Citations

AbstractThe diagnosis of primary plasma cell leukemia (pPCL) has been made by quantifying circulating plasma cells (cPCs) morphologically on a peripheral blood (PB) smear. However, this technique is not sufficiently sensitive. Multiparametric flow cytometry (MFC) provides a readily available and highly sensitive method to identify and quantify cPCs that could complement PB smear assessment. However, an optimal quantitative cutoff for cPCs by MFC to identify pPCL has not been established. Thus, a total of 591 patients newly diagnosed multiple myeloma (NDMM) patients who had their PB samples evaluated morphologically by PB smear, and immunophenotypically by MFC prior to beginning therapy were evaluated. The presence of ≥200 cPCs/μL by MFC (N = 25 or 5% of the total population) was chosen to identify patients with ≥5% cPCs by PB smear with a specificity of 99% and a sensitivity of 77%. For patients with ≥200 cPCs/μL by MFC compared to the remainder of the cohort, the median Time to next therapy (TTNT) was 18 vs 30 months and the median OS was 38 vs 70 months respectively. Thus, MFC assessment of PB can be utilized in conjunction with the morphological assessment of a PB smear to aid in improving the identification of pPCL among NDMM patients.

AbstractBackgroundThe American Heart Association (AHA) guidelines for infective endocarditis (IE) management recommend end-of-therapy (EOT) echocardiography (ETE) to “establish a new baseline” and based on “expert opinion.”MethodsMedical records of IE patients treated between January 2005 and December 2011 were reviewed. Utilization of ETE and cumulative incidence of re-treatment with antimicrobials or cardiovascular surgery (re-Rx/CVS) within 1 year after EOT were evaluated.ResultsA total of 243 patients completed clinical follow-up at EOT and 170 at 1 year after EOT. One hundred seventy-seven of 243 (72.8%) underwent ETE, the majority (51.4%) transthoracic echocardiography. One hundred thirty-three of 177 (75.1%) were without new/worsened signs or symptoms (new/w-SSx). One hundred forty-one of 177 (79.7%) overall and 117/133 (87.9%) patients without new/w-SSx had no new ETE findings as compared with initial echocardiography. Among 36/177 (20.3%) with new ETE findings, 20/36 (55.6%) had new/w-SSx; ETE findings were more likely in patients with new/w-SSx (39.2% vs 8.3%; P < 0.001) at EOT. Patients were at increased risk of re-Rx/CVS with either new ETE findings (hazard ratio [HR], 25.86; 95% confidence interval [CI], 7.64–87.56; P < .001) or new/w-SSx (HR, 5.35; 95% CI, 2.87–9.95; P < .001). The highest risk of re-Rx/CVS was in patients with both new/w-SSx and new ETE findings (HR, 45.94; 95% CI, 19.07–110.71). Conversely, only 7/187 (3.4%) patients without new/w-SSx who had an ETE required re-Rx/CVS.ConclusionsThe majority of patients without new/w-SSx at EOT will not have new ETE findings or need re-Rx/CVS within 1 year after EOT. EOT new/w-SSx is associated with new ETE findings and predicts the need for re-Rx/CVS. Further study is needed to determine whether patients without new/w-SSx need ETE.

Abstract Background: Lipid traits have been inconsistently linked to risk of non-Hodgkin lymphoma (NHL). We examined the association of genetically predicted lipid traits with risk of diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), and marginal zone lymphoma (MZL) using Mendelian randomization (MR) analysis. Methods: Genome-wide association study data from the InterLymph Consortium were available for 2,661 DLBCLs, 2,179 CLLs, 2,142 FLs, 824 MZLs, and 6,221 controls. SNPs associated (P < 5 × 10−8) with high-density lipoprotein (HDL, n = 164), low-density lipoprotein (LDL, n = 137), total cholesterol (TC, n = 161), and triglycerides (TG, n = 123) were used as instrumental variables (IV), explaining 14.6%, 27.7%, 16.8%, and 12.8% of phenotypic variation, respectively. Associations between each lipid trait and NHL subtype were calculated using the MR inverse variance–weighted method, estimating odds ratios (OR) per standard deviation and 95% confidence intervals (CI). Results: HDL was positively associated with DLBCL (OR = 1.14; 95% CI, 1.00–1.30) and MZL (OR = 1.09; 95% CI, 1.01–1.18), while TG was inversely associated with MZL risk (OR = 0.90; 95% CI, 0.83–0.99), all at nominal significance (P < 0.05). A positive trend was observed for HDL with FL risk (OR = 1.08; 95% CI, 0.99–1.19; P = 0.087). No associations were noteworthy after adjusting for multiple testing. Conclusions: We did not find evidence of a clear or strong association of these lipid traits with the most common NHL subtypes. While these IVs have been previously linked to other cancers, our findings do not support any causal associations with these NHL subtypes. Impact: Our results suggest that prior reported inverse associations of lipid traits are not likely to be causal and could represent reverse causality or confounding.

