Citations

Introduction: Impaired left atrial (LA) function may limit optimal cardiac performance, reflecting both LA load and atrial dysfunction in HFpEF. The link between MRI-derived LA characteristics and exercise capacity in HFpEF has not been studied. Hypothesis: We hypothesized that total LA emptying fraction (LAEF) is reduced in HFpEF vs. healthy controls and LA functional impairment would be correlated with LV diastolic dysfunction, vascular dysfunction, and exercise intolerance. As LA hypertension may increase right ventricular load and limit increases in pulmonary perfusion with exercise, the correlation of LAEF with ventilatory efficiency (VE/VCO2 slope) was also examined. Methods: Baseline exercise, echo, and cardiac MRI data from RELAX (a study of sildenafil in HFpEF) in patients in sinus rhythm with a measureable LAEF by MRI (n=100) were utilized. Healthy volunteers (n=21) were included for comparison. LAV was measured by the biplane area-length method using 2-/4-chamber SSFP CMR. LAEF was defined as total (ΔLAVmax-min), passive/conduit (ΔLAVmax-before atrial contraction ), and active (ΔLAVbefore atrial contraction-min), each divided by maximal LAV. Results: As compared to controls, LAEF (particularly passive conduit function) was reduced in HFpEF (Table 1). In HFpEF, patients with lower LAEF had a larger LA, more echo diastolic dysfunction, higher PA systolic pressure and NT-proBNP, reduced aortic distensibility, worse exercise capacity, and ventilatory inefficiency (Table 2). Conclusions: LA function is impaired in HFpEF, may serve as a marker of chronic LA hypertension and may contribute to impaired exercise intolerance and ventilatory inefficiency.

Abstract Introduction In this pilot study, sleep biomarker-based neurodegenerative disorder (NDD) risk was assessed in a clinical cohort of patients diagnosed with varying severity of obstructive sleep apnea (OSA). Methods Consecutive in-home multi-night Sleep Profiler records from a community sleep clinic were screened for age >54 years old. Cases with comorbid restless leg syndrome, hypersomnia, missing apnea-hypopnea indexes (AHI), AHI< 5 or single-night recordings were excluded. The 67 remaining records were 40% female, ages 63 + 7.4 years and up to 84 years old. NDD risk was assigned using a machine-learning algorithm combining age and nine sleep biomarkers to assign group probabilities: for Alzheimer’s disease, Lewy Body disease, prodromal synucleinopathy and controls (CG). Sleep biomarkers included: time-REM, non-REM hypertonia, autonomic-activation index, spindle-duration, atypical-N3, time-supine, sleep-efficiency, relative-theta, and theta/alpha. Those with CG probability score >70% were classified as “Probably-normal”. Those with CG probability between 45 - 70% were classified as “Likely-normal”. Insomnia severity >14 and a PHQ 9 > 5 were used as cutoffs for clinical insomnia and depression. Mann-Whitney U-tests were used to evaluate group differences. Results This cohort had 37% mild, 34% moderate, and 29% severe OSA. Self-reported comorbid insomnia and depression were present in 43%. Seventy-three percent of patients were classified as “Probably-normal”, 16% “Likely-normal”, 11% “Likely-NDD” or “Probable-NDD”. The “Probably-normal” group was younger than the rest of the cohort (62 + 6.2 years vs. 68 + 8.6 years, p< 0.01). Of those classified as “Probably-normal” (n=49), OSA was mild in 16, moderate in 17 and severe in 16. Mean AHI trended higher in the “Probably-normal” group than in those with elevated NDD risk (29 + 23.9 vs. 19 + 13.6 events/h, p=0.085). Conclusion Approximately 89% of the clinical cohort was classified as “Probably-normal” or “Likely-normal”. NDD risk was age-dependent. Interactions between OSA severity and NDD risk were not apparent in these findings, possibly related to group-wide effects. NDD risk, as measured by this model, did not appear to be adversely biased by untreated OSA. These results suggest a need for longitudinal studies to compare NDD risk in untreated OSA versus controls without sleep disordered breathing. Support (if any) NIH grants R44AG050326, R44AG054256, RO1AG060477, R33AG064271, ULRR024150, and R34AG056639.

