Citations

We describe 22 examples of a novel, usually paratubal, adnexal tumor associated with Peutz-Jeghers syndrome in nearly 50% of cases that harbored STK11 alterations in all tested (n=21). The patients ranged from 17 to 66 years (median=39 y) and the tumors from 4.5 to 25.5 cm (median=11 cm). Most (n=18) were paratubal, with metastases noted in 11/22 (50%) and recurrences in 12/15 (80%). Morphologically, they were characterized by interanastomosing cords and trabeculae of predominantly epithelioid cells, set in a variably prominent myxoid to focally edematous stroma, that often merged to form tubular, cystic, cribriform, and microacinar formations, reminiscent of salivary gland-type tumors. The tumor cells were uniformly atypical, often with prominent nucleoli and a variable mitotic index (median=9/10 HPFs). The tumors were usually positive to a variable extent for epithelial (CAM5.2, AE1/AE3, cytokeratin 7), sex cord (calretinin, inhibin, WT1), and mesothelial (calretinin, D2-40) markers, as well as hormone receptors. PAX8, SF1, and GATA-3 were rarely positive, while claudin-4, FOXL2, and TTF-1 were consistently negative. All sequenced tumors (n=21) harbored alterations in STK11, often with a loss of heterozygosity event. There were no other recurrently mutated genes. Recurrent copy number alterations included loss of 1p and 11q, and gain of 1q, 15q, and 15p. Despite an extensive morphologic, immunohistochemical, and molecular evaluation, we are unable to determine with certainty the histogenesis of this unique tumor. Wolffian, sex cord stromal, epithelial, and mesothelial origins were considered. We propose the term STK11 adnexal tumor to describe this novel entity and emphasize the importance of genetic counseling in these patients as a significant number of neoplasms occur in association with Peutz-Jeghers syndrome.

Abstract Cardiac amyloidosis is a serious and progressive infiltrative disease that is caused by the deposition of amyloid fibrils at the cardiac level. It can be due to rare genetic variants in the hereditary forms or as a consequence of acquired conditions. Thanks to advances in imaging techniques and the possibility of achieving a non-invasive diagnosis, we now know that cardiac amyloidosis is a more frequent disease than traditionally considered. In this position paper the Working Group on Myocardial and Pericardial Disease proposes an invasive and non-invasive definition of cardiac amyloidosis, addresses clinical scenarios and situations to suspect the condition and proposes a diagnostic algorithm to aid diagnosis. Furthermore, we also review how to monitor and treat cardiac amyloidosis, in an attempt to bridge the gap between the latest advances in the field and clinical practice.

AbstractBackgroundAlthough both age‐related and highly prevalent, little is known regarding the prevalence of hearing loss among persons with dementia (PwD). Current understanding is based on convenience samples primarily from specialized memory clinics. The Atherosclerosis Risk in Communities Neurocognitive Study (ARIC‐NCS) is a large, prospective study of a population‐based cohort from 4 U.S. community sites with audiometric and neurocognitive testing and bi‐racial representation. We examined the prevalence of hearing loss and hearing aid use among older adults with cognitive impairment and whether cognitive status influences hearing aid use.MethodWe analyzed audiometric and hearing care data from ARIC‐NCS Visit 6 (2016‐2018). Participants underwent a full neurocognitive battery and audiometric evaluation at Visit 6. Participants with complete audiometric data and an adjudicated diagnosis of cognitively normal, mild cognitive impairment (MCI), or dementia were included in the analytical cohort (N=3,385). Differences in participant characteristics by cognitive status were descriptively compared using Chi‐square tests or one‐way ANOVAs. We performed a series of logistic regression models to estimate the odds of hearing aid non‐use by cognitive status.ResultPrevalence of hearing loss was greater with increasing cognitive impairment (cognitively normal:64.7%; MCI:71.3%; dementia:83.3%). Prevalence of hearing aid use among those with hearing loss and cognitive impairment varied by race (African Americans 7.2%; whites 32.8%). In a multivariable‐adjusted model, cognitive impairment was independently associated with higher odds of non‐use of hearing aids (MCI odds ratio (OR):1.4 (95%CI:1.0‐1.8); dementia OR:1.8 (95%CI:1.2‐2.9) versus cognitively normal). The strongest risk factor for non‐use of hearing aids was race, where African Americans have almost a 5 times higher odds of not using hearing aids compared to whites (95% CI:2.9‐7.4).ConclusionHearing loss is highly prevalent but vastly untreated among older adults with cognitive impairment, particularly African Americans, and cognitive impairment is independently associated with hearing aid use. These estimates are some of the first population‐based estimates of audiometric hearing loss among diverse older adults with adjudicated diagnoses of MCI or dementia. With increased calls to address ethnic/racial disparities, we must include hearing loss, as one of the most common co‐morbidities, in order to optimize health and well‐being among all PwD.

