Citations

Abstract Background: End-stage liver disease (ESLD) is a major burden on public health, particularly in sub-Saharan Africa, where hepatitis B virus (HBV) is an important risk factor. We aimed to describe clinical characteristics of ESLD from cirrhosis or hepatocellular carcinoma (HCC) and the performance of aspartate aminotransferase (AST) - platelet ratio index (APRI) and alpha fetoprotein (AFP) in Ghana. Methods: We performed an observational cross-sectional study in outpatient hepatology clinics at three teaching hospitals in Ghana, West Africa. One hundred and forty-one HCC, 216 cirrhosis and 218 chronic HBV patients were recruited by convenience sampling. Sociodemographic, history and examination, laboratory, and disease staging information were shown using descriptive statistics. Performance of the APRI score in diagnosis of cirrhosis and AFP in the diagnosis of HCC was determined using AUROC analysis.Results: Median age at presentation was 44 years for HCC and 46 years for cirrhosis. HBV was found in 69.5% of HCC and 47.2% of cirrhosis cases, and HCV in 6.4% and 3.7% respectively. APRI cut-off of 2 had sensitivity of 45.4% and specificity of 95% in diagnosis of cirrhosis, and cut-off of 1 had sensitivity of 75.9% and specificity of 89%. AUC of AFP was 0.88 (95% CI 0.81-0.94) in diagnosis of HCC. Low monthly income was associated with lower odds of undertaking AFP. Thirty one percent of cirrhotic persons were Child-Pugh C, and 67.9% of HCC patients had advanced or terminal disease at presentation. Conclusions: Our findings emphasize the young age of ESLD patients in Ghana and the advanced nature at presentation. It highlights shortcomings in surveillance and the need for policies to address the burden and improve outcomes in Ghana.

Abstract Background The survival benefit of combination antifungal therapy for invasive mucormycosis (IM) in patients with hematologic malignancy (HM) and hematopoietic cell transplant (HCT) is not well defined. Methods This multicenter, retrospective study included HM and HCT recipients with proven or probable IM between January 1, 2007 and December 31, 2017 from 10 transplant centers across North America. Results Sixty-four patients with proven (n = 47) or probable (n = 17) IM defined by 2008 European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) consensus definitions were included. Thirty-nine (61%) were HCT recipients (95% allogeneic). Sites of infection included rhino-orbital-cerebral (33), pulmonary (30%), disseminated (19%), gastrointestinal (3%), and cutaneous (3%). Surgical debridement was performed in 66%. Initial antifungal treatment consisted of the following: lipid formulation of amphotericin B (AmB) alone (44%), AmB + posaconazole (25%), AmB + echinocandin (13%), AmB + isavuconazole (8%), posaconazole alone (5%), and isavuconazole alone (3%). All-cause mortality at 30 days and 1 year were 38% and 66%, respectively. Initial treatment with AmB plus posaconazole or isavuconazole (n = 28) was associated with a trend toward lower treatment failure compared with AmB (n = 21) (42% vs 64%, P = .136). Conclusions Long-term survival with IM among HM and HCT populations remains poor. However, initial use of AmB + azole in conjunction with surgery may result in less treatment failure. More evidence from prospective controlled studies is needed to confirm this observation.

Abstract Background: End-stage liver disease (ESLD) is a major burden on public health, particularly in sub-Saharan Africa, where hepatitis B virus (HBV) is an important risk factor. We aimed to describe clinical characteristics of ESLD from cirrhosis or hepatocellular carcinoma (HCC) and the performance of aspartate aminotransferase (AST) - platelet ratio index (APRI) and alpha fetoprotein (AFP) in Ghana. Methods: We performed an observational cross-sectional study in outpatient hepatology clinics at three teaching hospitals in Ghana, West Africa. One hundred and forty-one HCC, 216 cirrhosis and 218 chronic HBV patients were recruited by convenience sampling. Sociodemographic, history and examination, laboratory, and disease staging information were shown using descriptive statistics. Performance of the APRI score in diagnosis of cirrhosis and AFP in the diagnosis of HCC was determined using AUROC analysis.Results: Median age at presentation was 44 years for HCC and 46 years for cirrhosis. HBV was found in 69.5% of HCC and 47.2% of cirrhosis cases, and HCV in 6.4% and 3.7% respectively. APRI cut-off of 2 had sensitivity of 45.4% and specificity of 95% in diagnosis of cirrhosis, and cut-off of 1 had sensitivity of 75.9% and specificity of 89%. AUC of AFP was 0.88 (95% CI 0.81-0.94) in diagnosis of HCC. Low monthly income was associated with lower odds of undertaking AFP. Thirty one percent of cirrhotic persons were Child-Pugh C, and 67.9% of HCC patients had advanced or terminal disease at presentation. Conclusions: Our findings emphasize the young age of ESLD patients in Ghana and the advanced nature at presentation. It highlights shortcomings in surveillance and the need for policies to address the burden and improve outcomes in Ghana.

