Cardiovascular Magnetic Resonance Imaging in Patients With Ibrutinib-Associated Cardiotoxicity.

Importance: Ibrutinib has been associated with serious cardiotoxic arrhythmias. In preclinical models, these events are paralleled or proceeded by diffuse myocardial injury (inflammation and fibrosis). Yet whether this is seen in patients or has implications for future cardiotoxic risk is unknown. Objective: To assess the incidence and outcomes of myocardial injury among patients with ibrutinib-related cardiotoxicity. Design, Setting, and Participants: This cohort study included consecutive patients treated with ibrutinib from 2012 to 2019, phenotyped using cardiovascular magnetic resonance (CMR) from a large US Comprehensive Cancer Center registry. Exposures: Ibrutinib treatment for cancer control. Main Outcomes and Measures: The primary outcome was the presence of late gadolinium enhancement (LGE) fibrosis. The secondary outcome was the occurrence of major adverse cardiac events (MACE), defined as atrial fibrillation, heart failure, symptomatic ventricular arrhythmias, and sudden death of probable or definite ibrutinib association after CMR. We also assessed parametric-mapping subclinical fibrosis (native-T1, extracellular volume fraction) and inflammation/edema (max-T2) measures. Cardiovascular magnetic resonance measures were compared with those obtained in similar consecutive patients with cancer without ibrutinib treatment (pretreatment controls). Observed measures were also compared with similar-aged broad population rates (general-population controls) and a broader pool of cardiovascular disease (CVD) risk-matched cancer controls. Multivariable regression was used to assess the association between CMR measures and MACE. Results: Overall, 49 patients treated with ibrutinib were identified, including 33 imaged after treatment initiation (mean [SD] age, 65 [10] years, 9 [27%] with hypertension, and 23 [69.7%] with index-arrhythmias); median duration of ibrutinib-use was 14 months. The mean (SD) pretreatment native T1 was 977.0 (73.0) ms, max-T2 56.5 (4.0) ms, and 4 (13.3%) had LGE. Posttreatment initiation, mean (SD) native T1 was 1033.7 (48.2) ms, max-T2 61.5 (4.8) ms, and 17 (54.8%) had LGE (P < .001, P = .01, and P < .001, respectively, pre- vs post-ibrutinib treatment). Native T12SDs was elevated in 9 (28.6%), and max-T22SDs in 21 (63.0%), respectively. Cardiovascular magnetic resonance measures were highest in those with suspected toxic effects (P = .01 and P = .01, respectively). There was no association between traditional CVD-risk or cancer-treatment status and abnormal CMR measures. Among those without traditional CVD, 16 (58.6%) had LGE vs 38 (13.3%) in matched-controls (relative-risk, 4.8; P < .001). Over a median follow-up of 19 months, 13 (39.4%) experienced MACE. In multivariable models inclusive of traditional CVD risk factors, LGE (hazard ratio [HR], 4.9; P = .04), and native-T12SDs (HR, 3.3; P = .05) associated with higher risks of MACE. Conclusions and Relevance: In this cohort study, myocardial injury was common in ibrutinib users, and its presence was associated with higher cardiotoxic risk.

Early toxicity and clinical outcomes after chimeric antigen receptor T-cell (CAR-T) therapy for lymphoma.

BACKGROUND: Chimeric antigen receptor T-cell (CAR-T) infusion is associated with early toxicity. Yet, whether early toxicity development holds ramifications for long-term outcomes is unknown. METHODS: From a large cohort of consecutive adult patients treated with CAR-T therapies for relapsed or refractory lymphomas from 2016 to 2019, we assessed progression-free survival (PFS), by toxicity development (cytokine release syndrome (CRS), neurotoxicity, or cardiotoxicity]. We also assessed the relationship of toxicity development to objective disease response, and overall survival (OS). Multivariable regression was utilized to evaluate relationships between standard clinical and laboratory measures and disease outcomes. Differences in outcomes, by toxicity status, were also assessed via 30-day landmark analysis. Furthermore, we assessed the effects of early anti-CRS toxicity therapy use (at ≤grade 2 toxicity) on maximum toxicity grade observed, and long-term disease outcomes (PFS and OS). RESULTS: Overall, from 102 CAR-T-treated patients, 90 were identified as treated with single-agent therapy, of which 88.9% developed toxicity (80 CRS, 41 neurotoxicity, and 17 cardiotoxicity), including 28.9% with high-grade (≥3) events. The most common manifestations were hypotension at 96.6% and fever at 94.8%. Among patients with cardiac events, there was a non-significant trend toward a higher prevalence of concurrent or preceding high-grade (≥3) CRS. 50.0% required tocilizumab or corticosteroids. The median time to toxicity was 3 days; high grade CRS development was associated with cardiac and neurotoxicity. In multivariable regression, accounting for disease severity and traditional predictors of disease response, moderate (maximum grade 2) CRS development was associated with higher complete response at 1 year (HR: 2.34; p=0.07), and longer PFS (HR: 0.41; p=0.02, in landmark analysis), and OS (HR: 0.43; p=0.03). Among those with CRS, relative blood pressure (HR: 2.25; p=0.004), respectively, also associated with improved PFS. There was no difference in disease outcomes, or maximum toxicity grade (CRS, neurotoxicity, or cardiotoxicity) observed, based on the presence or absence of the use of early CRS-directed therapies. CONCLUSIONS: Among adult lymphoma patients, moderate toxicity manifest as grade 2 CRS after CAR-T infusion may associate with favorable clinical outcomes. Further studies are needed to confirm these findings.

