Michele Klain

Relationship Between Tumor Burden and Serum Thyroglobulin Level in Patients with Papillary and Follicular Thyroid Carcinoma

Serum thyroglobulin (Tg) is a reliable marker for detecting recurrent and persistent disease during the follow-up of patients with papillary and follicular thyroid carcinoma. The goal of this study was to assess the relationship between the serum Tg level measured after thyroid hormone withdrawal and the tumor mass in thyroid cancer patients who underwent surgery with the use of an intraoperative probe for lymph node metastases with (131)I uptake. Patients were classified into one of three groups according to the Tg level: undetectable (n = 18); 1-10 ng/mL (n = 21); and greater than 10 ng/mL (n = 33). The main clinical characteristics and the extent of the disease at the time of initial treatment were similar in these three groups. Lymph node metastases were found in 13 of the 18 patients with undetectable Tg level. Eight patients had persistent foci of uptake after surgery that were located behind the sterno-clavicular joint in six patients. The number of metastatic lymph nodes and their total surface (in mm(2)) or their total volume (in mm(3)) were significantly linked with serum Tg/thyrotropin [TSH] level (p = 0.002 and p < 0.0001, respectively). For a given metastatic surface or volume, the serum Tg/TSH value was no longer linked with the number of metastatic lymph nodes (p = 0.32), suggesting that the total surface or total volume is the characteristic that best summarizes the influence of the disease on the serum Tg/TSH level. In conclusion, patients with higher serum Tg levels tend to have more extensive disease and should undergo more aggressive treatment modalities. Nevertheless, undetectable serum Tg should not be considered as a reliable criteria to exclude a minimal tumor burden in patients who have already been treated with (131)I.

Effect of 2 years of cortisol normalization on the impaired bone mass and turnover in adolescent and adult patients with Cushing's disease: a prospective study.

background Osteoporosis is a frequent, severe and often underestimated consequence of long‐term hypercortisolism, often presenting as bone fracture.

Effectiveness of chronic treatment with alendronate in the osteoporosis of Cushing's disease

Osteoporosis is common in patients with Cushings disease and is likely due to an imbalance between bone formation and resorption. Alendronate is an aminobisphosphonate that is able to increase bone mass mainly by inhibiting bone resorption.

Prolactinomas in adolescents: persistent bone loss after 2 years of prolactin normalization

To evaluate the effect of hyperprolactinaemia and its treatment with dopamine‐agonists on bone mass and turnover in adolescent patients compared to adults.

Severe impairment of bone mass and turnover in Cushing's disease: comparison between childhood-onset and adulthood-onset disease.

background Osteoporosis is an important, frequently unrecognized consequence of hypercortisolism.

Technetium-99m tetrofosmin imaging in thyroid diseases: comparison with Tc-99m-pertechnetate, thallium-201 and Tc-99m-methoxyisobutylisonitrile scans.

Technetium-99m tetrofosmin is a lipophilic phosphine used for myocardial perfusion imaging. Biodistribution studies have shown significant thyroid uptake of tetrofosmin and preliminary reports have suggested that tetrofosmin imaging may be of value in patients with thyroid cancer. In this study, tetrofosmin whole-body scintigraphy was performed in 35 patients with evidence of thyroid diseases. All patients underwent laboratory evaluation of thyroid function as well as99mTc pertechnetate scan, thallium-201 (n=16)99mTc-methoxyisobutylisonitrile (MIBI) (n=19) whole-body studies. Thyroid images were semi-quantitatively analysed by a 4-point score: O=no significant uptake; 1=uptake increased as compared to background activity, but inferior to normal thyroid tissue; 2=uptake equal to normal thyroid tissue; 3=uptake superior to normal thyroid tissue. Pathology examinations were obtained. A total of 41 thyroid nodules were detected, of which 15 were goitre nodules, 13 adenomas and 13 malignant lesions. In goitre nodules, concordant results of tetrofosmin and pertechnetate uptake (score 1 or 0) were observed in the majority of lesions (87%). In function adenomas (n=10), both tetrofosmin uptake and pertechnetate uptake were score 3. In non-function adenomas (n=3), tetrofosmin uptake was score 3, while pertechnetate uptake was score 0. In six malignant lesions, tetrofosmin uptake was score 3, while pertechnetate uptake was score 0; in the other seven lesions, where a prevalence of goitre abnormalities was observed, results of tetrofosmin and pertechnetate uptake were similar (score 0 or 1). In seven (70%) of the ten patients with malignant nodules, whole-body tetrofosmin images showed increased abnormal uptake in a total of 28 extra-thyroid tumour sites, as subsequently confirmed by other techniques. When tetrofosmin images were compared to 201T1 and99mTc-MIBI scans, concordant results were observed in all cases. In conclusion, tetrofosmin imaging may be particularly useful to characterize and stage patients with malignant thyroid nodules; it shows similar results to thallium but provides better image quality. Comparable findings were observed between tetrofosmin and MIBI studies. Thus, tetrofosmin may be an alternative to thallium and MIBI in the aforementioned patients.

