Citations

Abstract Background In 2008, bevacizumab received accelerated Food and Drug Administration (FDA) approval for use in human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC). Based on the preclinical and preliminary clinical activity of the trastuzumab and bevacizumab combination, ECOG-ACRIN E1105 trial was developed to determine if the addition of bevacizumab to a chemotherapy and trastuzumab combination for first-line therapy would improve progression-free survival (PFS) in patients with HER2-positive MBC. Findings: 96 patients were randomized to receive standard first-line chemotherapy and trastuzumab with or without bevacizumab between November 2007 and October 2009, and 93 began protocol therapy. Induction therapy was given for 24 weeks, followed by maintenance trastuzumab with or without bevacizumab. 60% (56/93) began carboplatin and 74% (69/93) completed 6 cycles of induction therapy. Primary endpoint was PFS. Median PFS was 11.1 and 13.8 months for placebo and bevacizumab arms, respectively (hazard ratio [HR] 95%, Confidence Interval [Cl] for bevacizumab vs. placebo: 0.73 [0.43–1.23], p = 0.24), and at a median follow-up of 70.7 months, median survival was 49.1 and 63 months (HR [95% Cl] for OS: 1.09 [0.61–1.97], p = 0.75). The most common toxicities across both arms were neutropenia and hypertension, with left ventricular systolic dysfunction, fatigue, and sensory neuropathy reported more frequently with bevacizumab. Conclusions In this trial, the addition of bevacizumab did not improve outcomes in patients with metastatic HER2-positive breast cancer. Although the trial was underpowered due to smaller than anticipated sample size, these findings corroborated other clinical trials during this time.

Importance Effects of antiamyloid agents, targeting either fibrillar or soluble monomeric amyloid peptides, on downstream biomarkers in cerebrospinal fluid (CSF) and plasma are largely unknown in dominantly inherited Alzheimer disease (DIAD). Objective To investigate longitudinal biomarker changes of synaptic dysfunction, neuroinflammation, and neurodegeneration in individuals with DIAD who are receiving antiamyloid treatment. Design, Setting, and Participants From 2012 to 2019, the Dominantly Inherited Alzheimer Network Trial Unit (DIAN-TU-001) study, a double-blind, placebo-controlled, randomized clinical trial, investigated gantenerumab and solanezumab in DIAD. Carriers of gene variants were assigned 3:1 to either drug or placebo. The present analysis was conducted from April to June 2023. DIAN-TU-001 spans 25 study sites in 7 countries. Biofluids and neuroimaging from carriers of DIAD gene variants in the gantenerumab, solanezumab, and placebo groups were analyzed. Interventions In 2016, initial dosing of gantenerumab, 225 mg (subcutaneously every 4 weeks) was increased every 8 weeks up to 1200 mg. In 2017, initial dosing of solanezumab, 400 mg (intravenously every 4 weeks) was increased up to 1600 mg every 4 weeks. Main Outcomes and Measures Longitudinal changes in CSF levels of neurogranin, soluble triggering receptor expressed on myeloid cells 2 (sTREM2), chitinase 3–like 1 protein (YKL-40), glial fibrillary acidic protein (GFAP), neurofilament light protein (NfL), and plasma levels of GFAP and NfL. Results Of 236 eligible participants screened, 43 were excluded. A total of 142 participants (mean [SD] age, 44 [10] years; 72 female [51%]) were included in the study (gantenerumab, 52 [37%]; solanezumab, 50 [35%]; placebo, 40 [28%]). Relative to placebo, gantenerumab significantly reduced CSF neurogranin level at year 4 (mean [SD] β = −242.43 [48.04] pg/mL; P < .001); reduced plasma GFAP level at year 1 (mean [SD] β = −0.02 [0.01] ng/mL; P = .02), year 2 (mean [SD] β = −0.03 [0.01] ng/mL; P = .002), and year 4 (mean [SD] β = −0.06 [0.02] ng/mL; P < .001); and increased CSF sTREM2 level at year 2 (mean [SD] β = 1.12 [0.43] ng/mL; P = .01) and year 4 (mean [SD] β = 1.06 [0.52] ng/mL; P = .04). Solanezumab significantly increased CSF NfL (log) at year 4 (mean [SD] β = 0.14 [0.06]; P = .02). Correlation analysis for rates of change found stronger correlations between CSF markers and fluid markers with Pittsburgh compound B positron emission tomography for solanezumab and placebo. Conclusions and Relevance This randomized clinical trial supports the importance of fibrillar amyloid reduction in multiple AD-related processes of neuroinflammation and neurodegeneration in CSF and plasma in DIAD. Additional studies of antiaggregated amyloid therapies in sporadic AD and DIAD are needed to determine the utility of nonamyloid biomarkers in determining disease modification. Trial Registration ClinicalTrials.gov Identifier: NCT04623242

