Additional Prognostic Information Research Articles

Effect of C-reactive protein on the risk of Heart failure: a mendelian randomization study

BackgroundTraditional observational studies have shown positive associations between c-reactive protein (CRP) and heart failure (HF) risk. However, this association has not been fully elucidated. Therefore, Mendelian randomization was used to examine CRP’s possible etiological roles with HF.MethodsWe implemented a two-sample Mendelian randomization framework to examine the causality of the association between CRP and HF based on summary statistics by large-scale genome-wide association studies (GWAS) datasets of European ancestry through inverse-variance weighted, weighted median, MREgger regression, and MR-PRESSO methods. The summary statistics dataset on the association of genetic variants with CRP was used from the published GWAS of European descent in UK Biobank participants (N = 427,367) and the CHARGE consortium (N = 575,531). The GWAS dataset used to identify genetic variants underlying HF from the HERMES consortium includes 977,323 participants (47,309 cases and 930,014 controls). The odds ratio (OR) with 95% confidence intervals (CIs) was employed to examine this association.ResultsThe results of our IVW indicated that CRP was strongly associated with HF (OR = 4.18, 95% CI = 3.40–5.13, p < 0.001). The Cochran heterogeneity test showed significant heterogeneity among SNPs of CRP (Q = 317.55, p < 0.001; I2 = 37.6%), and no considerable pleiotropy was detected for the association of CRP with HF [intercept = 0.003; p = 0.234]. This finding remained consistent using different Mendelian randomization methods and sensitivity analyses.ConclusionOur MR study did identify convincing evidence to support CRP associated with HF risk. Human genetic data suggest that CRP is a causative factor in HF. Hence, CRP assessment may offer additional prognostic information as an adjuvant to overall risk assessment in HF patients. These findings prompt significant questions about the function of inflammation in the progression of HF. More research into the role of inflammation in HF is needed to guide trials of anti-inflammation management.

Automated Ki-67 labeling index assessment in prostate cancer using artificial intelligence and multiplex fluorescence immunohistochemistry.

The Ki-67 labeling index (Ki-67 LI) is a strong prognostic marker in prostate cancer, although its analysis requires cumbersome manual quantification of Ki-67 immunostaining in 200-500 tumor cells. To enable automated Ki-67 LI assessment in routine clinical practice, a framework for automated Ki-67 LI quantification, which comprises three different artificial intelligence analysis steps and an algorithm for cell-distance analysis of multiplex fluorescence immunohistochemistry (mfIHC) staining, was developed and validated in a cohort of 12,475 prostate cancers. The prognostic impact of the Ki-67 LI was tested on a tissue microarray (TMA) containing one 0.6mmsample per patient. A 'heterogeneity TMA' containing three to six samples from different tumor areas in each patient was used to model Ki-67 analysis of multiple different biopsies, and 30 prostate biopsies were analyzed to compare a 'classical' bright field-based Ki-67 analysis with the mfIHC-based framework. The Ki-67 LI provided strong and independent prognostic information in 11,845 analyzed prostate cancers (p< 0.001 each), and excellent agreement was found between the framework for automated Ki-67 LI assessment and the manual quantification in prostate biopsies from routine clinical practice (intraclass correlation coefficient: 0.94 [95% confidence interval: 0.87-0.97]). The analysis of the heterogeneity TMA revealed that the Ki-67 LI of the sample with the highest Gleason score (area under the curve [AUC]: 0.68) was as prognostic as the mean Ki-67 LI of all six foci (AUC: 0.71 [p= 0.24]). The combined analysis of the Ki-67 LI and Gleason score obtained on identical tissue spots showed that the Ki-67 LI added significant additional prognostic information in case of classical International Society of Urological Pathology grades (AUC: 0.82 [p= 0.002]) and quantitative Gleason score (AUC: 0.83 [p= 0.018]). The Ki-67 LI is a powerful prognostic parameter in prostate cancer that is now applicable in routine clinical practice. In the case of multiple cancer-positive biopsies, the sole automated analysis of the worst biopsy was sufficient. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Identification of distinct tumor cell patterns with single-cell RNA sequencing integrating primary lung adenocarcinoma and brain metastasis tumor.

Lung adenocarcinoma (LUAD) is the most common form of lung cancer and is often accompanied by brain metastasis (BM). The heterogeneity of the tumor renders all current conventional treatments less effective. This study aims to dissect tumor cell heterogeneity and identify potential therapeutic targets. We conducted single-cell RNA-sequencing (scRNA-seq) in 8 patients with treatment-naïve LUAD BM and included scRNA-seq data of 10 primary LUAD samples and their matched adjacent normal tissue from GSE131907 to determine the tumor cell heterogeneity. Our analyses revealed tumor cells derived from brain metastases were more heterogeneous. Tumor cells from BM harbored significantly more copy number variants (CNVs), and cells of magnoid subtype were the critical source of malignant cells both in BM and the primary lung tumor. Pseudo-time trajectory analysis revealed that malignant cells had upregulated genes enriched for cell cycle and cell division. Integrated analysis of tumor cells revealed 2 distinct malignant cell clusters (cluster 4 and cluster 6) and their marker genes. The signatures identified in the single-cell profile had prognostic value in the bulk tumor profiles. Moreover, the signature of cluster 4 had significant prognostic value in predicting patients surviving longer than 3.5 years, while the signature of cluster 6 showed better predictive ability within 1 year. Magnoid-type cells are most likely to develop into the riskiest cell type and potentially promote tumor progression. scRNA profiling that integrates LUAD BM and primary LUAD can provide information on those malignant cells with BM potential, offering additional prognostic information at cellular level, and may serve as a foundational resource for further tumor cell dissection and therapeutic target exploration.

