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1. Use of low-molecular weight heparin, transfusion and mortality in COVID-19 patients not requiring ventilation

Author

Grandone, E, Tiscia, G, Pesavento, R, De Laurenzo, A, Ceccato, D, Sartori, M, Mirabella, L, Cinnella, G, Mastroianno, M, Dalfino, L, Colaizzo, D, Vettor, R, Intrieri, M, Ostuni, A, Margaglione, M, Alboini, P, Antonioni, A, Aucella, F, Bochicchio, G, Carbonelli, C, Carella, M, Castori, M, Centonze, A, Ciliberti, G, Copetti, M, Corritore, M, De Cosmo, S, D'Aloiso, L, D'Errico, M, de Matthaeis, A, Del Gaudio, A, Di Giorgio, A, Giambra, V, Greco, A, Florio, L, Fontana, A, Inchingolo, V, Inglese, M, Labonia, M, La Marca, A, Latiano, T, Leone, M, Maiello, E, Mangia, A, Marciano, C, Massa, V, Massafra, S, Orciuli, G, Palladino, N, Perna, R, Piscitelli, P, Piemontese, M, Prencipe, M, Raggi, P, Rodriquenz, M, Russo, R, Sancarlo, D, Simeone, A, Trischitta, V, Zarrelli, M, Vaira, P, Vergara, D, Vescovi, A, Grandone E., Tiscia G., Pesavento R., De Laurenzo A., Ceccato D., Sartori M. T., Mirabella L., Cinnella G., Mastroianno M., Dalfino L., Colaizzo D., Vettor R., Intrieri M., Ostuni A., Margaglione M., Alboini P. E., Antonioni A., Aucella F., Bochicchio G. B., Carbonelli C., Carella M., Castori M., Centonze A., Ciliberti G., Copetti M., Corritore M., De Cosmo S., D'Aloiso L., D'Errico M. M., de Matthaeis A., Del Gaudio A., Di Giorgio A., Giambra V., Greco A., Florio L., Fontana A., Inchingolo V., Inglese M., Labonia M., La Marca A., Latiano T., Leone M., Maiello E., Mangia A., Marciano C., Massa V., Massafra S., Orciuli G., Palladino N., Perna R., Piscitelli P., Piemontese M., Prencipe M. A., Raggi P., Rodriquenz M. G., Russo R., Sancarlo D., Simeone A., Trischitta V., Zarrelli M., Vaira P., Vergara D., Vescovi A., Grandone, E, Tiscia, G, Pesavento, R, De Laurenzo, A, Ceccato, D, Sartori, M, Mirabella, L, Cinnella, G, Mastroianno, M, Dalfino, L, Colaizzo, D, Vettor, R, Intrieri, M, Ostuni, A, Margaglione, M, Alboini, P, Antonioni, A, Aucella, F, Bochicchio, G, Carbonelli, C, Carella, M, Castori, M, Centonze, A, Ciliberti, G, Copetti, M, Corritore, M, De Cosmo, S, D'Aloiso, L, D'Errico, M, de Matthaeis, A, Del Gaudio, A, Di Giorgio, A, Giambra, V, Greco, A, Florio, L, Fontana, A, Inchingolo, V, Inglese, M, Labonia, M, La Marca, A, Latiano, T, Leone, M, Maiello, E, Mangia, A, Marciano, C, Massa, V, Massafra, S, Orciuli, G, Palladino, N, Perna, R, Piscitelli, P, Piemontese, M, Prencipe, M, Raggi, P, Rodriquenz, M, Russo, R, Sancarlo, D, Simeone, A, Trischitta, V, Zarrelli, M, Vaira, P, Vergara, D, Vescovi, A, Grandone E., Tiscia G., Pesavento R., De Laurenzo A., Ceccato D., Sartori M. T., Mirabella L., Cinnella G., Mastroianno M., Dalfino L., Colaizzo D., Vettor R., Intrieri M., Ostuni A., Margaglione M., Alboini P. E., Antonioni A., Aucella F., Bochicchio G. B., Carbonelli C., Carella M., Castori M., Centonze A., Ciliberti G., Copetti M., Corritore M., De Cosmo S., D'Aloiso L., D'Errico M. M., de Matthaeis A., Del Gaudio A., Di Giorgio A., Giambra V., Greco A., Florio L., Fontana A., Inchingolo V., Inglese M., Labonia M., La Marca A., Latiano T., Leone M., Maiello E., Mangia A., Marciano C., Massa V., Massafra S., Orciuli G., Palladino N., Perna R., Piscitelli P., Piemontese M., Prencipe M. A., Raggi P., Rodriquenz M. G., Russo R., Sancarlo D., Simeone A., Trischitta V., Zarrelli M., Vaira P., Vergara D., and Vescovi A.

Abstract

It is still debated whether prophylactic doses of low-molecular- weight heparin (LMWH) are always effective in preventing Venous Thromboembolism (VTE) and mortality in COVID-19. Furthermore, there is paucity of data for those patients not requiring ventilation. We explored mortality and the safety/efficacy profile of LMWH in a cohort of Italian patients with COVID-19 who did not undergo ventilation. From the initial cohort of 422 patients, 264 were enrolled. Most (n = 156, 87.7%) received standard LMWH prophylaxis during hospitalization, with no significant difference between medical wards and Intensive Care Unit (ICU). Major or not major but clinically relevant hemorrhages were recorded in 13 (4.9%) patients: twelve in those taking prophylactic LMWH and one in a patient taking oral anticoagulants (p: n.s.). Thirty-nine patients (14.8%) with median age 75 years. were transfused. Hemoglobin (Hb) at admission was significantly lower in transfused patients and Hb at admission inversely correlated with the number of red blood cells units transfused (p < 0.001). In-hospital mortality occurred in 76 (28.8%) patients, 46 (24.3%) of whom admitted to medical wards. Furthermore, Hb levels at admittance were significantly lower in fatalities (g/dl 12.3; IQR 2.4 vs. 13.3; IQR 2.8; Mann–Whitney U-test; p = 0.001). After the exclusion of patients treated by LMWH intermediate or therapeutic doses (n = 32), the logistic regression showed that prophylaxis significantly and independently reduced mortality (OR 0.31, 95% CI 0.13–0.85). Present data show that COVID-19 patients who do not require ventilation benefit from prophylactic doses of LMWH.

