95% confidence interval [CI], 3.389-30.239; p < 0.001; validation phase HR, 18.619; 95% CI, 1.684-205.906; p = 0.017; combined HR, 12.264; 95% CI, 4.529-33.207; p < 0.001). Inthetrainingcohort,the mortality rate of HBsAg (-)/HBcAb (+) B-cell NHL caused by HBV-R was 14.3% (2/14) while that for HBV reactivated HBsAg (-)/HBsAb (-)/HBeAg (-)/HBeAb (+)/HBcAb (+) population was up to 44.4% (4/9). As a high incidence of HBV-R and high mortality after HBV-R was found in HBsAg (-)/HBsAb (-)/HBcAb (+)/HBeAg (-)/HBeAb (+) patients with B-cell NHL receiving rituximab based immunochemotherapy, prophylactic antiviral therapy is recommended for these patients.

Prognostic significance of KMT2A-PTD in patients with acute myeloid leukaemia: a systematic review and meta-analysis

ObjectivesWhether KMT2A-PTD has a prognostic impact on patients with acute myeloid leukaemia (AML) is controversial. Therefore, we conducted a meta-analysis to assess the prognostic value of KMT2A-PTD in patients with...

The relationship between pre-operative psoas and skeletal muscle parameters and survival following endovascular aneurysm repair: a systematic review and meta-analysis

Sarcopenia is characterised by chronically reduced skeletal muscle volume and function, and is determined radiologically by psoas and skeletal muscle measurement. The present systematic review and meta-analysis aims to examine the relationship between pre-operative CT-derived psoas and skeletal muscle parameters and outcomes in patients undergoing EVAR and F/B-EVAR for aortic aneurysm. The MEDLINE database was interrogated for studies investigating the effect of pre-operative CT-diagnosed sarcopenia on outcomes following EVAR and F/B-EVAR. The systematic review was carried out in accordance with PRISMA guidelines. The primary outcome was overall mortality. RevMan 5.4.1 was used to perform meta-analysis. PROSPERO Database Registration Number: CRD42021273085. Ten relevant studies were identified, one reporting skeletal muscle parameters, and the remaining nine reporting psoas muscle parameters, which were used for meta-analysis. There were a total of 2563 patients included (2062 EVAR, 501 F/B-EVAR), with mean follow-up ranging from 25 to 101 months. 836 patients (33%) were defined as radiologically sarcopenic. In all studies, the combined HR for all-cause mortality in sarcopenic versus non-sarcopenic patients was 2.61 (1.67–4.08), p < .001. Two studies reported outcomes on patients undergoing F/B-EVAR; the combined HR for all-cause mortality in sarcopenic versus non-sarcopenic patients was 3.08 (1.66–5.71), p = .004. Radiological sarcopenia defined by psoas or skeletal muscle parameters was associated with inferior survival in patients undergoing both EVAR and F/B-EVAR. Current evidence is limited by heterogeneity in assessment of body composition and lack of a consensus definition of radiological sarcopenia.

Incremental value of global longitudinal strain in long-term risk prediction after acute coronary syndrome. A SWEDEHEART registry based echo study

Abstract Background Global longitudinal strain (GLS) by 2D speckle tracking echocardiography has emerged as a new method for assessing left ventricular (LV) function, however its added value in long-term risk prediction after Acute Coronary Syndrome (ACS) has not been clearly established. This study aimed to investigate GLS as a predictor of death and heart failure re-hospitalization after ACS in relation to more established echocardiographic measures. Method 1385 consecutive patients with acute coronary syndrome (47% STEMI, 45% NSTEMI, unstable angina 3.6% and unspecified ACS 4.5%), admitted between 2008 and 2014 to the three participating Swedish university hospitals were reported to the SWEDEHEART registry and underwent routine echocardiography during their hospital stay. The echo data was retrospectively collected from each study site and reviewed at a Core Lab. The prognostic value of systolic left ventricular function parameters (LVEF and GLS) regarding all-cause mortality and heart failure (HF) hospitalizations (median follow-up 6.8 years) was studied using the Cox proportional Hazards model. A nested model comparison was performed with C-statistics. Results In the 942 patients remaining after exclusion (median age 65 years, 77% men) median LVEF was 55% (inter quartile range (IQR) 47–60) and median GLS −14.8% (IQR −17.8–11.8). The combined endpoint of HF hospitalization and all-cause death was reached in 17.7% of the patients, 12.1% of the patients died and 8.7% were re-admitted due to HF. After adjustment for baseline characteristics, both LVEF and GLS were individual independent predictors of the combined endpoint, HR 0.964 (95% CI 0.949–0.980, p&amp;lt;0.001) and HR 1.042 (95% CI 1.002–1.084, p=0.042) respectively. The C-statistics increased from 0.752 (95% CI 0.712–0.792) to 0.755 (95% CI 0.706–0.785) when GLS entered the model with clinical data and LVEF. Conclusion In a large cohort of patients with ACS and normal or near-normal ejection fraction, GLS emerged as an independent long-term risk predictor of all-cause mortality and heart failure hospitalizations. The incremental predictive value of GLS on top of clinical background and LVEF was statistically significant, but of limited clinical significance. Funding Acknowledgement Type of funding sources: None.