Abstract OT2-05-01: FLEX: 30K Full Transcriptome, Real-World Evidence Database for Early-Stage Breast Cancer, and Investigator-Initiated Protocols

Abstract FLEX: 30K Full Transcriptome, Real-World Evidence Database for Early-Stage Breast Cancer, and Investigator-Initiated Protocols BACKGROUND: Genomic signatures, such as the 70-gene MammaPrint, provide additional prognostic information for early-stage breast cancer (EBC), such as tumor metastatic potential, and expand the available information clinicians and patients require for shared treatment decision making beyond the standard clinicopathologic factors. EBC tumors are further stratified into clinically actionable subtypes by molecular assays such as the 80-gene molecular profiling assay BluePrint, improving pathological complete response rates (pCR) and outcomes as evidenced by a number of recent trials. The ongoing FLEX Study (NCT03053193) is designed to expand the genomic information available for EBC cases, and to increase the speed of data generation for rare and underserved research areas. To date, FLEX is the largest international multicenter real-world evidence (RWE) EBC registry, with more than 10,000 patients enrolled in fewer than five years since opening. FLEX pairs full genome data with more than 800 clinical data points collected over 10 years of follow up to provide the most comprehensive big data database available for early-stage breast cancer. The FLEX enrollment has a goal of a minimum of 30,000 patients within 10 years. METHODS: The FLEX study is a multicenter, prospective, observational trial for patients ≥18 years old with histologically proven stage I-III invasive breast cancer that is node negative or positive (up to three nodes) who receive MammaPrint, with or without BluePrint as standard of care management. Patients consent to the collection of clinically annotated full transcriptome data. Additionally, this study protocol allows physicians to investigate targeted populations or clinical trial investigator-initiated studies (IIS) upon approval by a peer-driven Scientific Review Committee. As patients enrolled in the FLEX study meet all eligibility criteria for inclusion no additional consent is required. The FLEX enrollment has already surpassed 1/3 of set target goal. As of April 2022, the trial has surpassed 10,000 patients enrolled at nearly 100 trial sites across the US and Europe, Middle East and Africa (EMEA). To date, there have been 36 publications in international scientific congresses with 39 FLEX IIS and in progress. With over 250 active and collaborating physicians leveraging the shared infrastructure, the IIS have enabled the ability to address disparities in treatment to underrepresented populations, rare subtypes, age, and patient centered specific topics. Current and future questions investigated via this platform will continue to strive to improve outcomes for early-stage breast cancer patients. Citation Format: Alejandra Perez, Hannah Linden, Nathalie Johnson, Sami Diab, Chirag Jani, Chelsea D. Gawryletz, Richard Fine, Laura Lawson, Megan Baker, Victoria Poillucci, Lisa E. Blumencranz, William Audeh. FLEX: 30K Full Transcriptome, Real-World Evidence Database for Early-Stage Breast Cancer, and Investigator-Initiated Protocols [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT2-05-01.

Abstract P6-01-08: Gene signatures provide independent prognostic information in elderly breast cancer patients

Abstract Background: Elderly breast cancer patients (≥70 years old) are under-represented in clinical trials and remain an undertreated population. Gene expression signatures have been shown to add additional prognostic information beyond that of routine clinicopathological factors, however their utility in elderly breast cancer patients remains unclear. As such, the main aim of this study is to determine if gene signatures can provide prognostic information that may help to aid treatment decisions for elderly breast cancer patients. Material and methods: Research versions of the genomic grade index (GGI), 70-gene, 21-gene recurrence score (RS), cell cycle score (CCS), PAM50 and PAM50 Risk of Relapse score - Proliferation (ROR-P) signatures were applied to 39 open access breast cancer datasets totalling 9583 patients. After filtering based on age ≥ 70 years old, the presence of Estrogen Receptor (ER) and survival information availability 871 patients remained. The prognostic capacity of signatures was tested in all (N=871), Estrogen Receptor positive/Lymph node positive (ER+/LN+, N=335) and Estrogen Receptor positive/Lymph node negative (ER+/LN-, N=374) patients using Kaplan-Meier and multi-variable Cox proportional hazard modeling. Models were adjusted for tumor size, grade, ER and lymph node status in all patients, and tumor size and grade in the ER+/LN+ and ER+/LN- subgroup analyses. Recurrence Free Survival (RFS) censored at 10 years was used as clinical endpoint and defined as the time from date of curative surgery to the time of recurrence or death. Both loco-regional recurrences and distant metastatic events were included in this endpoint. Results: Tumours from patients ≥ 70 years of age showed high levels of ER (87%), were large (69% ≥ 20 mm) and were of intermediate or high grade (82%). All gene signatures were statistically significant in Kaplan-Meier analysis of all and ER+/LN+ patients (Logrank P &amp;lt; 0.001). This significance remained in multi-variable analysis (Cox proportional hazards, P ≤ 0.05) with the exception of PAM50 which showed a trend (P ≤ 0.1) in ER+/LN+ patients. In ER+/LN- patients the GGI, 70-gene, PAM50, ROR-P, and CCS signatures were significant in Kaplan-Meier analysis (Logrank P ≤ 0.05) but only the 70-gene, PAM50, ROR-P, and CCS signatures remained so in multi-variable analysis (Cox proportional hazards, P ≤ 0.05). Conclusions: In general, we found that gene signatures provide statistically significant prognostic information in Kaplan-Meier and multi-variable analyses of all, ER+/LN+ and ER+/LN- breast patients over the age of 70. Table 1: Multivariable proportional hazard (Cox) analyses for all gene signatures for patients above age of 70. NOTE: Bold values indicate P &amp;lt; 0.05. aAdjusted for tumor size, tumor grade, estrogen receptor status, and lymph node status. bAdjusted for tumor size and tumor grade. Citation Format: Miguel Castresana Aguirre, Annelie Johansson, Linda S. Lindström, Nick Tobin. Gene signatures provide independent prognostic information in elderly breast cancer patients [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-01-08.

