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AbstractBackgroundGiven the challenges of conventional therapies in managing right‐sided infective endocarditis (RSIE), percutaneous mechanical aspiration (PMA) of vegetations has emerged as a novel treatment option. Data on trends, characteristics, and outcomes of PMA, however, have largely been limited to case reports and case series.Aims:The aim of the current investigation was to provide a descriptive analysis of PMA in the United States and to profile the frequency of PMA with a temporal analysis and the patient cohort.MethodsThe International Classification of Diseases, 10th Revision codes were used to identify patients with RSIE in the national (nationwide) inpatient sample (NIS) database between 2016 and 2020. The clinical characteristics and temporal trends of RSIE hospitalizations in patients who underwent PMA was profiled.ResultsAn estimated 117,955 RSIE‐related hospital admissions in the United States over the 5‐year study period were estimated and 1675 of them included PMA. Remarkably, the rate of PMA for RSIE increased 4.7‐fold from 2016 (0.56%) to 2020 (2.62%). Patients identified with RSIE who had undergone PMA were young (medial age 36.5 years) and had few comorbid conditions (median Charlson Comorbidity Index, 0.6). Of note, 36.1% of patients had a history of hepatitis C infection, while only 9.9% of patients had a cardiovascular implantable electronic device. Staphylococcus aureus was the predominant (61.8%) pathogen. Concomitant transvenous lead extraction and cardiac valve surgery during the PMA hospitalization were performed in 18.2% and 8.4% of admissions, respectively. The median hospital stay was 19.0 days, with 6.0% in‐hospital mortality.ConclusionsThe marked increase in the number of PMA procedures in the United States suggests that this novel treatment option has been embraced as a useful tool in select cases of RSIE. More work is needed to better define indications for the procedure and its efficacy and safety.

The evaluation, classification, and treatment of significant bone loss after total knee arthroplasty (TKA) continue to be a complex and debated topic in revision TKA (rTKA). Despite the introduction of new evidence and innovative technologies aimed at addressing the approach and care of severe bone loss in rTKA, there is no single document that systematically incorporates these newer surgical approaches. Therefore, a comprehensive review of the treatment of severe bone loss in rTKA is necessary. The Stavros Niarchos Foundation Complex Joint Reconstruction Center Hospital for Special Surgery, dedicated to clinical care and research primarily in revision hip and knee replacement, convened a Management of Bone Loss in Revision TKA symposium on June 24, 2022. At this meeting, the 42 international invited experts were divided into groups; each group was assigned to discuss questions related to 1 of the 4 topics: (1) assessing preoperative workup and imaging, anticipated bone loss, classification system, and implant surveillance; (2) achieving durable fixation in the setting of significant bone loss in revision TKA; (3) managing patellar bone loss and the extensor mechanism in cases of severe bone loss; and (4) considering the use of complex modular replacement systems: hinges, distal femoral, and proximal tibial replacements. Each group came to consensus, when possible, based on an extensive literature review and interactive discussion on their group topic. This document reviews each these 4 areas, the consensus of each group, and directions for future research.

AbstractThe DPYD gene encodes dihydropyrimidine dehydrogenase, the rate‐limiting enzyme for the metabolism of fluoropyrimidines 5‐fluorouracil and capecitabine. Genetic variants in DPYD have been associated with altered enzyme activity, therefore accurate detection and interpretation is critical to predict metabolizer status for individualized fluoropyrimidine therapy. The most commonly observed deleterious variation is the causal variant linked to the previously described HapB3 haplotype, c.1129‐5923C>G (rs75017182) in intron 10, which introduces a cryptic splice site. A benign synonymous variant in exon 11, c.1236G>A (rs56038477) is also linked to HapB3 and is commonly used for testing. Previously, these single‐nucleotide polymorphisms (SNPs) have been reported to be in perfect linkage disequilibrium (LD); therefore, c.1236G>A is often utilized as a proxy for the function‐altering intronic variant. Clinical genotyping of DPYD identified a patient who had c.1236G>A, but not c.1129‐5923C>G, suggesting that these two SNPs may not be in perfect LD, as previously assumed. Additional individuals with c.1236G>A, but not c.1129‐5923C>G, were identified in the Children's Mercy Data Warehouse and the All of Us Research Program version 7 cohort substantiating incomplete SNP linkage. Consequently, testing only c.1236G>A can generate false‐positive results in some cases and lead to suboptimal dosing that may negatively impact patient therapy and prospect of survival. Our data show that DPYD genotyping should include the functional variant c.1129‐5923C>G, and not the c.1236G>A proxy, to accurately predict DPD activity.