Published
2021

2. Use of low-molecular weight heparin, transfusion and mortality in COVID-19 patients not requiring ventilation

Author

Grandone, E., Tiscia, G., Pesavento, R., De Laurenzo, A., Ceccato, D., Sartori, M. T., Mirabella, L., Cinnella, G., Mastroianno, M., Dalfino, L., Colaizzo, D., Vettor, R., Intrieri, M., Ostuni, A., Margaglione, M., Alboini, P. E., Antonioni, A., Aucella, F., Bochicchio, G. B., Carbonelli, C., Carella, M., Castori, M., Centonze, A., Ciliberti, G., Copetti, M., Corritore, M., De Cosmo, S., D'Aloiso, L., D'Errico, M. M., de Matthaeis, A., Del Gaudio, A., Di Giorgio, A., Giambra, V., Greco, A., Florio, L., Fontana, A., Inchingolo, V., Inglese, M., Labonia, M., La Marca, A., Latiano, T., Leone, M., Maiello, E., Mangia, A., Marciano, C., Massa, V., Massafra, S., Orciuli, G., Palladino, N., Perna, R., Piscitelli, P., Piemontese, M., Prencipe, M. A., Raggi, P., Rodriquenz, M. G., Russo, R., Sancarlo, D., Simeone, A., Trischitta, V., Zarrelli, M., Vaira, P., Vergara, D., Vescovi, A., Grandone, E, Tiscia, G, Pesavento, R, De Laurenzo, A, Ceccato, D, Sartori, M, Mirabella, L, Cinnella, G, Mastroianno, M, Dalfino, L, Colaizzo, D, Vettor, R, Intrieri, M, Ostuni, A, Margaglione, M, Alboini, P, Antonioni, A, Aucella, F, Bochicchio, G, Carbonelli, C, Carella, M, Castori, M, Centonze, A, Ciliberti, G, Copetti, M, Corritore, M, De Cosmo, S, D'Aloiso, L, D'Errico, M, de Matthaeis, A, Del Gaudio, A, Di Giorgio, A, Giambra, V, Greco, A, Florio, L, Fontana, A, Inchingolo, V, Inglese, M, Labonia, M, La Marca, A, Latiano, T, Leone, M, Maiello, E, Mangia, A, Marciano, C, Massa, V, Massafra, S, Orciuli, G, Palladino, N, Perna, R, Piscitelli, P, Piemontese, M, Prencipe, M, Raggi, P, Rodriquenz, M, Russo, R, Sancarlo, D, Simeone, A, Trischitta, V, Zarrelli, M, Vaira, P, Vergara, D, and Vescovi, A

Subjects
Male, Time Factors, 030204 cardiovascular system & hematology, Logistic regression, law.invention, 0302 clinical medicine, law, Risk Factors, 80 and over, 030212 general & internal medicine, Hospital Mortality, Hematology, Low-Molecular-Weight, COVID-19, Low-molecular-weight heparin, Mortality, Ventilation, Aged, Aged, 80 and over, Anticoagulants, Clinical Decision-Making, Female, Heparin, Low-Molecular-Weight, Hospitalization, Humans, Middle Aged, Protective Factors, Risk Assessment, Thromboembolism, Treatment Outcome, Blood Transfusion, Heparin, Intensive care unit, Cohort, Breathing, Cardiology and Cardiovascular Medicine, medicine.drug, medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), medicine.drug_class, Low molecular weight heparin, Article, 03 medical and health sciences, Internal medicine, medicine, low-molecular-weight heparin, mortality, ventilation, aged, aged 80 and over, anticoagulants, clinical decision-making, female, low-molecular-weight, hospital mortality, hospitalization, humans, male, middle aged, protective factors, risk assessment, risk factors, thromboembolism, time factors, treatment outcome, blood transfusion, business.industry, business
Abstract

It is still debated whether prophylactic doses of low-molecular- weight heparin (LMWH) are always effective in preventing Venous Thromboembolism (VTE) and mortality in COVID-19. Furthermore, there is paucity of data for those patients not requiring ventilation. We explored mortality and the safety/efficacy profile of LMWH in a cohort of Italian patients with COVID-19 who did not undergo ventilation. From the initial cohort of 422 patients, 264 were enrolled. Most (n = 156, 87.7%) received standard LMWH prophylaxis during hospitalization, with no significant difference between medical wards and Intensive Care Unit (ICU). Major or not major but clinically relevant hemorrhages were recorded in 13 (4.9%) patients: twelve in those taking prophylactic LMWH and one in a patient taking oral anticoagulants (p: n.s.). Thirty-nine patients (14.8%) with median age 75 years. were transfused. Hemoglobin (Hb) at admission was significantly lower in transfused patients and Hb at admission inversely correlated with the number of red blood cells units transfused (p < 0.001). In-hospital mortality occurred in 76 (28.8%) patients, 46 (24.3%) of whom admitted to medical wards. Furthermore, Hb levels at admittance were significantly lower in fatalities (g/dl 12.3; IQR 2.4 vs. 13.3; IQR 2.8; Mann–Whitney U-test; p = 0.001). After the exclusion of patients treated by LMWH intermediate or therapeutic doses (n = 32), the logistic regression showed that prophylaxis significantly and independently reduced mortality (OR 0.31, 95% CI 0.13–0.85). Present data show that COVID-19 patients who do not require ventilation benefit from prophylactic doses of LMWH.

