Cardiac toxicity associated with pharmacokinetic drug-drug interaction between crizotinib and sofosbuvir/velpatasvir: A case report.

This case report describes a pharmacokinetic drug-drug interaction between crizotinib, a tyrosine kinase inhibitor, and sofosbuvir/velpatasvir, a direct-acting antiviral drug, leading to cardiac toxicity. A 75-year-old man, with no cardiovascular history but a diagnosis of metastatic nonsmall cell lung cancer with mesenchymal-epithelial transition exon-14 deletion and hepatitis C virus infection genotype 1A, received both crizotinib and sofosbuvir/velpatasvir. Crizotinib was well tolerated, but 1 week after sofosbuvir/velpatasvir initiation, the patient experienced bilateral lower-limb oedema and class III New York Heart Association dyspnoea. We assumed that increased exposure to crizotinib could account for this cardiac toxicity. Drug causality was probable according to the Naranjo scale. We hypothesized a reciprocal interaction between crizotinib and velpatasvir, mediated by both cytochrome 3A4 (CYP3A4) and P-glycoprotein (P-gp). Clinicians should be aware of the risk of drug-drug interactions between direct-acting antiviral agents that inhibit CYP3A4 (glecaprevir) and/or P-gp (voxilaprevir, velpatasvir) and anticancer tyrosine kinase inhibitors that are mostly CYP3A4 and/or P-gp substrates (gefitinib, afatinib, erlotinib, crizotinib, ceritinib, lorlatinib, brigatinib, capmatinib etc.).

Cardiac Metastasis from Medullary Thyroid Cancers with Long-Term Survival under Vandetanib.

BACKGROUND: Cardiac metastases from thyroid cancers are uncommon with a poor prognosis. There is a lack of long-term follow-up studies. CASES: We report 2 cases of cardiac metastasis from medullary thyroid cancer (MTC). Both patients presented limited metastatic disease apart from a cardiac metastasis. The initial diagnosis was challenging and was facilitated by functional imaging with an immuno-PET-CT using an anti-CEA bispecific antibody and a 68Ga-labeled peptide. Both patients were treated with the multitarget kinase inhibitor vandetanib with prolonged stability. The first patient was alive at the last follow-up, 14 years after the diagnosis of cardiac metastasis. The second patient required surgical excision of the cardiac mass because of disease progression under vandetanib. CONCLUSION: These cases illustrate long-term survival and effectiveness of clinical management of 2 patients who developed cardiac metastases from MTC, in the current era of personalized medicine with targeted therapy.

Frequency and Incidence of Carney Complex Manifestations: A Prospective Multicenter Study With a Three-Year Follow-Up.

INTRODUCTION: Carney Complex (CNC) is a rare multiple endocrine and nonendocrine neoplasia syndrome. Manifestations and genotype-phenotype correlations have been described by retrospective studies, but no prospective study evaluating the occurrence of the different manifestations has been available so far. METHODS: This multicenter national prospective study included patients with CNC, primary pigmented nodular adrenal disease (PPNAD), or a pathogenic PRKAR1A mutation; after a full initial workup, participants were followed for 3 years with annual standardized evaluation. RESULTS: The cohort included 70 patients (50 female/20 male, mean age 35.4 ± 16.7 years, 81% carrying PRKAR1A mutation). The initial investigations allowed identification of several manifestations. At the end of the 3-year follow-up, the newly diagnosed manifestations of the disease were subclinical acromegaly in 6 patients, bilateral testicular calcifications in 1 patient, and cardiac myxomas in 2 patients. Recurrences of cardiac myxomas were diagnosed in 4 patients during the 3-year follow-up study period. Asymptomatic abnormalities of the corticotroph and somatotroph axis that did not meet criteria of PPNAD and acromegaly were observed in 11.4% and 30% of the patients, respectively. Patients carrying the PRKAR1A c.709-7del6 mutation had a mild phenotype. CONCLUSION: This study underlines the importance of a systematic follow-up of the CNC manifestations, especially a biannual screening for cardiac myxoma. By contrast, regular screening for the other manifestations after a first extensive workup could be spread out, leading to a lighter and more acceptable follow-up schedule for patients. These are important results for recommendations for long-term management of CNC patients.

close: Closure of patent foramen ovale, oral anticoagulants or antiplatelet therapy to prevent stroke recurrence: Study design.

