Correlation between intracoronary physiology and myocardial perfusion imaging in patients with severe aortic stenosis.

BACKGROUND: Aortic stenosis (AS) is frequently associated with coronary artery disease (CAD). However, the best tool to functionally assess CAD in AS remains undetermined. Fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR) have never been validated in AS. METHODS: FFR, iFR and stress single photon emission computed tomography (SPECT) were performed in a consecutive series of 28 patients with severe AS and 41 borderline coronary lesions during the work-up for valve replacement. RESULTS: Both FFR and iFR were correlated with an abnormal SPECT. At ROC analysis, FFR yielded an AUC = 0.91 with negative predictive value (NPV) = 95% in detecting ischemia according to SPECT. iFR showed significant worse agreement with myocardial perfusion imaging compared to FFR (59% vs 85%, p = 0.014). Specifically, a significant larger proportion of false positive measurements (negative SPECT and iFR < 0.89) was observed using iFR vs FFR: 39% vs 12%, p = 0.011. Using a pre-specified 0.82 cut-off, the iFR agreement with SPECT increased to 73%. CONCLUSIONS: FFR yielded a good correlation with SPECT and a high NPV in detecting ischemia-provoking lesions. iFR diagnostic metrics were inferior compared with FFR and improved adopting a lower ischemic threshold.

A Case Report of Insulinoma Relapse on Background Nesidioblastosis: A Rare Cause of Adult Hypoglycemia.

Context: Nesidioblastosis is a rare cause of adult hypoglycemia. Current medical therapy can mitigate disease symptoms. However, side effects and limited efficacy may prevent long-term disease management. Case Description: A 63-year-old white woman presented at our institution on April 2017 with a history of distal spleno-pancreatectomy for well-differentiated insulinoma in 2013. Hypoglycemic events did not resolve after surgery, and residual nesidioblastosis near the pancreatic resection margins was identified. Hypoglycemic episodes increased in frequency and severity despite high-dose diazoxide (DZX) therapy. On April 2016, octreotide was introduced but soon discontinued for inefficacy. When the patient arrived at our attention, add-on pasireotide was started and glucose levels monitored by subcutaneous sensor. Compared with DZX, 225 mg/d alone, sensor glucose during pasireotide + DZX 75 mg/d showed occurrence of severe hypoglycemia. Pasireotide was discontinued, and the instrumental workup (68Ga-DOTATOC CT/positron emission tomography, 99mTc-nanocolloid scintigraphy and echo-endoscopy + fine-needle aspiration biopsy) identified an insulinoma relapse. Subtotal pancreatectomy was performed without further recurrence of hypoglycemia over 9 months of follow-up. Conclusions: Although insulinoma relapses on background nesidioblastosis rarely occur, they should be considered as an alternate diagnosis when medical therapy fails to prevent hypoglycemia. Further studies are warranted to test whether the immunophenotypic signature of nesidioblastosis/insulinoma may provide insights for a tailored use of pasireotide.

Risk-related 18F-FDG PET/CT and new diagnostic strategies in patients with solitary pulmonary nodule: the ITALIAN multicenter trial.

PURPOSE: Diagnosis of solitary pulmonary nodule (SPN) is an important public health issue and 18F-FDG PET/CT has proven to be more effective than CT alone. Pre-test risk stratification and clinical presentation of SPN could affect the diagnostic strategy. A relevant issue is whether thoracic segmental (s)-PET/CT could be implemented in patients with SPN. This retrospective multicenter study compared the results of FDG whole-body (wb)-PET/CT to those of s-PET/CT. METHODS: 18F-FDG PET/CT of 502 patients, stratified for pre-test cancer risk, were retrospectively analyzed. The thoracic part of wb-PET/CT, considered s-PET/CT, was compared to wb-PET/CT. Clinical and PET/CT variables were investigated for SPN characterization as well as for identification of patients in whom s-PET/CT could be performed. Histopathology or follow-up data were used as a reference. RESULTS: In the study population, 36% had malignant, 35% benign, and 29% indeterminate SPN. 18F-FDG uptake indicative of thoracic and extra-thoracic lesions was detectable in 13% and 3% of the patients. All patients with extra-thoracic metastases (n = 13) had thoracic lymph node involvement and highest 18F-FDG uptake at level of SPN (negative predictive value 100%). Compared to wb-PET/CT, s-PET/CT could save about 2/3 of 18F-FDG dose, radiation exposure or scan-time, without affecting the clinical impact of PET/CT. CONCLUSION: Pre-test probability of malignancy can guide the diagnostic strategy of 18FDG-PET/CT in patients with SPN. In subjects with low-intermediate pretest probability s-PET/CT imaging might be planned in advance, while in those at high risk and with thoracic lymph node involvement a wb-PET/CT is necessary.

