Emilia Zampella

A novel NKX2.1 mutation in a family with hypothyroidism and benign hereditary chorea.

BACKGROUND We studied a boy with congenital hypothyroidism, benign hereditary chorea, and respiratory distress. His mother and his grandfather were affected by hypothyroidism with a late onset and benign hereditary chorea. The aim of this study was to establish the genetic defects that cause that phenotype and study the molecular mechanisms of the pathology. METHODS NKX2.1, PAX8, NKX2.5, and TAZ genes were sequenced. RESULTS Direct sequencing of the NKX2.1 gene showed, in all the affected, a new heterozygous mutation from cytosine to adenine in the second base of the triplet encoding for the amino acid at position 145. The mutation (C609A) is responsible for a change from serine to a stop codon (S145X). We also demonstrated that the mutant protein is predominantly in the cytoplasm and unable to translocate into the nucleus. Of note, the S145X mutation produces variable phenotypes in the affected members of the family. No mutations have been identified in the NKX2.5, PAX8, and TAZ genes. CONCLUSIONS Our study extends the knowledge of the functional effect of NKX2.1 mutations and further highlights the complexities of genotype-phenotype correlation in the NKX2.1 deficiency syndromes.

Incremental prognostic value of stress myocardial perfusion imaging in asymptomatic diabetic patients

OBJECTIVE Stress myocardial perfusion single-photon emission computed tomography (MPS) variables are robust estimators of prognosis. No data are available on the comparative ability of stress MPS risk markers using varied iterative and risk classification approaches in asymptomatic diabetic patients. We compared analytical approaches to estimate the added value of MPS variables in estimating coronary artery disease (CAD) outcomes in asymptomatic diabetic patients. We also evaluated the temporal characteristics of cardiac risk according to MPS findings. METHODS A total of 436 consecutive asymptomatic diabetic patients who underwent stress-rest gated MPS were prospectively enrolled. Multivariable Cox proportional hazards model was employed to estimate cardiac death and nonfatal myocardial infarction (MI). Risk reclassification was calculated and parametric survival analysis was used to predict time to events. RESULTS At multivariable analysis, post-stress left ventricular ejection fraction (LVEF) and stress MPS ischemia were independent predictors of CAD death or MI (both p < 0.01). The net reclassification improvement by adding MPS results to a model including pre-test CAD likelihood was 0.25 (95% confidence interval 0.06-0.44; p < 0.01). Parametric survival analysis showed the highest probability of CAD death or MI and the major risk acceleration in time in patients with stress MPS ischemia and post-stress LVEF ≤45%. CONCLUSION In asymptomatic diabetic patients, analytical approaches that establish the reclassification of events may serve for estimation of improved outcomes for stress MPS. Post-stress LVEF and stress-induced ischemia by gated MPS influence the temporal characteristic of the patients risk at long-term follow-up.

Characterization of a novel loss-of-function mutation of PAX8 associated with congenital hypothyroidism

Background  Congenital hypothyroidism (CH) is a common endocrine disease that occurs in about 1:3000 newborns. In 80–85% of the cases, CH is presumably secondary to thyroid dysgenesis (TD), a defect in the organogenesis of the gland leading to an ectopic (30–45%), absent (agenesis, 35–40%) or hypoplastic (5%) thyroid gland. The pathogenesis of TD is still largely unknown. Most cases of TD are sporadic, although familial occurrences have occasionally been described. Recently, mutations in the PAX8 transcription factor have been identified in patients with TD.

Quantitative relationship between coronary artery calcium and myocardial blood flow by hybrid rubidium-82 PET/CT imaging in patients with suspected coronary artery disease

BackgroundWe assessed the relationship between coronary artery calcium (CAC) score, myocardial blood flow (MBF) and coronary flow reserve (CFR) in patients undergoing hybrid 82Rb positron emission tomography (PET)/computed tomography (CT) imaging for suspected CAD. We also evaluated if CAC score is able to predict a reduced CFR independently from conventional coronary risk factors.MethodsA total of 637 (mean age 58 ± 13 years) consecutive patients were studied. CAC score was measured according to the Agatston method and patients were categorized into 4 groups (0, 0.01-99.9, 100-399.9, and ≥400). Baseline and hyperemic MBF were automatically quantified. CFR was calculated as the ratio of hyperemic to baseline MBF and it was considered reduced when <2.ResultsGlobal CAC score showed a significant inverse correlation with hyperemic MBF and CFR (both P < .001), while no correlation between CAC score and baseline MBF was found. At multivariable logistic regression analysis age, diabetes and CAC score were independently associated with reduced CFR (all P < .001). The addition of CAC score to clinical data increased the global chi-square value for predicting reduced CFR from 81.01 to 91.13 (P < .01). Continuous net reclassification improvement, obtained by adding CAC score to clinical data, was 0.36.ConclusionsCAC score provides incremental information about coronary vascular function over established CAD risk factors in patients with suspected CAD and it might be helpful for identifying those with a reduced CFR.