RATIONALE: Currently available data do not provide definitive evidence on the comparative benefits of closure of patent foramen ovale, oral anticoagulants and antiplatelet therapy in patients with patent foramen ovale-associated cryptogenic stroke AIM: To assess whether transcatheter patent foramen ovale closure plus antiplatelet therapy is superior to antiplatelet therapy alone and whether oral anticoagulant therapy is superior to antiplatelet therapy, for secondary stroke prevention in patients aged 16 to 60 years with a large patent foramen ovale or a patent foramen ovale associated with an atrial septal aneurysm, and an otherwise unexplained ischaemic stroke or retinal ischaemia. SAMPLE SIZE: Six hundred and sixty-four patients were included in the study. METHODS AND DESIGN: CLOSE is an academic-driven, multicentre, randomized, open-label, three-group, superiority trial with blinded adjudication of outcome events. The trial has been registered with Clinical Trials Register (Clinicaltrials.gov, NCT00562289). Patient recruitment started in December 2007. Patient follow-up will continue until December 2016. Expected mean follow-up = 5.6 years. STUDY OUTCOMES: The primary efficacy outcome is the occurrence of fatal or nonfatal stroke. Safety outcomes include fatal, life-threatening or major procedure- or device-related complications and fatal, life-threatening or major haemorrhagic complications. DISCUSSION: CLOSE is the first specifically designed trial to assess the superiority of patent foramen ovale closure over antiplatelet therapy alone and the superiority of oral anticoagulants over antiplatelet therapy to prevent stroke recurrence in patients with patent foramen ovale-associated cryptogenic stroke.

[Tyrosine kinase inhibiting the VEGF pathway and elderly people: Tolerance, pre-treatment assessment and side effects management]. / Inhibiteurs de tyrosine kinase ciblant l'angiogenèse et sujets âgés : tolérance, évaluation pré-thérapeutique et gestion des effets indésirables.

Angiogenesis inhibition is a major antitumor strategy that has emerged during the last decade. Oral tyrosine kinase inhibitors (TKI) targeting the VEGF receptor, including sunitinib, sorafenib, axitinib, regorafenib, pazopanib, and vandetanib reduce tumor growth and metastasis. These agents are approved for the treatment of metastatic diseases in first or second-line. They display a narrow therapeutic index. However, data in the elderly and/or in patients with multiple illnesses remain scarce. This population is classically excluded from clinical trials. The aim of this review is to provide an overview of existing literature regarding antiangiogenic TKI tolerance in the elderly (>70 years old). We also highlight key points of the pre-therapeutic evaluation and summarize the management of common toxicities.

Severe mitral stenosis as the first manifestation of systemic lupus erythematosus in a 20-year-old woman: the value of magnetic resonance imaging in the diagnosis of Libman-Sacks endocarditis.

We report a case of severe mitral stenosis caused by Libman-Sacks endocarditis, as an initial manifestation of systemic lupus erythematosus (SLE) in a 20-year-old woman. Cardiac magnetic resonance imaging (MRI) demonstrated a thickening of the mitral valve with basal endocardial thickening exhibiting defect on first-pass perfusion short-axis acquisition and delayed enhancement in keeping with extensive fibrous endocarditis. The patient underwent successful mechanical mitral valve replacement. This case illustrates that MRI is useful in diagnosing this recognised but uncommon cardiac complication of SLE and excluding differential diagnosis such as valve tumour and infective endocarditis with perivalvular abscesses.

Variability of sorafenib toxicity and exposure over time: a pharmacokinetic/pharmacodynamic analysis.