The use of prognostic models in allogeneic transplants: a perspective guide for clinicians and investigators

AbstractAllogeneic hematopoietic cell transplant (HCT) can cure many hematologic diseases, but it carries the potential risk of increased morbidity and mortality rates. Prognostic evaluation is a scientific entity at the core of care for potential recipients of HCT. It can improve the decision-making process of transplant vs no transplant, help choose the best transplant strategy and allows for future trials targeting patients’ intolerances to transplant; hence, it ultimately improves transplant outcomes. Prognostic models are key for appropriate actuarial outcome estimates, which have frequently been shown to be better than physicians’ subjective estimates. To make the most accurate prognostic evaluation for HCT, one should rely on >1 prognostic model. For relapse and relapse-related mortality risks, the refined disease risk index is currently the most informative model. It can be supplemented with disease-specific models that consider genetic mutations as predictors in addition to information on measurable residual disease. For nonrelapse mortality and HCT-related morbidity risks, the HCT-comorbidity index and Karnofsky performance status have proven to be the most reliable and most accepted by physicians. These can be supplemented with gait speed as a measure of frailty. Some other global prognostic models might add additional prognostic information. Physicians’ educated perceptions can then put this information into context, taking into consideration conditioning regimen and donor choices. The future of transplant mandates (1) clinical investigators specifically trained in prognostication, (2) increased reliance on geriatric assessment, (3) the use of novel biomarkers such as genetic variants, and (4) the successful application of novel statistical methods such as machine learning.

Pulmonary Artery Systolic Pressure and Cava Vein Status in Acute Heart Failure with Preserved Ejection Fraction: Clinical and Prognostic Implications

Peak tricuspid regurgitation (TR) velocity and inferior cava vein (ICV) distention are two recognized features of increased pulmonary artery pressure (PASP) and right atrial pressure, respectively. Both parameters are related to pulmonary and systemic congestion and adverse outcomes. However, few data exist about the assessment of PASP and ICV in acute patients affected by heart failure with preserved ejection fraction (HFpEF). Thus, we investigated the relationship existing among clinical and echocardiographic features of congestion, and we analyzed the prognostic impact of PASP and ICV in acute HFpEF patients. We analyzed clinical congestion PASP and ICV value in consecutive patients admitted in our ward by echocardiographic examination using peak Doppler velocity tricuspid regurgitation and ICV diameter and collapse for the assessment of PASP and ICV dimension, respectively. A total of 173 HFpEF patients were included in the analysis. The median age was 81 and median left ventricular ejection fraction (LVEF) was 55% [50-57]. Mean values of PASP was 45 mmHg [35-55] and mean ICV was 22 [20-24] mm. Patients with adverse events during follow-up showed significantly higher values of PASP (50 [35-55] vs. 40 [35-48] mmHg, (p = 0.005) and increased values of ICV (24 [22-25] vs. 22 [20-23] mm, p < 0.001). Multivariable analysis showed prognostic power of ICV dilatation (HR 3.22 [1.58-6.55], p = 0.001) and clinical congestion score ≥ 2 (HR 2.35 [1.12-4.93], p = 0.023), but PASP increase did not reach statistical significance (p = 0.874). The combination of PASP > 40 mmHg and ICV > 21 mm was capable of identifying patients with increased events (45% vs. 20%). ICV dilatation provides additional prognostic information with respect to PASP in patients with acute HFpEF. A combined model adding PASP and ICV assessment to clinical evaluation is a useful tool for predicting HF related events.

