Genetic mutation screening in an Italian cohort of nonsyndromic pheochromocytoma/paraganglioma patients

To assess the prevalence of genetic mutations in nonsyndromic pheochromocytoma/paraganglioma (PHEO/PGL) patients we have performed a systematic search for mutations in the succinate dehydrogenase (SDH) B, C, and D subunits, von Hippel-Lindau (VHL), and RET genes by direct bidirectional sequencing. Patients were selected from the medical records of hypertension centers. After exclusion of syndromic patients, 45 patients with familial (F+, n=3) and sporadic (F-, n=42) cases of isolated PHEO/PGL were considered. They included 35 patients with PHEO, 7 with PGL, and 3 with head/neck PGL (hnPGL). Three patients with PHEO (2F-, 1F+) presented VHL mutations (P86A, G93C, and R167W), six with PGL (4F-, 2F+) were positive for SDH or VHL mutations (SDHB R230G in two patients, SDHB S8F, R46Q, R90Q, and VHL P81L in one subject each), and one with hnPGL carried the SDHD 348-351delGACT mutation. We have also detected missense (SDHB S163P, SDHD H50R and G12S), synonymous (SDHB A6A, SDHD S68S), and intronic mutations that have been considered nonpathological polymorphic variants. No mutation was found in SDHC or RET genes. Our data indicate that germline mutations of VHL and SDH subunits are not infrequent in familial as well as in sporadic cases of nonsyndromic PHEO/PGL (overall, 12 of 45 probands, 22%). Accordingly, screening for such mutations seems to be justified. However, a more precise characterization of the functional relevance of any observed sequence variant and of other genetic and environmental determinants of neoplastic transformation is essential in order to plan appropriate protocols for family screening and follow-up

Prevalence of C-reactive protein elevation and time course of normalization in acute pericarditis: Implications for the diagnosis, therapy, and prognosis of pericarditis

Background-The role of inflammatory markers is not well defined for either diagnosis or treatment of pericarditis. The aim of this study is to prospectively evaluate the frequency of high-sensitivity C-reactive protein (hs-CRP) elevation in patients with acute pericarditis, its time course of normalization, and the possible importance for diagnosis, therapy, and prognosis. Methods and Results-Two hundred consecutive patients with viral or idiopathic acute pericarditis (mean age, 53 +/- 15.5 years; 103 men) were studied from August 2005 to August 2007 in 2 Italian referral centers. Hs-CRP was determined at presentation and then every week until normalization. Hs-CRP elevation was recorded in 156 of 200 cases (78%) at presentation. Recognized causes of a negative hs-CRP at presentation were early assessment in 15 of 44 cases (34%) and previous anti-inflammatory therapies in 22 of 44 cases (50%). Hs-CRP normalization was achieved with the following time course: 120 of 200 (60%) at week 1, 170 of 200 (85%) at week 2, 190 of 200 (95%) at week 3, and all cases (100%) at week 4. In multivariable analysis, incomplete response to empirical anti-inflammatory therapy at week 1 (hazard ratio, 2.98; 95% confidence interval, 1.80 to 4.94; P < 0.001), corticosteroid therapy (hazard ratio, 2.80; 95% confidence interval, 1.59 to 4.95; P < 0.001), and the presence of elevated hs-CRP at week 1 (hazard ratio, 2.36; 95% confidence interval, 1.32 to 4.21; P=0.004) were independent risk factors for recurrence. Conclusions-Hs-CRP is elevated at the initial presentation in approximate to 3 of 4 cases of acute pericarditis, identifies patients at higher risk of recurrence, and could be used to monitor disease activity and select appropriate therapy length

Risk of constrictive pericarditis after acute pericarditis

Background-Constrictive pericarditis (CP) is considered a rare, dreaded possible complication of acute pericarditis. Nevertheless, there is a lack of prospective studies that have evaluated the specific risk according to different etiologies. The aim of this study is to evaluate the risk of CP after acute pericarditis in a prospective cohort study with long-term follow-up. Methods and Results-From January 2000 to December 2008, 500 consecutive cases with a first episode of acute pericarditis (age, 51 +/- 16 years; 270 men) were prospectively studied to evaluate the evolution toward CP. Etiologies were viral/idiopathic in 416 cases (83.2%), connective tissue disease/pericardial injury syndromes in 36 cases (7.2%), neoplastic pericarditis in 25 cases (5.0%), tuberculosis in 20 cases (4.0%), and purulent in 3 cases (0.6%). During a median follow-up of 72 months (range, 24 to 120 months), CP developed in 9 of 500 patients (1.8%): 2 of 416 patients with idiopathic/viral pericarditis (0.48%) versus 7 of 84 patients with a nonviral/nonidiopathic etiology (8.3%). The incidence rate of CP was 0.76 cases per 1000 person-years for idiopathic/viral pericarditis, 4.40 cases per 1000 person-years for connective tissue disease/pericardial injury syndrome, 6.33 cases per 1000 person-years for neoplastic pericarditis, 31.65 cases for 1000 person-years for tuberculous pericarditis, and 52.74 cases per 1000 person-years for purulent pericarditis. Conclusions-CP is a relatively rare complication of viral or idiopathic acute pericarditis (<0.5%) but, in contrast, is relatively frequent for specific etiologies, especially bacterial