The role of radiolabeled somatostatin analogs in adrenal imaging.

We investigated the role of radiolabeled somatostatin analogs (SAs) in adrenal imaging. We evaluated 15 patients (6 men and 9 women, mean age 47 +/- 17 years) with imaging-detected adrenal tumors. Patient population was divided into two groups on the basis of the nature of adrenal lesions. Group 1 consisted of patients with benign adrenal lesions (n = 10). Group 2 consisted of patients with malignant adrenal lesions (n = 5). Pathology examinations were obtained in 13 cases: 7 pheochromocytomas, 2 adenomas, 2 cysts, 1 carcinoma, and 1 fibro-histiocytoma. One patient had a proven diagnosis of non-small-cell lung cancer associated with the presence of a right adrenal mass. The last patient had a clinical diagnosis of Werner syndrome associated with the presence of a large left adrenal mass. All patients underwent scientigraphic studies using radiolabeled SAs, of which indium-111 (In-111) pentetreotide was used in 11 cases and technetium-99m (Tc-99m)-labeled peptides (P-587 or P-829) were used in the remaining four cases. No significant labeled SAs uptake was observed in the majority (8 of 10, 80%) of the benign adrenal lesions (Group 1); however, increased uptake was found in two benign pheochromocytomas. Conversely, significant labeled SAs uptake was observed in the majority (4 of 5, 80%) of the malignant adrenal lesions (Group 2); however, the last lesion (carcinoma) did not show abnormal uptake. Results of this study show that the majority of benign adrenal tumors do not concentrate radiolabeled SAs; conversely, the majority of malignant adrenal lesions show significant SAs uptake, suggesting the presence of somatostatin receptors. This finding may allow the use of somatostatin as a treatment agent in malignant adrenal tumors. Thus, the main role of labeled SAs in adrenal imaging consists of lesion characterization rather than tumor detection and localization.

Effects of two years of growth hormone (GH) replacement therapy on bone metabolism and mineral density in childhood and adulthood onset GH deficient patients