Published
2021

3. Correction to: Use of low-molecular weight heparin, transfusion and mortality in COVID-19 patients not requiring ventilation

Author

Grandone, E., Tiscia, G., Pesavento, R., De Laurenzo, A., Ceccato, D., Sartori, M. T., Mirabella, L., Cinnella, G., Mastroianno, M., Dalfino, L., Colaizzo, D., Vettor, R., Intrieri, M., Ostuni, A., Margaglione, M., Alboini, P. E., Antonioni, A., Aucella, F., Bochicchio, G. B., Carbonelli, C., Carella, M., Castori, M., Centonze, A., Ciliberti, G., Copetti, M., Corritore, M., De Cosmo, S., D'Aloiso, L., D'Errico, M. M., de Matthaeis, A., Del Gaudio, A., Di Giorgio, A., Giambra, V., Greco, A., Florio, L., Fontana, A., Inchingolo, V., Inglese, M., Labonia, M., La Marca, A., Latiano, T., Leone, M., Maiello, E., Mangia, A., Marciano, C., Massa, V., Massafra, S., Orciulo, G., Palladino, N., Perna, R., Piscitelli, P., Piemontese, M., Prencipe, M. A., Raggi, P., Rodriquenz, M. G., Russo, R., Sancarlo, D., Simeone, A., Trischitta, V., Zarrelli, M., Vaira, P., Vergara, D., and Vescovi, A.

Subjects
Male, 2019-20 coronavirus outbreak, medicine.medical_specialty, Time Factors, Coronavirus disease 2019 (COVID-19), medicine.drug_class, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Clinical Decision-Making, Low molecular weight heparin, Risk Assessment, Risk Factors, Internal medicine, Thromboembolism, medicine, Humans, Blood Transfusion, Hospital Mortality, Aged, Aged, 80 and over, Hematology, business.industry, Correction, Anticoagulants, COVID-19, Heparin, Low-Molecular-Weight, Middle Aged, Protective Factors, CSS COVID-19 Group, Covid-19, research groups, Hospitalization, Treatment Outcome, Emergency medicine, Breathing, Female, Cardiology and Cardiovascular Medicine, business
Abstract

It is still debated whether prophylactic doses of low-molecular- weight heparin (LMWH) are always effective in preventing Venous Thromboembolism (VTE) and mortality in COVID-19. Furthermore, there is paucity of data for those patients not requiring ventilation. We explored mortality and the safety/efficacy profile of LMWH in a cohort of Italian patients with COVID-19 who did not undergo ventilation. From the initial cohort of 422 patients, 264 were enrolled. Most (n = 156, 87.7%) received standard LMWH prophylaxis during hospitalization, with no significant difference between medical wards and Intensive Care Unit (ICU). Major or not major but clinically relevant hemorrhages were recorded in 13 (4.9%) patients: twelve in those taking prophylactic LMWH and one in a patient taking oral anticoagulants (p: n.s.). Thirty-nine patients (14.8%) with median age 75 years. were transfused. Hemoglobin (Hb) at admission was significantly lower in transfused patients and Hb at admission inversely correlated with the number of red blood cells units transfused (p 0.001). In-hospital mortality occurred in 76 (28.8%) patients, 46 (24.3%) of whom admitted to medical wards. Furthermore, Hb levels at admittance were significantly lower in fatalities (g/dl 12.3; IQR 2.4 vs. 13.3; IQR 2.8; Mann-Whitney U-test; p = 0.001). After the exclusion of patients treated by LMWH intermediate or therapeutic doses (n = 32), the logistic regression showed that prophylaxis significantly and independently reduced mortality (OR 0.31, 95% CI 0.13-0.85). Present data show that COVID-19 patients who do not require ventilation benefit from prophylactic doses of LMWH.

Published
2021

4. Correction to: Use of low-molecular weight heparin, transfusion and mortality in COVID-19 patients not requiring ventilation (Journal of Thrombosis and Thrombolysis, (2021), 52, 3, (772-778), 10.1007/s11239-021-02429-z)

Author

Grandone, E., Tiscia, G., Pesavento, R., De Laurenzo, A., Ceccato, D., Sartori, M. T., Mirabella, L., Cinnella, G., Mastroianno, M., Dalfino, L., Colaizzo, D., Vettor, R., Intrieri, M., Ostuni, A., Margaglione, M., Alboini, P. E., Antonioni, A., Aucella, F., Bochicchio, G. B., Carbonelli, C., Carella, M., Castori, M., Centonze, A., Ciliberti, G., Copetti, M., Corritore, M., De Cosmo, S., D'Aloiso, L., D'Errico, M. M., de Matthaeis, A., Del Gaudio, A., Di Giorgio, A., Giambra, V., Greco, A., Florio, L., Fontana, A., Inchingolo, V., Inglese, M., Labonia, M., La Marca, A., Latiano, T., Leone, M., Maiello, E., Mangia, A., Marciano, C., Massa, V., Massafra, S., Orciulo, G., Palladino, N., Perna, R., Piscitelli, P., Piemontese, M., Prencipe, M. A., Raggi, P., Rodriquenz, M. G., Russo, R., Sancarlo, D., Simeone, A., Trischitta, V., Zarrelli, M., Vaira, P., Vergara, D., and Vescovi, A.