RET mutation and increased angiogenesis in medullary thyroid carcinomas.

Advanced medullary thyroid cancers (MTCs) are now being treated with drugs that inhibit receptor tyrosine kinases, many of which involved in angiogenesis. Response rates vary widely, and toxic effects are common, so treatment should be reserved for MTCs likely to be responsive to these drugs. RET mutations are common in MTCs, but it is unclear how they influence the microvascularization of these tumors. We examined 45 MTCs with germ-line or somatic RET mutations (RETmut group) and 34 with wild-type RET (RETwt). Taqman Low-Density Arrays were used to assess proangiogenic gene expression. Immunohistochemistry was used to assess intratumoral, peritumoral and nontumoral expression levels of VEGFR1, R2, R3, PDGFRa, PDGFB and NOTCH3. We also assessed microvessel density (MVD) and lymphatic vessel density (LVD) based on CD31-positive and podoplanin-positive vessel counts, respectively, and vascular pericyte density based on staining for a-smooth muscle actin (a-SMA), a pericyte marker. Compared with RETwt tumors, RETmut tumors exhibited upregulated expression of proangiogenic genes (mRNA and protein), especially VEGFR1, PDGFB and NOTCH3. MVDs and LVDs were similar in the two groups. However, microvessels in RETmut tumors were more likely to be a-SMA positive, indicating enhanced coverage by pericytes, which play key roles in vessel sprouting, maturation and stabilization. These data suggest that angiogenesis in RETmut MTCs may be more intense and complete than that found in RETwt tumors, a feature that might increase their susceptibility to antiangiogenic therapy. Given their increased vascular pericyte density, RETmut MTCs might also benefit from combined or preliminary treatment with PDGF inhibitors.

A Dirichlet process mixture model for automatic (18)F-FDG PET image segmentation: Validation study on phantoms and on lung and esophageal lesions.

PURPOSE: The aim of this study was to implement a Dirichlet process mixture (DPM) model for automatic tumor edge identification on (18)F-fluorodeoxyglucose positron emission tomography ((18)F-FDG PET) images by optimizing the parameters on which the algorithm depends, to validate it experimentally, and to test its robustness. METHODS: The DPM model belongs to the class of the Bayesian nonparametric models and uses the Dirichlet process prior for flexible nonparametric mixture modeling, without any preliminary choice of the number of mixture components. The DPM algorithm implemented in the statistical software package R was used in this work. The contouring accuracy was evaluated on several image data sets: on an IEC phantom (spherical inserts with diameter in the range 10-37 mm) acquired by a Philips Gemini Big Bore PET-CT scanner, using 9 different target-to-background ratios (TBRs) from 2.5 to 70; on a digital phantom simulating spherical/uniform lesions and tumors, irregular in shape and activity; and on 20 clinical cases (10 lung and 10 esophageal cancer patients). The influence of the DPM parameters on contour generation was studied in two steps. In the first one, only the IEC spheres having diameters of 22 and 37 mm and a sphere of the digital phantom (41.6 mm diameter) were studied by varying the main parameters until the diameter of the spheres was obtained within 0.2% of the true value. In the second step, the results obtained for this training set were applied to the entire data set to determine DPM based volumes of all available lesions. These volumes were compared to those obtained by applying already known algorithms (Gaussian mixture model and gradient-based) and to true values, when available. RESULTS: Only one parameter was found able to significantly influence segmentation accuracy (ANOVA test). This parameter was linearly connected to the uptake variance of the tested region of interest (ROI). In the first step of the study, a calibration curve was determined to automatically generate the optimal parameter from the variance of the ROI. This "calibration curve" was then applied to contour the whole data set. The accuracy (mean discrepancy between DPM model-based contours and reference contours) of volume estimation was below (1 ± 7)% on the whole data set (1 SD). The overlap between true and automatically segmented contours, measured by the Dice similarity coefficient, was 0.93 with a SD of 0.03. CONCLUSIONS: The proposed DPM model was able to accurately reproduce known volumes of FDG concentration, with high overlap between segmented and true volumes. For all the analyzed inserts of the IEC phantom, the algorithm proved to be robust to variations in radius and in TBR. The main advantage of this algorithm was that no setting of DPM parameters was required in advance, since the proper setting of the only parameter that could significantly influence the segmentation results was automatically related to the uptake variance of the chosen ROI. Furthermore, the algorithm did not need any preliminary choice of the optimum number of classes to describe the ROIs within PET images and no assumption about the shape of the lesion and the uptake heterogeneity of the tracer was required.