Recent Advances in Cervical Cancer Management: A Review on Novel Prognostic Factors in Primary and Recurrent Tumors

Several pathological parameters, including tumor size, depth of stromal invasion, lympho-vascular space invasion and lymph node status, have been proposed as prognostic predictors in cervical cancer. However, given the high mortality and recurrence rate of cervical cancer, novel parameters that are able to provide additional prognostic information are needed in order to allow a better prognostic stratification of cervical cancer patients. A search was conducted on PubMed to identify relevant literature data regarding prognostic factors in cervical cancer. The key words "cervical cancer", "prognostic factors", "pathology", and "outcome" were used. The novel pathological grading system based on tumor budding and cell nest size appeared the most relevant prognostic factor in primary neoplasms. Moreover, other potentially useful prognostic factors were tumor size, depth of stromal invasion, lympho-vascular space invasion, perineural invasion, tumor-free distance and tumor-infiltrating lymphocytes. Prognostic factors related to advanced-stage cervical cancer, including lymph-nodes status, endometrial and cervical involvement as well as distant metastases, were also taken into consideration. According to our findings, tumor budding and cell nest size grading system, depth of stromal invasion, lympho-vascular space invasion, perineural invasion, tumor-free distance and tumor-infiltrating lymphocytes appeared the most relevant factors included in the pathology report.

The performance of the WHO COVID-19 severity classification, COVID-GRAM, VACO Index, 4C Mortality, and CURB-65 prognostic scores in hospitalized COVID-19 patients: data on 4014 patients from a tertiary center registry

To evaluate the predictive properties of several common prognostic scores regarding survival outcomes in hospitalized COVID-19 patients. We retrospectively reviewed the medical records of 4014 consecutive COVID-19 patients hospitalized in our tertiary level institution from March 2020 to March 2021. Prognostic properties of the WHO COVID-19 severity classification, COVID-GRAM, Veterans Health Administration COVID-19 (VACO) Index, 4C Mortality Score, and CURB-65 score regarding 30-day mortality, in-hospital mortality, presence of severe or critical disease on admission, need for an intensive care unit treatment, and mechanical ventilation during hospitalization were evaluated. All of the investigated prognostic scores significantly distinguished between groups of patients with different 30-day mortality. The CURB-65 and 4C Mortality Score had the best prognostic properties for prediction of 30-day mortality (area under the curve [AUC] 0.761 for both) and in-hospital mortality (AUC 0.757 and 0.762, respectively). The 4C Mortality Score and COVID-GRAM best predicted the presence of severe or critical disease (AUC 0.785 and 0.717, respectively). In the multivariate analysis evaluating 30-day mortality, all scores mutually independently provided additional prognostic information, except the VACO Index, whose prognostic properties were redundant. Complex prognostic scores based on many parameters and comorbid conditions did not have better prognostic properties regarding survival outcomes than a simple CURB-65 prognostic score. CURB-65 also provides the largest number of prognostic categories (five), allowing more precise risk stratification than other prognostic scores.

GC-MS Techniques Investigating Potential Biomarkers of Dying in the Last Weeks with Lung Cancer.

Predicting when a patient with advanced cancer is dying is a challenge and currently no prognostic test is available. We hypothesised that a dying process from cancer is associated with metabolic changes and specifically with changes in volatile organic compounds (VOCs). We analysed urine from patients with lung cancer in the last weeks of life by headspace gas chromatography mass spectrometry. Urine was acidified or alkalinised before analysis. VOC changes in the last weeks of life were identified using univariate, multivariate and linear regression analysis; 12 VOCs increased (11 from the acid dataset, 2 from the alkali dataset) and 25 VOCs decreased (23 from the acid dataset and 3 from the alkali dataset). A Cox Lasso prediction model using 8 VOCs predicted dying with an AUC of 0.77, 0.78 and 0.85 at 30, 20 and 10 days and stratified patients into a low (median 10 days), medium (median 50 days) or high risk of survival. Our data supports the hypothesis there are specific metabolic changes associated with the dying. The VOCs identified are potential biomarkers of dying in lung cancer and could be used as a tool to provide additional prognostic information to inform expert clinician judgement and subsequent decision making.

Prognostic Value of Late Gadolinium Enhancement Detected on Cardiac Magnetic Resonance in Cardiac Sarcoidosis

BackgroundSarcoidosis is a complex multisystem inflammatory disorder, with approximately 5% of patients having overt cardiac involvement. Patients with cardiac sarcoidosis are at an increased risk of both ventricular arrhythmias and sudden cardiac death. Previous studies have shown that the presence of late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) is associated with an increased risk of mortality and ventricular arrhythmias and may be useful in predicting prognosis. ObjectivesThis systematic review and meta-analysis assessed the value of LGE on CMR imaging in predicting prognosis for patients with known or suspected cardiac sarcoidosis. MethodsThe authors searched the Embase and MEDLINE databases from inception to March 2022 for studies reporting individuals with known or suspected cardiac sarcoidosis referred for CMR with LGE. Outcomes were defined as all-cause mortality, ventricular arrhythmia, or a composite outcome of either death or ventricular arrhythmias. The primary analysis evaluated these outcomes according to the presence of LGE. A secondary analysis evaluated outcomes specifically according to the presence of biventricular LGE. ResultsThirteen studies were included (1,318 participants) in the analysis, with an average participant age of 52.0 years and LGE prevalence of 13% to 70% over a follow-up of 3.1 years. Patients with LGE on CMR vs those without had higher odds of ventricular arrhythmias (odds ratio [OR]: 20.3; 95% CI: 8.1-51.0), all-cause mortality (OR: 3.45; 95% CI: 1.6-7.3), and the composite of both (OR: 9.2; 95% CI: 5.1-16.7). Right ventricular LGE is invariably accompanied by left ventricular LGE. Biventricular LGE is also associated with markedly increased odds of ventricular arrhythmias (OR: 43.6; 95% CI: 16.2-117.2). ConclusionsPatients with known or suspected cardiac sarcoidosis with LGE on CMR have significantly increased odds of both ventricular arrhythmias and all-cause mortality. The presence of biventricular LGE may confer additional prognostic information regarding arrhythmogenic risk.