Background: Arsenic is a well-known toxin which may contaminate household water. It is harmful when ingested over prolonged periods of time. As a result, public health experts recommend that water should be screened and treated to prevent arsenic ingestion. In the United States, the responsibility of testing and treatment of private wells falls on homeowners. Despite recommendations for routine screening, this is rarely done. Objectives: To assess the prevalence of well water use in a Midwestern patient population, how patients and clinicians perceive the risks of arsenic in well water, and whether additional resources on well water testing are desired. These findings will be used to influence tools for clinicians regarding symptom and examination findings of chronic arsenic exposure and potentiate the distribution of informational resources on well water testing. Methods: Surveys were sent via email to all actively practicing primary care clinicians at the Mayo Clinic in the United States Midwest, and all active adult patients at the Mayo Clinic in the same region. Our team analyzed survey data to determine whether both patients and clinicians are aware of the health effects of chronic arsenic toxicity from well water, the need for routine well water testing and whether each group wants more information on the associated risks. Results: Both patients and primary care clinicians worry about arsenic exposure. Patients with well water are concerned about their water safety yet feel uninformed about testing options. Clinicians do not know how prevalent well water use is among their patients, feel uninformed about the chronic risks of arsenic exposure and the physical examination associated with it. Both groups unanimously want more information on testing options. Conclusions: Our findings show a significant reliance on well water use in the American Midwest, and unanimous support for the need for further well water testing information and resources for patients and their clinicians.

Abstract There has been an increase in volume as well as an improvement in overall survival (OS) after hematopoietic cell transplantation (HCT) for hematologic disorders. It is unknown if these changes have affected racial/ethnic minorities equally. In this observational study from the Center for International Blood and Marrow Transplant Research of 79 904 autologous (auto) and 65 662 allogeneic (allo) HCTs, we examined the volume and rates of change of autoHCT and alloHCT over time and trends in OS in 4 racial/ethnic groups: non-Hispanic Whites (NHWs), non-Hispanic African Americans (NHAAs), and Hispanics across 5 2-year cohorts from 2009 to 2018. Rates of change were compared using Poisson model. Adjusted and unadjusted Cox proportional hazards models examined trends in mortality in the 4 racial/ethnic groups over 5 study time periods. The rates of increase in volume were significantly higher for Hispanics and NHAAs vs NHW for both autoHCT and alloHCT. Adjusted overall mortality after autoHCT was comparable across all racial/ethnic groups. NHAA adults (hazard ratio [HR] 1.13; 95% confidence interval [CI] 1.04-1.22; P = .004) and pediatric patients (HR 1.62; 95% CI 1.3-2.03; P < .001) had a higher risk of mortality after alloHCT than NHWs. Improvement in OS over time was seen in all 4 groups after both autoHCT and alloHCT. Our study shows the rate of change for the use of autoHCT and alloHCT is higher in NHAAs and Hispanics than in NHWs. Survival after autoHCT and alloHCT improved over time; however, NHAAs have worse OS after alloHCT, which has persisted. Continued efforts are needed to mitigate disparities for patients requiring alloHCT.

