Immunologic predictors of vaccine responsiveness in patients with lymphoma and CLL.

Patients with B-cell lymphomas have altered cellular components of vaccine responses due to malignancy and therapy, and the optimal timing of vaccination relative to therapy remains unknown. SARS-CoV-2 vaccines created an opportunity for new insights in vaccine timing because patients were challenged with a novel antigen across multiple phases of treatment. We studied serologic mRNA vaccine response in retrospective and prospective cohorts with lymphoma and CLL, paired with clinical and research immune parameters. Reduced serologic response was observed more frequently during active therapies, but non-response was also common within observation and post-treatment groups. Total IgA and IgM correlated with successful vaccine response. In individuals treated with CART-19, non-response was associated with reduced B and T follicular helper cells. Predictors of vaccine response varied by disease and therapeutic group, and therefore further studies of immune health during and after cancer therapies are needed to allow individualized vaccine timing.

Front-line, dose-escalated immunochemotherapy is associated with a significant progression-free survival advantage in patients with double-hit lymphomas: a systematic review and meta-analysis.

'Double-hit lymphomas' (DHL), defined by concurrent MYC and BCL2 (or, alternatively, BCL6) rearrangements, have a very poor outcome compared to standard-risk, diffuse large B-cell lymphomas (DLBCL). Consequently, dose-intensive (DI) therapies and/or consolidation with high-dose therapy and transplant have been explored in DHL, although benefit has been debated. This meta-analysis compared survival outcomes in DHL patients receiving dose-escalated regimens [DI: R-Hyper-CVAD (rituximab, cyclophosphamide, vincristine, doxorubicin, dexamethasone) or R-CODOX-M/IVAC (rituximab, cyclophosphamide, doxorubicin, vincristine, methotrexate/ifosfamide, etoposide, high dose cytarabine); or intermediate-dose: R-EPOCH (rituximab, etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone)] versus standard-dose regimens (R-CHOP; rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) in the first-line setting. Data were synthesized to estimate hazard ratios of dose-escalated treatments versus R-CHOP using a Weibull proportional hazards model within a Bayesian meta-analysis framework. Eleven studies examining 394 patients were included. Patients were treated with either front-line R-CHOP (n = 180), R-EPOCH (n = 91), or R-Hyper-CVAD/rituximab, methotrexate, cytarabine (R-M/C), R-CODOX-M/R-IVAC (DI) (n = 123). Our meta-analysis revealed that median progression-free survival (n = 350) for the R-CHOP, R-EPOCH and DI groups was 12·1, 22·2, and 18·9 months, respectively. First-line treatment with R-EPOCH significantly reduced the risk of a progression compared with R-CHOP (relative risk reduction of 34%; P = 0·032); however, overall survival (n = 374) was not significantly different across treatment approaches. A subset of patients might benefit from intensive induction with/without transplant. Further investigation into the role of transplant and novel therapy combinations is necessary.

Relationship between renal dysfunction and outcomes in emergency department patients with potential acute coronary syndromes.

OBJECTIVES: To determine whether patients with elevated creatinine who present to the emergency department (ED) with potential acute coronary syndrome (ACS) are at an increased risk of acute myocardial infarction (AMI) or 30-day cardiovascular (CV) events. METHODS: A secondary analysis of a cohort study of patients presenting to the ED with potential ACS with serum creatinine measurements. Research assistants collected demographics, history, symptoms, hospital course and 30-day follow-up. Outcomes measured were in-hospital AMI and 30-day CV events (death, nonfatal AMI, revascularisation). Prespecified multivariable models included age, gender, race and cardiac risk factors and presenting electrocardiogram (ECG). We used a creatinine cut-off point of 132.6 mmol/l. Data are presented as OR and 95% CI. RESULTS: 3451 patients were enrolled (age, 52.9±13.2; 55% female patients; 64% black patients). There were 120 AMI during initial visit and 232 patients had 30-day CV events (43 deaths, 128 AMI, 120 revascularisations). Creatinine values were normal in 3086 (89.4%) and abnormal in 365 (10.5%) patients. In multivariable models the adjusted OR (95% CI) for the association between abnormal creatinine and AMI was 1.43 (0.88 to 2.30) and 30-day CV events was 1.57 (1.10 to 2.25). The odds of 30-day CV events were increased for patients who were older, male subjects, white, had hyperlipidaemia, hypertension or a history of CAD, or presented with an abnormal ECG. CONCLUSION: In patients with potential ACS in the ED, renal dysfunction predicts a higher likelihood of 30-day CV events, but not an independent predictor after controlling for other risk factors. It appears to be a marker of other CV risks.