Prognostic value of SPARC in hepatocellular carcinoma: A systematic review and meta-analysis.

Hepatocellular carcinoma (HCC) is characterized by a high degree of malignancy, rapid proliferation of tumor cells, and early liver metastasis. Resistance to multiple drugs independent of the high expression of secreted protein acidic and rich in cysteine (SPARC) is associated with a high risk of recurrence and mortality. However, the prognostic value of SPARC in patients with HCC remains unclear. Therefore, we performed a meta-analysis to evaluate the relationship between the expression of SPARC and the prognosis of patients with HCC. We searched for relevant articles in the CNKI, PubMed, EMBASE, and Web of Science databases. The 95% confidence intervals (CIs) were calculated for combined overall survival (OS) and disease-free survival (DFS) to assess the prognostic value of expression of SPARC in patients with HCC. In six of the studies, SPARC expression status was significantly associated with OS (combined hazard ratio [HR], 1.38; 95% CI, 1.0-1.82; Z = 2.27, P = 0.02) but not with DFS (combined HR, 0.79; 95% CI, 0.16-4.00, Z = 0.28, P = 0.78). Therefore, it cannot be assumed that upregulated SPARC expression has an effect on DFS in patients with HCC. Elevated SPARC expression is associated with a low survival rate but not with DFS in patients with HCC. Further studies are needed to confirm our conclusions. INPLASY registration number: INPLASY202180115. https://inplasy.com/inplasy-2021-8-0115/.

PD-L1 and the Clinical Outcomes of Ovarian Cancer: Meta-Analysis and Bioinformatical Analysis.

A meta-analysis was performed to analyze the association between PD-L1 expression and overall survival (OS) in various tumors and to identify potential targets through biological information analysis. the data were collected from PubMed and Cochrane library, the all analysis of our study were conducted by STATA software and online website. Ten articles (including 11 studies) that met all inclusion criteria were obtained. The combined HR showed that high PD-L1 expression was significantly associated with poor overall survival (HR = 1.84, 95% CI: 1.15-2.93). Pathway analysis revealed that the upregulated genes were primarily involed in biological processes, including nucleic acid transcription, biosynthesis and negative regulation of cell metabolism. The downregulated genes were primarily involed in the regulation of cell cycle, including chromosome separation and DNA metabolism. The top ten genes that were identified were hub genes (CDK1, CCNB1, CCNA2, KIF11, CDC20, UBE2C, NCAPG, AURKA, AURKB, CHEK1), which had significant function in cell differentiation and virus infection. The Kaplan-Meier survival curve indicated that CCNB1, KIF11, UBE2C, NCAPG, AURKA and CHEK1 were statistically significant (P<0.05). PD-L1 was found to be a latent biomarker for predicting the prognostic value of cancer and also a therapeutic target.

Western United States and Canada perspective: are herbicide-resistant crops the solution to herbicide-resistant weeds?

AbstractHerbicide-resistant (HR) crops are widely grown throughout the United States and Canada. These crop-trait technologies can enhance weed management and therefore can be an important component of integrated weed management (IWM) programs. Concomitantly, evolution of HR weed populations has become ubiquitous in agricultural areas where HR crops are grown. Nevertheless, crop cultivars with new or combined (stacked) HR traits continue to be developed and commercialized. This review, based on a symposium held at the Western Society of Weed Science annual meeting in 2021, examines the impact of HR crops on HR weed management in the U.S. Great Plains, U.S. Pacific Northwest, and the Canadian Prairies over the past 25 yr and their past and future contributions to IWM. We also provide an industry perspective on the future of HR crop development and the role of HR crops in resistance management. Expanded options for HR traits in both major and minor crops are expected. With proper stewardship, HR crops can reduce herbicide-use intensity and help reduce selection pressure on weed populations. However, their proper deployment in cropping systems must be carefully planned by considering a diverse crop rotation sequence with multiple HR and non-HR crops and maximizing crop competition to effectively manage HR weed populations. Based on past experiences in the cultivation of HR crops and associated herbicide use in the western United States and Canada, HR crops have been important determinants of both the selection and management of HR weeds.