BACKGROUND COVID-19 convalescent plasma (CCP) virus-specific antibody levels that translate into recipient posttransfusion antibody levels sufficient to prevent disease progression are not defined. METHODS This secondary analysis correlated donor and recipient antibody levels to hospitalization risk among unvaccinated, seronegative CCP recipients within the outpatient, double-blind, randomized clinical trial that compared CCP to control plasma. The majority of COVID-19 CCP arm hospitalizations (15/17, 88%) occurred in this unvaccinated, seronegative subgroup. A functional cutoff to delineate recipient high versus low posttransfusion antibody levels was established by 2 methods: (i) analyzing virus neutralization–equivalent anti–Spike receptor-binding domain immunoglobulin G (anti-S-RBD IgG) responses in donors or (ii) receiver operating characteristic (ROC) curve analysis. RESULTS SARS-CoV-2 anti–S-RBD IgG antibody was volume diluted 21.3-fold into posttransfusion seronegative recipients from matched donor units. Virus-specific antibody delivered was approximately 1.2 mg. The high-antibody recipients transfused early (symptom onset within 5 days) had no hospitalizations. A CCP-recipient analysis for antibody thresholds correlated to reduced hospitalizations found a statistical significant association between early transfusion and high antibodies versus all other CCP recipients (or control plasma), with antibody cutoffs established by both methods-donor-based virus neutralization cutoffs in posttransfusion recipients (0/85 [0%] versus 15/276 [5.6%]; P = 0.03) or ROC-based cutoff (0/94 [0%] versus 15/267 [5.4%]; P = 0.01). CONCLUSION In unvaccinated, seronegative CCP recipients, early transfusion of plasma units in the upper 30% of study donors’ antibody levels reduced outpatient hospitalizations. High antibody level plasma units, given early, should be reserved for therapeutic use. TRIAL REGISTRATION ClinicalTrials.gov NCT04373460. FUNDING Department of Defense (W911QY2090012); Defense Health Agency; Bloomberg Philanthropies; the State of Maryland; NIH (3R01AI152078-01S1, U24TR001609-S3, 1K23HL151826NIH); the Mental Wellness Foundation; the Moriah Fund; Octapharma; the Healthnetwork Foundation; the Shear Family Foundation; the NorthShore Research Institute; and the Rice Foundation.

Introduction: IL2 soluble receptor (IL2Rs) and neopterin (NPT) are peripheral markers of T cell and monocyte activation investigated extensively in auto-immune disorders. We assessed these biomarkers in subjects with non ischemic cardiomyopathy of recent onset (ROCM) from the IMAC2 (Intervention in Myocarditis and Acute Cardiomyopathy) registry. We compared the degree of cellular activation in peripartum cardiomyopathy (PPCM) with that evident in non-peripartum women and men with ROCM. Methods: 130 subjects were investigated: 96 subjects with ROCM including 37 women with PPCM (group 3), 27 non-peripartum women (group 2) and 32 men (group 1), and 34 controls without cardiac disease (CTL). All subjects with ROCM had serum obtained at entry and an assessment of LVEF by transthoracic echocardiography. LVEF was reassessed 6 months after enrollment. Results: The ROCM cohort (n=96, 64F/32M, mean age 30±6) had a mean LVEF at baseline of 0.24±0.08 which increased to 0.43±0.13 at 6 months. For controls (mean age 45±6, 24F/10M) the mean LVEF was 0.58±0.10. Both IL2Rs and NPT were markedly elevated in ROCM subjects compared to controls (IL2Rs: ROCM=1411±671, CTL=970±329 pg/ml, p<0.001; NPT: ROCM=9.2±5.6, CTL=6.2±3.1 nmol/l, p=0.003). Increased NYHA class was associated with higher serum levels for both NPT (p=0.013) and IL2Rs (p=0.009). No differences were evident in subjects with PPCM versus men and women with ROCM for either IL2Rs (group 1/2/3 =1524±504/1531±904/1225±566 pg/ml, p=0.10) or NPT (group 1/2/3=9.4±6.5 /9.3±5.8 /8.9±4.7 nmol/l, p=0.92). IL2Rs levels were lower in black subjects: blacks (n=25) IL2Rs=1123±496; whites (n=71) 1513±698, p=0.012. Levels of IL2Rs and NPT did not predict the degree of recovery at 6 months, although there was a nonsignificant trend towards more recovery with lower IL2Rs levels. Conclusions: Marked elevation of IL2Rs and NPT, biomarkers of cellular immune activation, are evident in subjects with ROMC. The degree of activation in subjects with PPCM appears similar to that seen in men and non-peripartum women with ROCM, suggesting similar inflammatory pathogenesis for these syndromes of acute heart failure. The relationship of cellular activation to myocardial injury and recovery in ROCM should be further investigated.

