Dario Casara

Myocardial dysfunction and adrenergic cardiac innervation in patients with insulin-dependent diabetes mellitus

BACKGROUND Insulin-dependent diabetes mellitus (IDDM) is associated with an increased incidence of heart failure due to several factors, and in some cases a specific cardiomyopathy has been suggested. OBJECTIVES This study sought to assess the mechanisms of exercise-induced left ventricular (LV) dysfunction in asymptomatic patients with IDDM in the absence of hypertensive or coronary artery disease. METHODS Fourteen consecutive patients with IDDM were enrolled (10 men, 4 women; mean [+/- SD] age 28.5 +/- 6 years); 10 healthy subjects matched for gender (7 men, 3 women) and age (28.5 +/- 3 years) constituted the control group. LV volume, LV ejection fraction (LVEF) and end-systolic wall stress were calculated by two-dimensional echocardiography at rest and during isometric exercise. LV contractile reserve was assessed by post-extrasystolic potentiation (PESP) obtained by transesophageal cardiac electrical stimulation and dobutamine infusion. Myocardial iodine-123 metaiodobenzylguanidine (MIBG) scintigraphy was performed to assess adrenergic cardiac innervation. RESULTS Diabetic patients were classified into group A (n = 7), with an abnormal LVEF response to handgrip (42 +/- 7%), and group B (n = 7), with a normal response (72 +/- 8%). Baseline LVEF was normal in both group A and B patients (60 +/- 6% vs. 61 +/- 7%, p = NS). In group A patients, the LV circumferential wall stress-LVEF relation showed an impairment in LVEF disproportionate to the level of LV afterload. No significant changes in LVEF occurred during dobutamine (60 +/- 6% vs. 64 +/- 10%, p = NS), whereas PESP significantly increased LVEF (60 +/- 6% vs. 74 +/- 6%, p < 0.001); PESP at peak handgrip normalized the abnormal LVEF (42 +/- 7% vs. 72 +/- 5%, p < 0.001); and MIBG uptake normalized for body weight or for LV mass was lower than that in normal subjects (1.69 +/- 0.30 vs. 2.98 +/- 0.82 cpm/MBq per g, p = 0.01) and group B diabetic patients (vs. 2.79 +/- 0.94 cpm/MBq per g, p = 0.01). Finally, a strong linear correlation between LVEF at peak handgrip and myocardial MIBG uptake normalized for LV mass was demonstrated in the study patients. CONCLUSIONS Despite normal contractile reserve, a defective blunted recruitment of myocardial contractility plays an important role in determining exercise LV dysfunction in the early phase of diabetic cardiomyopathy. This abnormal response to exercise is strongly related to an impairment of cardiac sympathetic innervation.

Combined chemotherapy with bleomycin, adriamycin, and platinum in advanced thyroid cancer

Twenty-two advanced consecutive thyroid cancer patients with varying histologies were treated with the so called BAP regime which consisted of bleomycin (B) 30 mg a day for three days, adriamycin (A) 60 mg/m2 iv in day 5, and cisplatinum (P) 60 mg/m2 iv in day 5. Patients with progressive, symptomatic recurrent or disseminated disease unresponsive to hormonal and/or isotopic treatment were eligible. Nine patients had an objective response: two long-lasting complete and seven partial responses were observed out of 21 evaluable patients. Stable disease was observed in four additional patients. The median duration of response was 12 months (range, 6–29). The total series experienced a median survival of 11 months (range, 1 to 57), with 2 patients actually disease free. Several histologic types of thyroid carcinoma responded, but the best responses were observed in medullary and anaplastic giant-cell carcinomas. Toxicity was reversible in all but one patient. Of the patients failing on BAP chemotherapy three responded to a four drug second line combination containing vincristine, fluorouracil, BCNU and methotrexate. BAP regime can achieve reasonable palliation, and probably increases survival, in poor-prognosis thyroid cancers.