Background: Invasive hemodynamic evaluation through right heart catheterization plays an essential role in the diagnosis, categorization, and risk stratification of patients with pulmonary hypertension. Methods: Subjects enrolled in the PVDOMICS (Redefining Pulmonary Hypertension through Pulmonary Vascular Disease Phenomics) program undergo an extensive invasive hemodynamic evaluation that includes repeated measurements at rest and during several provocative physiological challenges. It is a National Institutes of Health/National Heart, Lung, and Blood Institute initiative to reclassify pulmonary hypertension groups based on clustered phenotypic and phenomic characteristics. At a subset of centers, participants also undergo an invasive cardiopulmonary exercise test to assess changes in hemodynamics and gas exchange during exercise. Conclusions: When coupled with other physiological testing and blood -omic analyses involved in the PVDOMICS study, the comprehensive right heart catheterization protocol described here holds promise to clarify the diagnosis and clustering of pulmonary hypertension patients into cohorts beyond the traditional 5 World Symposium on Pulmonary Hypertension groups. This article will describe the methods applied for invasive hemodynamic characterization in the PVDOMICS program. Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02980887.

39 Background: The excess risk of high-grade prostate cancer in the Prostate Cancer Prevention Trial (PCPT) among men randomized to finasteride raised concerns that a chemoprevention benefit would be offset by increased mortality. Two 2019 publications had contrasting results whether 5-ARIs increased prostate cancer mortality. In PCPT, there was no excess prostate cancer mortality. In a VA study, 5-ARI use was associated with later stage at diagnosis and 39% higher prostate cancer mortality risk. We studied men with regular access to health care and screening to address this conflicting evidence. Methods: We performed two parallel analyses in the Health Professionals Follow-up Study. 5-ARI use was reported on biennial questionnaires starting in 1996. In line with PCPT, we studied 38,047 men for cancer incidence and mortality through 2016. In line with the VA study, we undertook a case-only study of 4,225 patients with localized/locally advanced cancers followed similarly. We estimated hazard ratios (HR) and 95% confidence intervals accounting for screening patterns, lifestyle factors, and concomitant medications. Results: 5-ARI ever-users (n = 4,101; 10.7%) were more likely to have had regular PSA screening (74% vs. 57% nonusers) and a negative prostate biopsy before diagnosis. Neither ever 5-ARI use (HR 1.08, 0.73-1.60, 445 events) nor long-term use ( > 4 years, HR 1.03, 1.03-2.02) were associated with lethal prostate cancer. There was no difference in stage. Diagnostic PSA levels were lower in 5-ARIs users (10.0 vs. 16.0 ng/ml in never-users). Among nonmetastatic cases, 278 men died of prostate cancer; there was no association between 5-ARIs and prostate cancer survival (HR 0.85, 0.51-1.43). Conclusions: Our results align with PCPT and show no excess risk of lethal prostate cancer, no higher stage at diagnosis, and no excess mortality after diagnosis associated with 5-ARI. Men on 5-ARIs had more interactions with health care, which may have led to higher quality care. This contrasts with the VA study where men on 5-ARIs were diagnosed later due to suppressed PSA and had worse survival. These results show the importance of real-world data in framing the benefits and risks associated with 5-ARIs.