Stress testing in young low-risk patients with potential acute coronary syndromes.

OBJECTIVE: Young patients are at low risk for an acute coronary syndrome (ACS); however, many of these patients still enter a "rule-out ACS" pathway and receive stress testing. We hypothesized that stress testing in patients younger than 40 years without known coronary disease will not identify patients at high risk for 30-day adverse cardiovascular events. METHODS: We conducted a cohort study of patients younger than 40 years evaluated in the emergency department for potential ACS. Patients were excluded if they used cocaine, had known cardiac disease, or had an abnormal electrocardiogram. Patients were followed up in-house; follow-up was performed by direct telephone contact and medical record review. The main outcome was a composite of death, acute myocardial infarction (AMI), and revascularization at 30 days. Comparisons between patients with and without stress testing were done using χ2 or t test, as appropriate; 95% confidence intervals were reported for the main outcomes. RESULTS: Of 8816 patient visits, 1144 patients met inclusion criteria. Within 30 days, 82 patients (7.2%) received stress testing, 2 of whom led to cardiac catheterization. Death (n=2), AMI (n=3), and revascularization (n=1) were not different between patients who did and did not receive stress testing (2.4% [0.2%-8.5%] vs 0.4% [0.1%-1.0%]). CONCLUSION: The 30-day cardiovascular complication rate is not different between young patients without known heart disease who do and do not receive stress testing when they present with symptoms of a potential ACS. Testing of young patients at low risk for disease should be reconsidered.

Young patients with chest pain: 1-year outcomes.

OBJECTIVE: Prior studies found that young adult chest pain patients without known cardiac disease with either no cardiac risk factors or a normal electrocardiogram (ECG) are at low risk (<1%) for acute coronary syndromes (ACS) and 30-day cardiovascular events. Longer-term event rates in this subset of patients are unknown. We hypothesized that patients younger than 40 years without past cardiac history and a normal ECG are at less than 1% risk for 1-year adverse cardiovascular events. METHODS: We conducted a prospective cohort study in an urban university emergency department evaluating patients younger than 40 years who received an ECG for evaluation of potential ACS. Cocaine users, cancer patients, and patients with a history of myocardial infarction or revascularization were excluded. Structured data collection at presentation included demographics, chest pain description, history, laboratory results, and ECG data. Hospital course was followed. Follow-up was obtained by telephone, record review, and social security death index search. Our main outcome was 1-year adverse cardiovascular events (death; acute myocardial infarction [AMI]; or revascularization-percutaneous coronary intervention [PCI] or coronary artery bypass graft). Descriptive statistics and 95% confidence intervals were used. RESULTS: Of 3846 chest pain patients, 609 met criteria. Of those, 35.5% were admitted. Patients had a mean age of 34.8 years (SD, 3.8 years). They were most often female (57.6%) and black (69.5%). There were 7 patients (1.1%; 95% CI, 0.5%-2.4%) with adverse cardiovascular events over the year. Of the subset of 560 patients with a normal/nonspecific ECG, there were 2 deaths (0.4%), 3 AMI (0.5%), and 2 PCIs (0.4%) by 1 year for a composite adverse cardiovascular event rate of 6 (1.1%; 95% CI, 0.4%-2.3%). Of the subset of 269 patients with no cardiac risk factors and a normal/nonspecific ECG, there were no deaths, 1 AMI, and 1 PCI for a composite adverse cardiovascular event rate at 1 year of 0.3% (0.01%-2.1%). The addition of an initial cardiac marker to this group resulted in a cohort that was event-free at 1 year (95% CI, 0%-1.4%). CONCLUSIONS: Patients younger than 40 years without a cardiac history who present to the ED with symptoms consistent with ACS but have either no risk factors or a normal or nonspecific ECG have a very low rate of adverse events during the subsequent year.