PURPOSE Patients with lower-risk (LR) myelodysplastic syndromes (MDS) who are RBC transfusion dependent and have experienced relapse after or are refractory to erythropoiesis-stimulating agent (ESA) have limited treatment options. High telomerase activity and human telomerase reverse-transcription expression in clonal hematopoietic cells have been reported in patients with MDS. Imetelstat, a first-in-class competitive inhibitor of telomerase enzymatic activity, targets cells with active telomerase. We report efficacy, safety, and biomarker data for patients with LR MDS who are RBC transfusion dependent and who were relapsed/refractory to ESAs. PATIENTS AND METHODS In this two-part phase II/III study (MDS3001), the primary end point was 8-week RBC transfusion independence (TI) rate, with key secondary end points of 24-week RBC TI rate, TI duration, and hematologic improvement-erythroid. RESULTS Data from the phase II part of the study are reported. Of 57 patients enrolled and treated (overall population), 38 were non-del(5q) and hypomethylating agent and lenalidomide naïve (subset population). The 8- and 24-week RBC TI rates in the overall population were 37% and 23%, respectively, with a median TI duration of 65 weeks. In the subset population, 8- and 24-week RBC TI rates were 42% and 29%, respectively, with a median TI duration of 86 weeks. Eight-week TI rate was observed across all subgroups evaluated. Cytogenetic and mutational data revealed a reduction of the malignant clones, suggesting disease modification activity. The most common adverse events were cytopenias, typically reversible within 4 weeks. CONCLUSION Imetelstat treatment results in a meaningful, durable TI rate across a broad range of heavily transfused patients with LR MDS who are ineligible for or relapsed/refractory to ESAs. Biomarker analyses indicated effects on the mutant malignant clone.

Abstract BackgroundNiemann–Pick disease type C (NPC) is a rare, progressive, neurodegenerative disease associated with neurovisceral manifestations resulting from lysosomal dysfunction and aberrant lipid accumulation. A multicentre, prospective observational study (ClinicalTrials.gov ID:NCT02435030) of individuals with genetically confirmed NPC1 or NPC2 receiving routine clinical care was conducted, to prospectively characterize and measure NPC disease progression and to investigate potential NPC-related biomarkers versus healthy individuals. Progression was measured using the abbreviated 5-domain NPC Clinical Severity Scale (NPCCSS), 17-domain NPCCSS and NPC clinical database (NPC-cdb) score. Cholesterol esterification and heat shock protein 70 (HSP70) levels were assessed from peripheral blood mononuclear cells (PBMCs), cholestane-3β,5α-,6β-triol (cholestane-triol) from serum, and unesterified cholesterol from both PBMCs and skin biopsy samples. The inter- and intra-rater reliability of the 5-domain NPCCSS was assessed by 13 expert clinicians’ rating of four participants via video recordings, repeated after ≥3 weeks. Intraclass correlation coefficients (ICCs) were calculated.ResultsOf the 36 individuals with NPC (2–18 years) enrolled, 31 (86.1%) completed the 6–14-month observation period; 30/36 (83.3%) were receiving miglustat as part of routine clinical care. A mean (±SD) increase in 5-domain NPCCSS scores of 1.4 (±2.9) was observed, corresponding to an annualized progression rate of 1.5. On the 17-domain NPCCSS, a mean (±SD) progression of 2.7 (±4.0) was reported. Compared with healthy individuals, the NPC population had significantly lower levels of cholesterol esterification (p<0.0001), HSP70 (p<0.0001) and skin unesterified cholesterol (p=0.0006). Cholestane-triol levels were significantly higher in individuals with NPC versus healthy individuals (p=0.008) and correlated with the 5-domain NPCCSS (Spearman’s correlation coefficient=0.265, p=0.0411). The 5-domain NPCCSS showed high ICC agreement in inter-rater reliability (ICC=0.995) and intra-rater reliability (ICC=0.937). ConclusionsProgression rates observed were consistent with other reports on disease progression in NPC. The 5-domain NPCCSS reliability study supports its use as an abbreviated alternative to the 17-domain NPCCSS that focuses on the most relevant domains of the disease. The data support the use of cholestane-triol as a disease monitoring biomarker and the novel methods of measuring unesterified cholesterol could be applicable to support NPC diagnosis. Levels of HSP70 in individuals with NPC were significantly decreased compared with healthy individuals.