Background: Patients with Crouzon syndrome develop various types of anatomic deformities due to different forms of craniosynostosis, yet they have similar craniofacial characteristics. However, exact homology is not evident. Different pathology then may be best treated by different forms of surgical technique. Therefore, precise classification of Crouzon syndrome, based on individual patterns of cranial suture involvement is needed. Methods: Ninety-five computed tomography (CT) scans (Crouzon, n = 33; control, n = 62) were included in this study. All the CT scans are divided into 4 types based on premature closure of sutures: class I = coronal and lambdoidal synostosis; class II = sagittal synostosis; class III = pansynostosis; and class IV = “Others.” The CT scan anatomy was measured by Materialise software. Results: The class III, pansynostosis, is the most prevalent (63.6%). The classes I, III, and IV of Crouzon have significantly shortened entire anteroposterior cranial base length, with the shortest base length in class III. The external cranial measurements in class I show primarily a decreased posterior facial skeleton, while the class III presented with holistic facial skeleton reduction. Class II has the least severe craniofacial malformations, while class III had the most severe. Conclusion: The morphology of patients with Crouzon syndrome is not identical in both cranial base and facial characteristics, especially when they associated with different subtypes of cranial suture synostosis. The classification of Crouzon syndrome proposed in this study, summarizes the differences among each subgroup of craniosynostosis suture involvement, which, theoretically, may ultimately influence both the timing and type of surgical intervention.

AbstractBackgroundAutonomic dysfunction can be present in patients with idiopathic and diabetic gastroparesis. The role of autonomic dysfunction relating to gastric emptying and upper gastrointestinal symptoms in patients with gastroparesis and chronic unexplained nausea and vomiting (CUNV) remains unclear. The aim of our study is to evaluate autonomic function in patients with gastroparesis and CUNV with respect to etiology, gastric emptying and symptom severity.MethodsWe studied 242 patients with chronic gastroparetic symptoms recruited at eight centers. All patients had a gastric emptying scintigraphy within 6 months of the study. Symptom severity was assessed using the gastroparesis cardinal symptom index. Autonomic function testing was performed at baseline enrollment using the ANX 3.0 autonomic monitoring system which measures heart rate variability and respiratory activity measurements.Key ResultsLow sympathetic response to challenge (Valsalva or standing) was the most common abnormality seen impacting 89% diabetic and 74% idiopathic patients. Diabetics compared to idiopathics, exhibited greater global hypofunction with sympathetic (OR = 4.7, 95% CI 2.2‐10.3; P < .001) and parasympathetic (OR = 7.2, 95% CI 3.4‐15.0; P < .001) dysfunction. Patients with delayed gastric emptying were more likely to have paradoxic parasympathetic excessive during sympathetic challenge [(Valsalva or standing) 40% vs. 26%, P = .05]. Patients with more severe symptoms exhibited greater parasympathetic dysfunction compared to those with mild‐moderate symptoms: resting sympathovagal balance [LFa/RFa 1.8 (1.0‐3.1) vs. 1.2 (0.6‐2.3), P = .006)] and standing parasympathetic activity [0.4 (0.1‐0.8) vs. 0.6 (0.2‐1.7); P = .03].ConclusionsAutonomic dysfunction was common in patients with gastroparesis and CUNV. Parasympathetic dysfunction was associated with delayed gastric emptying and more severe upper gastrointestinal symptoms. Conversely, sympathetic hypofunction was associated with milder symptoms.InferencesGastroparesis and CUNV may be a manifestation of GI autonomic dysfunction or imbalance, such that sympathetic dysfunction occurs early on in the manifestation of chronic upper GI symptoms, while parasympathetic dysfunction results in more severe symptoms and delayed gastric emptying.

