Managing Catecholamine Release Syndrome During and Following Lu-177-DOTATATE in High-Risk Pheochromocytoma Patients.

Pheochromocytomas and paragangliomas (PPGLs) are rare catecholamine-producing tumors that express somatostatin receptors (SSTR) that can be treated with lutetium-177 DOTATATE (Lu-177-TRT); however, treatment can be associated with life-threatening cardiovascular events. A patient case with management strategies for high-risk PPGL patients receiving Lu-177-TRT is described. The 78-year-old patient with metastatic paraganglioma was enrolled and treated under NCT03206060. Deemed to be at high risk, the patient was preemptively admitted to the intensive care unit (ICU) with central line access placed. Due to comorbidities, a reduced dose of 100 mCi x 4 cycles was used for this patient. Vital signs, blood work, and serum catecholamine levels were obtained at various time points. Despite reduced dosing, the patient still developed a severe hypertensive reaction with systolic blood pressure of 240 mmHg within minutes of Lu-177-TRT infusion, which was controlled with an intravenous nicardipine drip. The patient remained in the ICU for 24 hours post Lu-177-TRT before moving to an inpatient ward for an additional 24 hours. All subsequent infusions were performed using reduced doses with elective ICU admissions and were well-tolerated. Despite the increased risk, metastatic PPGL patients can be safely treated with proper staff training, monitoring, and preparation for intravenous medications, especially nicardipine.

Advancement of echocardiography for surveillance of iron overload cardiomyopathy: comparison to cardiac magnetic resonance imaging.

The prevalence of iron overload cardiomyopathy (IOC) is increasing. Patients with transfusion-dependent anemias or conditions associated with increased iron absorption over time are at a significant risk for the development of iron-overloaded states such as IOC. Current guidelines regarding the diagnostic evaluation and follow-up of patients at risk for IOC exist, and are composed of multiple components, including such as echocardiography, genetic testing, magnetic resonance imaging of liver, and cardiac magnetic resonance imaging (CMR). While these are considered reliable for the evaluation of patients at risk for an iron-overloaded state, there is an access challenge associated with initial and serial CMR scanning in this patient population. Furthermore, there are other limiting factors, such as patient characteristics that may preclude the use of CMR as a viable diagnostic imaging modality for these patients. On the other hand, recent evidence in the literature suggests that transthoracic echocardiography, which has had significant technological advances, can equal or even outperform CMR to identify cardiac functional abnormalities such as subclinical left ventricular strain and left atrial functional abnormalities in iron overload conditions. Therefore, there is a potential role of more frequent use of echocardiography for surveillance of the development of IOC. Our purpose with this narrative review is to describe recent advances in echocardiography and propose a potential increased use of echocardiography in the surveillance of the development of IOC.

Phase I Clinical Trial of an Autologous Dendritic Cell Vaccine Against HER2 Shows Safety and Preliminary Clinical Efficacy.

BACKGROUND: Despite recent advances, there is an urgent need for agents targeting HER2-expressing cancers other than breast cancer. We report a phase I study (NCT01730118) of a dendritic cell (DC) vaccine targeting HER2 in patients with metastatic cancer or bladder cancer at high risk of relapse. PATIENTS AND METHODS: Part 1 of the study enrolled patients with HER2-expressing metastatic cancer that had progressed after at least standard treatment and patients who underwent definitive treatment for invasive bladder cancer with no evidence of disease at the time of enrollment. Part 2 enrolled patients with HER2-expressing metastatic cancer who had progressed after anti-HER2 therapy. The DC vaccines were prepared from autologous monocytes and transduced with an adenoviral vector expressing the extracellular and transmembrane domains of HER2 (AdHER2). A total of five doses were planned, and adverse events were recorded in patients who received at least one dose. Objective response was evaluated by unidimensional immune-related response criteria every 8 weeks in patients who received at least two doses. Humoral and cellular immunogenicity were assessed in patients who received more than three doses. RESULTS: A total of 33 patients were enrolled at four dose levels (5 × 106, 10 × 106, 20 × 106, and 40 × 106 DCs). Median follow-up duration was 36 weeks (4-124); 10 patients completed five doses. The main reason for going off-study was disease progression. The main adverse events attributable to the vaccine were injection-site reactions. No cardiac toxicity was noted. Seven of 21 evaluable patients (33.3%) demonstrated clinical benefit (1 complete response, 1 partial response, and 5 stable disease). After ≥3 doses, an antibody response was detected in 3 of 13 patients (23.1%), including patients with complete and partial responses. Lymphocytes from 10 of 11 patients (90.9%) showed induction of anti-HER2 responses measured by the production of at least one of interferon-gamma, granzyme B, or tumor necrosis factor-alpha, and there were multifunctional responses in 8 of 11 patients (72.7%). CONCLUSIONS: The AdHER2 DC vaccine showed evidence of immunogenicity and preliminary clinical benefit in patients with HER2-expressing cancers, along with an excellent safety profile. It shows promise for further clinical applications, especially in combination regimens.