Abstract Pathogenicity of visceral adipose tissue (VAT) has been linked to the metabolic stress of enlarging mature adipocytes and a limited ability to recruit new adipocytes. One of the major distinguishing features of VAT preadipocytes is the high expression of the zinc metalloprotease, pregnancy-associated plasma protein-A (PAPP-A), when compared to subcutaneous adipose tissue (SAT). In this study we used 2 different approaches to investigate the effect of PAPP-A inhibition on different fat depots in mice on a high-fat diet (HFD) for 15 weeks. Conditional knockdown of PAPP-A gene expression in female adult mice resulted in significant decreases of 30% to 40% in adipocyte size in VAT (mesenteric and pericardial depots) compared to control mice. There was no effect on SAT (inguinal) or intra-abdominal perigonadal fat. Liver lipid was also significantly decreased without any effect on heart and skeletal muscle lipid. We found similar effects when using a pharmacological approach. Weekly injections of a specific immunoneutralizing monoclonal antibody (mAb-PA 1/41) or isotype control were given to male and female wild-type mice on HFD for 15 weeks. Adipocyte size was significantly decreased (30%-50%) only in VAT with mAb-PA 1/41 treatment. In this model, cell number was significantly increased in mesenteric fat in mice treated with mAb-PA 1/41, suggesting hyperplasia along with reduced hypertrophy in this VAT depot. Gene expression data indicated a significant decrease in F4/80 (macrophage marker) and interleukin-6 (proinflammatory cytokine) and a significant increase in adiponectin (anti-inflammatory adipokine with beneficial metabolic effects) in mesenteric fat compared to inguinal fat in mice treated with mAb-PA 1/41. Furthermore, there was significantly decreased liver lipid content with mAb-PA 1/41 treatment. Thus, using 2 different models systems we provide proof of principle that PAPP-A inhibition is a potential therapeutic target to prevent visceral obesity and its metabolic sequelae, such as fatty liver.

Abstract Introduction Elevated mammographic density (MD) is a strong and independent risk factor for breast cancer, though underlying mechanisms are unclear. Prior studies have suggested that increased cumulative exposure to sex-steroid hormones and growth factors may impact both MD and MD-related breast cancer risk; however, most studies have only evaluated individual hormones. In this study, we simultaneously explored the relationship between 29 circulating hormones and growth factors with MD among postmenopausal women undergoing diagnostic breast biopsy. Methods We used data from 89 postmenopausal women, aged 44-65, who had complete measurements of 29 serum hormones from a single pre-biopsy blood draw (i.e., sex-steroid hormones: 15 estrogen/estrogen metabolites, 7 progesterone/progesterone metabolites; and non-sex hormones: insulin-like growth factor I and binding proteins (IGFBPs) 2-7). Volumetric MD (% fibroglandular volume) was assessed in pre-biopsy digital mammograms using single X-ray absorptiometry. Sufficient dimension reduction methods were used to compute a composite marker score that accommodates correlations among hormones and their relationship to MD. Backward elimination was applied to select log-transformed hormones contributing to the score at α=0.05; multivariable linear regression was used to further examine associations between selected hormones and MD within a single model, adjusting for age and BMI. Results Pearson correlations between hormones were moderate-to-strong. Dimension reduction methods identified 6 hormones as associated with MD (p<0.05): estradiol, 2-hydroxyestradiol, 2-methoxyestrone, 16-ketoestradiol, IGFBP-2, and 17α-hydroxyprogesterone, in models that considered MD as either continuous or dichotomous (>median vs. ≤median); BMI was consistently identified as the most significant predictor of MD (P <0.0001). In a multivariable linear regression model that included these 6 hormones, in addition to age and BMI, higher levels of 2-methoxyestrone, IGFBP-2, and 17α-hydroxyprogesterone were significantly associated with increased MD, whereas higher levels of age and BMI were significantly associated with lower MD. Conclusions We identified 6 out of 29 correlated hormones that were significantly associated with MD among postmenopausal women. For several, the directions of their associations with MD were comparable to those observed in prior studies that have separately evaluated these hormones in relation to breast cancer risk. We plan to further explore how circulating hormones concurrently affect MD in premenopausal women, accounting for menstrual cycle phase. Incorporation of dimension reduction methods in studies of multiple correlated hormones can help uncover new etiologic insights into the role of hormones and growth factors in MD and breast carcinogenesis and inform strategies for prevention. Citation Format: Shaoqi Fan, Ruth M. Pfeiffer, Manila Hada, Roni T. Falk, Maeve Mullooly, Hannah Oh, Berta Geller, Pamela Vacek, Donald Weave, John Shepherd, Jeff Wang, Sally Herschorn, Louise A. Brinton, Xia Xu, Mark E. Sherman, Britton Trabert, Gretchen L. Gierach. Associations of circulating hormones with mammographic density in postmenopausal women referred to diagnostic breast biopsy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3488.