Tips for pandemic response planning for Internal Medicine training programs.

This article was migrated. The article was marked as recommended. The current Coronavirus Disease 2019 (COVID-19) pandemic has strained hospital systems and training programs across the world. As capacity issues mount and trainees are called upon to provide frontline medical care, programs and institutions have had to rapidly evolve to redefine the trainee experience. To that end, there is a paucity of literature regarding how healthcare training programs should operate during a global pandemic. Here, we aim to describe twelve evidence-based recommendations for coordinating a cohesive, systematic approach to pandemic response planning for Internal Medicine residency training programs. These tips encompass inpatient and outpatient practices, provider safety, resuscitation, virtual education programming and resident wellbeing. Though many of these considerations or recommendations were not described during the COVID-19 pandemic, these tips have been described previously in the literature, are applicable to the current pandemic and could be easily extrapolated to future crises.

Hypertension and incident cardiovascular events following ibrutinib initiation.

Ibrutinib is associated with dramatic efficacy against B-cell malignancies. Yet, it has been linked with potentially limiting cardiotoxicity, including emerging reports of profound hypertension (HTN). The long-term incidence, severity, and impact of HTN development with ibrutinib are unknown. Therefore, in 562 consecutive patients treated with ibrutinib for B-cell malignancies from 2009 through 2016, we assessed the new/incident or worsened HTN (systolic blood pressure [BP] cutoff, 130 mm Hg). Observed incident HTN rates were compared with Framingham-heart-predicted incident HTN rates. We also evaluated the relationship of HTN to the development of other major adverse cardiovascular events (MACEs), including arrhythmia, myocardial infarction, stroke, heart failure, and cardiovascular death. Further, we assessed the effects of different antihypertensive classes on ibrutinib-related HTN. Overall, 78.3% of ibrutinib users developed new or worsened HTN over a median of 30 months. New HTN developed in 71.6% of ibrutinib users, with a time to 50% cumulative incidence of 4.2 months. Among those without preceding HTN, 17.7% developed high-grade HTN (BP >160/100 mm Hg). In multivariate regression, new or worsened HTN was associated with increased MACEs (hazard ratio [HR], 2.17; 95% confidence interval [CI], 1.08-4.38). No single antihypertensive class was associated with prevention or control of ibrutinib-related HTN. However, antihypertensive initiation was associated with a lower risk of a MACE (HR, 0.40; 95% CI, 0.24-0.66). Collectively, these data suggest that ibrutinib is associated with a substantial increase in the incidence and severity of HTN, and that HTN development carries a higher risk of subsequent cardiotoxic events.

Morbidity Associated with Urinary Diversion in the United States: A Contemporary Evaluation Using the NSQIP Database.