Abstract P5-13-08: Identification of PD-L1+ status as a candidate predictive biomarker of response to talazoparib (TALA) in the phase 3 EMBRACA study

Abstract Background: Loss-of-function mutations in genes encoding components of the homologous recombination DNA damage response (DDR) machinery, notably BRCA1/2, are associated with tumor sensitivity to poly(ADP-ribose) polymerase inhibitors (PARPi). In EMBRACA, the PARPi TALA improved progression-free survival (PFS) (HR [95% CI] 0.54 [0.41-0.71], P&amp;lt;0.001) vs chemotherapy (CT) in germline BRCA-mutated (gBRCAm) HER2− advanced breast cancer. BRCA1/2 deficiency is associated with elevated PD-L1 expression in ovarian cancers, and PARP inhibition has been associated with PD-L1 upregulation in nonclinical models (Stewart et al, Cancer Res 2018;78:6717-25). Little is known about the potential for PD-L1 expression to modulate sensitivity to PARPi monotherapy in the clinic. Recently, a neoadjuvant study of olaparib in unselected, primary triple-negative breast cancer (TNBC), demonstrated a significant correlation between PD-L1 expression (using the 22C3 antibody) and response to olaparib (Eikesdal et al, Ann Oncol 2021;32:240-9). In contrast, this EMBRACA analysis assessed the contribution of PD-L1 status to TALA sensitivity in a uniformly gBRCAm patient (pt) population. Methods: Available baseline tumor tissue blocks from 120 of 431 EMBRACA pts (28% of intent-to-treat) were sectioned and slides immunostained using SP142/Ventana anti-PD-L1 at HistoGeneX (Naperville, Illinois). PD-L1 immunohistochemistry (IHC) status was assessed as the proportion of tumor area occupied by PD-L1 stained immune cells (IC) of any intensity, with ≥1% defined as PD-L1+. The overall response rate (ORR), defined as unconfirmed complete or partial response (CR/PR), was assessed by investigators. PFS was assessed by an Independent Review Facility. Results: 92/120 (77%) tumors were evaluable for PD-L1 IHC status. Of these 92 evaluable tumors, 9/36 (25%) TNBC and 15/56 (27%) hormone receptor-positive (HR+) tumors were PD-L1+ (24/92, 26% combined TNBC and HR+). In the TALA arm, the ORR was similar for PD-L1+ and PD-L1− tumors for TNBC pts: 2/5 (40%) and 6/19 (32%), respectively. In contrast, the ORR was higher for PD-L1+ vs PD-L1− tumors for HR+ pts: 11/12 (92%) vs 12/31 (39%), exact P value=0.002 (for combined TNBC and HR+, 13/17 [76%] vs 18/50 [36%], P=0.005). For the CT arm, the limited numbers evaluable for both PD-L1 and response (n=25 total), with only one response, precluded similar analysis. Based on the imbalanced results in ORR according to PD-L1 status in pts with HR+ disease, Cox regression analysis was used to explore potential associations of PD-L1 status with PFS. In the TALA arm, median PFS was similar for TNBC independent of PD-L1 status (6.3 mo and 7.0 mo, respectively; HR [95% CI] 1.207 [0.371-3.929]). Median PFS was numerically longer for PD-L1+ vs PD-L1− for HR+ tumors; this difference was not significant (20.2 mo vs 9.2 mo; HR [95% CI] 1.154 [0.395-3.367]). In the CT arm, PD-L1 status was not associated with PFS, although the PD-L1 subgroups were small (For HR+: PD-L1+, n=3; PD-L1−, n=10). Conclusions: Based on these exploratory, retrospective subgroup analyses, PD-L1 positivity by SP142/Ventana was lower in EMBRACA than previously reported in TNBC using the same scoring algorithm: 24/92 (26%) vs 369/902 (41%) in IMpassion130 (Schmid et al, Lancet Oncol 2020;21:44-59). PD-L1+ status was associated with higher ORR in HR+ EMBRACA pts receiving TALA. Interestingly, the enhanced responsiveness for PD-L1+ was not associated with improved PFS, although this assessment is complicated by low pt numbers. Further research is warranted to explore the relationship between baseline tumor PD-L1 status and sensitivity to PARPi, particularly in light of ongoing clinical studies evaluating combinations of immunotherapy and PARPi. Citation Format: Hope S. Rugo, Joanne L. Blum, A. Douglas Laird, Sara A. Hurvitz, Johannes Ettl, Lida A. Mina, Kyung-Hun Lee, Anthony Gonçalves, Rinat Yerushalmi, Young-Hyuck Im, Miguel Martin, Louis Fehrenbacher, Henri H. Roché, Ying Chen, Silvana Lanzalone, Jijumon Chelliserry, Wolfgang Eiermann, Jennifer K. Litton. Identification of PD-L1+ status as a candidate predictive biomarker of response to talazoparib (TALA) in the phase 3 EMBRACA study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-13-08.