BACKGROUND: Sorafenib displays major interpatient pharmacokinetic variability. It is unknown whether the pharmacokinetics of sorafenib influence its toxicity. METHODS: We analyzed the severity and kinetics of sorafenib-induced toxicities in unselected consecutive patients with cancer, as well as their relationship with biological, clinical, and pharmacokinetic parameters. Toxicity was recorded bimonthly. Sorafenib plasma concentrations were assessed by liquid chromatography. RESULTS: For 83 patients (median age, 62 years; range, 21-84 years), median sorafenib 12-hour area under the curve (AUC(0-12)) was 52.8 mg · h/L (range: 11.8-199.6). A total of 51 patients (61%) experienced grade 3-4 toxicities, including hand-foot skin reactions (23%), asthenia (18%), and diarrhea (11%). Sorafenib AUC(0-12) preceding grade 3-4 toxicities was significantly higher than that observed in the remaining population (61.9 mg · h/L vs. 53 mg · h/L). In 25 patients treated with fixed doses of sorafenib for the first 4 months, median dose-normalized AUC(0-12) on day 120 was significantly lower than on day 15 (63 vs. 102 mg · h/L). The incidence of hypertension and hand-foot skin reactions significantly decreased over time. CONCLUSION: Sorafenib AUC(0-12) decreases over time, similarly to the incidence of hypertension and hand-foot skin reactions. Monitoring of sorafenib plasma concentrations may help to prevent acute severe toxicities and detect patients with suboptimal exposure at disease progression.

Cardiovascular findings and management in Turner syndrome: insights from a French cohort.

OBJECTIVE: Congenital cardiovascular malformations and aortic dilatation are frequent in patients with Turner syndrome (TS). The objective of this study was to investigate the cardiovascular findings and management in a large cohort of patients, including children and adults. DESIGN/METHODS: We recruited 336 patients with TS from a network of tertiary centers. We reviewed their files, checking for cardiovascular events, cardiac valve abnormalities, and aortic diameters indexed to body surface area (BSA) from magnetic resonance imaging (n=110) or echocardiography (n=300). RESULTS: Informative cardiovascular data were available for only 233 patients. Vascular surgery was reported in 7.4% of the cohort. The first cause of surgery was aortic coarctation, detected in 6.9% at a median age of 9.5 (range: 0-60) years. Bicuspid aortic valve (BAV) was detected in 21% at a median age of 20 years (25th-75th percentiles: 15-30). At least one aortic diameter exceeded 32 mm in 12% of the cohort. This was detected at a median age of 19 (7-30) years. When indexed to BSA, at least one aortic diameter exceeded 20 mm/m(2) in 39% of the cohort. CONCLUSION: Our study shows that cardiovascular monitoring for TS patients is currently insufficient in France. BAV is present at birth, but often remains undiagnosed until later in life. Therefore, improved management in cardiovascular monitoring is required and a more systematic approach should be taken.

Treatment of bevacizumab-induced hypertension by amlodipine.

BACKGROUND: Hypertension is a common toxicity of anti-VEGF agents, but its optimal treatment remains to define. This study aimed to describe the efficacy and tolerability of amlodipine, a calcium channel blocker, in patients with metastatic malignancies treated with bevacizumab, a humanized monoclonal antibody to VEGF. PATIENTS AND METHODS: One hundred and eighty-seven patients with advanced or metastatic NSCLC, colorectal or ovarian cancer receiving bevacizumab (5 mg/kg every 2 weeks or 7.5 mg/kg every 3 weeks) and chemotherapy were eligible for this analysis. Blood pressure was measured at home twice daily according to international guidelines. Patients received amlodipine 5 mg daily for grade ≥ 2 bevacizumab-induced hypertension. RESULTS: Twenty-six patients received amlodipine 5 mg daily for de novo hypertension (group A), and another 10 patients received amlodipine for exacerbation of previously existing hypertension (group B). Hypertension was controlled within 7 days under amlodipine in 23/26 (88.5%, 95%CI: 76.2-100) patients in group A, and 8/10 (80%, 95%CI: 55.2-100) patients in group B, with a favourable toxicity profile. CONCLUSIONS: Amlodipine 5 mg daily appears safe and efficient for the treatment of hypertension in patients receiving bevacizumab at a dose-intensity of 2.5 mg/kg/week. Further prospective studies are warranted to confirm these results.