Molecular characteristics in papillary thyroid cancers (PTCs) with no 131I uptake

Objective  Papillary thyroid cancers (PTCs) with no iodine uptake have an aggressive behaviour and a poor prognosis. The aim of our study was to characterize, at molecular level, a subset of PTC with no 131 iodine (131I) uptake.

High prevalence of occult papillary thyroid carcinoma in a surgical series for benign thyroid disease.

In a surgical series of 277 consecutive patients operated on the thyroid for benign diseases, a high prevalence rate (10.5%) of occult papillary carcinoma was found by means of an accurate histologic examination. Indications for surgery were euthyroid multinodular goiter in 25 patients, autonomously hyperfunctioning adenoma in 2 and Graves’ disease in 2 patients. Neoplastic foci were unilaterally found in 25 cases but multifocally in 6 and bilaterally in 4 cases: the diameters ranged from 2-10 mm. After operation (14 subtotal and 15 total thyroidectomies), all patients received TSH-suppressive doses of T4. At a mean follow-up of 5.6 years, neither local recurrences nor lymph node or distant metastases had occurred; no patient died of the tumor. In keeping with other surgical and autopsy series, the prevalence of occult thyroid carcinoma in a normal population is calculated to be about 5-10%, whereas it is known that the prevalence of clinically evident thyroid cancer is only 0.05%. This means that only 1-2% of occult carcinomas may evolve in an overt tumor during life. In view of such an epidemiologic difference and the favorable course of our patients, although the mean follow-up is rather short, we suggest that lobectomy plus T4 treatment may be considered an adequate therapeutic approach in patients with occult papillary thyroid carcinoma.

Natural course of subclinical hypothyroidism in Down’s syndrome: Prospective study results and therapeutic considerations

Pathogenesis, natural course and therapeutic management of subclinical hypothyroidism (SH) in Down’s syndrome (DS) remain object of debate in literature. In the present study thyroid function, antithyroid antibody (ATA) prevalence and serum lipid concentrations were investigated in a group of 344 Down patients (DP) and data were compared with those obtained from a control group of 257 age and sex matched healthy subjects. Thyroid function and ATA prevalence were also studied in 120 parents of DP. SH prevalence was clearly higher in DP (32.5% of cases) than in controls (1.1%) and parents (0%). Similarly, ATA prevalence was higher in DP (18% of cases) than in controls (5.8%) and parents (6.6%). In spite of this, no correlation was found in DP between SH and ATA prevalences, since ATA were detected in 18.7% of SH-DP and in 15.8% of euthyroid DP. Thus, circulating ATA were not detected in the majority of SH-DP. No significant differences regarding T4, FT4, T3 and serum lipid levels among SH and euthyroid DP and controls were found. Moreover, TSH levels were only slightly increased, generally less than 10 μU/ml, in most cases of SH-DP. Follow-up was longer than 24 months (range 2–7 years, mean 3.1) in a group of 201 DP: two different patterns of SH course were observed, mainly depending on the presence or the absence of circulating ATA. In particular, 35.7% of ATA-positive SH-DP developed a clinically evident thyroid disease (overt hypothyroidism or hyperthyroidism), while no similar case was recorded among ATA-negative SH-DP. On the contrary, a significant number of these patients (33.9% of cases) showed a spontaneous normalization of TSH levels. The present data suggest that: a) DS per se seems to be a clinical risk condition in developing thyroid autoimmune diseases, b) SH represents a very common conditions in DP and in most cases it appears to be independent of the presence of circulating ATA, c) SH alone, that is in the absence of detectable ATA, does not seem to be predisposing condition to develop a clinically evident thyroid disease, as a spontaneous normalization of TSH levels is often observed. From the therapeutic point of view, it seems unlikely that L-thyroxine substitutive therapy could lead to some improvement in SH-DP in the absence of detectable ATA. A wait and see policy with frequent thyroid function screening could be considered adequate, thus avoiding chronic hormonal therapy at least in DP in whom TSH levels tend to spontaneously normalize. On the contrary, L-thyroxine should not be delayed in ATA-positive SH-DP due to the frequent evolution towards an overt thyroid disease.

