Fatal Allograft Rejection and Cardiac Allograft Vasculopathy After Treatment With Pembrolizumab for Metastatic Melanoma in a Heart Transplant Recipient: A Case Report.

Checkpoint inhibitors decrease the progression of many cancers. However, the experience in immunosuppressed patients is limited, with reports of possible serious adverse events. We present a heart transplant recipient treated with pembrolizumab for metastatic melanoma who developed fatal rejection. The patient was a 29 year-old man who underwent heart transplantation at the age of 10 years for congenital heart disease. Seventeen years after transplant, he was diagnosed with scalp melanoma pT3a, N2a, M0, Stage IIIA, positive for BRAF V600E mutation treated with excision, which metastasized to his lungs and brain a year later. Dabrafenib and trametinib were started with transient response. Additional options and their risks were discussed, and pembrolizumab was started 4 months later due to the incomplete response to previous therapy. Five days after initiation the patient presented with moderate cellular rejection and possible antibody mediated rejection (ISHLT Grade 2R, pAMR 1H). Pembrolizumab was discontinued, and he was treated with steroids. Seven months later he presented in cardiogenic shock and severe coronary allograft vasculopathy. Biopsy was negative for cellular rejection, but suspicious for antibody mediated rejection (ISHLT Grade 0R, pAMR 1H), and he had a new serum alloantibody. Despite steroids and plasmapheresis he remained in refractory cardiogenic shock and died of cardiac arrest.

Association between pregnancy and long-term cardiac outcomes in individuals with congenital heart disease.

BACKGROUND: As early life interventions for congenital heart disease improve, more patients are living to adulthood and are considering pregnancy. Scoring and classification systems predict the maternal cardiovascular risk of pregnancy in the context of congenital heart disease, but these scoring systems do not assess the potential subsequent risks following pregnancy. Data on the long-term cardiac outcomes after pregnancy are unknown for most lesion types. This limits the ability of healthcare practitioners to thoroughly counsel patients who are considering pregnancy in the setting of congenital heart disease. OBJECTIVE: We aimed to evaluate the association between pregnancy and the subsequent long-term cardiovascular health of individuals with congenital heart disease. STUDY DESIGN: This was a retrospective longitudinal cohort study of individuals identifying as female who were receiving care in two adult congenital heart disease centers from 2014 to 2019. Patient data were abstracted longitudinally from a patient age of 15 years (or from the time of entry into the healthcare system) to the conclusion of the study, death, or exit from the healthcare system. The primary endpoint, a composite adverse cardiac outcome (death, stroke, heart failure, unanticipated cardiac surgery, or a requirement for a catheterized procedure), was compared between parous (at least one pregnancy >20 weeks' gestation) and nulliparous individuals. By accounting for differences in the follow-up, the effect of pregnancy was estimated based on the time to the composite adverse outcome in a proportional hazards regression model adjusted for the World Health Organization class, baseline cardiac medications, and number of previous sternotomies. Participants were also categorized according to their lesion type, including septal defects (ventricular septal defects, atrial septal defects, atrioventricular septal defects, or atrioventricular canal defects), right-sided valvular lesions, left-sided valvular lesions, complex cardiac anomalies, and aortopathies, to evaluate if there is a differential effect of pregnancy on the primary outcome when adjusting for lesion type in a sensitivity analysis. RESULTS: Overall, 711 individuals were eligible for inclusion; 209 were parous and 502 nulliparous. People were classified according to the World Health Organization classification system with 86 (12.3%) being classified as class I, 76 (10.9%) being classified as class II, 272 (38.9%) being classified as class II to III, 155 (22.1%) being classified as class III, and 26 (3.7%) being classified as class IV. Aortic stenosis, bicuspid aortic valve, dilated ascending aorta or aortic root, aortic regurgitation, and pulmonary insufficiency were more common in parous individuals, whereas dextro-transposition of the great arteries, Turner syndrome, hypoplastic right heart, left superior vena cava, and other cardiac diagnoses were more common in nulliparous individuals. In multivariable modeling, pregnancy was associated with the composite adverse cardiac outcome (36.4%% vs 26.1%%; hazard ratio, 1.83; 95% confidence interval, 1.25-2.66). Parous individuals were more likely to have unanticipated cardiac surgery (28.2% vs 18.1%; P=.003). No other individual components of the primary outcome were statistically different between parous and nulliparous individuals in cross-sectional comparisons. The association between pregnancy and the primary outcome was similar in a sensitivity analysis that adjusted for cardiac lesion type (hazard ratio, 1.61; 95% confidence interval, 1.10-2.36). CONCLUSION: Among individuals with congenital heart disease, pregnancy was associated with an increase in subsequent long-term adverse cardiac outcomes. These data may inform counseling of individuals with congenital heart disease who are considering pregnancy.