Fast Clearance of the SARS-CoV-2 Virus in a Patient Undergoing Vaccine Immunotherapy for Metastatic Chordoma: A Case Report.

The emergence of the SARS-CoV-2 virus has been associated with perplexing clinical sequelae and phenomena that often have no clear link to the underlying infection. There is a wide spectrum of symptoms associated with infection, from minimal respiratory complaints to severe multi-organ failure, often resulting in death. Individuals with malignancies, particularly those whose treatments have left them immunocompromised or immunosuppressed, are among the patient populations thought to be at greater risk for more severe illness. A man with aggressive metastatic chordoma contracted the SARS-CoV-2 virus and was diagnosed with COVID-19 while undergoing intravenous brachyury vaccine immunotherapy. His disease course was remarkably mild, and the virus cleared rapidly. Despite a treatment delay of 3 months due to the COVID-19 pandemic, the patient's disease has been stable and tumor-related pain has significantly improved. This suggests not only an intact, functional immune system, but also one that appears to have been responsive to cancer treatment. It has been suggested that individuals undergoing treatment for metastatic cancer are at greater risk of severe SARS-CoV-2-related illnesses and complications. While immunosuppression may be a problem, particularly in those receiving conventional chemotherapeutic agents, it is possible that the non-specific effects of immune-enhancing therapies may confer some protection against SARS-CoV-2.

Pathophysiology and Acute Management of Tachyarrhythmias in Pheochromocytoma: JACC Review Topic of the Week.

Pheochromocytomas, arising from chromaffin cells, produce catecholamines, epinephrine and norepinephrine. The tumor biochemical phenotype is defined by which of these exerts the greatest influence on the cardiovascular system when released into circulation in high amounts. Action on the heart and vasculature can cause potentially lethal arrhythmias, often in the setting of comorbid blood pressure derangements. In a review of electrocardiograms obtained on pheochromocytoma patients (n = 650) treated at our institution over the last decade, severe and refractory sinus tachycardia, atrial fibrillation, and ventricular tachycardia were found to be the most common or life-threatening catecholamine-induced tachyarrhythmias. These arrhythmias, arising from catecholamine excess rather than from a primary electrophysiologic substrate, require special considerations for treatment and complication avoidance. Understanding the synthesis and release of catecholamines, the adrenoceptors catecholamines bind to, and the cardiac and vascular response to epinephrine and norepinephrine underlies optimal management in catecholamine-induced tachyarrhythmias.

Iron overload and arrhythmias: Influence of confounding factors.

Arrhythmias as a cardiac complication of iron overload (IO) have been well described for decades in the clinical literature. They are assumed to be directly associated with the myocardial accumulation of iron. However, the influence of heart failure and elevated oxidative stress, which are major arrhythmogenic confounding factors associated with IO on arrhythmias, has not been critically reviewed in the published literature. A comprehensive narrative review of published articles in PubMed was conducted to address the influence of confounding factors of IO on arrhythmias. The previous data may have been largely confounded by the other cardiac complications of IO, particularly heart failure. The previous studies on IO-related arrhythmias lack proper age-gender-matched control subjects and/or comparison groups with properly controlled confounding factors to assess accurately their etiology and clinical significance. Given the above considerations, further mechanistic investigations to clarify the etiology and clinical relevance of IO-induced arrhythmias are needed. In addition, investigations to develop arrhythmia management strategy specific to IO, are warranted.

Chronic kidney disease in propionic acidemia.