Discordance in prognostic ability between physician assessed NYHA classification and self-reported health status in patients with acute heart failure

Abstract Background Especially in patients with acute heart failure (AHF) the NYHA classification remains of uncertain representation of patients' actual health state. Alternatively, patient's subjective well-being, in terms of health-related quality of life (HRQL), showed to have an excellent prognostic ability in out clinic patients with chronic heart failure. Objectives It is unknown whether HRQL instruments can assess a more reliable prognostication in patients hospitalized due to AHF than the NYHA classification. Methods Goal Directed Afterload Reduction in Acute Congestive Cardiac Decompensation Study (GALACTIC) was a multicenter, randomized, open-label blinded-end-point trial that emphasized early intensive and sustained vasodilation in adult patients hospitalized due to AHF with NYHA functional class III/IV, however provided neutral findings. HRQL was assessed by the generic EQ-5D-3L which is a 3-leveled 5-item instrument and the disease-specific Kansas City Cardiomyopathy Questionnaire (KCCQ). Unadjusted and adjusted Cox regression models were performed after patients were grouped into low (EQ-5D −0.074&amp;lt;0.25; KCCQ 0&amp;lt;25), moderately low (0.25&amp;lt;0.5; 25&amp;lt;50), moderately high (0.5&amp;lt;0.75; 50&amp;lt;75) and high HRQL (0.75–1.0; 75–100). Results 781 patients were enrolled in 10 centres in 5 countries over 2 continents among which 536 (69%) patientshad completed theEQ-5D and 419 (54%) the KCCQ shortly after admission. Within 180 days of follow-up69 (13%) and 54 (13%) patients died and 151 (28%) and 122 (29%) died or were rehospitalized due to AHF, respectively. Cumulative incidence as well as HRs in patients grouped according to NYHA (n=536) indicated a comparable or significantly lower risk in patients with NYHA IV: e.g. for the combined outcome HR 1.07 (95% CI 0.777–1.473) and aHR 0.463 (95% CI 0.245–0.875). Whereas HRs in patients grouped according to both, EQ-5D (n=536) and KCCQ (n=419), increased from the group with highest to the group with the lowest HRQL: e.g. aHR for moderately high 1.11 (95% CI 0.718–1.715), for moderately low 1.721 (95% CI 1.102–2.688) and for low EQ-5D index 1.891 (95% CI 1.136–3.149) referenced to high HRQL (EQ-5D index 0.75–1.0). Conclusions These findings corroborate and extend previous work suggesting that NYHA classification poorly discriminates AHF patients' prognosis and challenge its' extensive application. HRQL might be a possible alternative to easily assess these patients' heath state. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Swiss National Science Foundation, the Swiss Heart Foundation A. 180-day mortality; B. composite outcome

Classical complement pathway inhibition reduces brain damage in a hypoxic ischemic encephalopathy animal model.