The loss of left atrial contractile function predicts a worse outcome in HFrEF patients.

In chronic heart failure, high intracardiac pressures induce a progressive remodeling of small pulmonary arteries up to pulmonary hypertension. At the end of left atrial conduit function, pulmonary and left heart end-systolic pressures equalization might affect left atrial systole. In this single-center prospective study, we aimed to investigate whether peak atrial contraction strain (PACS), measured by speckle tracking echocardiography, was independently associated with prognosis in heart failure with reduced ejection fraction (HFrEF). Outpatients with HFrEF and sinus rhythm referred to our echo-labs were enrolled. After clinical and echocardiographic evaluation, off-line speckle tracking echocardiography analysis was performed. Primary and secondary endpoint were cardiovascular death and heart failure hospitalization, respectively. Spline knotted survival model identified the optimal prognostic cut-off for PACS. The 152 patients were stratified based on PACS <8% (n = 76) or PACS ≥8% (n = 76). Patients with PACS <8% had lower left ventricle and left atrial reservoir strain and higher New York Heart Association (NYHA) class and left atrial volume index (LAVI). Over a mean follow-up of 3.4 ± 2 years, 117 events (51 cardiovascular death, 66 heart failure hospitalizations) were collected. By univariate and multivariate Cox analysis, PACS emerged as a strong and independent predictor of cardiovascular death and heart failure hospitalization, after adjusting for age, sex, left ventricle strain, and E/e', LAVI (HR 0.6 per 5 unit-decrease in PACS). Kaplan-Meier curves showed a sustained divergence in event-free survival rates for the two groups. The reduction of PACS significantly and independently affects cardiovascular outcome in HFrEF. Therefore, its assessment, although limited to patients with sinus rhythm, could offer additive prognostic information for HFrEF patients.

Abstract PR008: Development and testing of a polygenic risk score for breast cancer. Aggressiveness

Abstract Background: Aggressive breast cancers have increased proliferation or metastatic potential and portend a poor prognosis. The ability to identify women at elevated risk of aggressive cancers could have major implications for screening and prevention, yet there are no available tools for predicting aggressive cancer risk. We sought to construct a polygenic risk score (PRS) for aggressive breast cancers by leveraging the associations of single nucleotide polymorphisms (SNPs) with tumor gene expression. We used as our measure of aggressiveness the risk of recurrence score weighted on proliferation (ROR-P), a validated tumor prognostic signature. We hypothesized that known breast cancer susceptibility SNPs would have differential associations with ROR-P, which could then be used to construct a PRS for ROR-P. Methods: We developed our PRS in a case-only analysis of 3 studies containing SNP genotypes and tumor gene expression: The Cancer Genome Atlas, METABRIC, and the I-SPY 2 TRIAL (total n=2,363). We used linear regression models to evaluate individual SNP associations with ROR-P, adjusted for genetic ancestry and study. We then constructed PRS using varying p-value thresholds and used cross-validation to identify the PRS with highest model r2. To assess whether the ROR-P PRS was associated with poor prognosis, we performed survival analysis in two longitudinal cohorts of breast cancer patients: the UK Biobank (women with incident invasive cancers only) and the Pathways Study. These studies included 10,196 total cases with 785 deaths. We built Cox proportional hazards models to evaluate the association between the ROR-P PRS (adjusted for genetic ancestry) and breast cancer-specific survival (BCSS) in both studies. We then performed meta-analysis of the Cox model results. We also constructed joint models containing the ROR-P PRS and a PRS representing the case-case risk of ER-negative vs. ER-positive cancer, PRSER-/ER+. Results: We tested the associations between 226 breast cancer susceptibility SNPs and ROR-P. The best-performing PRS contained 76 SNPs and had a cross-validated r2 of 0.051. In the UK Biobank and Pathways Study, higher ROR-P PRS was associated with worse BCSS, with nearly identical effects observed in each study, HR per standard deviation of 1.13 (95% CI 1.05-1.21, p=9.0x10-4) in meta-analysis. The ROR-P PRS’s effect was minimally attenuated when adjusted for PRSER-/ER+, suggesting that the ROR-P PRS was providing additional prognostic information beyond ER status. Conclusions: We used breast cancer susceptibility SNPs to construct a PRS for ROR-P, a prognostic signature recapitulating aggressiveness, and found the ROR-P PRS to be associated with worse BCSS. Our findings represent an improvement on current PRS for overall breast cancer risk, which preferentially predict cancers with favorable prognosis. Given that aggressive cancers are more likely to present as advanced cancers even among women undergoing routine screening, our findings could potentially identify women who may benefit from more intensive screening. Citation Format: Yiwey Shieh, Jacquelyn Roger, Christina Yau, Denise Wolf, Gillian Hirst, Lamorna Swigart, Scott Huntsman, Donglei Hu, Jovia Nierenberg, Pooja Middha, Rachel Heise, Linda Kachuri, Qianqian Zhu, Song Yao, Christine Ambrosone, Marilyn Kwan, Bette Caan, John Witte, Lawrence Kushi, Laura van ’T. Veer, Laura Esserman, Elad Ziv. Development and testing of a polygenic risk score for breast cancer. Aggressiveness. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr PR008.