Break-apart interphase fluorescence in situ hybridization assay in papillary thyroid carcinoma: on the road to optimizing the cut-off level for RET/PTC rearrangements.

OBJECTIVE: Chromosomal rearrangements of the RET proto-oncogene is one of the most common molecular events in papillary thyroid carcinoma (PTC). However, their pathogenic role and clinical significance are still debated. This study aimed to investigate the prevalence of RET/PTC rearrangement in a cohort of BRAF WT PTCs by fluorescence in situ hybridization (FISH) and to search a reliable cut-off level in order to distinguish clonal or non-clonal RET changes. DESIGN: Forty BRAF WT PTCs were analyzed by FISH for RET rearrangements. As controls, six BRAFV600E mutated PTCs, 13 follicular adenomas (FA), and ten normal thyroid parenchyma were also analyzed. METHODS: We performed FISH analysis on formalin-fixed, paraffin-embedded tissue using a commercially available RET break-apart probe. A cut-off level equivalent to 10.2% of aberrant cells was accepted as significant. To validate FISH results, we analyzed the study cohort by qRT-PCR. RESULTS: Split RET signals above the cut-off level were observed in 25% (10/40) of PTCs, harboring a percentage of positive cells ranging from 12 to 50%, and in one spontaneous FA (1/13, 7.7%). Overall, the data obtained by FISH matched well with qRT-PCR results. Challenging findings were observed in five cases showing a frequency of rearrangement very close to the cut-off. CONCLUSIONS: FISH approach represents a powerful tool to estimate the ratio between broken and non-broken RET tumor cells. Establishing a precise FISH cut-off may be useful in the interpretation of the presence of RET rearrangement, primarily when this strategy is used for cytological evaluation or for targeted therapy.

Optimized PET imaging for 4D treatment planning in radiotherapy: the virtual 4D PET strategy.

The purpose of the study is to evaluate the performance of a novel strategy, referred to as "virtual 4D PET", aiming at the optimization of hybrid 4D CT-PET scan for radiotherapy treatment planning. The virtual 4D PET strategy applies 4D CT motion modeling to avoid time-resolved PET image acquisition. This leads to a reduction of radioactive tracer administered to the patient and to a total acquisition time comparable to free-breathing PET studies. The proposed method exploits a motion model derived from 4D CT, which is applied to the free-breathing PET to recover respiratory motion and motion blur. The free-breathing PET is warped according to the motion model, in order to generate the virtual 4D PET. The virtual 4D PET strategy was tested on images obtained from a 4D computational anthropomorphic phantom. The performance was compared to conventional motion compensated 4D PET. Tests were also carried out on clinical 4D CT-PET scans coming from seven lung and liver cancer patients. The virtual 4D PET strategy was able to recover lesion motion, with comparable performance with respect to the motion compensated 4D PET. The compensation of the activity blurring due to motion was successfully achieved in terms of spill out removal. Specific limitations were highlighted in terms of partial volume compensation. Results on clinical 4D CT-PET scans confirmed the efficacy in 4D PET count statistics optimization, as equal to the free-breathing PET, and recovery of lesion motion. Compared to conventional motion compensation strategies that explicitly require 4D PET imaging, the virtual 4D PET strategy reduces clinical workload and computational costs, resulting in significant advantages for radiotherapy treatment planning.

First human Cerenkography.