Abstract Purpose: The neutralizing peptibody trebananib prevents angiopoietin-1 and angiopoietin-2 from binding with Tie2 receptors, inhibiting angiogenesis and proliferation. Trebananib was combined with paclitaxel±trastuzumab in the I-SPY2 breast cancer trial. Patients and Methods: I-SPY2, a phase II neoadjuvant trial, adaptively randomizes patients with high-risk, early-stage breast cancer to one of several experimental therapies or control based on receptor subtypes as defined by hormone receptor (HR) and HER2 status and MammaPrint risk (MP1, MP2). The primary endpoint is pathologic complete response (pCR). A therapy “graduates” if/when it achieves 85% Bayesian probability of success in a phase III trial within a given subtype. Patients received weekly paclitaxel (plus trastuzumab if HER2-positive) without (control) or with weekly intravenous trebananib, followed by doxorubicin/cyclophosphamide and surgery. Pathway-specific biomarkers were assessed for response prediction. Results: There were 134 participants randomized to trebananib and 133 to control. Although trebananib did not graduate in any signature [phase III probabilities: Hazard ratio (HR)-negative (78%), HR-negative/HER2-positive (74%), HR-negative/HER2-negative (77%), and MP2 (79%)], it demonstrated high probability of superior pCR rates over control (92%–99%) among these subtypes. Trebananib improved 3-year event-free survival (HR 0.67), with no significant increase in adverse events. Activation levels of the Tie2 receptor and downstream signaling partners predicted trebananib response in HER2-positive disease; high expression of a CD8 T-cell gene signature predicted response in HR-negative/HER2-negative disease. Conclusions: The angiopoietin (Ang)/Tie2 axis inhibitor trebananib combined with standard neoadjuvant therapy increased estimated pCR rates across HR-negative and MP2 subtypes, with probabilities of superiority >90%. Further study of Ang/Tie2 receptor axis inhibitors in validated, biomarker-predicted sensitive subtypes is warranted.

ImportanceYoung women with breast cancer who have germline pathogenic variants in BRCA1 or BRCA2 face unique challenges regarding fertility. Previous studies demonstrating the feasibility and safety of pregnancy in breast cancer survivors included limited data regarding BRCA carriers.ObjectiveTo investigate cumulative incidence of pregnancy and disease-free survival in young women who are BRCA carriers.Design, Setting, and ParticipantsInternational, multicenter, hospital-based, retrospective cohort study conducted at 78 participating centers worldwide. The study included female participants diagnosed with invasive breast cancer at age 40 years or younger between January 2000 and December 2020 carrying germline pathogenic variants in BRCA1 and/or BRCA2. Last delivery was October 7, 2022; last follow-up was February 20, 2023.ExposurePregnancy after breast cancer.Main Outcomes and MeasuresPrimary end points were cumulative incidence of pregnancy after breast cancer and disease-free survival. Secondary end points were breast cancer–specific survival, overall survival, pregnancy, and fetal and obstetric outcomes.ResultsOf 4732 BRCA carriers included, 659 had at least 1 pregnancy after breast cancer and 4073 did not. Median age at diagnosis in the overall cohort was 35 years (IQR, 31-38 years). Cumulative incidence of pregnancy at 10 years was 22% (95% CI, 21%-24%), with a median time from breast cancer diagnosis to conception of 3.5 years (IQR, 2.2-5.3 years). Among the 659 patients who had a pregnancy, 45 (6.9%) and 63 (9.7%) had an induced abortion or a miscarriage, respectively. Of the 517 patients (79.7%) with a completed pregnancy, 406 (91.0%) delivered at term (≥37 weeks) and 54 (10.4%) had twins. Among the 470 infants born with known information on pregnancy complications, 4 (0.9%) had documented congenital anomalies. Median follow-up was 7.8 years (IQR, 4.5-12.6 years). No significant difference in disease-free survival was observed between patients with or without a pregnancy after breast cancer (adjusted hazard ratio, 0.99; 95% CI, 0.81-1.20). Patients who had a pregnancy had significantly better breast cancer–specific survival and overall survival.Conclusions and RelevanceIn this global study, 1 in 5 young BRCA carriers conceived within 10 years after breast cancer diagnosis. Pregnancy following breast cancer in BRCA carriers was not associated with decreased disease-free survival.Trial RegistrationClinicalTrials.gov Identifier: NCT03673306