Left ventricular myocardial work index and short-term prognosis in patients with light-chain cardiac amyloidosis: a retrospective cohort study

Reports show that the left ventricular myocardial work index (LVMWI) is a novel parameter for evaluating cardiac function. Decompensated heart failure leads to a high rate of early mortality in advanced patients with light-chain cardiac amyloidosis (AL-CA) and prevents them from a relatively delayed response to chemotherapy. This study aimed to assess the association of the LVMWI with short-term outcomes and to construct a simple model for risk stratification. A total of 79 patients with an initial diagnosis of AL-CA were included in this retrospective cohort study. LVMWI was calculated by integrating brachial artery cuff blood pressure and left ventricular longitudinal strain (LVLS). The short-term outcome was defined as 6-month all-cause mortality. Receiver operating characteristic (ROC), logistic regression, and Kaplan-Meier analysis were used in this study. The median follow-up time was 21 months (3-36 months), and 23 (29%) patients died in the first 6 months. The time-dependent ROC and the area under the curve (AUC) showed that the LVMWI had the best predictive potential at the 6-month time point [AUC =0.805; 95% confidence interval (CI): 0.690-0.920]. A bivariate prognostic model based on the LVMWI was constructed, and D-dimer showed a synergistic effect with optimum predicted potential (AUC =0.877; 95% CI: 0.791-0.964). Kaplan-Meier analysis demonstrated that patients with two, one, and none of the variates beyond the cut-off value bore a different risk of 6-month all-cause mortality (accumulated mortality was 86%, 30%, 3%, respectively; log-rank, P<0.001). Multivariate nested logistic regression showed that the level of D-dimer provided an incremental prognostic value (Δχ2=10.3; P=0.001) to the value determined from New York Heart Association (NYHA) classification and the LVMWI. The LVMWI is associated with the short-term outcome of patients with AL-CA. The D-dimer test provides additional prognostic information for the LVMWI.

Infiltrative Growth Predicts the Risk of Recurrence After Surgery in Well-Differentiated Non-Functioning Pancreatic Neuroendocrine Tumors.

The incidence of well-differentiated non-functioning pancreatic neuroendocrine tumors (NF-PanNET) increased during the last decades. The risk of relapse after curative surgery, albeit low, is not negligible; moreover, adjuvant treatment is currently not an option and a reliable predictive model based on prognostic characteristics is urgently needed for tailoring a follow-up strategy. The histological classification of PanNET now relies only on the proliferative activity (mitosis and Ki67) and staging. In contrast to other endocrine neoplasms, the role of infiltrative growth pattern in NF-PanNET is not taken into consideration at present. In the current study, 247 consecutive patients who underwent surgical resection for a NF-PanNET were examined for the histological growth pattern of the tumor. Two distinct patterns (non-infiltrative vs. infiltrative) were described with the latter being further subclassified according to the type of structures invaded by the tumor (non-infiltrative: pattern 1; infiltration of adjacent pancreatic parenchyma and/or peripancreatic soft tissue: pattern 2; invasion of nearby organs and/or major vessels: pattern 3). The infiltrative growth resulted to be strongly associated with a poorer survival compared to a non-infiltrative growth (p < 0.001). In particular, the distinction between pancreatic parenchyma and/or peripancreatic soft tissue invasion versus adjacent organs and/or major vessels invasion was the most powerful predictor of recurrence after surgery at multivariate analysis (pattern 2 vs. pattern 1: HR 10.136, p = 0.028; pattern 3 vs. pattern 1: HR 15.775, p = 0.015). The infiltrative growth pattern could therefore provide additional prognostic information implementing the current grading and staging system.

Loss of perceived social role, an index of social frailty, is an independent predictor of future adverse events in hospitalized patients with heart failure.

Although the impact of physical frailty on prognosis and the effect of cardiac rehabilitation in HF patients has been well established, data for the prognostic impact of social frailty (SF) in HF patients are limited. In addition, the relative importance of each SF domain in clinical outcomes remains unclear. We aimed to get a new insight into the associations of SF with clinical outcomes in elderly hospitalized HF patients. A single-center, retrospective cohort study was conducted using data from 310 in-hospital HF patients aged ≥ 65 years (mean age of 78 ± 8 years; 49% women). Makizako's five questions, a self-reported questionnaire, were used to define SF. The primary outcome was composite events defined by all-cause death and cardiovascular events. Of the 310 elderly HF patients, 188 patients (61%) had SF. Seventy-five patients (24%) had composite events during a mean follow-up period of 1.93 ± 0.91 years. Kaplan-Meier curves showed that patients with SF had a significantly higher composite event rate than patients without SF. In multivariate Cox regression analyses, SF was independently associated with a higher composite event rate after adjusting for prognostic markers [adjusted hazard ratio (HR), 2.01; 95% confidence interval (CI), 1.07-3.78; p = 0.04]. Of the 5 questions for defining SF, an answer of yes to the question about not feeling helpful toward friends or family, which indicates loss of perceived social role, was an independent predictor of composite events (adjusted HR, 2.28; 95% CI, 1.36-3.82; p < 0.01). Inclusion of loss of perceived social role into the baseline prognostic model improved both the continuous net reclassification improvement (0.562; 95% CI, 0.298-0.827; p < 0.01) and integrated discrimination improvement (0.031; 95% CI, 0.006-0.056; p = 0.02). Loss of perceived social role is associated with increased adverse event risk and provides additive prognostic information in elderly HF patients.