The aim of the current study was to evaluate bone metabolism and mass before and after 2 years of GH replacement therapy in adults with childhood or adulthood onset GH deficiency. Thirty-six adults with GH deficiency, 18 with childhood onset, 18 with adulthood onset GH deficiency and 28 sex-, age-, height- and weight-matched healthy subjects entered the study. Biochemical indexes of bone turnover such as serum osteocalcin, serum carboxyterminal telopeptide of type-I procollagen, urinary hydroxyproline/creatinine and deoxypyridinoline/creatinine, of soft tissue formation such as aminoterminal propeptide of type-III and bone mineral density were evaluated. Childhood onset GH deficient patients had significantly decreased bone (osteocalcin: 2.5±1.3 vs 6.6±4.8 mcg/l, p<0.001) and soft tissue formation (aminoterminal propeptide of type III: 273±49 vs 454±23 U/l, p<0.001) indexes and normal bone resorption indexes (serum carboxyterminal telopeptide of type-I procollagen: 105±48 vs 128±28 mcg/l p=NS; urinary hydroxyproline/creatinine: 0.19±0.16 vs 0.28±0.16 mmol/mol, p=NS; urinary deoxypyridinoline/creatinine: 21±10 vs 25±8 mcmol/mol, p=NS) compared to healthy subjects. On the contrary, no significant difference in bone turnover indexes between adulthood onset GH deficient patients and healthy subjects was found. Moreover, significantly decreased bone mineral density at any skeletal site and at whole skeleton was found in GH deficient patients compared to healthy subjects (e.g. femoral neck: 0.74±0.13 vs 0.97±0.11 g/cm2, p<0.001). In addition, a significant reduction of bone mineral density was found in childhood compared to adulthood onset GH deficient patients at any skeletal site, except at femoral neck. After 3–6 months of treatment, both groups of patients had a significant increase in bone turnover and in soft tissue formation. In particular, in childhood onset GH deficient patients after 3 months osteocalcin increased from 2.5±1.3 to 7.9±2.1 mcg/l, p<0.001 aminoterminal propeptide of type-III from 273±49 to 359±15 U/l p<0.001; serum carboxyterminal telopeptide of type-I procollagen from 105±48 to 201±45 mcg/l, p<0.001; urinary hydroxyproline/creatinine from 0.19±0.16 to 0.81±0.17 mmol/mol, p<0.001; urinary deoxypyridinoline/creatinine from 21±10 to 54±20 mcmol/mol, p<0.001; while in adulthood onset GH deficient patients after 6 months osteocalcin increased from 4.2±3.6 to 6.5±1.9 mcg/l, p<0.05; aminoterminal propeptide of type-III from 440±41 to 484±37 U/l, p<0.05; serum carboxyterminal telopeptide of type-I procollagen from 125±40 to 152±22 mcg/l, p<0.05; urinary hydroxyproline/creatinine from 0.24±0.12 to 0.54±0.06 mmol/mol, p<0.001; urinary deoxypyridinoline/creatinine from 23±8 to 42±5 mcmol/mol, p<0.001. No significant difference in bone turnover between pre- and post-treatment period was found after 18-24 months of GH therapy. Conversely, bone mineral density was slightly reduced after 3–6 months of GH therapy, while it was significantly increased after 18–24 months. In fact, femoral neck bone mineral density values significantly rose from 0.74±0.13 g/cm2 to 0.87±0.11 g/cm2 (pre-treatment vs 2 years of GH treatment values). In conclusion, patients with childhood or adulthood onset GH deficiency have osteopenia that can be improved by long-term treatment with GH.

Assessment of Metabolic Response to Radioimmunotherapy with 90Y–Ibritumomab Tiuxetan in Patients with Relapsed or Refractory B-Cell Non–Hodgkin Lymphoma

PURPOSE To prospectively compare the assessment of metabolic response to yttrium 90 ((90)Y)-ibritumomab tiuxetan radioimmunotherapy (RIT) by using fluorine 18 ((18)F) fluorodeoxyglucose (FDG) combined positron emission tomographic-computed tomographic (PET/CT) imaging at 2 and 6 months to determine the most appropriate time to detect therapeutic response in refractory non-Hodgkin lymphoma (NHL) patients treated with RIT. MATERIALS AND METHODS The ethical committee of the university approved the protocol and all patients signed informed consent. Twenty-three consecutive patients (10 women, 13 men; mean age, 51.8 years +/-7.3 [standard deviation]) treated by using RIT for relapsed or refractory follicular NHL were enrolled. For all patients, (18)F FDG PET/CT scanning was performed at baseline and at 2 and 6 months after RIT. Response was assessed by using the International Workshop Criteria (IWC) and revised criteria (IWC + PET) as well as the criteria of the European Organization for Research and Treatment of Cancer. One-way analysis of variance for repeated measures, receiver operator curve analysis, and Kaplan-Meier curves were used for statistical analysis. RESULTS PET/CT performed at 2 months revealed complete (n = 12) or partial (n = 4) metabolic response in 16 of 23 patients with complete or partial clinical response. These findings were all confirmed at 6-month scanning. PET/CT indicated refractory or persistent disease at 2 and 6 months in the remaining seven patients. Better overall survival was observed for patients with a reduction in the maximum standard uptake value of 49% or higher (both at 2 and 6 months after RIT) when compared with those with a decrease of less than 49% (P < .05). CONCLUSION Early assessment of response to RIT by using PET/CT might be useful in the identification of patients needing additional therapeutic strategies.