Introduction While chimeric antigen receptor (CAR)-T cell therapy has transformed the management of hematologic malignancies, it requires frequent monitoring for acute toxicities, almost universally achieved through mandatory hospitalizations, therefore utilizing a significant amount of healthcare resources. At Mayo Clinic in Rochester, MN, our standard practice is administering CAR-T cell therapy in the outpatient setting through a multi-disciplinary hospital-based outpatient (HBO) unit and remote patient monitoring (RPM) program. Our CAR-T RPM program consists of in-home, electronic health record-integrated technology to monitor vital signs and neurologic symptoms for 30 days post CAR-T infusion. Here we report the healthcare utilization outcomes of CAR-T patients managed in the outpatient setting enrolled in the RPM program. Methods Patients undergoing FDA-approved CAR-T cell treatment in the outpatient setting and participating in the CAR-T RPM program at Mayo Clinic Rochester were included in this IRB-approved study. Patient characteristics, healthcare utilization metrics, inpatient interventions, and patient satisfaction data regarding the RPM program were reviewed. Length of stay (LOS) includes any hospitalizations for which the admission date falls within the RPM monitoring period (CAR-T cell infusion to day +30), even if the hospitalization continued past day +30. Results A total of 123 patients participated in the CAR-T RPM program and underwent treatment in the outpatient setting. Median age at CAR-T infusion was 63 years (range 22 - 83), and most patients were male (n=78, 63%). Non-Hodgkin lymphoma was the most common diagnosis (n=74, 60%), followed by multiple myeloma (n=47, 38%), ALL (n=1, 1%) and other (n=1, 1%). During the PRM monitoring period, 19 (16%) patients were managed entirely in the outpatient setting. The remaining 104 (84%) patients required at least one hospitalization, with most patients (n=70, 57%) hospitalized only once [26 (21%) patients were hospitalized twice, and 7 (6%) patients were hospitalized 3 times, and 1 (1%) patient hospitalized 4 times during the monitoring period]. When considering the first hospitalization post CAR-T infusion, the median LOS was 6 days (range 2 - 47). When considering all hospitalizations post CAR-T, the median LOS was 8 days (range 2 - 47). Only 7 (6%) patients required an ICU stay, with a mean ICU stay of 0.2 days (standard deviation 0.9). Cytokine release syndrome (CRS) was noted in 92 (75%) of patients at a median of 3 days (range 0 - 18) post CAR-T infusion. All patients with CRS received tocilizumab, at a median of 4 days post CAR-T infusion. Steroids for CRS were administered in 63 (68%) of these patients. Neurotoxicity was reported in 45 (37%) patients at a median of 7 days (range 1 - 19) post CAR-T infusion. During the RPM monitoring period, patients were seen in our HBO unit with a median of 18 outpatient visits (range 4 - 30). Patient survey data, obtained at the end of the RPM monitoring period, were available from 37 patients. The majority of patients felt that the RPM program helped them feel comfortable managing their health at home, were able to reach a team member, and receive an appropriate response promptly. The majority of patients felt comfortable using the RPM equipment and interacting with providers virtually. Overall, 83% of patients were satisfied with the RPM program and 6% were neither satisfied nor dissatisfied. When asked about the reason for disappointment, technical difficulties/issues with the devices were the themes mentioned by the few patients (11%) who were unsatisfied with the RPM program. Conclusion: Despite the complexities and frequent monitoring associated with CAR-T cell therapy, outpatient CAR-T cell treatment is a feasible model of care. As the standard practice at our institution, the CAR-T RPM program was part of the management of nearly all patients undergoing an FDA-approved CAR-T product in the outpatient setting. RPM in the acute setting post CAR-T infusion is a well-received practice initiative by the majority of patients, including a high level of comfort utilizing the RPM equipment and virtual interaction with the RPM providers.