Myocardial contraction fraction predicts mortality in the oldest old.

People over the age of 85 are the world's most rapidly growing age group. Ejection fraction (EF) may be limited prognostically in this population and myocardial contraction fraction (MCF) may be more accurate. The objective of this longitudinal study was to assess the prognosis of MCF in an age-homogenous, community-dwelling population of subjects. Subjects were recruited from the Jerusalem Longitudinal Cohort Study. Echocardiography was performed with a portable echocardiograph at the subjects place of residence. Standard echocardiographic assessment of cardiac structure and function including MCF was performed. Values of EF and MCF above and below the median for males and females were defined as normal and abnormal in categorical analysis. 5-year mortality was assessed via a centralized government database. 418 subjects (199 males, 219 females) were enrolled in the study of whom 113 (27%) died at the time of 5-year follow-up. Subjects who died had significantly lower MCF (32±14% vs 36±12%; p<0.004) and EF (51.6±11.6% vs 56.3±9.4%; p<0.0001) than survivors. The association between MCF and mortality remained significant on clinical multivariate analysis as both a categorical and continuous variable while EF was only significant as a continous variable. When both EF and MCF were added to the model only MCF as a categorical variable remained significant. MCF assessed by home echocardiography provides additional prognostic information to EF and may be a superior predictor of 5-year mortality in a community-dwelling population of the oldest old.

Central blood pressure augmentation and central-to-peripheral blood pressure amplification in relation to cardiovascular end points.

Background: Central hemodynamic indices might provide additional prognostic information for cardiovascular risk beyond blood pressure (BP) and other conventional risk factors. The aim of the study is to investigate whether indices of central BP augmentation and central-to-peripheral BP amplification were associated with cardiovascular end points. Methods: In a population-based cohort study of 5,608 adults recruited in Europe, Asia and South America, baseline measurements included cardiovascular risk factors, central hemodynamic measurements derived from the radial pulse wave analysis by the tonometric method with the SphygmoCor device (Atcor, Australia). The primary outcome was a composite cardiovascular end point. Secondary end points included total mortality, fatal and nonfatal coronary events and fatal and nonfatal stroke. The multivariable-adjusted hazard ratios (HR) were expressed as the risk per 1-SD increment in central hemodynamic indices. Results: Among 5,608 participants (54.1% women; mean age, 54.2 years), median follow-up was 4.1 years. Central augmentation index, augmentation pressure, systolic BP (SBP) amplification (brachial SBP minus central SBP), pulse pressure (PP) amplification (brachial PP minus central PP) and PP amplification ratio (brachial PP/central PP*100%) averaged 26.8%, 12.7 mmHg, 10.3 mmHg, 11.4 mmHg and 130.9%, respectively. The primary composite cardiovascular end point occurred in 255 participants (4.5%). Central augmentation index (HR, 1.21; 95%CI, 1.00-1.47; P=0.048) and augmentation pressure (HR, 1.17; 95%CI, 1.01-1.36; P=0.033), but not amplification indices (P>=0.18), were significantly associated with the primary outcome. For secondary end points, central augmentation index (HR, 1.56; 95%CI, 1.17-2.09; P=0.003), augmentation pressure (HR, 1.36; 95%CI, 1.06-1.75; P=0.017) and PP amplification ratio (HR, 0.63; 95%CI, 0.44-0.91; P=0.015) were significantly associated with coronary end points, while there was no significant association with total mortality and stroke. Conclusions: In adult populations, central BP augmentation indices were associated with cardiovascular outcomes independent of conventional cardiovascular risk factors.

Incremental value of left ventricular global longitudinal strain in moderate aortic stenosis and reduced left ventricular ejection fraction

BackgroundModerate aortic stenosis (AS) often coexists with left ventricular (LV) systolic dysfunction and may affect survival through afterload mismatch. Because outcomes are ultimately driven by the condition of the LV, accurate assessment of LV performance is crucial to improve risk stratification. This study investigated the prognostic value of LV global longitudinal strain (GLS) in patients with moderate AS and reduced LV systolic dysfunction. MethodsPatients with moderate AS (aortic valve area 1.0–1.5 cm2) and reduced LV ejection fraction (EF) (<50%) were identified. LVGLS was evaluated with speckle-tracking echocardiography. Patients were divided into 2 groups according to an LVGLS value of 11%, based on spline curve analysis. The primary endpoint was all-cause mortality. ResultsA total of 166 patients (mean age 73 ± 11 years, 71% male) were included. The cumulative 1- and 5-year mortality rates were higher in patients with LVGLS <11% (25% and 60%) versus LVGLS ≥11% (10% and 27%) (p < 0.001). On multivariable analysis, LVGLS as a continuous variable (HR 0.753; 95% CI 0.673–0.843; p < 0.001) and as a categorical variable (<11%) (HR 3.028; 95% CI 1.623–5.648; p < 0.001) were independently associated with outcomes, whereas LVEF was not. LVGLS provided additional prognostic information in patients with/without coronary artery disease and with mildly versus severely reduced LVEF. In addition, LVGLS had incremental prognostic value over established risk factors, including LVEF. ConclusionThe combination of moderate AS and reduced LV systolic dysfunction is associated with a high mortality risk. LVGLS, but not LVEF, is independently associated with mortality and provides incremental prognostic value over established risk factors in patients with moderate AS and reduced LVEF.

