Ioana Maria Lambrescu

Predictive Markers of Response to Everolimus and Sunitinib in Neuroendocrine Tumors

Neuroendocrine tumors (NETs) represent a large and heterogeneous group of malignancies with various biological and clinical characteristics, depending on the site of origin and the grade of tumor proliferation. In NETs, as in other cancer types, molecularly targeted therapies have radically changed the therapeutic landscape. Recently two targeted agents, the mammalian target of rapamycin inhibitor everolimus and the tyrosine kinase inhibitor sunitinib, have both demonstrated significantly prolonged progression free survival in patients with advanced pancreatic NETs. Despite these important therapeutic developments, there are still significant limitations to the use of these agents due to the lack of accurate biomarkers for predicting tumor response and efficacy of therapy. In this review, we provide an overview of the current clinical data for the evaluation of predictive factors of response to/efficacy of everolimus and sunitinib in advanced pancreatic NETs. Surrogate indicators discussed include circulating and tissue markers, as well as non-invasive imaging techniques.

Takotsubo cardiomyopathy and transient thyrotoxicosis during combination therapy with interferon-alpha and ribavirin for chronic hepatitis C

BackgroundThyroid dysfunction is a common complication of chronic hepatitis C (CHC) and its therapy. Takotsubo cardiomyopathy (TCM) is a multifactorial, stress related cardiomyopathy, rarely reported in association with thyrotoxicosis. Simultaneous occurrence of TCM and thyrotoxicosis due to hepatitis C and its treatment has never been reported.Case presentationA 47-year-old woman was admitted for acute chest pain, dyspnea, palpitations and diaphoresis. She had been diagnosed with CHC and had undergone 7 months of IFNα and Ribavirin therapy. At admission electrocardiogram (ECG) showed ST segment elevation, negative T waves and troponin was elevated suggesting ST segment elevation myocardial infarction (STEMI). Echocardiography demonstrated left ventricular apical akinesia and ballooning, with a left ventricular ejection fraction (LVEF) of 35%. Contrast angiography showed normal epicardial coronaries, yet a ventriculogram revealed left ventricular apical ballooning, consistent with TCM. Cardiac MRI showed left ventricle apical ballooning and no late enhancement suggesting the absence of any edema, scar or fibrosis in the left myocardium. She was diagnosed with non-autoimmune destructive thyroiditis: TSH=0.001 mU/L, free T4=2.41 ng/dl, total T3=199 ng/dl and negative thyroid antibodies. The thyroid ultrasonography showed a diffuse small goiter, no nodules and normal vascularization of the parenchyma. Following supportive treatment she experienced a complete recovery after a few weeks and she successfully completed her antiviral treatment, with no thyroid or cardiovascular dysfunction ever since. In patients treated with IFNα for CHC, the prevalence of thyroid dysfunction varies between 2.5–45.3% of cases. TCM is a stress related cardiomyopathy characterized by elevated cardiac enzymes, normal coronary angiography and an acute, transient, left ventricular apical dysfunction that mimics myocardial infarction. Most of the patients survive the initial acute event, typically recover normal ventricular function within one to four weeks and have a favorable outcome, as was the case with our patient. Thyrotoxicosis induced stress cardiomyopathy is rare and has been mostly reported in association with Graves’ disease, thyroid storm, thyrotoxicosis factitia or following radioiodine therapy for toxic multinodular goiter.ConclusionRoutine thyroid screening should be done in patients receiving IFN-alpha and Ribavirin for CHC and thyrotoxicosis should be considered as a possible and treatable underlying cause of TCM.

Iatrogenic Cushing's syndrome related to the interaction between oral budesonide with fluvoxamine: a case report.

Budesonide, an oral glucocorticoid indicated for the treatment of Crohns disease, rarely interferes with the hypothalamic–pituitary–adrenal axis because more than 80% of it is metabolized by cytochrome P450 enzymes.

Long-term thyroid disorders in pediatric survivors of hematopoietic stem cell transplantation after chemotherapy-only conditioning

Abstract Background: Thyroid dysfunction (TD) was usually described in hematopoietic stem cell transplantation (HSCT) recipients who were given total body irradiation (TBI) in the conditioning regimen. Because previous studies have reported discrepant results regarding the presence of long-term thyroid complications in HSCT survivors following chemotherapy-only conditioning, we investigated the frequency of thyroid abnormalities in a series of children treated with HSCT for different disorders without TBI as part of the conditioning protocol. Methods: We compared thyroid-stimulating hormone, free thyroxine, total triiodothyronine (TT3), anti-peroxidase (TPO Ab) and anti-thyroglobulin antibodies and thyroid volume z-score in 28 HSCT survivors and 16 healthy subjects matched for age and sex. Results: HSCT recipients had a higher frequency of TD and thyroid complications in total, including TD and euthyroid Hashimoto thyroiditis, compared to the control group. Patients transplanted for Hodgkin lymphoma (HL) were more likely to develop a thyroid complication compared to patients with non-malignant hematologic diseases and leukemia patients. BEAM (carmustine, etoposide, citarabin and melphalan) conditioning compared to busulfan (Bu) and fludarabine (Flu)-based regimens and autologous compared to allogenic grafting were associated with a higher prevalence of TD in our study. HSCT survivors had higher mean serum TT3 levels. A multivariate analysis revealed that autologous (auto)-HSCT recipients had higher mean serum titers of TPO Ab compared to allogenic (allo)-HSCT recipients and controls and the mean thyroid volume z-score was significantly higher in controls compared to auto-/allo-HSCT survivors. Conclusions: We identified a 35.7% prevalence of thyroid abnormalities, emphasizing the need for a long-term surveillance of thyroid function and morphology even in this group of patients who were not exposed to TBI.

Graves’ orbitopathy after allogeneic bone marrow transplantation in a patient with Fanconi anemia - side effect of alemtuzumab therapy?

A few cases of thyroid eye disease following alemtuzumab therapy have been described in patients with multiple sclerosis. Our patient is the first case of Graves’ orbitopathy after alemtuzumab conditioning for hematopoietic stem cell transplantation.

Everolimus-related adverse events in neuroendocrine tumors and comparative considerations with breast and renal cancer: a critical overview

ABSTRACT Introduction: Everolimus, an inhibitor of mammalian target of rapamycin (mTOR), is approved as an anti-tumor therapy, as single agent or in combination, for advanced neuroendocrine tumors (NETs), breast and renal carcinomas. Areas covered: In this review we analyzed some general features of everolimus toxicity profile and evidence data about its adverse events (AEs) coming from the most relevant phase III clinical trials. Furthermore we critically discuss this by comparing the different clinical areas of neuroendocrine, breast and kidney malignancies and addressing the clinical management of the everolimus toxicity. Most of the AEs related to everolimus are mild to moderate and manageable with dose reduction or temporary interruptions of therapy. However, a few severe AEs can lead to definitive discontinuation of therapy. Therefore clinicians employing this therapy regardless of tumor type should provide patients with prevention and management strategies in order to increase treatment adherence and improve quality of life (QoL). Risk factors like co administration of other therapies that could interfere with everolimus and increase its toxicity should also be taken into account. Expert opinion: Class adverse effects related to everolimus are similar among clinical trials conducted in solid tumors. Active treatment and monitoring can prevent severe toxicity and unnecessary drug discontinuation that can lead in time to disease progression. Designing future trials and employing toxicity predictive biomarkers are strategies useful for selecting patients that can benefit from mTOR inhibitors.