Prognostic role of 18F-FDG PET/CT in the postoperative evaluation of differentiated thyroid cancer patients

Purpose The aim of this study was to evaluate the role of 18F-FDG PET/CT performed after surgery but before radioiodine therapy in patients with differentiated thyroid cancer. Procedures FDG PET/CT was performed off l-thyroxine in 60 newly diagnosed differentiated thyroid cancer patients. Clinical and hematological evaluation as well as high-resolution neck ultrasound were performed. All patients underwent a complete follow-up (range, 6-67 months; mean [SD], 31.7 [20.6] months). The date of recurrence or the most recent office visit was recorded. Progression-free survival (PFS) is the primary end point of this study. Analysis was performed by Cox proportional hazards model. Survival curves were generated using Kaplan-Meier estimates, and the log-rank test was used to assess significance. Results FDG PET/CT was negative in 63% of patients, 20% had FDG thyroid bed uptake, 5% distant metastases, and 12% lymph node FDG uptake. In patients with positive FDG PET/CT scan (ie, those with distant metastases or lymph node uptake), a higher rate of recurrence was observed (50% vs 6%, P < 0.05). Thyroglobulin, neck ultrasound, stage, and FDG PET/CT correlated with PFS at univariate analysis. At multivariate analysis, only thyroglobulin and FDG PET/CT continued to be predictors of PFS. Patients with a negative FDG PET/CT scan have a better PFS either in the whole group or in those with elevated thyroglobulin level (both >2 ng/mL and >10 ng/mL). Conclusions FDG PET/CT was abnormal in 17% of patients. Moreover, FDG PET/CT has an independent prognostic role, with a better PFS in patients with a negative scan.

Mutations in TAZ/WWTR1, a co-activator of NKX2.1 and PAX8 are not a frequent cause of thyroid dysgenesis

Aim: In 80–85% of cases, congenital hypothyroidism is associated with thyroid dysgenesis (TD), but only in a small percentage of cases mutations in thyroid transcription factors (NKX2.1, PAX8, FOXE1, and NKX2.5) have been associated with the disease. Several studies demonstrated that the activity of the transcription factors can be modulated by the interaction with other proteins, such as coactivators and co-repressors, and TAZ (transcriptional co-activator with PDZ-binding motif or VVWTR1) is a co-activator interacting with both NKX2.1 and PAX8. In the present study we investigate the role of TAZ in the pathogenesis of TD. Material and methods: By Single Stranded Conformational Polymorphism, we screened the entire TAZ coding sequence for mutations in 96 patients with TD and in 96 normal controls. Results: No mutations were found in patients and controls, but we found several polymorphisms in both groups. No significant differences could be demonstrated in the prevalence of the mutations between patients and controls. Conclusions: Our data indicate that TAZ mutations are not a cause of TD in the series of patients studied.

Long-Term Survival Benefit of Coronary Revascularization in Patients Undergoing Stress Myocardial Perfusion Imaging

BACKGROUND We assessed the relationship between clinical outcome and coronary revascularization according to stress-gated myocardial perfusion single-photon emission computed tomography (MPS) in an observational series of patients with suspected or known coronary artery disease (CAD), on long-term follow-up. METHODSANDRESULTS The study group consisted of 2,059 patients. During a median follow-up of 61 months, 184 events occurred (126 cardiac deaths and 58 non-fatal MI). The impact of revascularization during follow-up on event-free survival was evaluated using an extended Cox regression model, adjusting for potential clinical and MPS confounders. Revascularization was treated as a binary non-reversible time-dependent covariate. Predefined interactions tested were: (1) revascularization and summed difference score (SDS); (2) revascularization and post-stress left ventricular (LV) ejection fraction (EF); and (3) SDS and post-stress LVEF. Revascularization had a significant effect on event-free survival (adjusted HR, 0.19; P<0.001). Significant interactions were found between revascularization and SDS (P=0.045), and between LVEF and SDS (P=0.015). The protective effect of revascularization increased as SDS increased. For SDS <6 the reduction in HR was detectable only for reduced LVEF. CONCLUSIONS Both the degree of stress-induced ischemia and LVEF predict the effect of revascularization on outcome in patients with suspected or known CAD. The protective effect of revascularization appears to be greater in patients with severe ischemia and preserved LVEF.