Published
2021

11. Global Skeletal Uptake of 99mTc-Methylene Diphosphonate (GSU) in Patients Affected by Endocrine Diseases: Comparison with Biochemical Markers of Bone Turnover.

Author

Scillitani, A., Dicembrino, F., Chiodini, I., Minisola, S., Fusilli, S., Di Giorgio, A., Garrubba, M., D'Aloiso, L., Frusciante, V., Torlontano, M., Modoni, S., Trischitta, V., and Carnevale, V

Subjects
ENDOCRINE diseases, HYPERTHYROIDISM, THYROID diseases, FLUORIMETRY, ANALYTICAL chemistry, CHROMATOGRAPHIC analysis
Abstract

: This study aimed to clinically validate the global skeletal uptake (GSU) of 99mTc-methylene diphosphonate (99mTc-MDP), and to compare it with a marker of bone formation (i.e. serum osteocalcin or OC) and an index of bone resorption (i.e. urinary deoxypyridinoline or U-DPD) in different endocrine disorders affecting the skeleton. We studied 29 female patients with thyrotoxicosis (TT), 27 with primary hyperparathyroidism (PHPT), 16 with acromegaly (AC), 15 with Cushing’s syndrome (CS), and altogether 110 healthy women matched for age, BMI and menstrual status. In all subjects total body digital scan images (TBDS) were acquired at 5 min and at 4 h after the administration of 99mTc-MDP; the whole body retention (WBR) of the tracer was measured by counting two identical sets of rectangular ROIs, and GSU was subsequently calculated by drawing an irregular ROI on 4 h TBDS images. Serum OC was assessed by IRMA and urinary DPD by fluorometric detection after reverse phase high pressure chromatography. In TT patients GSU (40.0 ± 5.1 vs 36.5 ± 4.8%), OC (19.1 ± 11.8 vs 7.1 ± 2.9 mg/l) and U-DPD (62.4 ± 42.7 vs 19.5 ± 5.3 pmol/pmol) were significantly (p<0.01) higher than in controls. PHPT patients showed GSU (47.2 ± 6.6 vs 37.8 ± 5.3%), OC (38.6 ± 40.9 vs 8.2 ± 2.5 mg/l), and U-DPD (55.0 ± 51.3 vs 21.9 ± 6.1 pmol/pmol) values significantly (p<0.001) higher than controls. In CS patients, GSU (39.6 ± 6.4 vs 32.7 ± 3.5%; p<0.01) and U-DPD (22.8 ± 8.4 vs 16.5 ± 2.7 pmol/pmol; p<0.05) were higher, whereas OC (3.6 ± 2.4 vs 5.2 ± 1.9 mg/l; p<0,05) was lower than in controls. In AC patients, GSU (34.9 ± 5.3 vs 35.2 ± 3.4%) did not differ significantly from controls, whereas OC (16.8 ± 8.8 vs 6.9 ± 2.9 mg/l; p<0.001) and U-DPD (30.9 ± 13.6 vs 21.0 ± 5.7 pmol/pmol; p<0.01) were higher. Stepwise multivariate linear regression analysis was performed with disease activity, creatinine clearance, age, and years since menopause as predictor variables and GSU or OC or U-DPD as dependent variables. The significant partial regression coefficients (r) were: in TT, free triiodothyronine (fT3) with GSU (r = 0.37; p<0.005), Ln OC (r = 0.30; p = NS), Ln U-DPD (r = 0.76; p<0.0001), respectively; in PHPT, PTH with GSU (r = 0.74; p<0.001), Ln OC (r = 0.50; p<0.05), Ln U-DPD (r = 0.64; p<0.001); in CS Ln urinary free cortisol with OC (r = -0.68; p<0.001) and U-DPD (r = 0.66; p<0.05). Our data suggest that GSU could represent a valuable clinical tool for evaluating bone turnover rate in PHPT, CS, TT but not in AC. The behavior of GSU and OC and U-DPD is non-uniform in disorders characterized by a marked uncoupling between bone formation and resorption. [ABSTRACT FROM AUTHOR]

Published
2002
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12. Serum thyroglobulin and 131I whole body scan after recombinant human TSH stimulation in the follow-up of low-risk patients with differentiated thyroid cancer

Author

Torlontano, M, Crocetti, U, D'Aloiso, L, Bonfitto, N, Di Giorgio, A, Modoni, S, Valle, G, Frusciante, V, Bisceglia, M, Filetti, S, Schlumberger, M, and Trischitta, V