Background: The current commonly used regimens in newly diagnosed multiple myeloma (NDMM) utilize steroids (dexamethasone or prednisone) in various combinations: bortezomib, lenalidomide and dexamethasone (VRd), bortezomib, thalidomide and dexamethasone (VTd), daratumumab, lenalidomide and dexamethasone (DRd) and daratumumab, bortezomib, melphalan and prednisone (DVMP). However, steroid therapy may be associated with various adverse effects, including, but not limited to mood changes, insomnia, hypertension, hyperglycemia, osteoporosis, adrenal suppression, muscle weakness, and increased risk of opportunistic infections. A recent trial demonstrated improved tolerability of a regimen (Rd-R) involving an abbreviated course of dexamethasone, without compromising the efficacy in patients with intermediate-fit NDMM (Lorocca A., et al., ASH 2018). We designed a phase 2 clinical trial to examine the safety and efficacy of daratumumab, an anti-CD38 monoclonal antibody in combination with an all-oral regimen of ixazomib, a proteasome inhibitor, lenalidomide, an immunomodulatory drug, and modified dose dexamethasone (IRd). Patients and Methods: NDMM patients with measurable disease and adequate organ function were enrolled, irrespective of their transplant eligibility. The primary objective was to determine the rate of complete response (CR) to daratumumab-IRd. Treatment consisted of daratumumab, 16 mg/kg, weekly for two cycles, every other week during cycles 3-6 and then every 4 weeks, ixazomib, 4 mg days 1, 8, 15, lenalidomide, 25 mg days 1-21, and dexamethasone upto 40 mg intravenously weekly for no more than two cycles, followed by use only as a prophylactic premedication for daratumumab-associated infusion reactions. Myeloma risk stratification was assessed by cytoplasmic immunoglobulin fluorescence in-situ hybridization (cIg FISH) analysis. Results: Overall, 40 patients were accrued, with data available on all patients for analysis at the cutoff date of July 19, 2019. The median age at enrollment was 64.5 (33-81) years; 37.5% were female. Eight (20%) patients were high risk by FISH. The median number of cycles was 6 (2-11) and the median follow up was 6.1 (2-11.7) months. Among 40 patients who had received at least 2 cycles of therapy, responses were attained rapidly; at the end of cycle 2, 88% patients achieved at least a partial response and 33% at least a very good partial response (VGPR) that improved to 52% at the end of 4 cycles among 29 patients who had completed at least 4 cycles. The overall best confirmed response rate among all 40 patients (Figure 1) was 95%, including 10% stringent CR, 5% CR and 23% near CR (13% VGPR excluding nCR). Stem cell collection was completed in 17 patients so far, all of whom required filgrastim and plerixafor. The median CD34+ cell count was 7.7 (range 2.9-11.6) million/kg . All patients were alive and 39 (97.5%) patients were progression-free at last follow up. Four (10%) patients proceeded to autologous stem cell transplantation off study, per patient and/or investigator discretion (1 in CR, 2 in PR, 1 with progressive disease). Overall, 224 cycles have been administered across the study, with dose reduction/ hold required in a subset of patients; ixazomib (10%), lenalidomide (20%), daratumumab (0%) and dexamethasone (13%); the most frequent reasons for dose adjustment were skin rash and hematologic toxicities. A grade 3 or higher adverse event, at least possibly attributed to the study drugs, was observed in 40% of patients; hematologic in 30% (lymphopenia 25%, neutropenia 15%, thrombocytopenia 5% and anemia 2.5%) and non-hematologic in 18% of patients (hyperglycemia 8%, diarrhea 5%, infections 5%, ileus 2.5%, maculopapular rash 2.5%, and fatigue 2.5%). Updated results with additional 6 months of follow up and minimal residual disease assessment related data will be presented at the meeting. Conclusion: Our early results suggest that the combination of daratumumab, ixazomib, lenalidomide and modified dose dexamethasone is well-tolerated, with excellent activity, and does not adversely impact stem-cell mobilization in patients with NDMM. Disclosures Kapoor: Takeda: Honoraria, Research Funding; Amgen: Research Funding; Sanofi: Consultancy, Research Funding; Celgene: Honoraria; Janssen: Research Funding; Glaxo Smith Kline: Research Funding; Cellectar: Consultancy. Gertz:Spectrum: Honoraria, Research Funding; Janssen: Honoraria; Celgene: Honoraria; Prothena: Honoraria; Alnylam: Honoraria; Ionis: Honoraria. Dingli:alexion: Consultancy; Janssen: Consultancy; Millenium: Consultancy; Rigel: Consultancy; Karyopharm: Research Funding. Leung:Takeda: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; Aduro: Membership on an entity's Board of Directors or advisory committees; Omeros: Research Funding. Dispenzieri:Pfizer: Research Funding; Janssen: Consultancy; Intellia: Consultancy; Akcea: Consultancy; Takeda: Research Funding; Celgene: Research Funding; Alnylam: Research Funding. Lacy:Celgene: Research Funding. Kumar:Takeda: Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. OffLabel Disclosure: Daratumumab in combination with Ixazomib, lenalidomide and dexamethasone for the management of newly diagnosed multiple myeloma