INTRODUCTION: We identified preoperative differences between patients undergoing incontinent vs continent diversion, and compared 30-day complication outcomes between the 2 procedures. METHODS: Using the NSQIP® (National Surgical Quality Improvement Program) database we identified patients undergoing urinary diversion incorporating bowel, with or without cystectomy, between 2010 and 2012. We compared preoperative characteristics, surgical parameters and 30-day postoperative outcomes. We stratified patients based on the continence status of the diversion as incontinent vs continent. RESULTS: We identified 1,959 urinary diversions in the NSQIP database, including 1,568 incontinent diversions (80.0%) and 391 continent diversions (20.0%). Significantly higher rates of chronic obstructive pulmonary disease (9.1% vs 4.3%), previous cardiac surgery (4.3% vs 1.8%), hypertension (63.3% vs 47.1%) and disseminated disease (4.7% vs 2.1%) were noted in patients undergoing incontinent diversion. Patients undergoing continent diversion were significantly more likely to have received preoperative chemotherapy (10.5% vs 5.2%). Operative time was longer for continent diversion (388 vs 336 minutes). Postoperative urinary tract infection (13.8% vs 7.9%) and sepsis rates (11.5% vs 7.9%) were significantly higher with continent diversion, whereas transfusion rates were higher with incontinent diversion (45.2% vs 37.1%). Thirty-day readmission rates (18.2% vs 15.6%), length of stay (10.2 vs 10.7 days), presence of at least 1 NSQIP captured complication (61.4% vs 64.0%) and mortality (1.5% vs 2.1%) were not statistically different between continent diversion and incontinent diversion. CONCLUSIONS: Urinary diversion incorporating bowel continues to carry a significant risk of postoperative morbidity. While continent diversion offers potential long-term advantages, these must be balanced against longer operative times and higher rates of postoperative infectious complications.

NSQIP® Indexed Complications Following Transurethral Bladder Tumor Resection and Contemporary Financial Implications.

INTRODUCTION: We determined the incidence of NSQIP (National Surgical Quality Improvement Project) indexed complications by tumor size and investigated the related financial implications based on contemporary reimbursement schedules. METHODS: Transurethral bladder tumor resection procedures performed from 2010 to 2012 were identified and stratified by size specific CPT coding. Preoperative characteristics, surgical parameters and 30-day perioperative outcomes were compared using chi-square analysis and Student's t-test. Financial data for all inpatient transurethral bladder tumor resections performed during the most recent fiscal year at our institution were collected and analyzed, and a comparison was made using up-to-date Medicare reimbursement schedules. RESULTS: We identified 8,116 cases, including 3,533 coded as small (43.3%), 2,734 medium (33.5%) and 1,849 large (22.6%). Large resections required longer operative time (small-25.8 minutes, medium-33.0 minutes, large-49.0 minutes, p <0.01) and length of stay (small-0.67 days, medium-1.1 days, large-1.9 days, p <0.006), and had higher rates of transfusion (small-0.74%, medium-1.5%, large-3.7%, p <0.001), sepsis (small-0.23%, medium-0.44%, large-0.92%, p <0.05), renal insufficiency (small-0.17%, medium-0.15%, large-0.60%, p <0.01) and 30-day mortality (small-0.2%, medium-1%, large-1.8%, p <0.05) independent of preoperative parameters. Large resections were also associated with higher rates of 30-day readmission (small-4.3%, medium-6.3%, large-9.4%, p <0.001) and reoperation (small-2.1%, medium-2.7%, large-4.5%, p <0.001). Institutional data demonstrate that the most common Diagnosis Related Group classification results in an operating loss when treating Medicare beneficiaries. CONCLUSIONS: Urologist selected coding directly correlates with NSQIP indexed postoperative complications. Many cases of transurethral bladder tumor resection with associated complications may result in financial loss for the performing institutions. Efforts to improve quality of care and reimbursement seem warranted.

Eleven-year trends of inpatient pacemaker implantation in patients diagnosed with sick sinus syndrome.

BACKGROUND: Pacemakers (PM) are used for managing sick sinus syndrome (SSS). This study evaluates predictors and trends of PM implantation for SSS. METHODS: Patients were identified from the National Inpatient Sample dataset (2003-2013). Included patients were ≥18 years old, had a diagnosis of sinus node dysfunction and atrial arrhythmia (i.e., SSS). Patients who died, transferred out, who had prior device, or had a defibrillator or resynchronization therapy device implanted were excluded. Included patients were then stratified by if a PM was implanted. Data regarding SSS, trends of PM utilization, and multivariable models of factors associated with PM implantation are presented. RESULTS: Note that 328,670 patients satisfied study criteria. This study compared patients who underwent (87.4%) PM implantation to those who did not undergo (12.6%) PM implantation. The annual trends for hospitalization with SSS and PM placement have been decreasing (P <0.001). Variables associated with lower likelihood for PM implantation include young age, female sex, non-Caucasian race, chronic heart failure, Charlson Comorbidity Score ≥1, emergency room and weekend admission, hospital stay ≤3 days, and high cardiology inpatient volume. Greater likelihood for PM implantation was associated with hyperlipidemia, hypertension, and hospitals that were either private, large, Northeastern location, or with high cardiac procedural volume. CONCLUSIONS: Analyzing 11-year data from a national inpatient database demonstrate a number of relevant variables that impact PM utilization that include not only clinical but also nonclinical variables such as socioeconomic status, gender, and hospital features. Racial and gender bias toward PM implantation are unchanged and persist through 2013.