Corticosteroids for Recurrent Pericarditis : High Versus Low Doses: A Nonrandomized Observation

Background - Corticosteroid use is widespread in recurrent pericarditis, even if rarely indicated, and high doses ( eg, prednisone 1.0 to 1.5 mg . kg(-1) . d(-1)) are generally recommended, although only weak evidence supports their use with possible severe side effects. The aim of this work was to compare side effects, recurrences and other complications, and hospitalizations of a low- versus high- dose regimen of prednisone for recurrent pericarditis. Methods and Results - A retrospective review of all cases of recurrent pericarditis treated with corticosteroids according to different regimens from January 1996 to June 2004 was performed in 2 Italian referral centers. One hundred patients with recurrent pericarditis ( mean age, 50.1 +/- 15.8 years; 57 females) were included in the study; 49 patients ( mean age, 47.5 +/- 16.0; 25 females) were treated with low doses of prednisone ( 0.2 to 0.5 mg . kg (-1) . d(-1)), and 51 patients ( mean age, 52.6 +/- 15.3; 32 females) were treated with prednisone 1.0 mg . kg(-1) . d(-1). Baseline demographic and clinical characteristics were well balanced across the groups. Each initial dose was maintained for 4 weeks and then slowly tapered. After adjustment for potential confounders ( age, female gender, nonidiopathic origin), only high doses of prednisone were associated with severe side effects, recurrences, and hospitalizations ( hazard ratio, 3.61; 95% confidence interval, 1.96 to 6.63; P < 0.001). Conclusions - Use of higher doses of prednisone ( 1.0 mg . kg(-1) . d(-1)) for recurrent pericarditis is associated with more side effects, recurrences, and hospitalizations. Lower doses of prednisone should be considered when corticosteroids are needed to treat pericarditis

CEACAM1 and MICA as novel serum biomarkers in patients with acute and recurrent pericarditis

BACKGROUND: The immune response plays a significant role in pericarditis, but the mechanisms of disease are poorly defined. Further, efficient monitoring and predictive clinical tools are unavailable. Carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1) is an immune-inhibitory protein, while MHC class I chain related protein A (MICA) and B (MICB) have an immune-stimulating function. METHODS AND RESULTS: Serum CEACAM1, MICA and MICB concentrations were measured by ELISA in ~50 subjects of each group: acute pericarditis (AP), recurrent pericarditis (RP) and lupus (SLE) patients, metastatic melanoma patients as well as healthy donors. Serum CEACAM1 was dramatically elevated in AP and RP patients, but not in SLE patients, and displayed a highly accurate profile in ROC curve analyses. MICA and MICB were elevated in some pericarditis patients. All markers were enhanced in metastatic melanoma patients irrespective of neoplastic pericardial involvement. Etiology-guided analysis of RP patients showed that very low MICA levels were associated with idiopathic RP, while high MICA was associated with autoimmune and post-operative RP. Importantly, MICA was significantly associated with recurrences, independently of other potentially confounding parameters such as age, time of follow up or treatment modality. CONCLUSIONS: Here we report for the first time on CEACAM1 as a potentially novel biomarker for pericarditis, as well as on MICA as an innovative prognostic marker in these patients. Determination of the roles of these immune factors, as well as their diagnostic and prognostic values should be determined in future prospective studies

Good prognosis for pericarditis with and without myocardial involvement: Results from a multicenter, prospective cohort study