High-intensity endurance training is associated with left atrial fibrosis.

INTRODUCTION: Endurance athletes are at higher risk for developing atrial fibrillation as compared to the general population. The exact mechanism to explain this observation is incompletely understood. Our study aimed to determine whether degree of left atrial fibrosis detected by late gadolinium-enhancement magnetic resonance imaging (LGE-MRI) differed between Masters athletes and non-athlete controls. METHODS: We recruited 20 endurance healthy Masters athletes and 20 healthy control subjects who underwent cardiac MRI. Healthy controls were recruited during screening colonoscopies and Masters athletes were recruited through word of mouth and at competitions. The two groups were age and gender matched. None of the participants were known to have an arrhythmia. Fibrosis, as measured by late gadolinium-enhancement, was measured in each participant by blinded readers. The degree of left atrial fibrosis was compared between the two groups. All participants were recruited from the Salt Lake City region and scanned at the University of Utah healthcare complex. RESULTS: Left ventricular function was normal in all study participants. Left atrial volumes were significantly larger in the athletes (74.2 ml ±â€¯14.4) as compared to the healthy control subjects (60.8 mL ±â€¯21.4) (P = .02). Mean left atrial fibrosis score, reported as a percentage of the LA, was 15.5% ±â€¯5.9 in the athlete cohort compared to 9.6% ±â€¯4.9 in the controls (P = .002). CONCLUSIONS: To our knowledge this is the first study that describes, characterizes and specifically quantifies fibrotic changes within the left atrium of highly trained endurance athletes. Increased atrial fibrosis seen in this population may be an early indicator for endurance athletes at risk of developing atrial arrhythmias.

Pathologic Grading of Malignant Pleural Mesothelioma: An Evidence-Based Proposal.

INTRODUCTION: A pathologic grading system (PGS) for malignant pleural mesothelioma (MPM) is warranted to better identify different risk categories of patients, plan therapeutic options, and activate clinical trials. METHODS: A series of 940 patients with MPM (328 in a training set and 612 in a validation set) that was diagnosed between October 1980 and June 2015 at the participant institutions was retrospectively assembled. A PGS was constructed by attributing to each histologic parameter, independent at multivariate analysis with excellent reproducibility (κ > 0.75), different scores based on the increase in corresponding hazard ratios. The relevant PGS score thus ranged from 0 to 8 points for individual patients with MPM. CONCLUSIONS: The PGS was constructed by taking into consideration the histological subtyping of MPM (epithelioid/biphasic = 0 points; sarcomatoid = 2 points), necrosis (absent = 0 points versus present = 1 point), mitotic count per 1 mm2 (cutoffs as follows: 1-2 = 0 points, 3-5 = 1 point, 6-9 = 2 points, or ≥10 = 4 points), and Ki-67 labeling index based on 2000 cells (<30% = 0 points versus ≥30 = 1 point), all of which are independent factors in both patient sets after adjustment for stage and age at diagnosis. No heterogeneity was seen across the validation centers (p = 0.19). Epithelioid/biphasic MPM patterning and biopsy versus resection did not affect survival, whereas the PGS outperformed mitotic count and Ki-67 LI in both the training (area under the curve receiver operating characteristic = 0.76) and validation sets (area under the curve receiver operating characteristic = 0.73) (p < 0.01). Patient survival progressively deteriorated from a score of 0 (median times of 26.3 and 26.9 months) to a score 1 to 3 (median times of 12.8 and 14.4 months) and a score of 4 to 8 (median times of 3.7 and 7.7 months) in both sets of patients, with the hazard ratio for a 1-point increase in score being 1.46 (95% confidence interval: 1.36-1.56) in the training set and 1.28 (95% confidence interval: 1.22-1.34) in the validation set (after adjustment for age and [when available] tumor stage). The PGS was effective even in subgroup analysis (epithelioid, biphasic, and sarcomatoid tumors). DISCUSSION: A simple and reproducible multiparametric PGS effectively predicted survival in patients with MPM.

Longitudinal Assessment of Vascular Function With Sunitinib in Patients With Metastatic Renal Cell Carcinoma.