AbstractProblemPrevious studies identified circulating CD14+HLA‐DRlo/− monocytic cells as an immune suppressive subset in solid malignancies, such as prostate, renal cell carcinoma, and pancreatic cancer. Such monocytic cells have been implicated not only in tumour progression but also as a potential barrier for immunotherapy. This study examined the relationship between the frequency of circulating monocytic cells and epithelial ovarian cancer (EOC) progression pre‐ and post‐frontline chemotherapy, defined by disease stage, which is a leading prognostic factor for this malignancy.Method of studyIncident cases of 236 women with EOC were recruited and comprehensive flow cytometry was utilized to assess the frequency of peripheral blood CD33+CD11b+HLA‐DR−/lowCD14+CD15− monocytic cells, henceforth termed CD14+HLA‐DRlo/− monocytic cells, prior to and after completion of frontline chemotherapy. Multivariable odds ratios (OR) were used to estimate the association between CD14+HLA‐DRlo/− monocytic cell percentages and disease stage. Wilcoxon signed‐rank tests evaluated changes in these monocytic cell levels pre‐ and post‐chemotherapy in a patient subset (n = 70).ResultsPatients with elevated frequencies of circulating CD14+HLA‐DRlo/− monocytic cells at diagnosis were at 3.33‐fold greater odds of having advanced stage (III/IV) EOC (CI: 1.04‐10.64), with a significant trend in increasing CD14+HLA‐DRlo/−monocytic cell levels (P = .04). There was a 2.02% median decrease of these monocytic cells post‐chemotherapy among a subset of patients with advanced stage disease (P < .0001).ConclusionThese findings support the potential clinical relevance of CD14+HLA‐DRlo/−monocytic cells in EOC for prognosis and may indicate a non‐invasive biomarker to measure disease progression.