Cerenkov luminescence imaging is an emerging optical preclinical modality based on the detection of Cerenkov radiation induced by beta particles when traveling though biological tissues with a velocity greater than the speed of light. We present the first human Cerenkography obtained by detecting Cerenkov radiation escaping the thyroid gland of a patient treated for hyperthyroidism. The Cerenkov light was detected using an electron multiplied charge coupled device and a conventional C-mount lens. The system set-up has been tested by using a slab of ex vivo tissue equal to a 1 cm slice of chicken breast in order to simulate optical photons attenuation. We then imaged for 2 min the head and neck region of a patient treated orally 24 h before with 550 MBq of I-131. Co-registration between photographic and Cerenkov images showed a good localization of the Cerenkov light within the thyroid region. In conclusion, we showed that it is possible to obtain a planar image of Cerenkov photons escaping from a human tissue. Cerenkography is a potential novel medical tool to image superficial organs of patients treated with beta minus radiopharmaceuticals and can be extended to the imaging of beta plus emitters.

Age and gender substantially influence the relationship between thyroid status and the lipoprotein profile: results from a large cross-sectional study.

BACKGROUND: Conflicting data are reported on the association between mild thyroid failure and lipid profile, primarily regarding serum triglyceride values and patients with slightly elevated thyrotropin (TSH, <10 mIU/L). In this study, we assessed the possible influence of gender and age on this relationship. METHODS: The study included 2308 consecutive patients who were seen for suspected or diagnosed thyroid disease (1874 women, 434 men, mean age 47.5±14.1 and 46.9±14.0 years, respectively) and on whom studies of thyroid status and lipoprotein profile were conducted after an overnight fast. Patients with uncontrolled diabetes mellitus and those taking lipid-lowering drugs were excluded. RESULTS: There were 628 patients receiving L-thyroxine who had a diagnosis of hypothyroidism: 200 were hyperthyroid, and 120 were still hypothyroid. Overall, 648 patients were hypothyroid, and 290 were hyperthyroid. No gender difference in the frequency of TSH values in the ranges studied (i.e., TSH frequency distribution) was observed. Total cholesterol (TC) and low-density lipoprotein cholesterol (LDLc) values (p<0.0003 and p<0.003, respectively) as well as the LDL/high-density lipoprotein cholesterol (HDLc) ratio (p<0.03) were elevated not only in unselected women with TSH values in the 4th TSH group (>10 mIU/L) but also in those of the 3rd group (3.6-10.0 mIU/L) who were older than 50 years (TC and LDLc p=0.01, LDL/HDLc ratio p=0.02 vs. euthyroid women). Among unselected men, only those of the 4th TSH group had elevated triglyceride (p<0.0001) but not cholesterol values. However, men of the 3rd and 4th TSH group who were older than 65 years had significantly higher TC, LDLc, and LDL/HDLc values as well (p=0.03, p=0.02 and p=0.01, respectively vs. euthyroid men). In the final model of stepwise regression for predicting each lipid parameter variation on the basis of age, TSH, free thyroxine (FT4), and body mass index (BMI) analysis, age had the highest standardized coefficient (0.36 and 0.37, respectively), followed by TSH (0.20 and 0.11, respectively) and FT4 (-0.11 and -0.09, respectively) when looking at TC and LDLc; whereas BMI had the highest standardized coefficient (0.28), followed by age (0.15) and TSH (0.11) when looking at triglyceride variation. CONCLUSIONS: This study confirms a gender differentiation in the relationship between hypothyroidism and the lipid profile, which is substantially influenced by age, especially in patients with mild thyroid impairment (TSH<10 mIU/L).

Long-term surveillance of papillary thyroid cancer patients who do not undergo postoperative radioiodine remnant ablation: is there a role for serum thyroglobulin measurement?

CONTEXT: Serum thyroglobulin (Tg) assays are considered fundamental in postoperative surveillance of differentiated thyroid cancer (DTC) patients. However, the postsurgical profile of Tg levels has never been specifically investigated in patients who do not undergo radioiodine remnant ablation (RRA). OBJECTIVES: Our objective was to explore the evolution of Tg levels over time in DTC patients treated with total or near-total thyroidectomy without RRA. DESIGN: We retrospectively analyzed 290 consecutively diagnosed cases of low-risk (American Thyroid Association criteria) DTC treated with thyroidectomy alone and followed yearly with neck ultrasonography and serum Tg assays. We compared final Tg values in this group and a matched group of 495 RRA-positive patients. Temporal trends of serial Tg levels were also analyzed in 78 of the RRA-negative patients monitored with a high-sensitivity immunoradiometric assay. RESULTS: After follow-up of 2.5-22 yr (median 5 yr), final Tg levels were undetectable (<1 ng/ml) in 274 of 290 RRA-negative patients (95%) and 492 of 495 RRA-positive controls (99%). In the subset of 78 RRA-negative patients, undetectable Tg levels (<0.2 ng/ml) were recorded in 60% at the first postoperative evaluation (3-12 months) and in 79% after 5 yr. Tg levels increased in the single patient who experienced disease recurrence during the observation period. CONCLUSION: In most RRA-negative patients, postoperative serum Tg values spontaneously drop to undetectable levels within 5-7 yr after thyroidectomy. Thus, in later phases, Tg assays may be a valuable tool for follow-up even in patients who do not undergo RRA.