New trends in parathyroid scintigraphy

Abstract. The paper focusses on the recent advances in parathyroid imaging in both diagnostic and surgical fields which justify the present favourable trend towards a considerable expansion of nuclear medicine applications in this area. The main methodological advances in parathyroid scintigraphy are the rebirth of the dual-tracer (subtraction) technique with technetium-99m sestamibi, the possibility of also using 99mTc-tetrofosmin within a dual-tracer (subtraction) methodology and the more extensive use of single-photon emission tomography, which the authors believe will become the standard methodology. The indications for parathyroid scintigraphy have been affected by advances in hyperparathyroidism surgery, including wider use of unilateral neck exploration and of minimally invasive radioguided surgery. As these techniques can only be performed in hyperparathyroid patients with a single adenoma, careful pre-operative assessment is required, and parathyroid scintigraphy undoubtedly is the most accurate localisation method. To date, the majority of papers have also demonstrated the cost-effectiveness of scintigraphically guided limited neck surgery. The authors conclude that: (1) parathyroid scintigraphy can be recommended not only in persistent or recurrent hyperparathyroidism but also in hyperparathyroid patients prior to first surgery; (2) scintigraphy should always be performed by applying the most accurate technique available because reliable scintigraphy gains or reinforces the surgeons trust, reliably guides cost-effective operative strategies and justifies the recognition of new potential diagnostic indications.

Distant metastases in differentiated thyroid cancer: Long-term results of radioiodine treatment and statistical analysis of prognostic factors in 214 patients

Long-term results and statistical analysis of prognostic factors in a series of 214 patients with distant metastases from differentiated thyroid cancer (DTC) are reported here. These 214 were part of a total series of 1457 patients with DTC referred to our center from 1967 to 1987. All patients underwent surgery and 131-I therapy and were treated with TSH suppressive doses of thyroid hormones. After a mean follow-up of 7.3 years including clinical, scintigraphic, radiological and laboratory investigations, 24.4 % of patients were alive without disease, 36.5 % alive with disease, 1.8 % dead without disease and 37.3 % dead with disease. One of the main factors influencing the survival in our series was 131-I uptake (RIU) by metastatic tissue. No case of complete remission of disease was observed among patients with nonfunctioning metastases. Another important factor was the site of metastases, patients with bone metastases having the worst prognosis. The patients age at diagnosis represented another important factor for survival; patients over 40 years, particularly those over 60 years had a bad prognosis. A clear interrelation was found among the factors advanced age, nonfunctioning metastases and bone metastases. Patients with these last clinical features were considered to be at high risk and generally had a fatal outcome. Another significant prognostic factor revealed by univariate analysis was the histologic type. Patients with follicular tumor showed a poorer prognosis in comparison to papillary tumor. When multivariate analysis was applied, the factors age at diagnosis, site of metastases and RIU proved to have a significant influence on survival, but not the histologic type. Lastly, the relative rate of males was higher in the group of patients with metastases in comparison to the whole series of DTC patients. Despite this, the factor sex did not influence survival.

Pregnancy after high therapeutic doses of iodine-131 in differentiated thyroid cancer: potential risks and recommendations

Seventy female patients who had been treated with high doses of iodine-131 for differentiated thyroid cancer (DTC) and who had a subsequent pregnancy were evaluated. The total 131I dose ranged from 1.85 to 16.55 GBq (mean±SD=4.39±25.20 GBq). Age at first therapy ranged from 15 to 36 years (mean±SD = 24.3±5.0 years) and the interval from 131I therapy topregnancy varied from 2to 10 years (mean±SD = 5.3±2.8 years). The estimated radiation doseto the gonads ranged from 10 to 63 cGy (mean±SD = 24.0±13.5 eGy). All patients were treated with l-thyroxine at doses capable of suppressing thyroid-stimulating hormone. Seventy-three children were followed-up and seven pregnancies are still in progress. One child was affected by Fallots trilogy and three had a low birth weight though with subsequent normal growth; the others were healthy with subsequent normal growth. No newborn with clinical or biochemical thyroid dysfunctions was found. Two spontaneous abortions during the second month of pregnancy were recorded. One of two patients in question subsequently had two healthy children. On the basis of these data, previous administration of high 131I doses does not appear to be a valid reason for dissuading young female DTC patients from considering pregnancy. However, patients should be advised to avoid pregnancy after 131I administration for a period sufficient to ensure complete elimination of the radionuclide and to permit confirmation of complete disease remission, i.e. at least 1 year in our opinion.