Abstract

OBJECTIVE: The 'standard' postoperative follow-up of patients with differentiated thyroid cancer (DTC) has been based upon serum thyroglobulin (Tg) measurement and (131)I whole body scan ((131)I-WBS) after thyroid hormone (T(4)) treatment withdrawal. However, (131)I-WBS sensitivity has been reported to be low. Thyroid hormone withdrawal, often associated with hypothyroidism-related side effects, may now be replaced by recombinant human thyroid stimulating hormone (rhTSH). The aim of our study was to evaluate the diagnostic accuracy of (131)I-WBS and serum Tg measurement obtained after rhTSH stimulation and of neck ultrasonography in the first follow-up of DTC patients. DESIGN: Ninety-nine consecutive patients previously treated with total thyroidectomy and (131)I ablation, with no uptake outside the thyroid bed on the post-ablative (131)I-WBS (low-risk patients) were enrolled. METHODS: Measurement of serum Tg and (131)I-WBS after rhTSH stimulation, and ultrasound examination (US) of the neck. RESULTS: rhTSH-stimulated Tg was 1 ng/ml (Tg+) in 21 patients, including 6 patients with Tg levels >5 ng/ml. (131)I-WBS was negative for persistent or recurrent disease in all patients (i.e. sensitivity = 0%). US identified lymph-node metastases (confirmed at surgery) in 4/6 (67%) patients with stimulated Tg levels >5 ng/ml, in 2/15 (13%) with Tg>1<5 ng/ml, and in 2/78 (3%) who were Tg-negative. CONCLUSIONS: (i) diagnostic (131)I-WBS performed after rhTSH stimulation is useless in the first follow-up of DTC patients; (ii) US may identify lymph node metastases even in patients with low or undetectable serum Tg levels.

Published
2003

13. A thyroid hormone receptor β gene polymorphism associated with Graves’ disease

Author

Tassi, V, Scarnecchia, L, Di Cerbo, A, Pirro, M T, Di Paola, R, Liuzzi, A, Torlontano, M, Zingrillo, M, D’Aloiso, L, and De Filippis, V

Abstract

Autoimmune thyroid diseases (AITDs) are clustered in families, but the nature of this clustering is still poorly understood. One possible approach to the identification of genetic factors interacting with the AITDs is the study of the association between polymorphic markers and AITDs themselves. In the present study we have shown an association between an allele of a HindIII restriction fragment length polymorphism (EAβH) intragenic to c-erbAβ, which codes for the thyroid hormone β receptor, and Graves’ disease. This polymorphism can be detected by PCR followed by digestion with the restriction enzyme HindIII. The allelic frequencies were analysed in a panel of DNAs extracted from a population of individuals affected by thyroid disease and originating from southern Italy. A control group (n=120) from the same area was also analysed. The distribution of EAβH alleles was significantly different (P<0·001) in Graves’ disease (n=94) but not in autoimmune thyroiditis (n=60), as compared with controls. Also the distribution of the EAβH genotypes was significantly different in Graves’ patients (P=0·003), as compared with controls, the homozygous state EAβH+/EAβH+ being more frequent in Graves’ patients than in all the other groups. We did not find any association between EAβH genotypes and clinical parameters in Graves’ patients, including eye signs, thyroid volume and level of TSH-binding inhibiting immunoglobulins. Our data support the idea that Graves’ disease is a genetically distinct group within the AITDs.

Published
1995
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14. Clinical case seminar: in vivo and in vitro characterization of a novel germline RET mutation associated with low-penetrant nonaggressive familial medullary thyroid carcinoma

Author

Leonardo, D'Aloiso, Francesca, Carlomagno, Michele, Bisceglia, Suresh, Anaganti, Elisabetta, Ferretti, Antonella, Verrienti, Franco, Arturi, Daniela, Scarpelli, Diego, Russo, Massimo, Santoro, Sebastiano, Filetti, D'Aloiso, L, Carlomagno, Francesca, Bisceglia, M, Anaganti, S, Ferretti, E, Verrienti, A, Arturi, F, Scarpelli, D, Russo, D, Santoro, Massimo, and Filetti, S.

Subjects
Male, Heterozygote, Proto-Oncogene Proteins c-ret, Multiple Endocrine Neoplasia Type 2a, Transfection, Pedigree, Carcinoma, Medullary, thyroid cancer, Humans, Female, Thyroid Neoplasms, RET, Germ-Line Mutation, Skin
Abstract

RET mutation analysis provides useful information on the clinical outcome of medullary thyroid carcinomas (MTCs) and the risk of disease in the family members.The objective of this study was to document genotype-phenotype relationships in an Italian family with a novel RET mutation.RET gene alterations were investigated in a patient with unifocal MTC and her relatives. The identified mutation was subjected to in vitro functional testing.Patients included a female proband who developed MTC at age 60, her five children, and three grandchildren.DNA extracted from the blood and the proband's tumor were analyzed for RET alterations. The transforming potential and mitogenic properties of the identified mutation were investigated.A novel heterozygous germline RET mutation at codon 777 (AAC--AGC, N--S) (RET/N777S) was identified in the proband and three of her relatives. Two of the latter presented thyroid nodules, but none had MTC or C cell hyperplasia. The proband's MTC was characterized by late onset and limited aggressiveness, with no evidence of regional lymph node or distant metastases 10 yr after total thyroidectomy. This phenotype is consistent with the RET/N777S mutant's low-grade transforming potential and limited activation of RET tyrosine kinase.Our findings indicate that the newly identified RET/N777S mutation is a low-penetrant cause of MTC disease. This phenotype might be less aggressive than that associated with MEN2A of familial MTC, although close clinical follow-up of carriers is essential.