MIBG molecular imaging for evaluating response to chemotherapy in patients with malignant pheochromocytoma: preliminary results.

Abstract Malignant pheochromocytomas respond to chemotherapy with a reduction in tumor size and catecholamine secretion. We investigated the usefulness of molecular imaging with meta-iodobenzylguanidine (MIBG) for evaluating the effects of chemotherapy in patients with malignant pheochromocytoma. Six patients were studied before and after 6 ± 4 months of combination chemotherapy with cyclophosphamide, vincristine, and dacarbazine. Urinary catecholamines, metanephrines, and vanillylmandelic acid (VMA) levels were measured before and after chemotherapy. [131I]MIBG uptake was calculated for each tumor lesion on images before and after chemotherapy. An intensity ratio (IR) of abnormal to normal tissue count density was used to evaluate the change in lesion activity with therapy. Urinary catecholamines, metanephrines, and VMA significantly decreased with chemotherapy. MIBG uptake decreased in most lesions and the reduction in overall IR correlated with the reduction in urinary VMA. However, the change in individual lesions was variable and MIBG IR did not change or increased in a number of lesions. In conclusion, MIBG imaging is useful in the evaluation of patients with malignant pheochromocytoma who are receiving chemotherapy. It can provide not only a measure of overall effectiveness of treatment but also allows a lesion-by-lesion evaluation of the heterogeneity of response to chemotherapy.

Coronary atherosclerotic burden vs. coronary vascular function in diabetic and nondiabetic patients with normal myocardial perfusion: a propensity score analysis

PurposeTo assess the relationship between coronary atherosclerotic burden and vascular function in diabetic and nondiabetic patients after balancing for coronary risk factors.MethodsWe studied 672 patients without overt coronary artery disease and normal myocardial perfusion on stress 82Rb PET/CT imaging. To account for differences in baseline characteristics between diabetic patients and nondiabetic patients, we created a propensity score-matched cohort considering clinical variables and coronary risk factors.ResultsBefore matching, diabetic patients had higher coronary artery calcium (CAC) scores (p < 0.001) and lower coronary flow reserve (CFR; p < 0.001) than nondiabetic patients. After matching, CAC scores were comparable between diabetic and nondiabetic patients, but diabetic patients still had lower hyperaemic myocardial blood flow (p < 0.001) and CFR (p < 0.05). Patients were categorized by ln(CAC score) quartiles. There was a decrease in CFR with increasing CAC score quartile in both diabetic patients (p for trend < 0.01) and nondiabetic patients (p for trend < 0.005). Diabetes was associated with lower CFR across quartile categories (p < 0.002). In a multivariable linear regression analysis, CAC score was inversely related to CFR in both diabetic patients (p < 0.05) and nondiabetic patients (p < 0.001).ConclusionDiabetic patients had higher CAC scores than nondiabetic patients, but the difference disappeared when clinical characteristics were taken into account. Of note, diabetic patients also had lower CFR regardless of CAC score than nondiabetic patients after matching. Thus, coronary atherosclerotic burden and vascular function have to be seen as two different entities.

Reclassification of cardiovascular risk by myocardial perfusion imaging in diabetic patients with abnormal resting electrocardiogram

BACKGROUND AND AIMS Despite an extensive use of stress myocardial perfusion single-photon emission computed tomography (MPS), no study addressed the role of perfusion imaging in diabetic patients with abnormal resting electrocardiogram (ECG). We compared analytical approaches to assess the added value of stress MPS variables in estimating coronary heart disease outcomes in diabetic patients with abnormal resting ECG. METHODS AND RESULTS A total of 416 patients with diabetes and abnormal resting ECG who underwent stress MPS were prospectively followed up after the index study. The end point was the occurrence of a major cardiac event, including cardiac death and nonfatal myocardial infarction. At the end of follow-up (median 58 months), 42 patients experienced events. MPS data increased the predictive value of a model including traditional cardiovascular risk factors and left ventricular (LV) ejection fraction (likelihood ratio χ² from 17.54 to 24.15, p < 0.05, with a C statistic of 0.72, 95% confidence interval: 0.65-0.79). The addition of MPS data resulted in reclassification of 25% of the sample with a net reclassification improvement of 0.20 (95% confidence interval: 0.05-0.36). Overall, 63 patients were reclassified to a lower risk category, with a 5-year event rate of 3.5%, and 40 patients were reclassified to a higher risk category, with a 5-year event rate of 20%. CONCLUSION The addition of MPS findings to a model based on traditional cardiovascular risk factors and LV ejection fraction improves risk classification for incident cardiac events in diabetic patients with abnormal resting ECG.