99mTc-MIBI radio-guided minimally invasive parathyroidectomy: experience with patients with normal thyroids and nodular goiters.

The surgical approach to primary hyperparathyroidism (HPT) is changing. In patients with a high probability to be affected by a solitary parathyroid adenoma (PA), a unilateral neck exploration (UNE) or a minimally invasive radio-guided surgery (MIRS) using the intraoperative gamma probe (IGP) technique have recently been proposed. We investigated the role of IGP in a group of 84 patients with primary HPT who were homogeneously evaluated before surgery by a single-day imaging protocol including 99mTcO4/MIBI subtraction scan and neck ultrasound (US) and then operated on by the same surgical team. Quick parathyroid hormone (QPTH) was intraoperatively measured in all cases to confirm successful parathyroidectomy. In 70 patients with scan/US evidence of a single enlarged parathyroid gland (EPG) and with a normal thyroid gland, MIRS was planned. In the other 14 patients, the IGP technique was utilized during a standard bilateral neck exploration (BNE) because of the presence of concomitant nodular goiter (11 cases) or multiglandular disease (MGD) (3 cases). The IGP technique consisted of the following: (1) in the operating room, a low 99mTc-MIBI dose (37 MBq) was injected intravenously during anesthesia induction; (2) subsequently, the patients neck was scanned with the probe by the surgeon to localize the cutaneous projection of the EPG; (3) in patients who underwent MIRS, the EPG was detected intraoperatively with the probe and removed through a small, 2 to 2.5 cm skin incision; (4) radioactivity was measured on the EPG both in vivo and ex vivo, the thyroid, the background and the parathyroid bed after EPG removal. In patients with concomitant nodular goiter, the radioactivity was also measured on the thyroid nodules. Surgical and pathologic findings were consistent with a single PA in 78 patients, parathyroid carcinoma in 2, and MGD in 4. MIRS was successfully performed in 67 of the 70 patients (97.7%) in whom this approach was planned. It must be pointed out that the IGP technique was particularly useful in detecting the PAs located in ectopic site (5 in the upper mediastinum, 2 at the carotid bifurcation) and deep in the neck (6 in the paratracheal/paraesophageal space). Moreover, MIRS was also successfully performed in the seven patients who had undergone previous parathyroid or thyroid surgery. In the other 3 of 70 patients (4.3%), a conversion to BNE was required because a parathyroid carcinoma (2 cases) and a MGD (1 case) were diagnosed during surgical intervention. It is worth noting that in this latter patient affected by MGD, in contrast with the other patients from our series, QPTH remained elevated after the removal of the preoperatively visualized EPG suggesting the persistence of occult hyperfunctioning parathyroid tissue, and another contralateral EPG was found at BNE. Regarding the group of patients in whom a BNE was planned, the IGP helped the surgeon to localize a supernumerary EPG ectopic in the thymus in a patient with MGD, and to localize a PA ectopic to the right carotid bifurcation in a patient with nodular goiter. However, it has to be pointed out that it was difficult for the surgeon to differentiate intraoperatively with the probe the radioactivity of the EPG from that of thyroid nodule(s) in the other 10 patients with HPT with a concomitant nodular goiter, particularly in 6 patients in whom 99mTc-MIBI uptake was higher in thyroid nodule(s) than in EPG. On the basis of these data we can conclude that: (1) in patients with primary HPT with a high scan/US probability to be affected by a single PA and with a normal thyroid gland, IGP appears to be an useful technique with the aim of performing MIRS; (2) a 99mTc-MIBI dose as low as 37 MBq appears to be adequate to successfully perform MIRS; (3) the measurement of QPTH is strongly recommended in patients with HPT selected for MIRS to confirm complete removal of hyperfunctioning parathyroid tissue; (4) MIRS can be useful also in patients with HPT who previously received parathyroid/thyroid surgery with the aim of limiting surgical trauma at reoperation and minimizing the related risk of complications; (5) with the exception of PA located in ectopic sites, IGP does not seem to be a recommendable technique in patients with HPT concomitant nodular goiter.