Background The natural history of myopericarditis/perimyocarditis is poorly known, and recently published studies have presented contrasting data on their outcomes. The aim of the present article is to assess the prognosis of myopericarditis/perimyocarditis in a multicenter, prospective cohort study. Methods and Results A total of 486 patients (median age, 39 years; range, 18-83 years; 300 men) with acute pericarditis or a myopericardial inflammatory syndrome (myopericarditis/perimyocarditis; 85% idiopathic, 11% connective tissue disease or inflammatory bowel disease, 5% infective) were prospectively evaluated from January 2007 to December 2011. The diagnosis of acute pericarditis was based on the presence of 2 of 4 clinical criteria (chest pain, pericardial rubs, widespread ST-segment elevation or PR depression, and new or worsening pericardial effusion). Myopericardial inflammatory involvement was suspected with atypical ECG changes for pericarditis, arrhythmias, and cardiac troponin elevation or new or worsening ventricular dysfunction on echocardiography and confirmed by cardiac magnetic resonance. After a median follow-up of 36 months, normalization of left ventricular function was achieved in >90% of patients with myopericarditis/perimyocarditis. No deaths were recorded, as well as evolution to heart failure or symptomatic left ventricular dysfunction. Recurrences (mainly as recurrent pericarditis) were the most common complication during follow-up and were recorded more frequently in patients with acute pericarditis (32%) than in those with myopericarditis (11%) or perimyocarditis (12%; P<0.001). Troponin elevation was not associated with an increase in complications. Conclusions The outcome of myopericardial inflammatory syndromes is good. Unlike acute coronary syndromes, troponin elevation is not a negative prognostic marker in this setting

The predictive value of ultrasound findings in the management of thyroid nodules

BACKGROUND: Thyroid nodules are a common medical problem, but whether fine-needle aspiration cytology (FNAC) is mandated for smaller non-palpable nodules, is controversial. AIM: To evaluate whether ultrasonographic features of thyroid nodules are associated with histological malignancy, and to identify useful criteria for clinical decision-making. DESIGN: Prospective observational study. METHODS: From January 1991 to September 2004, 5198 patients were referred to our hospital for ultrasound evaluation of thyroid nodules. Overall, 7455 nodules (diameters from 6 to 100 mm) were examined; 2865 (38.4%) were <10 mm in diameter. All patients with suspicious or malignant cytology underwent surgery. RESULTS: Of the 349 nodules undergoing surgery, 284 were malignant. The prevalence of cancer was slightly higher in nodules>or=10 mm in diameter vs. thoseor=10 mm (77.4% vs. 64.9%; p<0.001; OR 1.9, 95%CI 1.4-2.5) and intranodular vascular pattern type 2 (61.6% vs. 49.7%; p<0.001; OR 1.6, 95%CI 1.2-2.0) were all significantly more frequent in malignant than in benign nodules. These associations were similar when large and small nodules were analysed separately. DISCUSSION: No single parameter, including nodule size, satisfactorily identifies a subset of patients to be electively investigated by FNAC, although several may be useful in this regard

Prevalenza ed aggressività del carcinoma tiroideo nei noduli con diametro inferiore al centimetro in aree iodio carenti.

BACKGROUND: The introduction of highly sensitive imaging techniques has made it possible to detect many non-palpable thyroid nodules with size less than 1 centimetre. The prevalence of these lesions appears to be high in the general population and increases in iodine deficiency areas. Fine needle aspiration biopsy (FNAB) is considered the most reliable test for the diagnosis of thyroid nodules. METHODS: From January 1991 to December 2000, 6627 nodules were referred for FNAB to our department. In 4871 (73.5%) euthyroid patients the mean daily urinary excretion of iodine was 73+/-18 micromg/day. RESULTS: In 2401 nodules (36.2%) the diameter was less than one centimetre. Histologic confirmation of malignancy was available in 187 (89.9%) of 208 operated nodules with diameter more than 1 cm and in 64 (78%) of 82 with diameter less than 1 cm. Logistic regression analysis indicated that a solid hypoechoic feature was a useful criterion to predict malignancy (p<0.001), as well as the presence of calcification (p<0.5) and blurred margins (p<0.5). Lymph node metastases were present in 24.3% of carcinomas with diameter more than 1 cm but, surprisingly, also in 20.3% of those with diameter less than 1 cm. No correlation was seen between diameter of carcinoma nodules and presence of lymph node metastasis. CONCLUSIONS: These data suggest that the potential malignancy of thyroid nodules is not only correlated to the diameter but to other parameters such as the biological difference of thyroid cancer that could be hypothesized in an iodine deficiency area. In conclusion, FNAB is recommended for nodules with diameter less than 1 centimetre when sonographic findings suggest malignancy such as a hypoechoic pattern, an irregular margin or internal microcalcification