Off-label use of sunitinib in patients with advanced, epithelial thyroid cancer: a retrospective analysis.

Tyrosine kinase receptors play an important role in tumor angiogenesis and, their implication in epithelial thyroid tumor growth has been highlighted. Sunitinib is a novel tyrosine kinase inhibitor, approved in 2006 by Food and Drug Administration for the treatment of advanced renal cell and gastrointestinal stromal tumors. Preliminary promising results have been also obtained in patients with RAI-resistant thyroid neoplasia. In the current study, our experience on 9 patients with advanced thyroid epithelial cancer is analyzed and discussed in relation to the new patents in this field. According to RECIST criteria, partial response was obtained in 5/9 (55.5%) patients at 3 months and in 6/9 (66.6%) at 6 months. Median treatment follow-up was 13.0 months and median overall survival and progression-free survival were 20 [95% confidence interval (CI) 9.3 - 30.6] and 21 months (95% CI 6.9 - 35.1), respectively. One case of severe thoracic hemorrhage was observed, the most common adverse events being represented by fatigue, (44.4% ), skin rash (33.3% ), headache (33.3% ), and one case each of hypertension, macrocytosis and acute pneumonia. These results confirm sunitinib as a potential useful tool for the treatment of advanced thyroid cancers and may open the way for new patents of molecules with more specific target selectivity.

The effect of Ginkgo biloba extract on genotoxic damage in patients with differentiated thyroid carcinoma receiving thyroid remnant ablation with iodine-131.

BACKGROUND: Radioiodine ((131)I) therapy is usually performed in patients with differentiated thyroid cancer (DTC). Although (131)I is generally considered safe, genotoxic damage has been demonstrated both in vivo and in vitro. The aim of the current study was to evaluate the effect of Ginkgo biloba extract (GBE) on the time-course of appearance, after (131)I therapy for DTC, of plasma factors with chromosome-damaging properties (so-called "clastogenic" factors [CFs]) and of micronuclei (MN) in lymphocytes. METHODS: Twenty-three patients (median age 42 years, range 18-73) with DTC receiving (131)I activity (3.7 GBq) for thyroid remnant ablation were randomly assigned to receive GBE (120 mg/day for one month; n=10) or placebo (n=13) in a double-blind manner. Blood samples were taken at various intervals (from baseline to 90 days) after (131)I therapy. The frequency of MN in blood lymphocytes was determined, and CFs were assayed in plasma by a method that used MN increase in lymphocytes from an healthy donor as the endpoint of the assay. RESULTS: MN in blood lymphocytes increased significantly after (131)I treatment in the placebo group, peaking at the 7th day (p=0.002) and slowly declining thereafter. In contrast, in similarly treated patients who were also treated with GBE both before and after (131)I treatment, a significant increase of blood lymphocyte MN level was not observed. In addition, only the placebo group showed a significant, progressive increase in CFs activity. This peaked at the 14th day (p=0.003 vs. baseline) and was still noted for the last plasma sample. The differences in the change in lymphocyte MN and CFs activity between the placebo and GBE-treated groups were significant (p<0.01 and p<0.05, respectively). Thyroid function tests, including serum thyroglobulin (Tg) and anti-Tg antibody levels, were never significantly different. CONCLUSIONS: GBE may protect from possible oxidative and genotoxic damage associated with (131)I treatment in patients requiring (131)I therapy for thyroid cancer, without affecting the clinical outcome. Further studies with larger cohorts of patients are needed to confirm this report and verify the beneficial effect of GBE in patients requiring (131)I therapy, particularly for those in whom repeated treatments and high activities of (131)I are required.

Identification and optimal postsurgical follow-up of patients with very low-risk papillary thyroid microcarcinomas.

CONTEXT: Most papillary thyroid microcarcinomas (PTMCs; ≤ 1 cm diameter) are indolent low-risk tumors, but some cases behave more aggressively. Controversies have thus arisen over the optimum postoperative surveillance of PTMC patients. OBJECTIVES: We tested the hypothesis that clinical criteria could be used to identify PTMC patients with very low mortality/recurrence risks and attempted to define the best strategy for their management and long-term surveillance. DESIGN: We retrospectively analyzed data from 312 consecutively diagnosed PTMC patients with T1N0M0 stage disease, no family history of thyroid cancer, no history of head-neck irradiation, unifocal PTMC, no extracapsular involvement, and classic papillary histotypes. Additional inclusion criteria were complete follow-up data from surgery to at least 5 yr after diagnosis. All 312 had undergone (near) total thyroidectomy [with radioactive iodine (RAI) remnant ablation in 137 (44%) - RAI group] and were followed up yearly with cervical ultrasonography and serum thyroglobulin, TSH, and thyroglobulin antibody assays. RESULTS: During follow-up (5-23 yr, median 6.7 yr), there were no deaths due to thyroid cancer or reoperations. The first (6-12 months after surgery) and last postoperative cervical sonograms were negative in all cases. Final serum thyroglobulin levels were undetectable (<1 ng/ml) in all RAI patients and almost all (93%) of non-RAI patients. CONCLUSION: Accurate risk stratification can allow safe follow-up of most PTMC patients with a less intensive, more cost-effective protocol. Cervical ultrasonography is the mainstay of this protocol, and negative findings at the first postoperative examination are highly predictive of positive outcomes.

Non-thyroidal illness syndrome and short-term survival in a hospitalised older population.

BACKGROUND: non-thyroidal illness syndrome (NTIS) has been associated with an adverse clinical outcome. OBJECTIVE: to evaluate the prevalence of NTIS, its impact on patients' survival and the possible pathogenic role of systemic inflammation. DESIGN: observational cross-sectional analysis. PARTICIPANTS AND SETTING: three hundred and one acutely ill older patients (156 women; median age 81 years, range 65-101) consecutively admitted to a primary care unit. METHODS: serum FT(3), FT(4) and thyrotropin levels as well as acute inflammation indexes were evaluated. RESULTS: the NTIS prevalence (specifically low T3 syndrome) was 31.9%. A significant association was found between NTIS and acute renal failure (P = 0.006), New York Heart Association classification (NYHA) IV heart failure (P = 0.003) and metastasised cancer disease (P = 0.0002). Serum FT(3) values correlated inversely with serum C-reactive protein (P < 0.0001), lactate dehydrogenase (P = 0.0004), fibrinogen (P = 0.03) and erythrocyte sedimentation rate (P < 0.0001) values, and progressively decreased with increasing tertiles of age (P = 0.0004). The mortality rate was significantly higher (P = 0.0002) among patients with low T3 syndrome, which emerged as the sole predictive factor of death (odds ratio 4.3; 95% confidence interval 1.7-10.5). CONCLUSIONS: low T3 syndrome is very common in the hospitalised older population, emerging as the most sensitive independent predictor of short-term survival. Serum FT(3) determination should be included in the assessment of short-term prognosis of acutely ill older patients.

Chromosome translocation frequency after radioiodine thyroid remnant ablation: a comparison between recombinant human thyrotropin stimulation and prolonged levothyroxine withdrawal.

BACKGROUND: Thyroid remnant ablation of differentiated thyroid carcinoma (DTC) patients is traditionally performed after levothyroxine withdrawal. Recombinant human TSH (rhTSH) administration increases serum TSH levels without inducing hypothyroidism. AIM: The aim of the study was to investigate the frequency of chromosome translocations in DTC patients after the first (131)I therapeutic dose and compare the frequency of translocations between DTC patients off levothyroxine and those receiving rhTSH. PATIENTS AND METHODS: A total of 20 DTC patients were randomly assigned to levothyroxine withdrawal [(30 d) group A; n=10, nine women; mean age 48.5+/- 19.2 yr] or rhTSH injections [(0.9 mg im per 2 consecutive days) group B; n=10, eight women; mean age 50.4+/- 18.8 yr] before undergoing (131)I activity (3.7 GBq). The frequency of translocations in peripheral lymphocytes was analyzed by tricolor fluorescence in situ hybridization with whole-chromosome-specific probes for chromosomes 1, 4, and 8. Lymphocytes were stained routinely (about 500 each time). RESULTS: The two groups showed similar baseline translocation frequency. After (131)I administration, the total chromosomal translocation rate was significantly lower in group B than group A (P = 0.02). The frequency of translocations increased significantly in group A only (P = 0.01 vs. baseline). Rearrangement specifically involved chromosomes 4 and 8 (P = 0.02 vs. baseline). CONCLUSIONS: Our preliminary data show that in hypothyroid status (131)I ablation therapy induces a higher translocation rate, especially in chromosomes 4 and 8. This finding, in agreement with previous dosimetric reports, suggests that whereas inducing a low extrathyroid exposure, rhTSH reduces the potential risk of chromosomal aberration associated with blood irradiation.