Background Coronary microvascular dysfunction (CMD) represents an early functional characteristic of coronary vascular aging. Klotho (α‐klotho) is a circulating protein inversely linked to physiological aging. We examined low klotho as a potential marker for vascular aging in patients with CMD and no coronary artery disease. Methods and Results Patients undergoing nonurgent angiogram for chest pain who had no coronary artery disease underwent invasive coronary microvascular and endothelial function testing. CMD was defined by ≤50% increase in coronary blood flow (percentage change in coronary blood flow) in response to intracoronary acetylcholine or coronary flow reserve ≤2. Fresh arterial whole blood was used to analyze circulating endothelial progenitor cells with flow cytometry. Stored arterial plasma was used for klotho analysis by ELISA. Participants with CMD (n=62) were compared with those without CMD (n=36). Those with CMD were age 55±10 years (versus 51±11 years; P =0.07) and 73% women (versus 81%; P =0.38). Traditional risk factors for coronary artery disease were similar between groups. Patients with CMD had less klotho (0.88±1.50 versus 1.75±2.38 ng/mL; P =0.03), and the odds of low klotho in CMD were significant in a logistic regression model after adjusting for traditional cardiovascular risk factors (odds ratio [OR], 0.80 [95% CI, 0.636–0.996]; P =0.05). Higher klotho was associated with higher numbers of endothelial progenitor cells with vascular regenerative potential (CD34 + and CD34 + CD133 + KDR + ). Among a subgroup of patients with atherosclerotic cardiovascular disease risk <5% (n=58), CMD remained associated with lower klotho (OR, 0.80 [95% CI, 0.636–0.996]; P =0.047). Conclusions Klotho may be a biomarker for CMD and may be a therapeutic target for groups of patients without significant traditional cardiovascular risk.

AbstractInterstitial lung disorders are a group of respiratory diseases characterized by interstitial compartment infiltration, varying degrees of infiltration, and fibrosis, with or without small airway involvement. Although some are idiopathic (e.g., idiopathic pulmonary fibrosis, idiopathic interstitial pneumonias, and sarcoidosis), the great majority have an underlying etiology, such as systemic autoimmune rheumatic disease (SARD, also called Connective Tissue Diseases or CTD), inhalational exposure to organic matter, medications, and rarely, genetic disorders. This review focuses on diagnostic approaches in interstitial lung diseases associated with SARDs. To make an accurate diagnosis, a multidisciplinary, personalized approach is required, with input from various specialties, including pulmonary, rheumatology, radiology, and pathology, to reach a consensus. In a minority of patients, a definitive diagnosis cannot be established. Their clinical presentations and prognosis can be variable even within subsets of SARDs.

Abstract Introduction/Aims Biomarkers have shown promise in amyotrophic lateral sclerosis (ALS) research, but the quest for reliable biomarkers remains active. This study evaluates the effect of debamestrocel on cerebrospinal fluid (CSF) biomarkers, an exploratory endpoint. Methods A total of 196 participants randomly received debamestrocel or placebo. Seven CSF samples were to be collected from all participants. Forty‐five biomarkers were analyzed in the overall study and by two subgroups characterized by the ALS Functional Rating Scale‐Revised (ALSFRS‐R). A prespecified model was employed to predict clinical outcomes leveraging biomarkers and disease characteristics. Causal inference was used to analyze relationships between neurofilament light chain (NfL) and ALSFRS‐R. Results We observed significant changes with debamestrocel in 64% of the biomarkers studied, spanning pathways implicated in ALS pathology (63% neuroinflammation, 50% neurodegeneration, and 89% neuroprotection). Biomarker changes with debamestrocel show biological activity in trial participants, including those with advanced ALS. CSF biomarkers were predictive of clinical outcomes in debamestrocel‐treated participants (baseline NfL, baseline latency‐associated peptide/transforming growth factor beta1 [LAP/TGFβ1], change galectin‐1, all p < .01), with baseline NfL and LAP/TGFβ1 remaining ( p < .05) when disease characteristics ( p < .005) were incorporated. Change from baseline to the last measurement showed debamestrocel‐driven reductions in NfL were associated with less decline in ALSFRS‐R. Debamestrocel significantly reduced NfL from baseline compared with placebo (11% vs. 1.6%, p = .037). Discussion Following debamestrocel treatment, many biomarkers showed increases (anti‐inflammatory/neuroprotective) or decreases (inflammatory/neurodegenerative) suggesting a possible treatment effect. Neuroinflammatory and neuroprotective biomarkers were predictive of clinical response, suggesting a potential multimodal mechanism of action. These results offer preliminary insights that need to be confirmed.