BACKGROUND: Sunitinib, used widely in metastatic renal cell carcinoma, can result in hypertension, left ventricular dysfunction, and heart failure. However, the relationships between vascular function and cardiac dysfunction with sunitinib are poorly understood. METHODS AND RESULTS: In a multicenter prospective study of 84 metastatic renal cell carcinoma patients, echocardiography, arterial tonometry, and BNP (B-type natriuretic peptide) measures were performed at baseline and at 3.5, 15, and 33 weeks after sunitinib initiation, correlating with sunitinib cycles 1, 3, and 6. Mean change in vascular function parameters and 95% confidence intervals were calculated. Linear regression models were used to estimate associations between vascular function and left ventricular ejection fraction, longitudinal strain, diastolic function (E/e'), and BNP. After 3.5 weeks of sunitinib, mean systolic blood pressure increased by 9.5 mm Hg (95% confidence interval, 2.0-17.1; P=0.02) and diastolic blood pressure by 7.2 mm Hg (95% confidence interval, 4.3-10.0; P<0.001) across all participants. Sunitinib resulted in increases in large artery stiffness (carotid-femoral pulse wave velocity) and resistive load (total peripheral resistance and arterial elastance; all P<0.05) and changes in pulsatile load (total arterial compliance and wave reflection). There were no statistically significant associations between vascular function and systolic dysfunction (left ventricular ejection fraction and longitudinal strain). However, baseline total peripheral resistance, arterial elastance, and aortic impedance were associated with worsening diastolic function and filling pressures over time. CONCLUSIONS: In patients with metastatic renal cell carcinoma, sunitinib resulted in early, significant increases in blood pressure, arterial stiffness, and resistive and pulsatile load within 3.5 weeks of treatment. Baseline vascular function parameters were associated with worsening diastolic but not systolic function.

Prospective Evaluation of Sunitinib-Induced Cardiotoxicity in Patients with Metastatic Renal Cell Carcinoma.

Purpose: To prospectively evaluate cardiotoxicity risk with sunitinib in metastatic renal cell carcinoma (mRCC) routine clinical practice using comprehensive echocardiography and biomarker phenotyping.Experimental Design: In a multicenter prospective study of 90 patients with mRCC, echocardiography and biomarkers of cardiovascular injury and stress were quantified at baseline, 3.5, 15, and 33 weeks following sunitinib initiation. These "on-drug" visits corresponded to cycles 1, 3, and 6, respectively. Left ventricular (LV) dysfunction was defined as an absolute decline in LV ejection fraction (LVEF) by ≥10% to a value of <50%. Conditional survival analyses predicted the risk of LV dysfunction. Linear mixed-effects models estimated changes in LVEF, high-sensitivity Troponin I (hsTnI), and B-type natriuretic peptide (BNP) over time.Results: The predicted risk of LV dysfunction by cycle 6 was 9.7% (95% confidence interval, 3%-17%). The majority of events occurred in the first treatment cycle. This risk diminished to 5% and 2% in patients who had not experienced dysfunction by the completion of cycles 1 and 3, respectively. All evaluable patients who experienced LV dysfunction had subsequent improvement in LVEF with careful management. Six patients (6.7%) developed hsTnI elevations >21.5 pg/mL, and 11 additional patients (12.2%) developed BNP elevations >100 pg/mL. These elevations similarly tended to occur early and resolved over time.Conclusions: On average, patients with mRCC receiving sunitinib exhibit modest declines in LVEF and nonsignificant changes in hsTnI and BNP. However, approximately 9.7% to 18.9% of patients develop more substantive abnormalities. These changes occur early and are largely recoverable with careful management. Clin Cancer Res; 23(14); 3601-9. ©2017 AACR.

Dose-dense primary chemotherapy, as part of multidisciplinary treatment, for inoperable stage III B breast cancer--long-term results of a phase II trial.

BACKGROUND: Primary chemotherapy as part of multidisciplinary approach is the established treatment for inoperable stage III B breast cancer. The primary endpoints were conversion to operable disease and feasibility of conservative surgery (breast-conserving therapy: BCT); secondary were clinical and pathological complete response rate, local and distant control and safety of the primary regimen. METHODS: Between 1998 and 2001, 40 inoperable breast cancer patients < or =60 years, 72% T4abc and 28% T4d, received 6 cycles of primary PEV dose-dense regimen: cisplatin 50 mg/m2, epirubicin 100 mg/m2 and vinorelbine 25 mg/m2, i.v. (q 14). Modified radical mastectomy (MRM) or BCT was performed, followed by adjuvant chemotherapy, radiotherapy and hormone therapy. RESULTS: All patients were converted to operable disease, and BCT was feasible in 24% of T4abc patients. After a median follow-up of 84 months (range 58-96), local and distant relapses were 7.5% (0% in BCT ) and 25% (25% in BCT), respectively. Clinical response was 80% (clinical complete response [cCR]: 20%); pathological complete response (pCR) was 40% in breast, 50% in axilla (pLN0); 32% both in breast and axilla. Neutropenia (G4, 30%), leukopenia (G4, 25%), alopecia (G2, 100%), nausea and vomiting (G4, 20%) were the most common toxicities. CONCLUSIONS: The PEV dose-dense regimen seems to be highly effective in terms of resectability and pCR. Toxicity, mainly hematological, was acceptable. Successful BCT is feasible, in selected patients, without compromising local and distant control.