The role of technetium-99m methoxyisobutylisonitrile scintigraphy in the planning of therapy and follow-up of patients with differentiated thyroid carcinoma after surgery

Abstract.The aim of this study was to investigate the possible role of technetium-99m methoxyisobutylisonitrile (MIBI) scan in planning post-surgical therapy and follow-up in patients with differentiated thyroid carcinoma (DTC). Four groups of DTC patients were considered: Group 1 comprised 122 patients with high serum thyroglobulin (s-Tg) levels and negative high-dose iodine-131 scan during follow-up who had previously undergone total thyroidectomy and 131I treatment. Group 2 consisted of 27 patients who had previously undergone total thyroidectomy and 131I treatment but were now considered disease-free; this group was considered as controls. Group 3 comprised 49 patients studied after total thyroidectomy but prior to 131I scan. Finally, group 4 consisted of 21 patients who had previously undergone partial thyroidectomy alone. MIBI scan, neck ultrasonography (US), and s-Tg measurements during suppressive hormonal therapy (SHT) were obtained in all patients. Neck and chest computed tomography (CT) or magnetic resonance imaging (MRI) was also performed in group 1 patients. In group 1, MIBI scan and US were very sensitive in detecting cervical lymph node metastases (93.54% and 89.24%, respectively). Furthermore, MIBI scan and US played a complementary role in several patients, yielding a global sensitivity of 97.84%. In contrast, CT/MRI sensitivity for cervical lymph node metastases was very low (43.01%). MIBI scan also showed a higher sensitivity than CT/MRI in detecting mediastinal lymph node metastases (100% vs 57.89%). Regarding distant metastases, MIBI scan provided results similar to those of conventional imaging (CT, MRI, 99mTc-methylene diphosphonate bone scan). In group 2, no false-positive cases were observed with MIBI scan (100% specificity). In group 3, MIBI scan correctly identified all the 131I-positive metastatic foci, except in two patients with micronodular pulmonary metastases that were visualised with 131I scan. In contrast, both MIBI scan and US showed low sensitivity (46.15% and 61.53%, respectively) compared with 131I scan in detecting thyroid remnants. s-Tg was increased in all patients with distant metastases but only in 56% of those with lymph node metastases. Furthermore, s-Tg was increased in 21.42% of patients with thyroid remnants alone (false-positive results). In group 4, MIBI scan was the only examination capable of detecting at an early stage a mediastinal lymph node metastasis in one patient. We conclude that the integrated MIBI scan/neck US protocol: (a) can be proposed as a first-line diagnostic procedure in the follow-up of DTC patients with high s-Tg levels and negative high-dose 131I scan, and (b) may be helpful in the follow-up of DTC patients who undergo partial thyroidectomy alone. Moreover, the combined MIBI scan/neck US/s-Tg protocol appears to be highly sensitive in identifying patients with metastatic disease after total thyroidectomy and prior to 131I scan; consequently, it may play a prognostic role in distinguishing high-risk from low-risk DTC patients. However, due to the low sensitivity of MIBI scan and neck US in detecting thyroid remnants, this diagnostic approach cannot be used as a predictor of 131I scan results. Lastly, because of the high sensitivity of MIBI scan and neck US in revealing both functioning and non-functioning metastases, this integrated protocol might be helpful in the follow-up of high-risk DTC patients, particularly for the early detection of lymph node metastases in patients with undetectable s-Tg during SHT.