Published
2006

15. Coexistence of multiple endocrine neoplasia type 1 and type 2 in a large Italian family.

Author

Mastroianno S, Torlontano M, Scillitani A, D'Aloiso L, Verrienti A, Bonfitto N, De Bonis A, D'Agruma L, Muscarella LA, Guarnieri V, Dicembrino F, Maranghi M, Durante C, and Filetti S

Subjects
Adolescent, Adult, Child, Child, Preschool, Family, Female, Heterozygote, Humans, Male, Middle Aged, Multiple Endocrine Neoplasia Type 1 complications, Multiple Endocrine Neoplasia Type 2a complications, Pedigree, Proto-Oncogene Mas, Severity of Illness Index, Young Adult, Germ-Line Mutation, Multiple Endocrine Neoplasia Type 1 genetics, Multiple Endocrine Neoplasia Type 2a genetics, Proto-Oncogene Proteins genetics, Proto-Oncogene Proteins c-ret genetics
Abstract

To describe the coexistence of mutations of both the multiple endocrine neoplasia type 1 (MEN1) and type 2 (MEN2) genes in a large Italian family and evaluate if it could be associated with more aggressive clinical manifestations of the two syndromes. Blood samples were obtained for genetic and biochemical analyses. The RET gene exons (8, 10, 11, 13, 14, 15, 16, 18) and the MEN1 coding regions, including the exon-intron boundaries, were amplified by PCR and directly sequenced. We identified two germline mutations in the proband: the first one, K666M, located at the exon 11 of RET proto-oncogene and the second one, IVS4+1G>T, located in the MEN1 gene. The functional characterization of IVS4+1G>T variation, located in the splicing donor site of exon 4 of MEN1 gene, caused the in-frame junction of exon 3 to exon 5, thus obtaining a shorter protein. The same proband's germline mutations were found in 16 relatives out of 21 screened subjects: 8 carried IVS4+1G>T, 4 RET K666M, and 4 both the mutations. This is the second report in literature of coexistence in the same family of germline mutations of both RET proto-oncogene and MEN1 gene. The simultaneous presence of the two mutations was not apparently associated with more aggressive diseases, since at last follow-up all patients appeared to be disease-free or well compensated by medical therapy; finally, no one exhibited metastatic diseases.

Published
2011
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16. Clinical case seminar: in vivo and in vitro characterization of a novel germline RET mutation associated with low-penetrant nonaggressive familial medullary thyroid carcinoma.

Author

D'Aloiso L, Carlomagno F, Bisceglia M, Anaganti S, Ferretti E, Verrienti A, Arturi F, Scarpelli D, Russo D, Santoro M, and Filetti S

Subjects
Carcinoma, Medullary pathology, Female, Heterozygote, Humans, Male, Multiple Endocrine Neoplasia Type 2a genetics, Pedigree, Skin pathology, Thyroid Neoplasms pathology, Transfection, Carcinoma, Medullary genetics, Germ-Line Mutation, Proto-Oncogene Proteins c-ret genetics, Thyroid Neoplasms genetics
Abstract

Context: RET mutation analysis provides useful information on the clinical outcome of medullary thyroid carcinomas (MTCs) and the risk of disease in the family members., Objective: The objective of this study was to document genotype-phenotype relationships in an Italian family with a novel RET mutation., Design/setting: RET gene alterations were investigated in a patient with unifocal MTC and her relatives. The identified mutation was subjected to in vitro functional testing., Patients: Patients included a female proband who developed MTC at age 60, her five children, and three grandchildren., Main Outcome Measures: DNA extracted from the blood and the proband's tumor were analyzed for RET alterations. The transforming potential and mitogenic properties of the identified mutation were investigated., Results: A novel heterozygous germline RET mutation at codon 777 (AAC-->AGC, N-->S) (RET/N777S) was identified in the proband and three of her relatives. Two of the latter presented thyroid nodules, but none had MTC or C cell hyperplasia. The proband's MTC was characterized by late onset and limited aggressiveness, with no evidence of regional lymph node or distant metastases 10 yr after total thyroidectomy. This phenotype is consistent with the RET/N777S mutant's low-grade transforming potential and limited activation of RET tyrosine kinase., Conclusion: Our findings indicate that the newly identified RET/N777S mutation is a low-penetrant cause of MTC disease. This phenotype might be less aggressive than that associated with MEN2A of familial MTC, although close clinical follow-up of carriers is essential.

Published
2006
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17. Comparative evaluation of recombinant human thyrotropin-stimulated thyroglobulin levels, 131I whole-body scintigraphy, and neck ultrasonography in the follow-up of patients with papillary thyroid microcarcinoma who have not undergone radioiodine therapy.

Author

Torlontano M, Crocetti U, Augello G, D'Aloiso L, Bonfitto N, Varraso A, Dicembrino F, Modoni S, Frusciante V, Di Giorgio A, Bruno R, Filetti S, and Trischitta V

Subjects
Adult, Carcinoma, Papillary diagnostic imaging, Female, Gamma Cameras, Humans, Iodine Radioisotopes therapeutic use, Male, Middle Aged, Radionuclide Imaging, Recombinant Proteins, Recurrence, Thyroglobulin blood, Thyroid Neoplasms diagnostic imaging, Ultrasonography, Whole-Body Counting, Carcinoma, Papillary diagnosis, Neck diagnostic imaging, Thyroid Neoplasms diagnosis, Thyrotropin
Abstract

Context: Although the prognosis of papillary thyroid microcarcinoma (PTMC) is usually excellent, the optimal follow-up strategy has never been investigated., Objective: The objective of the study was to investigate the role of neck ultrasonography (US), whole-body scintigraphy (WBS), and serum thyroglobulin levels (Tg) after recombinant human (rh) TSH in the follow-up of very low-risk PTMC patients., Design: The study was a 5-yr observational study based on a 6- to 12-month follow-up after near total thyroidectomy., Setting: The study population consisted of ambulatory patients., Patients: Eighty consecutive patients diagnosed with PTMC, who had not undergone postoperative radioiodine treatment because of unifocal tumor without lymph node metastases and who did not have anti-Tg antibodies, were included., Main Outcome Measures: WBS and Tg after both rhTSH and neck US were measured., Results: rhTSH-Tg was 1 ng/ml or less in 45 (Tg-) and more than 1 in 35 (Tg+) patients. WBS showed no pathological uptake in any patient. US identified node metastases in two Tg (+) and one Tg (-) patients. rhTSH-Tg levels positively correlated with thyroid bed iodine uptake (r = 0.40, P < 0.0001). To date (32 +/- 13 months after surgery), all node-negative patients have undetectable Tg levels on LT(4) treatment and negative US., Conclusions: For the initial follow-up of PTMC patients without risk factors and anti-Tg antibodies and who did not undergo radioiodine treatment: 1) WBS is useless; 2) US is highly sensitive in detecting node metastases; and 3) detectable rhTSH-Tg levels mainly depend on small normal tissue remnants. In this subgroup of PTMC patients, neck US might be regarded as a primary tool for the initial follow-up.