Improving Displacement Signal-to-Noise Ratio for Low-Signal Radiation Force Elasticity Imaging Using Bayesian Techniques.

Radiation force-based elasticity imaging is currently being investigated as a possible diagnostic modality for a number of clinical tasks, including liver fibrosis staging and the characterization of cardiovascular tissue. In this study, we evaluate the relationship between peak displacement magnitude and image quality and propose using a Bayesian estimator to overcome the challenge of obtaining viable data in low displacement signal environments. Displacement data quality were quantified for two common radiation force-based applications, acoustic radiation force impulse imaging, which measures the displacement within the region of excitation, and shear wave elasticity imaging, which measures displacements outside the region of excitation. Performance as a function of peak displacement magnitude for acoustic radiation force impulse imaging was assessed in simulations and lesion phantoms by quantifying signal-to-noise ratio (SNR) and contrast-to-noise ratio for varying peak displacement magnitudes. Overall performance for shear wave elasticity imaging was assessed in ex vivo chicken breast samples by measuring the displacement SNR as a function of distance from the excitation source. The results show that for any given displacement magnitude level, the Bayesian estimator can increase the SNR by approximately 9 dB over normalized cross-correlation and the contrast-to-noise ratio by a factor of two. We conclude from the results that a Bayesian estimator may be useful for increasing data quality in SNR-limited imaging environments.

Combination of Lenalidomide and Rituximab Overcomes Rituximab Resistance in Patients with Indolent B-cell and Mantle Cell Lymphomas.

PURPOSE: Lenalidomide, an immunomodulatory agent that enhances antibody-dependent cell-mediated cytotoxicity, has the potential to synergize with rituximab, an anti-CD20 mAb. We hypothesized that the addition of lenalidomide to rituximab would improve clinical outcomes in patients with B-cell lymphomas who were previously rituximab resistant, defined as no response to or progression of lymphoma within 6 months of rituximab-based therapy. EXPERIMENTAL DESIGN: We conducted a single-center, phase II trial in patients with indolent B-cell or mantle cell lymphomas who were previously rituximab resistant. Patients received 10 mg lenalidomide daily for 8 weeks, and then received four weekly doses of 375 mg/m(2) rituximab; lenalidomide continued during and after rituximab. Response to therapy was assessed after 8 weeks of lenalidomide and 12 weeks after first dose of rituximab. The primary endpoint was overall response rate (ORR) after lenalidomide and rituximab. RESULTS: Fifty patients were enrolled and 43 patients completed both response assessments. ORR after 8 weeks of lenalidomide was 30.2%; 12 weeks after the addition of rituximab to lenalidomide, ORR increased to 62.8% (N = 43). For all patients (N = 50), median progression-free survival (PFS) is 22.2 months (median follow-up, 39.2 months). PFS after lenalidomide-rituximab was significantly longer than the PFS for the antecedent regimen used to define rituximab resistance (22.2 vs. 9.13 months, P = 0.0004). CONCLUSIONS: This trial is the first to show that the combination of lenalidomide and rituximab overcomes prior rituximab resistance in patients with indolent B-cell and mantle cell lymphomas.

Relationship between cocaine use and coronary artery disease in patients with symptoms consistent with an acute coronary syndrome.

OBJECTIVES: Observational studies of patients with cocaine-associated myocardial infarction have suggested more coronary disease than expected on the basis of patient age. The study objective was to determine whether cocaine use is associated with coronary disease in low- to intermediate-risk emergency department (ED) patients with potential acute coronary syndrome (ACS). METHODS: The authors conducted a cross-sectional study of low- to intermediate-risk patients<60 years of age who received coronary computerized tomographic angiography (CTA) for evaluation of coronary artery disease (CAD) in the ED. Patients were classified into three groups with respect to CAD: maximal stenosis <25%, 25% to 49%, and ≥50%. Prespecified multivariate modeling (generalized estimating equations) was used to assess relationship between cocaine and CAD. RESULTS: Of 912 enrolled patients, 157 (17%) used cocaine. A total of 231 patients had CAD ≥25%; 111 had CAD ≥50%. In univariate analysis, cocaine use was not associated with a lesion 25% or greater (12% vs. 14%; relative risk [RR]=0.89, 95% confidence interval [CI]=0.5 to 1.4) or 50% or greater (12% vs. 11%; RR=1.15, 95% CI=0.6 to 2.3). In multivariate modeling adjusting for age, race, sex, cardiac risk factors, and Thrombosis in Myocardial Infarction (TIMI) score, cocaine use was not associated with the presence of any coronary lesion (adjusted RR=0.95, 95% CI=0.69 to 1.31) or coronary lesions 50% or greater (adjusted RR=0.78, 95% CI=0.45 to 1.38). There was also no relationship between repetitive cocaine use and coronary calcifications or between recent cocaine use and CAD. CONCLUSIONS: In symptomatic ED patients at low to intermediate risk of an ACS, cocaine use was not associated with an increased likelihood of coronary disease after adjustment for age, race, sex, and other risk factors for coronary disease.