An observational study of bevacizumab-induced hypertension as a clinical biomarker of antitumor activity.

BACKGROUND: Hypertension is a common toxicity of bevacizumab, but the frequency of assessment of blood pressure and standardized grading remain to be defined. This study aimed to describe the incidence of bevacizumab-induced hypertension and factors associated with its development, then to retrospectively assess its relation with activity. PATIENTS AND METHODS: One hundred nineteen patients with advanced or metastatic non-small cell lung cancer, colorectal cancer, or ovarian cancer receiving bevacizumab (2.5 mg/kg per week) and chemotherapy were eligible for this analysis. Blood pressure was measured at home twice daily according to international guidelines, and graded according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC), version 3.0, and the European Society of Hypertension (ESH) criteria. RESULTS: Home-based measurements detected significantly more cases of hypertension than in-clinic measurements did, according to the ESH criteria (54.6% versus 24.4%; p < .001) or the NCI-CTC (42.9% versus 22.7%; p = .0015). Very early hypertension (within 42 days, according to the ESH criteria) but not hypertension (occurring at any time during treatment period) was predictive of response (p = .0011 and p = .26, respectively). CONCLUSIONS: Our preliminary results indicate that home-based measurement and grading according to the ESH criteria represents a reliable method to detect bevacizumab-induced hypertension. Whether hypertension is a biomarker of bevacizumab activity remains to be determined in a prospective study.

Turner syndrome and pregnancy: clinical practice. Recommendations for the management of patients with Turner syndrome before and during pregnancy.

Following the death in France by acute aortic dissection of two women with Turner syndrome who were pregnant following oocyte donation, the Director of the French Biomedicine Agency (Agence de la biomédecine) sent a letter to the President of the French College of Obstetricians and Gynaecologists (FCOG). He requested the College's expertise in reviewing point-by-point the cases and risk factors and in determining whether there are grounds to propose additional measures complementary to the recommendations made by the Haute autorité de santé or French National Authority for Health (HAS) in 2008 in terms of indication and monitoring of patients. A joint practice committee of the FCOG, the French Cardiologic Society, the French Chest and Cardiovascular Surgery Society, the French Society of Anaesthesia and Intensive Care, the French Endocrine Society, the French study group for oocyte donation, and the Biomedicine Agency defined the exact questions to be put to the experts, chose these experts, followed them up and drafted the synthesis of recommendations resulting from their work. The questions concerned the check-up before pregnancy of Turner patients, contraindication and acceptance of pregnancy, information for the patients, and recommendations for antenatal care, delivery and postnatal follow-up.

Toxicity of sorafenib: clinical and molecular aspects.

IMPORTANCE OF THE FIELD: Sorafenib is a novel oral bis-aryl urea compound originally developed as an inhibitor of RAF kinase for its anti-proliferative property. Sorafenib also inhibits receptor tyrosine kinases of multiple pro-angiogenic factors such as VEGFR-1/2/3, Flt-3 and PDGFR-beta. The combination of both its anti-proliferative and anti-angiogenic properties makes sorafenib an attractive agent in cancer treatment. Sorafenib has been approved for the treatment of metastatic renal cell carcinoma as well as hepatocellular cancer. Despite its inherent selectivity, sorafenib can cause unusual adverse events whose the management represents a challenge for oncologists. AREAS COVERED IN THIS REVIEW: Relevant literature was identified using a Pubmed search of articles published up to June 2009. Search terms included 'sorafenib' and 'toxicity'. Original articles were reviewed and relevant citations from these articles were also considered. WHAT THE READER WILL GAIN: The clinical aspect of sorafenib-induced adverse events and the molecular basis behind this toxicity are discussed. Finally, recommendations for the management of these adverse events are proposed. TAKE HOME MESSAGE: Although not life-threatening, toxicity of sorafenib can severely impact the physical, psychological and social well-being of patients. The management of this unusual toxicity highlights the particular need of new pluridisciplinarities linking oncologist, cardiologist and dermatologist.