Thyroid and Parathyroid Tumors

Thyroid cancer occurred in approximately 45,000 patients, in the USA in 2010. There is a 3:1 ratio of women to men. Histologic types are divided into categories of differentiated thyroid cancer (DTC): papillary, mixed papillary and follicular, and follicular—including Hurthle cell variant, undifferentiated (anaplastic), and medullary cancer (arising from parafollicular C-cells). Other rare thyroid carcinoma accounts non-epithelial tumors, lymphoma and carcinomas characterized by the presence of mucin-producing cells and keratin. Differentiated thyroid cancer usually presents as a thyroid nodule. Thyroid ultrasonography is useful to detect and characterize thyroid nodules, as well as guide fine needle aspiration (FNA) biopsy. Radioiodide or 99mTc-pertechnetate thyroid scan has a low diagnostic specificity and sensitivity for characterizing thyroid nodules. X-ray of the neck is useful to disclose a deviation of the trachea or lumen restriction, in large nodules and in multinodular goiter. CT or MRI are generally reserved for mediastinal thyroid masses, or the identification of regional or distant metastasis. The most widely used staging system for thyroid carcinoma is the TNM classification system defined jointly by the UICC and by AJCC. 131I-iodide thyroid remnant ablation is indicated in differentiated thyroid cancer patients with a moderate to high likelihood of recurrence. 131I-iodide therapy is usually administered in the amount of 1.85 to 3.7 GBq for ablation. Patients are prepared with rhTSH and low iodine diet. Whole body scan (preferably with SPECT/CT of the neck) is performed 4–7 days after radioiodine therapy to detect lymph node involvement or unexpected metastases. The major diagnostic modalities employed to follow patients with differentiated thyroid cancer treated with remnant ablation is measurement of serum Tg, 131I-WBS, and neck US examination. Neck US examination is an integral component of follow-up evaluation in all DTC patients. If a lymph node metastasis is suspected, an FNA should be performed. Serum Tg levels that become detectable upon TSH stimulation indicate the need for further evaluation, possibly with additional radioiodine therapy. Although CT and MRI can in principle localize very small lesions in the neck, chest, and bones, the features of such lesions are rarely specific for recurrent/metastatic DTC. Patients with recurrent thyroid cancer may develop lesions which cannot concentrate radioiodide. [18F]FDG PET/CT is useful in these patients to determine the sites and extent of these metastases. The anaplastic thyroid carcinoma (ATC) is a rare tumor (<3% of all thyroid cancers) with poor prognosis derived from follicular cells. The most clinical presentation of an ATC is a new, large, firm thyroid nodule, often associated with signs/symptoms of local compression/invasion. Multimodality treatment of ATC includes surgery, EBRT, and combination chemotherapy. Therapy with 131I-iodide is not useful, since these tumors rarely concentrate radioiodide. Preoperative imaging with US, CT, MRI play an important role, and [18F]FDG PET is useful. Medullary thyroid carcinoma (MTC) is a well-differentiated thyroid tumor arising from the parafollicular, calcitonin-producing C cells. Its prevalence is 5–10% in all thyroid malignancies. Sporadic and familial forms are recognized. Elevated baseline serum levels of calcitonin (above 10 ng/mL) are diagnostic for MTC. Following surgery, MTC patients are monitored with serum calcitonin and CEA levels, and serial neck US examinations are performed. Calcitonin doubling time in serum is the most sensitive biomarker for MTC progression. Scintigraphy with 123I-MIBG has very high sensitivity for staging patients with MEN II and familial MTC. However, it has a low sensitivity in patients with increased serum calcitonin but no clinical site of disease. [18F]FDG PET is accurate in detecting lymph node involvement. Radionuclide therapy with the radiolabeled somatostatin analog 90Y-DOTA-Tyr3-octreotide (90Y-DOTA-TOC) has been tested in metastatic MTC. Parathyroid carcinoma is a very rare endocrine malignancy that occurs in <1% of primary HPTH. The initial clinical manifestations of parathyroid carcinoma are primarily linked to the effects of markedly elevated serum PTH levels. At initial presentation, very few patients have metastasis at regional lymph nodes or at distant sites. Parathyroid carcinoma tends to infiltrate adjacent structures in the neck. US, CT, and MRI have been used to localize parathyroid carcinomas and to detect mediastinal and thoracic recurrences or distant metastases. 99mTc-Sestamibi scintigraphy can be successful for preoperative localization of the neoplasia and can identify metastases in lymph nodes and at distant sites. PET with [18F]FDG can also detect metastatic parathyroid cancers. Parathyroid carcinoma recurs in more than 50% of the cases and imaging studies should be performed in all patients before reoperation.