Background: Refractory angina(Ang) effects 150 –250,000 pts in the US alone. These individuals have exhausted options for revasc and continue to have lifestyle limiting ang despite optimal medical Rx. Pre-clinical studies provided evidence that human CD34+ cells(CD34) can stimulate new blood vessel formation in ischemic myocardium(Myo), improving perfusion and function. We performed a phase 2 study of intraMyo injection of autologous CD34 in pts with CCS Class 3 and 4 Ang to obtain evidence for feasibility, safety and bioactivity. Methods: A phase 2 randomized, double-blind, placebo-controlled clinical trial was performed at 26 centers in the United States. There were 3 treatment groups: placebo, low dose (1×10^5 CD34/kg body wt) and high dose (5×10^5 CD34/kg). All pts underwent mobilization with GCSF 5 mcg/kg/day SC for 5 d, followed by apheresis on d5 to collect mononuclear cells. On day 6 CD34 were purified from the collected cells using the Isolex 300i device. After lot release testing, CD34 were injected endocardially at 10 locations in the ischemic Myo using the Myostar catheter following NOGA mapping. Placebo injections consisted of identical volumes of the diluent only. Results: A total of 167 pts were randomized and completed the injection procedure and 162 completed the 6 mo evaluation. The mean age of subjects was 61.0±8.9, there were 22 female and 145 male subjects. Trop was elevated in 26 pts at baseline and in 71 at some point following GCSF or injection. At 6 mo CD34 treated pts showed more reduction in ang frequency (−8.6 placebo vs 14.2 low dose) and improved ETT time (+69 sec placebo vs. +138 low dose). At 12m CD34 treated continue to show more reduction in angina (−8.2 placebo vs. −15.0 low dose) and improved ETT (+58 sec placebo vs. + 139 sec low dose). For key endpoints the high dose group results were inferior to low dose. The 12m data set has been locked and is being analyzed and the results of the completed analysis will be presented. Conclusions: Autologous CD34 cell therapy was associated with improved exercise tolerance and reduced angina in no-option pts with intractable angina. Ongoing analysis will determine endpoints, sample size and suitability of this therapy for a phase III study in no-option pts with refractory angina.

Increased oxidative stress has been suggested to play an important role in the biology of mesenchymal stem cells (MSCs). However, little is known of the effect of increased oxidative stress in-vivo, partly due to the lack of appropriate imaging technologies for monitoring of stem cell biology in the living subject. Recent developments in molecular imaging permit, for the first time, the longitudinal monitoring of stem cell biology in vivo. We hypothesize that changes in oxidative stress can be monitored using a reporter gene strategy (molecular imaging). Methods: We have developed a novel oxidative stress sensor, using a two-step transcriptional amplification strategy to enhance the expression of firefly luciferase (Fluc), driven by the pro-oxidant enzyme NAD(P)H promoter, and used to monitor oxidative stress in rMSCs. rMSCs was induced by hypoxia (1% O2 for 24 hours) and serum deprivation (SD) and confirmed using a dichlorofluorescein colorimetric assay (measures the production of hydrogen peroxide-H2O2-) and NAD(P)H protein expression. Results: Both serum deprivation and hypoxia led to a pro-oxidant state (Fig. A–B ). Most importantly, increased oxidative stress led to increased activity of the novel reporter gene sensor (Fig. C ) which was decreased in the presence of antioxidants (superoxide dismuatse mimetic Tempol, 5mM, SD+T, Fig D ). Results were reproduced in a different cell type (rat cardiomyoblast, data not shown). Conclusion: Changes in oxidative stress in MSCs can be monitored using molecular imaging. Reporter Gene-based Molecular Imaging, a strategy that is clinically applicable, provides the opportunity to monitor stem cell survival in the living subject.