Abstract INTRODUCTION Accelerated atherosclerosis has been described in breast cancer patients receiving cardiac exposure from adjuvant radiotherapy (RT). As a result of multidisciplinary care, breast cancer cure rates have improved in recent decades. Therefore, evaluating radiation-induced heart disease (RIHD), especially coronary artery disease (CAD), is essential. The 2022 cardio-oncology European Society of Cardiology (ESC) guidelines recommend screening patients 5 to 10 years after RT for CAD according to cardiovascular risk factors. This screening is generally recommended with exercise stress echocardiography since it can assess the physiological functional performance. Until now, it is unknown if dobutamine stress echocardiography (DSE) is an equal screening tool and if it can predict major adverse cardiovascular events (MACE) (myocardial infarction, stroke, cardiac death, revascularization). PURPOSE Evaluate if DSE is an adequate tool to stratify and predict MACE in post-radiotherapy patients. Methods A retrospective, descriptive cohort study was conducted. Patients who had chest RT for breast cancer and underwent DSE from 2000 to 2022 were included. A bivariate analysis, including Kruskal Wallis and Pearson Chi-Squared test, was done to identify variables associated with a positive DSE. A multivariable Cox Model for MACE and a time-to-event curve for MACE were also performed. Results We identified 163 patients that underwent DSE after a median time of 5.8 years from the end of RT. The median age was 74 years, 98.2% were female, 50% had left and 45% right breast cancer, 81% had hypertension, 41% diabetes mellitus, 71% dyslipidemia, 34% were smokers, and 19% had a prior myocardial infarction. The average dose of photon RT to the chest was 55Gy in the cohort, and 40% received chemotherapy before RT. Patients were divided into two groups: positive and negative DSE. A positive DSE was seen in 19.6%. The median (Q1, Q3) regional wall motion abnormalities (RWMA) of patients with a positive DSE was 1 (1, 1.015) at baseline and 1.280 (1.190, 1.520) at peak stress, and for a negative DSE, was 1 (1, 1) at baseline and peak stress. 88.2% of negative DSE and 87.5% of positive DSE achieved the target heart rate of 85%. HTN, dyslipidemia, and prior MI were significantly associated with a positive DSE (p <0.023). The cumulative incidence of MACE was higher in the group of positive DSE (p<0.001), even after adjusting for hypertension, diabetes mellitus, dyslipidemia, smoking, and prior myocardial infarction, with a hazard ratio of 2.500 (1.51 – 4.13) and a p< 0.001. Similar results were observed regardless of RT laterality. Conclusions In breast cancer survivors that received adjuvant radiotherapy as part of multidisciplinary care, a positive DSE was an independent predictor of MACE compared to a negative result. These results support the usefulness of dobutamine stress echocardiography as a screening tool in breast cancer survivors.Kaplan-Meier Curve for MACE

Abstract Background Exercise stress echocardiography (ESE) is a non-invasive, radiation-free, and widely available technique that has demonstrated a reliable accuracy for the detection of coronary artery disease (CAD). Chest radiotherapy (RT) is associated with accelerated age-related atherosclerosis and fibrosis in a dose-dependent manner. ESE plays a role as a screening tool of RT induced heart disease, however, the prognostic value of changes in regional wall motion abnormalities in this population during ESE has not been evaluated. Methods This is a retrospective cohort study of breast cancer survivors treated with adjuvant RT that underwent ESE from 2000-2020 after treatment completion. Outcomes evaluated were: major adverse cardiovascular events (MACE: cardiovascular death, myocardial infarction, revascularization and stroke); and all-cause mortality. A univariate analysis was performed to characterize the population. Continuous variables were presented as means ± standard deviation (SD) or median with quartile 1 and 3 (Q1, Q3), and categorical variables as numbers and percentages. A Cox regression model adjusted by age and cardiovascular risk factors was used to evaluate variables associated with outcomes, and a time to first event approach was used. A p-value of <0.05 was considered statistically significant. Results From 2000-2020, 507 patients, with a mean age 66 ± 10 years, underwent ESE at a median of 5.8 years after RT completion. The most prevalent comorbidities were dyslipidemia (59%), HTN (55%) and obesity (37%). 55% underwent RT for left-sided breast cancer and 45% for right-sided, and median RT dose was 6000 cGy. Baseline characteristics are presented in Table 1. Most patients underwent Bruce Protocol (92%). Patients exercised a mean time of 6.6 minutes achieving 7.3 METS and 109% of functional aerobic capacity (Table 2). At a median follow up of 7.8 years, 61 MACE events occurred. Predictors of MACE were double product, baseline and stress EF, baseline and peak regional wall motion abnormalities (RWMA), development of new ischemic RWMA, inability to reach 85% of maximum HR, and an abnormal EF response with stress after adjusting for age, HTN, DM, smoking history, dyslipidemia, obesity, prior MI and cancer staging (Fig 1). Predictors of all-cause mortality were METS, LV mass index, baseline and peak RWMA, development of new ischemic RWMA and an abnormal EF change with stress even after adjusting for variables described previously (Fig 2). Conclusions The development of new or worsening RWMA of just 2 segments with stress, was a significant predictor of MACE and all-cause mortality in a large cohort of breast cancer survivors undergoing multidisciplinary management including adjuvant RT. Special emphasis on management of cardiovascular comorbidities and closer surveillance are recommended for these patients.