Abstract Background: Persons of African ancestry (AA) experience a 1.5-2-fold risk of multiple myeloma (MM) compared to persons of European ancestry (EA). We assembled a set of MM patients with self-reported AA in order to evaluate the contribution of genetics to etiology in this high-risk group. Methods: Here we present the results of a meta-analysis of two GWAS in 1,813 cases and 8,871 controls of AA. We also conducted an admixture mapping scan to identify risk alleles associated with local ancestry, fine-mapped the 23 known susceptibility loci to find markers that could better capture MM risk in individuals of AA, and constructed a polygenic risk score (PRS) to assess the aggregated effect of known MM risk alleles. Finally, we conducted an eQTL analysis measuring gene expression in those genes harboring a risk variant in malignant plasma cells from 292 of the patients from a single site. Results: In GWAS analysis, we identified two suggestive novel loci located at 9p24.3 and 9p13.1 at P&lt;1 × 10-6, but no genome-wide significant association was noted. In admixture mapping, we observed a genome-wide significant inverse association between local AA at 2p24.1-23.1 and MM risk in AA individuals. 20 of the 23 known EA risk variants showed directional consistency and 9 replicated at P&lt;0.05 in AA individuals. In eight regions, we identified markers that better capture MM risk in persons of AA. AA individuals with a PRS in the top 10% had a 1.82-fold (95%CI: 1.56, 2.11) increased MM risk compared to those with average risk (25-75%). The strongest functional association was between the risk allele for variant rs56219066 at 5q15 and lower ELL2 expression (P= 5.1 × 10–12). Conclusion: Our study shows that common genetic variation contributes to MM risk individuals of AA. This abstract is also being presented as Poster C040. Citation Format: Zhaohui Du, Niels Weinhold, Gregory Chi Song, Kristen A. Rand, David J. Van Den Berg, Amie E. Hwang, Xin Sheng, Victor Hom, Sikander Ailawadhi, Ajay K. Nooka, Seema Singhal, Karen Pawlish, Edward Peters, Cathryn Bock, Ann Mohrbacher, Alexander Stram, Sonja I. Berndt, William J. Blot, Graham Casey, Victoria L. Stevens, Rick Kittles, Phyllis J. Goodman, W. Ryan Diver, Anselm Hennis, Barbara Nemesure, Eric A. Klein, Benjamin A. Rybicki, Janet L. Stanford, John S. Witte, Lisa Signorello, Esther M. John, Leslie Bernstein, Antoinette Stroup, Owen W. Stephens, Maurizio Zangari, Frits Van Rhee, Andrew Olshan, Wei Zheng, Jennifer J. Hu, Regina Ziegler, Sarah J. Nyante, Sue Ann Ingles, Michael Press, John David Carpten, Stephen Chanock, Jayesh Mehta, Graham A Colditz, Jeffrey Wolf, Thomas G. Martin, Michael Tomasson, Mark A. Fiala, Howard Terebelo, Nalini Janakiraman, Laurence Kolonel, Kenneth C. Anderson, Loic Le Marchand, Daniel Auclair, Brian C.-H. Chiu, Elad Ziv, Daniel Stram, Ravi Vij, Leon Bernal-Mizrachi, Gareth J. Morgan, Jeffrey A. Zonder, Carol Ann Huff, Sagar Lonial, Robert Z. Orlowski, David V. Conti, Christopher A. Haiman, Wendy Cozen. A meta-analysis of genome-wide association study and eQTL analysis of multiple myeloma among African Americans [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr PR05.

Glial fibrillary acidic protein (GFAP) is cleared by the Food and Drug Administration (FDA) to determine need for head computed tomography (CT) within 12 h after mild traumatic brain injury (TBI) (Glasgow Coma Score [GCS] 13–15); S100 calcium-binding protein B (S100B) serves this function in Europe. This phase 1 biomarker cohort analysis of the multi-center, observational Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) study compares GFAP's diagnostic performance, measured on a rapid point-of-care platform, against protein S100B to predict intracranial abnormalities on CT within 24 h post-injury across the spectrum of TBI (GCS 3–15). Head CT scan performed in TBI subjects and blood was collected for all consenting subjects presenting to 18 United States level 1 trauma centers. Plasma was analyzed on a point-of-care device prototype assay for GFAP and serum was analyzed for S100B. In 1359 patients with TBI (GCS 3–15), mean (standard deviation [SD]) age = 40.1 (17.0) years; 68% were male. Plasma GFAP levels were significantly higher in CT+ TBI subjects (median = 1358 pg/mL, interquartile range [IQR]: 472–3803) than in CT- TBI subjects (median = 116 pg/mL, IQR: 26–397) or orthopedic trauma controls ( n = 122; median = 13 pg/mL, IQR: 7–20), p < 0.001. Serum S100B levels were likewise higher in CT+ TBI subjects (median = 0.17 μg/L, IQR: 0.09–0.38) than in CT- TBI subjects (median = 0.10 μg/L, IQR: 0.06–0.18), p < 0.001. Receiver operating characteristic curves were generated for prediction of intracranial injury on admission CT scan; area under the curve (AUC) for GFAP was significantly higher than for S100B in the same cohort (GFAP AUC – 0.85, 95% confidence interval [CI] 0.83–0.87; S100B AUC – 0.67, 95% CI 0.64-0.70; p < 0.001). GFAP, measured on a point-of-care platform prototype assay, has high discriminative ability to predict intracranial abnormalities on CT scan in patients with TBI across the full injury spectrum of GCS 3–15 through 24 h post-injury. GFAP substantially outperforms S100B.