Abstract Background: Advanced prostate cancer is defined as metastatic hormone-sensitive prostate cancer (mHSPC) or castration-resistant prostate cancer (CRPC). Newer and aggressive treatments are leading to increasing lifespans in this population. As such, studying quality of life could have a large impact on the survivorship experience. An important component of quality of life is financial toxicity, defined as the financial burden and distress that can arise for patients and their families because of cancer treatment. Objectives: To understand the prevalence and predictors of financial toxicity in advanced prostate cancer. Methods: IRONMAN (International Registry of Men with Advanced Prostate Cancer) is a prospective cohort of patients with newly diagnosed mHSPC or CRPC enrolling in 15 countries. Financial toxicity was collected using the EORTC QLQ-C30 (“has your physical condition or medical treatment caused you financial difficulties?”) at enrollment and every three months thereafter. For this analysis, we studied 997 patients cared for at 37 US sites enrolled from 7/2017 to 7/2023. We examined baseline and longitudinal reports of financial toxicity across clinical and demographic factors: age at enrollment, race and ethnicity, disease state, marital status, education, employment, military status, and type of health center. We conducted adjusted risk difference analysis and multivariable regression modeling to identify predictors of financial toxicity using a generalized estimating equations approach to calculate odds ratios (OR and 95% confidence intervals, CI). Results: At enrollment, 125 (13%) patients reported experiencing “quite a bit” or “very much” financial toxicity. 21% of Black patients experienced toxicity compared to 10% of White patients. Even after incorporating all other predictors, Black patients experienced 5% (95% CI: 0, 11) greater toxicity than White patients. Independently of other predictors, patients &gt;75 experienced 11% (CI: -17, -4) lower toxicity compared to those &lt;65 years (while patients in the 65-74 group experienced 6% less, CI: -12, 1). Toxicity was 6% greater in patients with mHSPC (CI: 2, 10) than in patients with CRPC, and disabled or unemployed patients were at substantially higher risk. In the multivariable longitudinal analyses, older age (&gt; 75) remained associated with significantly lower odds for financial toxicity (OR: 0.30, 0.15-0.61) while mHSPC (OR: 1.91, 1.14-3.20) and being unemployed (OR: 2.69, 1.03-6.99) or disabled (OR: 5.14, 2.29-11.6) were associated with higher odds. Conclusions: Financial toxicity is prevalent in advanced prostate cancer, especially in patients who are Black, younger than 75, diagnosed with mHSPC, or unemployed/disabled. These results may inform identification of patients at high risk for financial toxicity to support delivery of patient-situation-informed care by clinicians and targeted aid for patients at highest risk. Citation Format: Isani Singh, Bailey Vaselkiv, Emily Rencsok, Karen Autio, Deborah Enting, Alicia Morgans, Joel Nowak, Kevin Kensler, David Nanus, Robert Dreicer, Brian Lewis, Oliver Sartor, Elisabeth Heath, Phillip Kantoff, Deborah Kaye, Daniel George, Lorelei Mucci. Financial toxicity among patients with advanced prostate cancer in the United States [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3410.