PURPOSE: Propionic acidemia (PA) is a severe metabolic disorder characterized by multiorgan pathology, including renal disease. The prevalence of chronic kidney disease (CKD) in PA patients and factors associated with CKD in PA are not known. METHODS: Thirty-one subjects diagnosed with PA underwent laboratory and clinical evaluations through a dedicated natural history study at the National Institutes of Health (ClinicalTrials.gov identifier: NCT02890342). RESULTS: Cross-sectional analysis of the creatinine-based estimated glomerular filtration rate (eGFR) in subjects with native kidneys revealed an age-dependent decline in renal function (P < 0.002). Among adults with PA, 4/8 (50%) had eGFR <60 mL/min/1.73 m2. There was a significant discrepancy between eGFRs calculated using estimating equations based on serum creatinine compared with serum cystatin C (P < 0.0001). The tubular injury marker, plasma lipocalin-2, and plasma uric acid were strongly associated with CKD (P < 0.0001). The measured 24-hour creatinine excretion was below normal, even after adjusting for age, height, and sex. CONCLUSION: CKD is common in adults with PA and is associated with age. The poor predictive performance of standard eGFR estimating equations, likely due to reduced creatine synthesis in kidney and liver, could delay the recognition of CKD and management of ensuing complications in this population.

Diffuse atrophic papules and plaques, intermittent abdominal pain, paresthesias, and cardiac abnormalities in a 55-year-old woman.

KEY TEACHING POINTS.

Growth hormone and risk for cardiac tumors in Carney complex.

Carney complex (CNC) is a multiple neoplasia syndrome that is caused mostly by PRKAR1A mutations. Cardiac myxomas are the leading cause of mortality in CNC patients who, in addition, often develop growth hormone (GH) excess. We studied patients with CNC, who were observed for over a period of 20 years (1995-2015) for the development of both GH excess and cardiac myxomas. GH secretion was evaluated by standard testing; dedicated cardiovascular imaging was used to detect cardiac abnormalities. Four excised cardiac myxomas were tested for the expression of insulin-like growth factor-1 (IGF-1). A total of 99 CNC patients (97 with a PRKAR1A mutation) were included in the study with a mean age of 25.8 ± 16.6 years at presentation. Over an observed mean follow-up of 25.8 years, 60% of patients with GH excess (n = 46) developed a cardiac myxoma compared with only 36% of those without GH excess (n = 54) (P = 0.016). Overall, patients with GH excess were also more likely to have a tumor vs those with normal GH secretion (OR: 2.78, 95% CI: 1.23-6.29; P = 0.014). IGF-1 mRNA and protein were higher in CNC myxomas than in normal heart tissue. We conclude that the development of cardiac myxomas in CNC may be associated with increased GH secretion, in a manner analogous to the association between fibrous dysplasia and GH excess in McCune-Albright syndrome, a condition similar to CNC. We speculate that treatment of GH excess in patients with CNC may reduce the likelihood of cardiac myxoma formation and/or recurrence of this tumor.

Iron Overload or Oxidative Stress? Insight into a Mechanism of Early Cardiac Manifestations of Asymptomatic Hereditary Hemochromatosis Subjects with C282Y Homozygosity.

Hereditary hemochromatosis (HH) is a genetic disorder which affects the heart due to systemic iron overload and concomitant elevated oxidative stress. Increasing numbers of patients are diagnosed at an asymptomatic stage due to genetic testing. Subclinical abnormal left ventricular diastolic function (LVDF) and increased arrhythmias are noted in this population; however, the mechanism leading to these observances has not been well understood. In this study, we assessed the relationship between arrhythmia activity and biomarkers of oxidative stress and iron overload in order to elucidate the role of oxidative stress in this population since we observed a significant association with LVDF previously. A significant correlation between plasma malondialdehyde, a biomarker of oxidative stress, and supraventricular arrhythmia activity without a significant association with iron overload was identified (n = 22). Our findings further highlight a possible role of oxidative stress in early cardiac manifestations of HH. Further investigation is warranted to assess this role.

Romidepsin in peripheral and cutaneous T-cell lymphoma: mechanistic implications from clinical and correlative data.