Fast-Track Measurable Residual Disease Detection By Multiparametric Flow Cytometry in Acute Myeloid Leukemia before Allogeneic Hematopoietic Cell Transplantation

Introduction In acute myeloid leukemia (AML), measurable residual disease (MRD) becomes more and more important for individualized treatment decisions. The MRD status at the time of allogeneic hematopoietic cell transplantation (alloHCT) provides prognostic information beyond baseline risk features. Peri-transplant treatment strategies and conditioning intensity can be stratified according MRD-levels. However, therapeutic interventions (e.g. conditioning intensity) usually require the prompt availability of reliable information on the MRD status. We assessed the prognostic value of a standardized, reproducible, and fast turnover multiparametric flow cytometry (MFC) approach that has been validated at the end of intensive induction therapy to monitor MRD before alloHCT (Röhnert, Leukemia 2022). This approach allows for the simultaneous detection of MRD by the leukemia-associated immunophenotype (LAIP) and the different from normal (DfN) method. Methods Between October 2016 and March 2020, bone marrow (BM) aspirates of patients (pts) with AML were analyzed for the presence of MRD immediately before the start of conditioning. therapy with the aim of analyzing to predictive value of this fast-track parameter. Pts receiving sequential regimens (re-induction chemotherapy followed by reduced-intensity conditioning) were excluded. Briefly, the LAIP-based DfN analysis is based on a hierarchical gating strategy with fixed gates and encompasses the antigens CD34, CD117, HLA-DR (backbone markers), CD13, CD33 (myeloid markers), CD7 and CD56 (lymphoid markers). Within less than 5 minutes, the analysis checks for the presence of the aberrant categories i) deficiency of myeloid markers and ii) cross-lineage expression of lymphoid markers. Reference values for 32 immunophenotypically defined populations were established on BM aspirates of 90 leukemia free controls. An aberrant category already detectable at diagnosis on ≥10% of myeloid progenitors/ monocytes was termed aberrant LAIP (aLAIP) and a de-novo appearance (after chemotherapy) post-treatment DfN (ptDfN). In conclusion this approach is very fast and provides high reproducibility. Results We identified 58 pts with a median follow-up of 33.3 months after alloHCT (Table 1 with pts characteristics). Response assessment was performed in median 8 days before alloHCT. Most of the patients were in morphologic complete remission (CR n=37). A subset of 21 patients had refractory disease with a median BM blast count of 6.5%. Samples at AML diagnosis were available for 48/58 (83%) pts, of whom 34/48 (71%) showed at least one aLAIP at initial diagnosis. Before start of conditioning, 44/58 (76%) patients were MRDpos. The proportion of MRDpos in responders was lower compared to non-responders: 24/37 (65%) vs. 20/21 (95%) (p=0.0106). MRDpos was designated by aLAIPonly, ptDfNonly and aLAIP+ptDfN in 18%, 48% and 34% of cases, respectively. Noteworthy, 8 of 21 pts classified MRDpos by ptDfNonly had no sample available at diagnosis and therefore could not be assessed for aLAIP persistence. Amongst 37 pts in CR before alloHCT, 12/24 (50%) of MRDpos pts relapsed compared to 3/13 (23%) of MRDneg pts. TRM in these patients did not differ (13% vs. 8%). In a univariable Cox regression analysis, the 1-year Overall survival (OS) rate of MRDpos cohort was significantly shorter compared to MRDneg pts (64% vs. 93%, Hazard ratio (HR) 10.5, p=0.004). MRD was detected by ptDfNonly in 23/44 (52%) of MRDpos pts. The OS of these pts was comparable to MRDpos by aLAIP with or without ptDfN (Figure 1). As expected, the MRDpos cohort was enriched for non-responders. However, when the analysis was restricted to pts in CR (n=37), MRD status preserved its prognostic significance (HR 7.9, p=0.019). And even in the subpopulation of pts in first CR, MRDpos was associated with a significantly reduced OS compared to MRDneg (HR 6.3, p=0.043). Interestingly, a single non-responder was classified as MRDneg and showed a long-term OS. Conclusions Our fast-track LAIP-based DfN approach provides relevant prognostic information prior to conditioning for allo HCT. On top of the classical LAIP approach, the ptDfN analysis gives additional prognostic information. The LAIP-based DfN approach might be a suitable tool for fast-track and reliable MRD assessment before starting the preparative regimen for alloHCT and might help to guide potential treatment modifications. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal