Background Single-agent checkpoint blockade inhibitors have shown great promise in recent years but has unfortunately been limited to a subset of tumor types. The tumor mutation burden as well as the tumor microenvironment are two key important features that distinguish immunogenic, from non-immunogenic tumors. There is currently a massive effort, including a wide range of strategies, turning tumors from cold to hot including combining with small molecule inhibitors. For colorectal (CRC) cancers, anti-PD1 therapies have proven to be successful in the clinic for microsatellite instable (MSI-high) tumors but have no efficacy in the majority of patients with CRC that have microsatellite stable (MSS) cancers. Our primary goal is to determine if the addition of binimetinib (small molecule MEK inhibitor) and bevacizumab (anti-VEGF therapeutic antibody) increases the response rate of metastatic microsatellite stable colorectal cancer to pembrolizumab in humanized patient-derived xenografts (hPDXs) of CRC. We will also identify immune and pathway modulation in MSS CRC hPDXs treated with the combination of MEK, VEGF, and immune checkpoint inhibitors. Methods In six independent experiments, we implanted distinct MSS CRC PDXs, that were recently isolated from patients on a matching clinical trial, into the flanks of humanized BRGS (BALB/c, Rag2-/-, IL2RgC-/-, NODSIRPa) mice that had been engrafted with human hematopoietic stem cells at birth. For each PDX we generated humanized mice cohorts treated with vehicle, binimetinib, binimetinib/pembrolizumab combination, or binimetinib/pembroliumab/bevacizumab/DC101. The human immune system in the immune organs and tumors were interrogated by flow cytometry to assess changes in the cellular composition and the activation state of the immune system as a result of treatments, and the expression of immune-related molecules were assessed on the tumor cells. Results There were no significant differences in primary tumor growth in all treated models. However, immune modulation was observed in TILs in which we measured increased activated T cells (DR+, effector memory, TIM-3+), GrB+CD8+ and IFNg+CD8+ T cells. We also observed increased TNFa and IFNg and decreased T regulatory (FoxP3+CD25+) CD4+ T cells in the pembrolizumab/binimetinib and triple combination groups. Immune infiltrates were unique for the various PDXs. Conclusions In this preclinical examination of combination MEK, VEGF, and PD-1 inhibition in CRC hPDXs no significant differences in tumor growth were noted, but immune modulation in TILs and tumor were observed suggesting potential immune modulation of the tumor microenvironment that may lead to greater susceptibility to immune checkpoint inhibition in patients with MSS mCRC. Ethics Approval The human cord blood samples were generously provided as de-identified donors from Clinimmune Cord Blood Bank (Aurora, CO). All procedures and mouse husbandry were performed in accordance with IACUC protocols approved by the University of Colorado Denver Institutional Animal Care and Use Committee in the Office of Laboratory of Animal Resources (OLAR), a facility approved by the American Association for Laboratory Animal Care.

BACKGROUND:Coronary vasospasm is a known side effect of 5-FU (fluorouracil) therapy. Beyond switching to non-5FU-based chemotherapy, there are no established treatments for 5-FU associated coronary vasospam. Our objective was to assess the safety and efficacy of re-challenge with 5-FU after pre-treatment with calcium channel blockers (CCBs) and long-acting nitrates among patients 5-FU associated coronary vasospasm. METHODS:We conducted a retrospective study of patients with 5-FU coronary vasospasm at a single academic center. By protocol, those referred to cardio-oncology received pre-treatment with either combination [nitrates and CCBs] or single-agent therapy [nitrates or CCBs]) prior to re-challenge with 5-FU. Our primary outcome was overall survival. Other important outcomes included progression-free survival and safety. RESULTS:Among 6,606 patients who received 5-FU from January 2001 to Dec 2020, 115 (1.74%) developed coronary vasospasm. Of these 115 patients, 81 patients continued 5-FU therapy, while 34 stopped. Of the 81 who continued, 78 were referred to cardio-oncology and prescribed CCBs and/or nitrates prior to subsequent 5-FU, while the remaining 3 continued 5-FU without cardiac pre-treatment. Of the 78, 56.4% (44/78) received both nitrates and CCBs, 19.2% (15/78) received CCBs alone, and 24.4% (19/78) received nitrates alone. When compared to patients who stopped 5-FU, those who continued 5-FU after pre-treatment (single or combination therapy) had a decreased risk of death (HR 0.42, P = 0.005 [95% CI 0.23-0.77]) and a trend towards decreased cancer progression (HR 0.60, P = 0.08 [95% CI 0.34-1.06]). No patient in the pre-treatment group had a myocardial infarct after re-challenge; however, chest pain (without myocardial infarction) recurred in 19.2% (15/78) among those who received cardiac pre-treatment vs. 66.7% (2/3) among those who did not (P = 0.048). There was no difference in efficacy or the recurrence of vasospasm among patients who received pre-treatment with a single agent (nitrates or CCBs) or combination therapy (14.7% (5/34) vs. 25.0% (11/44), P = 0.26). CONCLUSION:Re-challenge after pre-treatment with CCBs and nitrates guided by a cardio-oncology service was safe and allowed continued 5-FU therapy.

BACKGROUND Sodium-glucose co-transporter-2 (SGLT2) inhibitors improve outcomes among patients with estab-lished heart failure. Despite supportive basic science studies, there are no data on the value of SGLT2 inhibitors among patients treated with anthracyclines.OBJECTIVES This study sought to test the cardiac efficacy and overall safety of SGLT2 inhibitors in patients treated with anthracyclines.METHODS This study identified 3,033 patients with diabetes mellitus (DM) and cancer who were treated with anthracyclines. Cases were patients with cancer and DM who were on SGLT2 inhibitor therapy during anthracycline treatment (n = 32). Control participants (n = 96) were patients with cancer and DM who were also treated with anthracyclines, but were not on an SGLT2 inhibitor. The primary cardiac outcome was a composite of cardiac events (heart failure incidence, heart failure admissions, new cardiomyopathy [>10% decline in ejection fraction to <53%], and clinically significant arrhythmias). The primary safety outcome was overall mortality.RESULTS Age, sex, ethnicity, cancer type, cancer stage, and other cardiac risk factors were similar between groups. There were 20 cardiac events over a median follow-up period of 1.5 years. The cardiac event incidence was lower among case patients in comparison to control participants (3% vs 20%; P = 0.025). Case patients also experienced lower overall mortality when compared with control participants (9% vs 43%; P < 0.001) and a lower composite of sepsis and neutropenic fever (16% vs 40%; P = 0.013). CONCLUSIONS SGLT2 inhibitors were associated with lower rate of cardiac events among patients with cancer and DM who were treated with anthracyclines. Additionally, SGLT2 inhibitors appeared to be safe. These data support the con-ducting of a randomized clinical trial testing SGLT2 inhibitors in patients at high cardiac risk treated with anthracyclines. (J Am Coll Cardiol HF 2022;10:559-567) (c) 2022 by the American College of Cardiology Foundation.

The aim of this study was to determine the effects of silver nanoparticles (AgNPs; speciation: NM-300 K) in the lab on the behavior of larvae in European Whitefish (Coregonus lavaretus), a relevant model species for temperate aquatic environments during alternating light and darkness phases. The behavioral parameters measured included activity, turning rate, and distance moved. C. lavaretus were exposed to AgNP at nominal concentrations of 0, 5, 15, 45, 135, or 405 µg/L (n = 33, each) and behavior was recorded using a custom-built tracking system equipped with light sources that reliably simulate light and darkness. The observed behavior was analyzed using generalized linear mixed models, which enabled reliable detection of AgNP-related movement patterns at 10-fold higher sensitivity compared to recently reported standard toxicological studies. Exposure to 45 µg/L AgNPs significantly resulted in hyperactive response patterns for both activity and turning rates after an illumination change from light to darkness suggesting that exposure to this compound triggered escape mechanisms and disorientation-like behaviors in C. lavaretus fish larvae. Even at 5 µg/L AgNPs some behavioral effects were detected, but further tests are required to assess their ecological relevance. Further, the behavior of fish larvae exposed to 135 µg/L AgNPs was comparable to the control for all test parameters, suggesting a triphasic dose response pattern. Data demonstrated the potential of combining generalized linear mixed models with behavioral investigations to detect adverse effects on aquatic species that might be overlooked using standard toxicological tests.

Background:The use of immune checkpoint inhibitors (ICI) is associated with cardiovascular (CV) events, and patients with pre-existing autoimmune disease are at increased CV risk.Objectives:The aim of this study was to characterize the risk for CV events in patients with pre-existing autoimmune disease post-ICI.Methods:This was a retrospective study of 6,683 patients treated with ICIs within an academic network. Autoimmune disease prior to ICI was confirmed by chart review. Baseline characteristics and risk for CV and non-CV immune-related adverse events were compared with a matched control group (1:1 ratio) of ICI patients without autoimmune disease. Matching was based on age, sex, history of coronary artery disease, history of heart failure, and diabetes mellitus. CV events were a composite of myocardial infarction, percutaneous coronary intervention, coronary artery bypass graft, stroke, transient ischemic attack, deep venous thrombosis, pulmonary embolism, or myocarditis. Univariable and multivariable Cox proportional hazards models were used to determine the association between autoimmune disease and CV events.Results:Among 502 patients treated with ICIs, 251 patients with and 251 patients without autoimmune disease were studied. During a median follow-up period of 205 days, there were 45 CV events among patients with autoimmune disease and 22 CV events among control subjects (adjusted HR: 1.77; 95% CI: 1.04-3.03; P = 0.0364). Of the non-CV immune-related adverse events, there were increased rates of psoriasis (11.2% vs 0.4%; P < 0.001) and colitis (24.3% vs 16.7%; P = 0.045) in patients with autoimmune disease.Conclusions:Patients with autoimmune disease have an increased risk for CV and non-CV events post-ICI.

Introduction: Myocarditis is a rare but highly morbid complication of immune-checkpoint inhibitors (ICI) use. Improved methods for detection and risk stratification are needed. Cytotoxic chemotherapy associates with reduced global circumferential strain (GCS) but no data is available on the utility of GCS in ICI myocarditis. Hypothesis: We hypothesized that GCS by echocardiography would be reduced in ICI myocarditis and the magnitude of reduction would have prognostic implications. Methods: In this retrospective cohort, GCS from 75 patients with ICI myocarditis (cases) and 49 ICI treated patients without myocarditis (controls) was compared. Pre-ICI GCS values were available for 10 cases and 39 controls. Measurements were performed by a reader blinded to group and time (TomTec, Germany). Major adverse cardiac event was defined as a composite of cardiogenic shock, cardiac arrest, complete heart block, and cardiac death. Results: Cases and controls had similar age (66±15 vs. 63±12 years; p=0.19), sex (male: 55% vs. 66%; p=0.22) and cancer type (p=0.08). Pre-ICI GCS values were lower in cases (n=10) than in controls (n=39) (-21.7±2.0 vs. -23.5±2.9, p=0.04), but within normal range. Overall, 56% (n=42) of cases had left ventricular ejection fraction (LVEF) >50% at presentation. The GCS was lower in cases than in controls (-17.5±4.2 vs. -23.5±3.0, p<0.001) in the entire cohort and in both preserved (-19.7±3.8 vs. -23.6±3.0, p<0.001) and reduced EF (-14.6±2.7 vs. -20.9±2.3, p<0.001) strata. Over a median follow-up of 30 days, 28 events occurred. An absolute GCS value < the median (17.1%) was associated with an increased rate of events (HR: 4.9, 95% CI: 1.6-15.0, p=0.005, Figure), adjusted for age and LVEF. The association was also noted when GCS is treated as continuous (HR: 1.18, 95% CI: 1.03-1.35, p=0.02). Conclusions: Global circumferential strain is lower in patients with ICI-myocarditis and the magnitude of the reduction in GCS has prognostic significance.

Objectives Skeletal myopathies are highly morbid, and in rare cases even fatal, immune-related adverse events (irAE) associated with immune checkpoint inhibitors (ICI). Skeletal myopathies are also a recognized statin-associated side effect. It is unknown whether concurrent use of statins and ICIs increases the risk of skeletal myopathies. Methods This was a retrospective cohort study of all patients who were treated with an ICI at a single academic institution (Massachusetts General Hospital, Boston, MA, USA). The primary outcome of interest was the development of a skeletal myopathy. The secondary outcome of interest was an elevated creatine kinase level (above the upper limit of normal). Results Among 2757 patients, 861 (31.2%) were treated with a statin at the time of ICI start. Statin users were older, more likely to be male and had a higher prevalence of cardiovascular and non-cardiovascular co-morbidities. During a median follow-up of 194 days (inter quartile range 65-410), a skeletal myopathy occurred in 33 patients (1.2%) and was more common among statin users (2.7 vs. 0.9%, P < 0.001). Creatine kinase (CK) elevation was present in 16.3% (114/699) and was higher among statin users (20.0 vs. 14.3%, P = 0.067). In a multivariable Cox model, statin therapy was associated with a > 2-fold higher risk for skeletal myopathy (HR, 2.19; 95% confidence interval, 1.07-4.50; P = 0.033). Conclusion In this large cohort of ICI-treated patients, a higher risk was observed for skeletal myopathies and elevation in CK levels in patients undergoing concurrent statin therapy. Prospective observational studies are warranted to further elucidate the potential association between statin use and ICI-associated myopathies.

Background There are limited data on the occurrence, associations and outcomes of pericardial effusions and pericarditis on or after treatment with immune checkpoint inhibitors (ICIs). Methods This was a retrospective study at a single academic center that compared 2842 consecutive patients who received ICIs with 2699 age- and cancer-type matched patients with metastatic disease who did not receive ICI. A pericardial event was defined as a composite outcome of pericarditis and new or worsening moderate or large pericardial effusion. The endpoints were obtained through chart review and were blindly adjudicated. To identify risk factors associated with a pericardial event, we compared patients who developed an event on an ICI with patients treated with an ICI who did not develop a pericardial event. Cox proportional-hazard model and logistical regression analysis were performed to study the association between ICI use and pericardial disease as well as pericardial disease and mortality. An additional 6-week landmark analysis was performed to account for lead-time bias. Results There were 42 pericardial events in the patients treated with ICI (n=2842) over 193 days (IQR: 64–411), yielding an incidence rate of 1.57 events per 100 person-years. There was a more than fourfold increase in risk of pericarditis or a pericardial effusion among patients on an ICI compared with controls not treated with ICI after adjusting for potential confounders (HR 4.37, 95% CI 2.09 to 9.14, p<0.001). Patients who developed pericardial disease while on an ICI had a trend for increased all-cause mortality compared with patients who did not develop a pericardial event (HR 1.53, 95% CI 0.99 to 2.36, p=0.05). When comparing those who developed pericardial disease after ICI treatment with those who did not, a higher dose of corticosteroid pre-ICI (>0.7 mg/kg prednisone) was associated with increased risk of pericardial disease (HR 2.56, 95% CI 1.00 to 6.57, p=0.049). Conclusions ICI use was associated with an increased risk of development of pericardial disease among patients with cancer and a pericardial event on an ICI was associated with a trend towards increase in mortality.

Introduction: Immune checkpoint inhibitors (ICI) leverage the immune system against cancer. Myocarditis is an uncommon but serious complication of ICI use. There are limited data on the utility of serum troponin levels in this setting. We assessed whether troponin values measured at different time points during admission have prognostic significance. Hypothesis: Baseline (admission), peak and inter-value trajectory (slope) of high-sensitivity cardiac Troponin T (hs-cTnT) levels predict cardiovascular events in ICI-myocarditis. Methods: A retrospective cohort of all patients admitted with ICI-myocarditis in a single integrated academic network was performed. Troponin measures were included from the 24 hours preceding admission until time of event/censoring. Optimal threshold values for baseline, peak hs-cTnT, and slope changes were obtained through ROC curves (Youden index). Major adverse cardiac event (MACE) was defined as a composite of cardiogenic shock, cardiac arrest, complete heart block and cardiac death. Results: A total of 980 hs-cTnT measures from 63 patients were identified (figure 1). Over a median follow-up period of 16 days, 24 events occurred. A higher baseline (>1248 ng/l, HR: 3.75, 95% CI: 1.57–9.00, p= 0.003) (figure 2) and peak hs-cTnT (>1959 ng/l, HR: 3.66, 95% CI: 1.49–8.98, p= 0.01) were associated with MACE adjusted for age and left ventricular ejection fraction (LVEF). Additional optimal threshold hs-cTnT values based on LVEF were also identified. For those with an LVEF < 50%, a baseline value >265 ng/l (HR: 4.9, 95% CI: 1.5-15.8, p< 0.01) and for those with an LVEF >50%, a baseline value >780 ng/l (HR: 3.6, 95% CI: 1.03-12.4, p=0.04) were associated with MACE. The hs-cTnT trajectory slope changes (baseline-to-peak, slope in first 24 hours, slope in first 48 hours) were not associated with events. Conclusion: Baseline and peak hs-cTnT during admission for ICI-related myocarditis associated with MACE. Cutoff values may vary by LVEF strata.

BACKGROUND:Immune checkpoint inhibitors (ICIs) are widely used cancer treatments. There are limited data on the risk for developing venous thromboembolism (VTE) among patients on an ICI. METHODS:This was a retrospective study of 2854 patients who received ICIs at a single academic centre. VTE events, defined as a composite of deep vein thrombosis or pulmonary embolism, were identified by individual chart review and blindly adjudicated using standard imaging criteria. A self-controlled risk-interval design was applied with an 'at-risk period' defined as the two-year period after and the 'control period', defined as the two-year before treatment. The hazard ratio (HR) was calculated using a fixed-effect proportional hazards model. RESULTS:Of the 2854 patients, 1640 (57.5%) were men; the mean age was 64 ± 13 years. The risk for VTE was 7.4% at 6 months and 13.8% at 1 year after starting an ICI. The rate of VTE was > 4-fold higher after starting an ICI (HR 4.98, 95% CI 3.65-8.59, p < 0.001). There was a 5.7-fold higher risk for deep vein thrombosis (HR 5.70, 95% CI 3.79-8.59, p < 0.001) and a 4.75-fold higher risk for pulmonary embolism (HR 4.75, 95% CI 3.20-7.10, p < 0.001). Comparing patients with and without a VTE event, a history of melanoma and older age predicted lower risk of VTE, while a higher Khorana risk score, history of hypertension and history of VTE predicted higher risk. CONCLUSIONS:The rate of VTE among patients on an ICI is high and increases after starting an ICI.

Background Myocarditis is a highly morbid complication of immune checkpoint inhibitor (ICI) use that remains inadequately characterized. The QRS duration and the QTc interval are standardized electrocardiographic measures that are prolonged in other cardiac conditions; however, there are no data on their utility in ICI myocarditis.Methods From an international registry, ECG parameters were compared between 140 myocarditis cases and 179 controls across multiple time points (pre-ICI, on ICI prior to myocarditis, and at the time of myocarditis). The association between ECG values and major adverse cardiac events (MACE) was also tested.Results Both the QRS duration and QTc interval were similar between cases and controls prior to myocarditis. When compared with controls on an ICI (93±19 ms) or to baseline prior to myocarditis (97±19 ms), the QRS duration prolonged with myocarditis (110±22 ms, p<0.001 and p=0.009, respectively). In contrast, the QTc interval at the time of myocarditis (435±39 ms) was not increased compared with pre-myocarditis baseline (422±27 ms, p=0.42). A prolonged QRS duration conferred an increased risk of subsequent MACE (HR 3.28, 95% CI 1.98 to 5.62, p<0.001). After adjustment, each 10 ms increase in the QRS duration conferred a 1.3-fold increase in the odds of MACE (95% CI 1.07 to 1.61, p=0.011). Conversely, there was no association between the QTc interval and MACE among men (HR 1.33, 95% CI 0.70 to 2.53, p=0.38) or women (HR 1.48, 95% CI 0.61 to 3.58, p=0.39).Conclusions The QRS duration is increased in ICI myocarditis and is associated with increased MACE risk. Use of this widely available ECG parameter may aid in ICI myocarditis diagnosis and risk-stratification.

Introduction: Immune checkpoint inhibitors (ICIs) treat an expanding range of cancers and the use of ICIs has been associated with an increase in atherosclerotic cardiovascular disease (ASCVD) events. The mechanisms involved in the increase in ASCVD with ICIs are incompletely understood. These same immune checkpoints targeted for cancer also regulate vascular function, yet there are no data testing the effect of ICIs on blood pressure. Hypothesis: Based on basic data on the role of these immune checkpoints in vascular function, we hypothesize that the use of ICIs would increase systolic and diastolic blood pressure. Methods: This was a single academic medical center study of 8,724 patients treated with an ICI. The primary analysis evaluated whether exposure to ICIs was associated with changes in blood pressure using repeated measures multivariate mixed linear regression models. The secondary analysis evaluated the effect of changes in blood pressure on all cause mortality using Cox proportional hazard models. Results: Of the 8,724 patients, 4,812 (55.2%) had a diagnosis of hypertension at ICI start. The average blood pressure at ICI start was 128.3±18.1/72.5±10.1mmHg. Among the entire cohort, there was a decrease of 2.9 mmHg in systolic blood pressure (95% CI: 2.70-3.02) after starting an ICI, and a drop of 1.6 mmHg (95% CI: 1.52-1.70) in diastolic blood pressure (adjusted, p<0.001 for both) (Figure 1). The effect of an ICI on blood pressure was independent of the development of any toxicity associated with an ICI. Patients who had an increase of ≥20 mmHg in systolic blood pressure after starting ICI had a lower risk of all-cause death (HR 0.74, 95% CI: 0.63-0.86) compared to patients with no or less than ≥20 mmHg increase. Conclusions: Among a large cohort of patients, ICI therapy is associated with a drop in systolic and diastolic blood pressure. However, patients who had an increase of at least ≥20 mmHg in systolic blood pressure had lower risk of all-cause death.

BACKGROUND Myocarditis is a potentially fatal complication of immune checkpoint inhibitor (ICI) therapy. Data on the utility of cardiovascular magnetic resonance (CMR) T1 and T2 mapping in ICI myocarditis are limited. OBJECTIVES This study sought to assess the value of CMR T1 and T2 mapping in patients with ICI myocarditis. METHODS In this retrospective study from an international registry of patients with ICI myocarditis, clinical and CMR findings (including T1 and T2 maps) were collected. Abnormal T1 and T2 were defined as 2 SD above site (vendor/field strength specific) reference values and a z-score was calculated for each patient. Major adverse cardiovascular events (MACE) were a composite of cardiovascular death, cardiogenic shock, cardiac arrest, and complete heart block. RESULTS Of 136 patients with ICI myocarditis with a CMR, 86 (63%) had T1 maps and 79 (58%) also had T2 maps. Among the 86 patients (66.3 +/- 13.1 years of age), 36 (41.9%) had a left ventricular ejection fraction <55%. Across alt patients, mean z-scores for T1 and T2 values were 2.9 +/- 1.9 (p < 0.001) and 2.2 +/- 2.1 (p < 0.001), respectively. On Siemens 1.5-T scanner (n = 67), native T1(1,079.0 +/- 55.5 ms vs. 1,000.3 +/- 221 ms; p < 0.001) and 12 (56.2 +/- 4.9 ms vs. 49.8 +/- 2.2 ms; p < 0.001) values were elevated compared with reference values. Abnormal T1 and T2 values were seen in 78% and 43% of the patients, respectively. Applying the modified Lake Louise Criteria, 95% met the nonischemic myocardial injury criteria and 53% met the myocardial edema criteria. Native T1 values had excellent discriminatory value for subsequent MACE, with an area under the curve of 0.91(95% confidence interval: 0.84 to 0.98). Native T1 values (for every 1-unit increase in z-score, hazard ratio: 1.44; 95% confidence interval: 1.12 to 1.84; p = 0.004) but not T2 values were independently associated with subsequent MACE. CONCLUSIONS The use of T1 mapping and application of the modified Lake Louise Criteria provides important diagnostic value, and T1 mapping provides prognostic value in patients with ICI myocarditis. (C) 2021 by the American College of Cardiology Foundation.