Romidepsin is an epigenetic agent approved for the treatment of patients with cutaneous or peripheral T-cell lymphoma (CTCL and PTCL). Here we report data in all patients treated on the National Cancer Institute 1312 trial, demonstrating long-term disease control and the ability to retreat patients relapsing off-therapy. In all, 84 patients with CTCL and 47 with PTCL were enrolled. Responses occurred early, were clinically meaningful and of very long duration in some cases. Notably, patients with PTCL receiving romidepsin as third-line therapy or later had a comparable response rate (32%) of similar duration as the total population (38%). Eight patients had treatment breaks of 3.5 months to 10 years; in four of six patients, re-initiation of treatment led to clear benefit. Safety data show slightly greater haematological and constitutional toxicity in PTCL. cDNA microarray studies show unique individual gene expression profiles, minimal overlap between patients, and both induction and repression of gene expression that reversed within 24 h. These data argue against cell death occurring as a result of an epigenetics-mediated gene induction programme. Together this work supports the safety and activity of romidepsin in T-cell lymphoma, but suggests a complex mechanism of action.

Succinate dehydrogenase gene mutations in cardiac paragangliomas.

Pheochromocytomas and paragangliomas are chromaffin cell tumors arising from neuroendocrine cells. At least 1/3 of paragangliomas are related to germline mutations in 1 of 17 genes. Although these tumors can occur throughout the body, cardiac paragangliomas are very rare, accounting for <0.3% of mediastinal tumors. The purpose of this study was to determine the clinical characteristics of patients with cardiac paragangliomas, particularly focusing on their genetic backgrounds. A retrospective chart analysis of 15 patients with cardiac paragangliomas was performed to determine clinical presentation, genetic background, diagnostic workup, and outcomes. The average age at diagnosis was 41.9 years. Typical symptoms of paraganglioma (e.g., hypertension, sweating, palpitations, headache) were reported at initial presentation in 13 patients (86.7%); the remaining 2, as well as 4 symptomatic patients, initially presented with cardiac-specific symptoms (e.g., chest pain, dyspnea). Genetic testing was done in 13 patients (86.7%); 10 (76.9%) were positive for mutations in succinate dehydrogenase (SDHx) subunits B, C, or D. Thirteen patients (86.7%) underwent surgery to remove the paraganglioma with no intraoperative morbidity or mortality; 1 additional patient underwent surgical resection but experienced intraoperative complications after removal of the tumor due to co-morbidities and did not survive. SDHx mutations are known to be associated with mediastinal locations and malignant behavior of paragangliomas. In this report, the investigators extend the locations of predominantly SDHx-related paragangliomas to cardiac tumors. In conclusion, cardiac paragangliomas are frequently associated with underlying SDHx germline mutations, suggesting a need for genetic testing of all patients with this rare tumor.

Impact of ABCB1 allelic variants on QTc interval prolongation.

PURPOSE: Although the ABCB1 (P-glycoprotein) drug transporter is a constituent of several blood-tissue barriers (i.e., blood-brain and blood-nerve), its participation in a putative blood-heart barrier has been poorly explored. ABCB1 could decrease the intracardiac concentrations of drugs that cause QT prolongation and cardiotoxicity. EXPERIMENTAL DESIGN: ABCB1-related romidepsin transport kinetics were explored in LLC-PK1 cells transfected with different ABCB1 genetic variants. ABCB1 plasma and intracardiac concentrations were determined in Abcb1a/1b (-/-) mice and wild-type FVB controls. These same mice were used to evaluate romidepsin-induced heart rate-corrected QT interval (QTc) prolongation over time. Finally, a cohort of 83 individuals with available QTcB and ABCB1 genotyping data were used to compare allelic variation in ABCB1 versus QTc-prolongation phenotype. RESULTS: Here, we show that mice lacking the ABCB1-type P-glycoprotein have higher intracardiac concentrations of a model ABCB1 substrate, romidepsin, that correspond to changes in QT prolongation from baseline (ΔQTc) over time. Consistent with this observation, we also show that patients carrying genetic variants that could raise ABCB1 expression in the cardiac endothelium have lower ΔQTc following a single dose of romidepsin. CONCLUSIONS: To our knowledge, this is the first evidence that Abcb1-type P-glycoprotein can limit intracardiac exposure to a drug that mediates QT prolongation and suggests that certain commonly inherited polymorphisms in ABCB1 may serve as markers for QT prolongation following the administration of ABCB1-substrate drugs.