Published
2006
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18. Percutaneous ethanol injection of large thyroid cystic nodules.

Author

Zingrillo M, Torlontano M, Ghiggi MR, D'Aloiso L, Nirchio V, Bisceglia M, and Liuzzi A

Subjects
Adult, Aged, Cysts diagnosis, Cysts therapy, Ethanol adverse effects, Female, Humans, Injections, Intralesional, Male, Middle Aged, Prospective Studies, Safety, Suction, Thyroid Nodule diagnosis, Thyroid Nodule therapy, Cysts drug therapy, Ethanol administration & dosage, Thyroid Nodule drug therapy
Abstract

To evaluate the effect of percutaneous ethanol injection (PEI) in the treatment of large compressive thyroid cystic nodules (TCN), we studied 20 patients, potential candidates for surgery (tracheal displacement, nodule volume over 10 mL at ultrasonography) and not cured by aspiration alone: 14 experienced a recurrence after two complete evacuations of cystic fluid (watery nodules, WN); in six an aspiration was impossible because the cystic fluid was very thick (viscous nodules, VN). To exclude malignancy, both cytocentrifugate from WN and the smears from VN were examined. WN were treated with 1-4 sessions of conventional PEI; in VN a first PEI session was performed with the purpose of reducing the density of cystic fluid; then if cystic fluid was successfully aspirated, one or more PEI sessions were performed. Thyroid palpation, ultrasonography with nodule volume assessment, and assays for FT3, FT4, and TSH were performed 1 and 6 months after the last PEI. At month 6, 17 patients (85%) had volume reduction of more than 90% of the initial nodule volume; in 2 patients (10%) there was a reduction between 50 and 90%, and in one patient (5%) an appreciable swelling persisted after 3 injections. Nodule volume was significantly decreased below baseline at month 1 (10.9 +/- 13.3 vs 39 +/- 24 mL, p < 0.001), with a further reduction at month 6 (5 +/- 11.7 mL, p < 0.01 vs 1st month value). In most of the nodules the cystic portion completely disappeared; the residual tissue showed fibrous features, often with calcifications. In 11 patients follow-up was prolonged over the sixth month (15 +/- 4 months); the nodule volume did not significantly differ from the sixth month (3 +/- 2.2 mL) and the end of the follow-up (2.8 +/- 2.3 mL). In conclusion, we demonstrate that PEI may be a safe and effective procedure in the treatment of large TCN.

Published
1996
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19. Thyroid hypoechogenicity after methimazole withdrawal in Graves' disease: a useful index for predicting recurrence?

Author

Zingrillo M, D'Aloiso L, Ghiggi MR, Di Cerbo A, Chiodini I, Torlontano M, and Liuzzi A

Subjects
Adolescent, Adult, Aged, Autoantibodies blood, Child, Female, Graves Disease drug therapy, Graves Disease immunology, Humans, Immunoglobulins, Thyroid-Stimulating, Male, Methimazole therapeutic use, Middle Aged, Prognosis, Prospective Studies, Receptors, Thyrotropin blood, Recurrence, Ultrasonography, Graves Disease diagnosis, Methimazole administration & dosage, Thyroid Gland diagnostic imaging
Abstract

Objective: A characteristic thyroid ultrasonographic picture with diffuse or scattered low echogenicity has been described in Graves' disease (GD). Thyroid hypoechogenicity in GD at onset has been considered a prognostic index of relapse after medical treatment; moreover, thyroid hypoechogenicity is regularly observed in GD at the onset, but not in patients with 'burned-out' disease. The aim of this study was to evaluate the usefulness of thyroid hypoechogenicity changes in predicting GD relapse., Design: Longitudinal prospective study of previously untreated patients with GD., Patients: Thirty-nine consecutive patients aged 10-72 years were treated with methimazole (MMI) for 12-24 months on a titration regimen. Evaluation of patients in remission or with relapse was done 12 and 24 months after MMI withdrawal., Measurements: Thyroid ultrasonography and TSH receptor antibodies (TRAb) were evaluated in basal conditions and then one month after MMI withdrawal. Thyroid hypoechogenicity score (assessed by the same observer with the same equipment) was graded as: 0 absent; 1 mild; 2 moderate; 3 marked. At the withdrawal evaluation a score < 2 and a TRAb value < 10 U/l were considered as normal., Results: Twelve and 24 months after withdrawal, there were 10 (25.6%) and 17 (44.7%) relapses, respectively. Neither thyroid hypoechogenicity score nor TRAb values evaluated in basal conditions, showed significant differences between patients remaining euthyroid and those who became again hyperthyroid. In the whole group, the thyroid hypoechogenicity score was significantly lower at the withdrawal than in basal conditions (1.1 +/- 1.1 vs 2 +/- 0.8; P < 0.0001); it was significantly lower in patients in remission (P < 0.001), but not in those who relapsed. The thyroid hypoechogenicity score at withdrawal was normal in 23/29 (79.3%) of patients still euthyroid and in 4/10 (40%) of those who relapsed up to the 12th month (P < 0.05); it was normal in 19/21 (90.4%) of patients still euthyroid and in 7/17 (41.2%) of those who relapsed up to the 24th month (P < 0.05). A normal thyroid hypoechogenicity score at withdrawal of MMI had a higher specificity (0.95) and sensitivity (0.59) with respect to TRAb values (0.86 and 0.53, respectively) for the prediction of the relapse of hyperthyroidism at the 24th month., Conclusions: Basal thyroid hypoechogenicity cannot be used as an index of relapse of GD. MMI treatment induces evident changes in thyroid hypoechogenicity, mainly in patients who subsequently go into remission. The absence or a low grade of thyroid hypoechogenicity after MMI treatment seems to be a favourable prognostic index of remission of hyperthyroidism in GD.