Short-term complications associated with the use of transvaginal mesh in pelvic floor reconstructive surgery: Results from a multi-institutional prospectively maintained dataset.

AIMS: Vaginal reconstructive surgery can be performed with or without mesh. We sought to determine comparative rates of perioperative complications of native tissue versus vaginal mesh repairs for pelvic organ prolapse. METHODS: Using the National Surgical Quality Improvement Program (NSQIP) database, we concatenated surgical data from vaginal procedures for prolapse repair, including anterior and posterior colporrhaphy, paravaginal defect repair, enterocele repair, and vaginal colpopexy using Current Procedural Terminology (CPT) coding. We stratified this data by the modifier associated with mesh usage at the time of the procedure. We then compared 30-day perioperative outcomes, postoperative complications (bleeding, infection, etc), and readmission rates between women with and without mesh-based repairs. RESULTS: We identified 10 657 vaginal reconstructive procedures without mesh and 959 mesh-based repairs from 2009 through 2013. Patients undergoing mesh repair were more likely to experience at least one complication than native tissue repair (9.28% vs 6.15%, P < 0.001), with the overall complication rate also being higher in the mesh group (11.37% vs 9.39%, P = 0.03). Procedures with mesh had a higher rate of perioperative bleeding requiring transfusion than native tissue repair (2.3% vs 0.49%, P < 0.001), and organ surgical site infection (SSI) (0.52% vs 0.17%, P = 0.02). There were no significant differences in rates of readmission, superficial, or deep SSIs, pneumonia, urinary tract infection, sepsis, or renal failure. CONCLUSIONS: The use of vaginal mesh for pelvic organ prolapse repair appears to result in a higher rate of perioperative complications than native tissue repair. Patients undergoing these procedures should be counselled preoperatively concerning these risks.

Anterior Urethroplasty Has Transitioned to an Outpatient Procedure Without Serious Rise in Complications: Data From the National Surgical Quality Improvement Program.

OBJECTIVE: To analyze the trend in inpatient vs outpatient performance of anterior urethroplasty and examine outcomes using data from the National Surgical Quality Improvement Program database. METHODS: A retrospective cross sectional analysis was performed using the National Surgical Quality Improvement Program database. Cases of single-stage anterior urethroplasty from 2006 to 2013 were identified using the International Classification of Diseases, Ninth Revision, procedure code 53410. Univariate analysis was performed to compare 30-day complication rates for inpatient and outpatient cases. A linear regression model was created for all years with greater than 50 reported cases. RESULTS: A total of 326 anterior urethroplasties were reported; 222 (68.1%) were inpatient procedures, and 104 (31.9%) were outpatient procedures. The most common complication, urinary tract infection, was consistent between inpatient (2.7%) and outpatient (2.9%) procedures. The rate of wound dehiscence was significantly higher among outpatient cases (1.92% vs 0%, P = .03). There were no significant differences in the rates of wound infection, bleeding, graft failure, deep vein thrombosis, pneumonia, or sepsis. The linear regression model shows a significant increase in outpatient procedures (R2 = 0.91) and equivalent decrease in inpatient procedures (R2 = 0.91) for the last 3 years of the study period. Resident involvement was associated with a decreased rate of reoperation (0% vs 8.3% P <.001). CONCLUSION: There has been a shift in the performance of anterior urethroplasty toward outpatient management. Overall, complication rates appear low. Future research is necessary to determine how to decrease overall cost of single-stage urethroplasty without compromising quality of care.

IgG4 can induce an M2-like phenotype in human monocyte-derived macrophages through FcγRI.

Antibodies evoke cellular responses through the binding of their Fc region to Fc receptors, most of which contain immunoreceptor tyrosine-based activation motif domains and are thus considered "activating." However, there is a growing appreciation of these receptors for their ability to deliver an inhibitory signal as well. We previously described one such phenomenon whereby interferon (IFN)γ signaling is inhibited by immune complex signaling through FcγRI. To understand the implications of this in the context of therapeutic antibodies, we assessed individual IgG subclasses to determine their ability to deliver this anti-inflammatory signal in monocyte-derived macrophages. Like IgG1, we found that IgG4 is fully capable of inhibiting IFNγ-mediated events. In addition, F(ab')2 fragments that interfere with FcγRI signaling reversed this effect. For mAbs developed with either an IgG1 or an IgG4 constant region for indications where inflammation is undesirable, further examination of a potential Fc-dependent contribution to their mechanism of action is warranted.