Abstract Cholangiocarcinoma (CCA) is an aggressive epithelial malignancy of the bile ducts. Recent reports have suggested a rise in the incidence of CCA globally. Current treatments for CCA have limited effectiveness, with only 20-30% response rates in patients with advanced cancer. Thus, there is a growing need to investigate new therapeutic targets for CCA. The tumor microenvironment (TME) is a potential target for novel therapies. The TME plays an important role in progression and metastasis of cancer through facilitating immune escape. Recent studies have demonstrated potential roles for heparan sulfate proteoglycans (HSPGs) in tumorigenesis. Sulfatase 2 (SULF2) is a heparan sulfate editing sulfatase that removes the 6-O sulfate moiety within the heparan sulfate (HS) chains and alters the affinity of HS chains for growth factors and cytokines and their receptors, thus modulating HSPG function in cell signaling pathways. HSPG specific sulfatases have been recently identified as a potential therapeutic target in CCA. We aimed to assess the effects of anti-Sulfatase-2 antibody on immune cells in the tumor microenvironment of syngeneic CCA xenografts in C57BL6 mice. Mice bearing syngeneic CCA xenografts were treated with an anti-sulf2 antibody, and the tumors compared to untreated control xenografts. After treatment, the tumors were harvested and analyzed by Cytometry by time of flight (Cytof) to identify changes in the types and numbers of immune cells in the tumor xenografts. Treatment with anti-sulf2 antibody resulted in a decrease in immunosuppressive cells such as tumor associated macrophages (TAMs) and myeloid derived suppressor cells (MDSC) compared to the control. There was also an increase in anti-tumor cells such as T-cells and NK cells, suggesting that suppressing sulf-2 in the microenvironment can shift the TME toward an anti-tumorigenic rather than a pro-tumorigenic environment. In summary, our work demonstrates the potential to target Sulfatase 2 as a therapeutic mechanism for immunomodulation of the tumor microenvironment. Future experiments to determine the relationship between specific clinical phenotypes and the number, activities and types of immune cells seen in the TME, and experiments in other hepatobiliary cancers models, such as hepatocellular carcinoma and gallbladder cancer, will be conducted. Citation Format: Tayla R. Brooks, Nellie Campbell, Melanie Keim, Lewis R. Roberts. Modulating the immune response in cholangiocarcinoma: Targeting sulfatase-2 for therapeutic intervention [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6525.

Abstract Background: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide. In sub-Saharan Africa, HCC is the second most common cancer in men and the sixth in women. African patients present with HCC at a young age and at advanced stage of disease. Improved surveillance can increase early HCC detection. The GALAD score has good sensitivity in the diagnosis of HCC in Asia, Europe and North America, however, it has not been validated in an African cohort. The aim of this study was to assess the performance of the GALAD score in the diagnosis of HCC in Ghanaian patients. Methods: Clinical data from patients with cirrhosis (n=93) or HCC (n=78) from out-patient hepatology clinics at 3 teaching hospitals in Ghana were abstracted, and serum samples analyzed. A logistic regression model predicting HCC status based on GALAD score was constructed to obtain the Receiver Operating Characteristics (ROC) curve for GALAD. The area under the curve (AUC) with 95% confidence interval was calculated and used to assess the performance of the GALAD score in surveillance for HCC. Results: The median AFP (5010.2 vs. 3.4), L3% (28.3 vs. 0.3) and DCP (507.6 vs. 0.2) levels were all significantly higher among HCC cases than the controls (p&lt;0.0001). The median GALAD score was also higher among HCC patients (8.0 vs. -4.1, p&lt;0.0001). The AUC of the GALAD score in the diagnosis of HCC was 0.86 (95% CI 0.79 - 0.92). At a cut-off value of -0.37, the GALAD score had a sensitivity of 0.81 and a specificity of 0.86. In a re-fit of the logistic regression model, the most significant factors in the GALAD model in our cohort were AFP-L3% and log(DCP). The AUC of the new GALAD model after model selection was 0.89. Conclusion: The GALAD score can be used to detect HCC in Ghana and has the potential to improve HCC surveillance in low-resource settings in sub-Saharan Africa. Citation Format: Yvonne Ayerki Nartey, Ju Dong Yang, Tyler Zemla, Joshua Ayawin, Shadrack Osei Asibey, Mohamed El-Kassas, Sally Afua Bampoh, Amoako Duah, Adwoa Agyei-Nkansah, Yaw Asante Awuku, Mary Yeboah Afihene, Hiroyuki Yamada, Jun Yin, Amelie Plymoth, Lewis Rowland Roberts. Accuracy of the GALAD serologic model in the diagnosis of hepatocellular carcinoma in Ghanaian patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4802.