Published
1996
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20. A thyroid hormone receptor beta gene polymorphism associated with Graves' disease.

Author

Tassi V, Scarnecchia L, Di Cerbo A, Pirro MT, Di Paola R, Liuzzi A, Torlontano M, Zingrillo M, D'Aloiso L, and De Filippis V

Subjects
Adult, Alleles, Autoimmune Diseases classification, Autoimmune Diseases epidemiology, Base Sequence, Deoxyribonuclease HindIII, Gene Frequency, Genotype, Graves Disease epidemiology, Graves Disease pathology, Humans, Italy epidemiology, Middle Aged, Molecular Sequence Data, Polymerase Chain Reaction, Receptors, Thyroid Hormone genetics, Thyroid Diseases epidemiology, Thyroid Diseases genetics, Thyroiditis, Autoimmune epidemiology, Thyroiditis, Autoimmune genetics, Autoimmune Diseases genetics, Graves Disease genetics, Polymorphism, Restriction Fragment Length
Abstract

Autoimmune thyroid diseases (AITDs) are clustered in families, but the nature of this clustering is still poorly understood. One possible approach to the identification of genetic factors interacting with the AITDs is the study of the association between polymorphic markers and AITDs themselves. In the present study we have shown an association between an allele of a HindIII restriction fragment length polymorphism (EA beta H) intragenic to c-erbA beta, which codes for the thyroid hormone beta receptor, and Graves' disease. This polymorphism can be detected by PCR followed by digestion with the restriction enzyme HindIII. The allelic frequencies were analysed in a panel of DNAs extracted from a population of individuals affected by thyroid disease and originating from southern Italy. A control group (n = 120) from the same area was also analysed. The distribution of EA beta H alleles was significantly different (P < 0.001) in Graves' disease (n = 94) but not in autoimmune thyroiditis (n = 60), as compared with controls. Also the distribution of the EA beta H genotypes was significantly different in Graves' patients (P = 0.003), as compared with controls, the homozygous state EA beta H+/EA beta H+ being more frequent in Graves' patients than in all the other groups. We did not find any association between EA beta H genotypes and clinical parameters in Graves' patients, including eye signs, thyroid volume and level of TSH-binding inhibiting immunoglobulins. Our data support the idea that Graves' disease is a genetically distinct group within the AITDs.

Published
1995
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21. [Unusual endocrine behavior in adrenal carcinoma. A case study].

Author

Zingrillo M, Errico M, D'Aloiso L, Torlontano M, Parracino T, and Gomes V

Subjects
Adrenal Cortex Neoplasms diagnostic imaging, Adrenal Cortex Neoplasms epidemiology, Adrenal Cortex Neoplasms therapy, Adrenalectomy, Adult, Carcinoma diagnostic imaging, Carcinoma epidemiology, Carcinoma therapy, Combined Modality Therapy, Humans, Incidence, Liver Neoplasms secondary, Male, Neoplasm Recurrence, Local diagnostic imaging, Neoplasm Recurrence, Local metabolism, Neoplasm Recurrence, Local therapy, Tomography, X-Ray Computed, Ultrasonography, Adrenal Cortex Neoplasms metabolism, Carcinoma metabolism, Hydrocortisone metabolism
Abstract

The Authors report a case of left adrenal mass incidentally discovered by upper abdominal echogram in a 40 year old man. Physical examination showed no signs of hypercortisolism and plasma cortisol and ACTH levels were in the normal range as well as urinary free cortisol. After adrenalectomy, 4 and 8 month follow-up was performed, without clinical, hormonal and TC evolution. Thirteen months later the patient was referred to our department for widespread oedema, hypertension, hypokalemia and alkalosis. These symptoms were associated with dramatically elevated concentrations of plasmatic and free urinary cortisol. TC showed a large mass in the same adrenal region and diffuse hepatic metastases. In spite of mitotane and ketoconazole therapy the patient died few weeks later.

Published
1991

22. [Cutaneous tumor metastasis. A possible first clinical event of visceral neoplasms].

Author

Puzzolante F, D'Aloiso L, Grilli M, Albano A, D'Amico G, and Giordano M

Subjects
Aged, Female, Humans, Male, Middle Aged, Adenocarcinoma secondary, Lung Neoplasms pathology, Skin Neoplasms secondary, Stomach Neoplasms pathology
Abstract

Two cases of visceral malignant tumours due to cutaneous metastases (stomach adenocarcinoma and left pulmonary adenocarcinoma). Are reported in both cases the cutaneous lesions represent the first clinical phenomenon of the disease.

Published
1991

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