Introduction: Myocarditis is as a major immune-related adverse event following the use of immune checkpoint inhibitors (ICI). Global radial strain (GRS) reflects both longitudinal and circumferential fiber shortening but no data exist regarding its utility for diagnosis and risk stratification of ICI-myocarditis. Hypothesis: We hypothesized that GRS from echocardiography data would be reduced in patients with ICI-myocarditis and its reduction would have prognostic implications. Methods: Leveraging a multicenter international registry, we measured GRS from 76 patients with myocarditis and 49 ICI treated patients with no myocarditis. Pre-ICI GRS values were available for 10 cases and 38 controls. Measures were performed in a central laboratory blinded to group and time (TomTec, Germany). Major adverse cardiac event was a composite of cardiogenic shock, cardiac arrest, complete heart block and cardiac death. Results: Groups had similar age (66±15 vs. 63±12 years; p=0.20), sex distribution (male: 72% vs. 61%; p= 0.27) and cancer type (p=0.07). Pre-ICI GRS values were similar between cases and controls (47.4±2.9 vs. 45.4±6.0; p=0.12). A total of 57% of myocarditis patients had LVEF of >50% at presentation. The GRS was lower in patients with myocarditis compared with controls (28.6±6.7 vs. 47±7.4; p<0.01). This lower GRS value was noted in patients with both preserved EF (31.7±5.5 vs. 47.0±7.6, p<0.001) and reduced EF (24.7±6.1 vs. 49.2±4.7, p<0.005). In total, 28 events occurred during a median follow-up of 30 days. In survival analysis, a GRS < the median (29.4%) was associated with an increased rate of events (HR: 3.92, 95% CI: 1.42-10.78, p=0.008) adjusted for age and LVEF. The association between GRS and events was also noted when the variable is treated as continuous adjusted for age and LVEF (HR: 1.07, 95% CI: 1.001-1.15 p=0.04). Conclusions: Global radial strain is lower in ICI- myocarditis and the magnitude of the reduction is associated with a higher rate of events.

BACKGROUND Coronary vasospasm is a recognized side effect of 5-fluorouracil (5-FU). There are limited and conflicting data on the incidence, risk factors, and prognostic effect of 5-FU-associated vasospasm. OBJECTIVES This study sought to assess the incidence, risk factors, and prognostic implications of 5-FU coronary vasospasm among patients receiving 5-FU regimens at a single tertiary care center. METHODS The study conducted a retrospective analysis of all patients who received 5-FU at a single academic center from January 2009 to July 2019. Vasospasm was defined as the occurrence of a typical chest pain syndrome in the presence of 5-FU. The presence of associated electrocardiogram changes or elevated biomarkers was used to further confirm the diagnosis. Patients with vasospasm were compared with patients treated with 5-FU without vasospasm in a 1:2 ratio. Data regarding demographics, medical history, and follow-up were collected by manual chart review. RESULTS From approximately 4,019 individual patients who received 5-FU from 2009 to 2019 at a single center, 87 (216%) developed vasospasm. Patients who developed vasospasm were younger (age 58 +/- 13 years vs. 64 +/- 13 years; p rr 0.001) and were less likely to have any cardiovascular risk factors (70.1% vs. 84.5%; p = 0.007). Patients with vasospasm and patients without vasospasm were otherwise similar in terms of types of cancer, stage of cancer, sex, and race. There was no significant difference in progression-free survival, overall mortality or cancer specific mortality between patients who developed vasospasm versus those who did not. CONCLUSIONS In a large, single-center report of 5-FU-associated vasospasm, patients who developed vasospasm were younger, had lower rates of traditional cardiovascular risk factors, and had no significant difference in progression-free or overall survival compared with those who did not develop vasospasm. (C) 2021 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation.