Perinatal hypoxic ischemic encephalopathy (HIE) remains a major contributor of infant death and long-term disability worldwide. The role played by the complement system in this ischemia-reperfusion injury remains poorly understood. In order to better understand the role of complement activation and other modifiable mechanisms of injury in HIE, we tested the dual-targeting anti-inflammatory peptide, RLS-0071 in an animal model of HIE. Using the well-established HIE rat pup model we measured the effects of RLS-0071 during the acute stages of the brain injury and on long-term neurocognitive outcomes. Rat pups subject to hypoxia-ischemia insult received one of 4 interventions including normothermia, hypothermia and RLS-0071 with and without hypothermia. We measured histopathological effects, brain C1q levels and neuroimaging at day 1 and 21 after the injury. A subset of animals was followed into adolescence and evaluated for neurocognitive function. On histological evaluation, RLS-0071 showed neuronal protection in combination with hypothermia (P = 0.048) in addition to reducing C1q levels in the brain at 1hr (P = 0.01) and at 8 hr in combination with hypothermia (P = 0.005). MRI neuroimaging demonstrated that RLS-0071 in combination with hypothermia reduced lesion volume at 24 hours (P<0.05) as well as decreased T2 signal at day 21 in combination with hypothermia (P<0.01). RLS-0071 alone or in combination with hypothermia improved both short-term and long-term memory. These findings suggest that modulation by RLS-0071 can potentially decrease brain damage resulting from HIE.

The Relationship between Time to Surgery (TTS) and Survival in Breast Cancer: A Systematic Review and Meta-Analysis.

Background:Curative operation is the practical and primary therapy for masses of breast cancers. In contrast, the correlation between the time interval from breast cancer diagnosis to curative surgery and survival is still uncertain.Methods:An electronic literature search was conducted on PubMed/Medline and EMBASE (between Jan 2000 and Jan 2020). Primary endpoints were overall survival (OS) or Disease-Free Survival (DFS). The HR with 95% confidence intervals were calculated using a random-effects or fixed-effects model.Results:The combined HR for OS was 1. 10 (95% CI 1. 08–1. 11; P=0. 000) by fixed-effects model, no statistically significant heterogeneity was found (P=1. 000; I2=0%), and this difference was statistically significant (Z=11. 99; P=0. 000).Conclusion:This meta-analysis showed a significant adverse association between more prolonged time to surgery (TTS) and lower overall survival in patients with breast cancer. It is reasonable to minimize that interval between diagnosis and curative surgery.

Subgroup and subtype-specific outcomes in adult medulloblastoma.

Medulloblastoma, a common pediatric malignant central nervous system tumour, represent a small proportion of brain tumours in adults. Previously it has been shown that in adults, Sonic Hedgehog (SHH)-activated tumours predominate, with Wingless-type (WNT) and Group 4 being less common, but molecular risk stratification remains a challenge. We performed an integrated analysis consisting of genome-wide methylation profiling, copy number profiling, somatic nucleotide variants and correlation of clinical variables across a cohort of 191 adult medulloblastoma cases identified through the Medulloblastoma Advanced Genomics International Consortium. We identified 30 WNT, 112 SHH, 6 Group 3, and 41 Group 4 tumours. Patients with SHH tumours were significantly older at diagnosis compared to other subgroups (p < 0.0001). Five-year progression-free survival (PFS) for WNT, SHH, Group 3, and Group 4 tumours was 64.4 (48.0-86.5), 61.9% (51.6-74.2), 80.0% (95% CI 51.6-100.0), and 44.9% (95% CI 28.6-70.7), respectively (p = 0.06). None of the clinical variables (age, sex, metastatic status, extent of resection, chemotherapy, radiotherapy) were associated with subgroup-specific PFS. Survival among patients with SHH tumours was significantly worse for cases with chromosome 3p loss (HR 2.9, 95% CI 1.1-7.6; p = 0.02), chromosome 10q loss (HR 4.6, 95% CI 2.3-9.4; p < 0.0001), chromosome 17p loss (HR 2.3, 95% CI 1.1-4.8; p = 0.02), and PTCH1 mutations (HR 2.6, 95% CI 1.1-6.2; p = 0.04). The prognostic significance of 3p loss and 10q loss persisted in multivariable regression models. For Group 4 tumours, chromosome 8 loss was strongly associated with improved survival, which was validated in a non-overlapping cohort (combined cohort HR 0.2, 95% CI 0.1-0.7; p = 0.007). Unlike in pediatric medulloblastoma, whole chromosome 11 loss in Group 4 and chromosome 14q loss in SHH was not associated with improved survival, where MYCN, GLI2 and MYC amplification were rare. In sum, we report unique subgroup-specific cytogenetic features of adult medulloblastoma, which are distinct from those in younger patients, and correlate with survival disparities. Our findings suggest that clinical trials that incorporate new strategies tailored to high-risk adult medulloblastoma patients are urgently needed.