Relation between thrombolysis in myocardial infarction risk score and one-year outcomes for patients presenting at the emergency department with potential acute coronary syndrome.

The Thrombolysis in Myocardial Infarction (TIMI) score, derived from unstable angina/non-ST-segment elevation acute myocardial infarction patient population, predicts 14-day cardiovascular events. It has been validated in emergency department (ED) patients with potential acute coronary syndrome with respect to 30-day outcomes. Our objective was to determine whether the initial TIMI score could risk stratify ED patients with potential acute coronary syndrome with respect to the 1-year outcomes. This was a prospective cohort study of patients presenting to the ED with chest pain who underwent electrocardiography. Patients with ST-segment elevation myocardial infarction (acute myocardial infarction) were excluded. Follow-up was conducted by telephone and record review >1 year after the index visit. The main outcome was the 1-year mortality, nonfatal acute myocardial infarction, or revascularization stratified by the TIMI score. Of 2,819 patients, 253 (9%) met the composite outcome. The overall incidence of the composite 1-year outcome of death (n = 119), acute myocardial infarction (n = 96), and revascularization (n = 90) according to TIMI score was TIMI 0 (n = 1,162), 4%; TIMI 1 (n = 901), 8%; TIMI 2 (n = 495), 13%; TIMI 3 (n = 193), 23%; TIMI 4 (n = 60), 28%; and TIMI 5 to 7 (n = 8), 88% (p <0.001). In conclusion, in addition to risk stratifying ED patients with chest pain at the initial ED evaluation, the TIMI score can also predict the 1-year cardiovascular events in this patient population.

One-year outcomes following coronary computerized tomographic angiography for evaluation of emergency department patients with potential acute coronary syndrome.

OBJECTIVES: Coronary computerized tomographic angiography (CTA) has high correlation with cardiac catheterization and has been shown to be safe and cost-effective when used for rapid evaluation of low-risk chest pain patients from the emergency department (ED). The long-term outcome of patients discharged from the ED with negative coronary CTA has not been well studied. METHODS: The authors prospectively evaluated consecutive low- to intermediate-risk patients who received coronary CTA in the ED for evaluation of a potential acute coronary syndrome (ACS). Patients with cocaine use, known cancer, and significant comorbidity reducing life expectancy and those found to have significant disease (stenosis > or = 50% or ejection fraction < 30%) were excluded. Demographics, medical and cardiac history, labs, and electrocardiogram (ECG) results were collected. Patients were followed by telephone contact and record review for 1 year. The main outcome was 1-year cardiovascular death or nonfatal acute myocardial infarction (AMI). RESULTS: Of 588 patients who received coronary CTA in the ED, 481 met study criteria. They had a mean (+/-SD) age of 46.1 (+/-8.8) years, 63% were black or African American, and 60% were female. There were 53 patients (11%) rehospitalized and 51 patients (11%) who received further diagnostic testing (stress or catheterization) over the subsequent year. There was one death (0.2%; 95% confidence interval [CI] = 0.01% to 1.15%) with unclear etiology, no AMI (0%; 95% CI = 0 to 0.76%), and no revascularization procedures (0%; 95% CI = 0 to 0.76%) during this time period. CONCLUSIONS: Low- to intermediate-risk patients with a Thrombosis In Myocardial Infarction (TIMI) score of 0 to 2 who present to the ED with potential ACS and have a negative coronary CTA have a very low likelihood of cardiovascular events over the ensuing year.