Introduction: Coronary vasospasm is a side effect of 5-FU (fluorouracil). Beyond switching chemotherapy regimens, there are no established treatments for vasospasm. Limited data exist regarding the efficacy of calcium channel blockers (CCBs) and/or nitrates with 5-FU vasospasm. Methods: We conducted a retrospective analysis of all patients at Massachusetts General Hospital who were diagnosed with 5-FU coronary vasospasm. As part of institutional practice, those referred to cardio-oncology receive pre-treatment with vasospasm therapies (either combination [nitrates and CCBs] or single agent therapy [nitrates or CCBs]) prior to re-challenge with 5-FU. Our primary outcomes were the safety and effectiveness of this cardiac pre-treatment approach. Results: Among 7,711 patients who received 5-FU from Jan 2001 to Jul 2017, 86 (1.11%) developed coronary vasospasm. Overall 64 patients continued to receive subsequent 5-FU, while 22 stopped. Of the 64 who continued, 60 were referred to cardio-oncology and prescribed CCBs and/or nitrates prior to subsequent 5-FU. Of these 60, 52% (31/60) received both nitrates and CCBs, 20% (12/60) received CCBs alone, and 28% (17/60) received nitrates alone, while 4 continued 5-FU without cardiac pre-treatment. Chest pain (without a myocardial infarct) recurred in 11.7% (7/60) among those who received cardiac pre-treatment vs. 50% (2/4) among those who did not (P=0.033). When those who stopped were compared to those who continued 5-FU (with cardiac pre-treatment), the cardiovascular profile, stage and type of cancer were similar. As compared to patients who stopped 5-FU, those who continued after nitrates/CCBs had improved progression free (HR 0.56, P=0.076 [95% CI 0.30-1.06]) and overall (HR 0.29, P<0.001 [95% CI 0.15-0.57]) survival. Conclusion: In the largest report of 5-FU associated vasospasm, re-challenge after pre-treatment with CCBs and nitrates was safe and effective, thus allowing patients to receive additional 5-FU.

One major environmental problem of our time are emerging contaminants in the aquatic environment. While nanoparticles exhibit attractive features such as antimicrobial properties in the case of silver nanoparticles (AgNPs), earlier studies suggest that NPs are not completely filtered out at wastewater treatment plants and may therefore be continuously introduced into the aquatic environment. Although adverse effects of AgNPs on aquatic organisms have been extensively studied, there is still a lack of knowledge on how this chemical stressor interacts with natural cues on the maternal and subsequent generation of aquatic organisms. We tested whether AgNPs (NM-300K, 14.9 ± 2.4 nm, concentration range: 2.5 µg/L – 20 µg/L) affect the kairomone-induced adaptive anti-predator defence mechanism in maternal Daphnia and their offspring. While maternal Daphnia developed typical anti-predator defence mechanisms when exposed to kairomones and AgNPs, their offspring could not develop such adaptive defensive traits. The lack of this defence mechanism in offspring could have dramatic negative consequences (e.g. reduced Daphnia population) for the entire complex food web in the aquatic ecosystem. For a realistic risk assessment, it is extremely important to test combinations of chemical stressors because aquatic organisms are exposed to several natural and artificial chemical stressors at the same time.

Introduction: Immune checkpoint inhibitors (ICI) lead to immune activation, increased inflammation and cancer cell death. Both immune activation and inflammation are critical pathobiological drivers for venous thromboembolism (VTE). There are no robust data testing the effect of ICIs on the risk of developing VTE. Methods: This is a retrospective study of 2854 patients who received ICIs at Massachusetts General Hospital, Boston, MA. VTE events, defined as a composite of deep vein thrombosis (DVT) or pulmonary embolism (PE), were identified by individual chart review and were blindly adjudicated using standard criteria. A case-crossover design was applied with an “at-risk period” defined as the two-year period after and the “control period” as the two years prior to treatment. Incidence rate ratio (IRR) was calculated using Poisson’s regression. Results: Immune checkpoint inhibitor use increased VTE risk by 1.84-fold from 4.85 per 100-person years to 8.91 per 100 person-years (IRR 1.84, 95% confidence interval: 1.54 - 2.19, p <0.001). Of the individual components, there was a 2.44-fold increase in DVT risk (2.30 to 5.58 per 100 person-years) and 1.68-fold increase in PE risk (2.96 to 5.00 per 100 person-years). Comparing patients with and without a VTE event, those with a VTE event after ICI initiation had a higher rate of prior VTE, lung cancer, urothelial cancer, and a higher platelet count and white blood cell count at baseline. At 6 months post ICI initiation, 165 (8.6%) patients had a VTE event and of these patients 136 (7.1%) had no prior VTE. Conclusions: Patients with cancer treated with ICIs are at increased risk of developing VTE. Whether prophylaxis for VTE among patients starting an ICI reduces this risk is unclear.