Cardiac involvement in systemic sclerosis assessed by tissue-doppler echocardiography during routine care: A controlled study of 100 consecutive patients.

OBJECTIVE: To assess the prevalence of primary cardiac complications in a large population of patients with systemic sclerosis (SSc), using recently developed echocardiographic techniques. METHODS: We prospectively studied 100 consecutive patients (mean +/- SD age 54 +/- 14 years; 86 women) presenting with SSc without pulmonary arterial hypertension or clinical manifestations of heart failure. All patients underwent standard echocardiography, along with measurements of longitudinal velocities by tissue Doppler imaging (TDI) to assess left ventricular (LV) and right ventricular (RV) contractility and LV diastolic function. Results were compared with those in 26 age- and sex-matched healthy controls. RESULTS: Patients with SSc had a wider mean left atrial diameter and impaired relaxation compared with the controls. A trend was observed toward a smaller LV ejection fraction (EF) in the patients (mean +/- SD 64.9 +/- 0.6%) than in the controls (67.2 +/- 0.7%), as well as higher pulmonary artery pressure (mean +/- SD 33.3 +/- 0.6 mm Hg versus 30.8 +/- 1.0 mm Hg). LVEF was <55% in 7 patients versus none of the controls. Peak systolic mitral annular velocity as measured by TDI was <7.5 cm/second in 14 patients versus none of the controls (P = 0.040). Mitral annulus early diastolic velocity was <10 cm/second in 30 patients versus 2 of the controls (P = 0.022). Fifteen patients and none of the controls had reduced peak systolic tricuspid annular velocity (P = 0.039). The TDI results correlated with each other, but not with lung abnormalities or other disease characteristics. CONCLUSION: Depression of LV and RV systolic and LV diastolic function is common in patients with SSc and is due to primary myocardial involvement. Considering the major contributions of TDI, the addition of this simple technique to standard measurements may improve the detection of heart involvement in patients with SSc.

Interobserver and intraobserver variability in detection of patent foramen ovale and atrial septal aneurysm with transesophageal echocardiography.

BACKGROUND: An accurate diagnosis of patent foramen ovale (PFO) and atrial septal aneurysm (ASA) may be of decisional importance in the management of patients with ischemic stroke. Very few studies have been devoted to observer agreement in the diagnosis of these atrial septum abnormalities using contrast transesophageal echocardiography, which is considered as the method of choice for the diagnosis. The aim of this study was to assess interobserver and intraobserver variability in the diagnosis of PFO and ASA with contrast echocardiography. METHODS: Three sonographers independently reviewed 100 contrast studies stored on videotape on 2 occasions each. The interobserver and intraobserver variability was assessed by calculating kappa statistics. RESULTS: The overall interobserver and intraobserver kappa values for the assessment of degree of shunting through a PFO were 0.77 (first and second reading) and 0.82, respectively. The best kappa statistics were obtained when no and small shunts (less than 10 microbubbles) were pooled and compared with larger shunts. For the diagnosis of ASA, the overall interobserver kappa value was 0.45 for the first reading and 0.71 for the second reading, whereas the overall intraobserver kappa value was 0.74. CONCLUSION: Interobserver and intraobserver agreements for the diagnosis of PFO and ASA by transesophageal echocardiography are not perfect and need to be improved, particularly for ASA. This variability has to be taken into account when deciding on a potential risky treatment to prevent recurrent strokes.