Abstract Background and Aims PH1 is a rare genetic disorder characterized by hepatic oxalate overproduction, leading to recurrent kidney stones, nephrocalcinosis, progressive kidney failure, and multiorgan damage from systemic oxalosis. There are no approved pharmacologic therapies for PH1. Lumasiran is a subcutaneously-administered investigational RNAi therapeutic that targets glycolate oxidase to reduce hepatic oxalate production. We report the first results from the six-month, double-blind period of ILLUMINATE-A, a randomized, placebo-controlled Phase 3 study to evaluate lumasiran in patients with PH1. Method Key inclusion criteria: age≥6 years, 24hr urinary oxalate (UOx)≥0.70 mmol/24hr/1.73m2, confirmed PH1 diagnosis, eGFR≥30 mL/min/1.73m2. Randomization: 2:1; lumasiran (n=26), placebo (n=13). Dosing: 3 mg/kg monthly×3, then quarterly. Primary endpoint: percent change in 24hr UOx excretion from baseline to month (M) 6. Primary comparison: least square (LS) mean treatment difference in percent change from baseline (average of M3-6). Results Lumasiran led to a statistically significant percent reduction in 24hr UOx excretion compared to placebo: the LS mean change from baseline to M6 (average of M3-6) was −65.4% with lumasiran and −11.8% with placebo (LS mean difference: −53.5%; p=1.7 × 10−14). Subgroup analyses of the primary endpoint showed a consistent effect of lumasiran across age, baseline UOx, eGFR, and concomitant pyridoxine use. Lumasiran led to statistically significant improvements in all hierarchically tested secondary endpoints, including: proportion of lumasiran-treated patients that achieved normalization or near-normalization of 24hr UOx at M6 (84% vs 0% of placebo-treated patients, p=8.3 × 10−7), and percent change in plasma oxalate from baseline to M6 (average of months 3-6) (-39.5%, p=2.9 × 10−8). There were no serious or severe adverse events. The most common adverse events related to lumasiran were mild, transient injection site reactions. Conclusion Lumasiran resulted in clinically meaningful, rapid, sustained, and statistically significant reductions in urinary and plasma oxalate levels compared to placebo during the six-month double-blind period. Lumasiran has a favorable safety profile.

Abstract Background: End-stage liver disease (ESLD) is a major burden on public health, particularly in sub-Saharan Africa, where hepatitis B virus (HBV) is an important risk factor. We aimed to describe clinical characteristics of ESLD from cirrhosis or hepatocellular carcinoma (HCC) and the performance of aspartate aminotransferase (AST) - platelet ratio index (APRI) and alpha fetoprotein (AFP) in Ghana. Methods: We performed an observational cross-sectional study in outpatient hepatology clinics at three teaching hospitals in Ghana, West Africa. One hundred and forty-one HCC, 216 cirrhosis and 218 chronic HBV patients were recruited by convenience sampling. Sociodemographic, history and examination, laboratory, and disease staging information were shown using descriptive statistics. Performance of the APRI score in diagnosis of cirrhosis and Alpha fetoprotein in the diagnosis of HCC was determined using AUROC analysis.Results: Median age at presentation was 44 years for HCC and 46 years for cirrhosis. HBV was found in 69.5% of HCC and 47.2% of cirrhosis cases, and HCV in 6.4% and 3.7% respectively. APRI cut-off of 2 had sensitivity of 45.4% and specificity of 95% in diagnosis of cirrhosis, and cut-off of 1 had sensitivity of 75.9% and specificity of 89%. AUC of AFP was 0.88 (95% CI 0.81-0.94) in diagnosis of HCC. Low monthly income was associated with lower odds of undertaking AFP. Thirty one percent of cirrhotic persons were Child-Pugh C, and 67.9% of HCC patients had advanced or terminal disease at presentation. Conclusions: Our findings emphasize the young age of ESLD patients in Ghana and the advanced nature at presentation. It highlights shortcomings in surveillance and the need for policies to address the burden and improve outcomes in Ghana.