Iron overload cardiomyopathy: better understanding of an increasing disorder.

The prevalence of iron overload cardiomyopathy (IOC) is increasing. The spectrum of symptoms of IOC is varied. Early in the disease process, patients may be asymptomatic, whereas severely overloaded patients can have terminal heart failure complaints that are refractory to treatment. It has been shown that early recognition and intervention may alter outcomes. Biochemical markers and tissue biopsy, which have traditionally been used to diagnose and guide therapy, are not sensitive enough to detect early cardiac iron deposition. Newer diagnostic modalities such as magnetic resonance imaging are noninvasive and can assess quantitative cardiac iron load. Phlebotomy and chelating drugs are suboptimal means of treating IOC; hence, the roles of gene therapy, hepcidin, and calcium channel blockers are being actively investigated. There is a need for the development of clinical guidelines in order to improve the management of this emerging complex disease.

Cardiomyopathy in congenital and acquired generalized lipodystrophy: a clinical assessment.

Lipodystrophy is a rare disorder characterized by loss of adipose tissue and low leptin levels. This condition is characterized by severe dyslipidemia, insulin resistance, diabetes mellitus, and steatohepatitis. Another phenotypic feature that occurs with considerable frequency in generalized lipodystrophy is cardiomyopathy. We report here the cardiac findings in a cohort of patients with generalized congenital and acquired lipodystrophy, and present a literature review of the cardiac findings in patients with generalized lipodystrophy. We studied 44 patients with generalized congenital and acquired lipodystrophy, most of them enrolled in a clinical trial of leptin therapy. Patients underwent electrocardiograms and transthoracic echocardiograms to evaluate their cardiac status. We followed these patients for an extended time period, some of them up to 8 years. Evaluation of our cohort of patients with generalized lipodystrophy shows that cardiomyopathy is a frequent finding in this population. Most of our patients had hypertrophic cardiomyopathy, and only a small number had features of dilated cardiomyopathy. Hypertrophic cardiomyopathy was more frequent in patients with seipin mutation, a finding consistent with the literature. The underlying mechanism for cardiomyopathy in lipodystrophy is not clear. Extreme insulin resistance and the possibility of a "lipotoxic cardiomyopathy" should be entertained as possible explanations.

Cardiac toxicity and efficacy of trastuzumab combined with pertuzumab in patients with [corrected] human epidermal growth factor receptor 2-positive metastatic breast cancer.

PURPOSE: To evaluate safety and efficacy of trastuzumab with pertuzumab in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer who had progressive disease on trastuzumab-based therapy. EXPERIMENTAL DESIGN: Patients with measurable HER2(+) metastatic breast cancer, < or = 3 trastuzumab-based regimens, and left ventricular ejection fraction (LVEF) > or = 55% received 8 or 6 mg/kg trastuzumab and 840 mg pertuzumab i.v. followed by 6 mg/kg trastuzumab and 420 mg pertuzumab every 3 weeks. Cardiac evaluation and tumor response were assessed every 3 and 6 weeks, respectively. RESULTS: Eleven patients received 64 cycles of trastuzumab plus pertuzumab. A total of 92 echocardiograms and 8 cardiac magnetic resonance imaging studies were done. With the lower limit of normal LVEF 55%, left ventricular systolic dysfunction was observed in six patients, three grade 1, two grade 2, and one grade 3 according to the National Cancer Institute Common Terminology Criteria for Adverse Events. The objective response rate was 18%. Two patients had partial responses, three had stable disease, and six had progressive disease. The median time to progression was 6 weeks. In baseline tumors from formalin-fixed paraffin-embedded primary and/or metastatic tumor biopsies, pHER2-Y1248 trended toward an increase in patients with partial response compared with those with stable disease/progressive disease (P = 0.095). CONCLUSION: Trastuzumab plus pertuzumab may have clinical benefit in selected patients who have previously been treated with trastuzumab. Cardiac toxicity, although asymptomatic in most cases, was associated with this treatment. Further evaluation of efficacy of this combination is required to define the overall risks and benefits.