Thyroid volumetric quantification: comparative evaluation between conventional and volumetric ultrasonography.

OBJECTIVE: Thyroid volume quantification is an important parameter for radiotherapy dosing in cases of major thyroid diseases such as thyroiditis and carcinoma. In clinical practice, this calculation is performed by means of ultrasonography on the basis of an ellipsoid formula obtained from the 3 axes. The aim of our study was to compare the accuracy of volume calculation between B-mode ultrasonography and volumetric ultrasonography (VUS). METHODS: Between April and May 2007, 27 consecutive patients selected for thyroidectomy were prospectively evaluated. One expert ultrasound operator calculated each thyroid volume with standard B-mode ultrasonography on the basis of the 3 axes of each lobe, and then the patients were analyzed with an offline workstation equipped with volumetric probes (VUS). On the offline workstation, 2 separate blinded operators (VUS1 and VUS2) calculated the thyroid volume with virtual organ computer-aided analysis. Data acquired were then compared with pathologic anatomy (PA). RESULTS: The mean time for B-mode analysis was 6 minutes, whereas VUS analysis needed a mean time of 16.5 minutes. Interobserver variability between the median VUS1 and VUS2 measurements was 0.36 mL (interquartile range [IQR], -0.79 to 0.37 mL; P < .156). The median variability between B-mode ultrasonography and PA was -9.6 mL (IQR, -16.7 to 1.5 mL; P < .001), and that between VUS and PA was -2.87 mL (IQR, -11.97 to 9.51 mL; P = .019). The overall performance of B-mode ultrasonography in comparison with PA was -29.1% (IQR, -47.5% to -5.9%), and that of VUS in comparison with PA was -6.3% (IQR, -26.3 to 13.7%; P < .001). CONCLUSIONS: Volumetric ultrasonography is a valid tool that compares better with PA than does B-mode ultrasonography.

Multidisciplinary approach including receptor radionuclide therapy with 90Y-DOTATOC ([90Y-DOTA0, Tyr3]-octreotide) and 177Lu-DOTATATE ([177Lu-DOTA0, Tyr3]-octreotate) in ectopic cushing syndrome from a metastatic gastrinoma: a promising proposal.

OBJECTIVE: To present a case of a young woman with Cushing syndrome caused by ectopic production of adrenocorticotropic hormone from a metastatic pancreatic gastrin-secreting endocrine carcinoma, who had a good response to combination peptide receptor radionuclide therapy. METHODS: We review the history, physical examination, laboratory investigations, and radiographic findings in this unusual patient. Moreover, the multimodal interventions are described and discussed. RESULTS: In a 38-year-old woman with typical signs of cortisol excess, laboratory studies revealed diabetes mellitus, hypokalemia, and high levels of adrenocorticotropic hormone, plasma cortisol, and urinary cortisol. Abdominal computed tomography showed a 4-cm pancreatic mass and multiple metastatic lesions in the liver, and ectopic Cushing syndrome was diagnosed. Treatment consisted of surgical debulking of the tumor, ketoconazole, somatostatin analogues, chemoembolization of the liver metastatic lesions, and peptide receptor radionuclide therapy with the radiolabeled somatostatin analogues 90Y-DOTATOC ([90Y-DOTA0, Tyr3]-octreotide) and 177Lu-DOTATATE ([177Lu-DOTA0, Tyr3]-octreotate). The 5 1/2-year follow-up showed positive results, which included complete regression of all clinical and hormonal evidence of the tumor and substantial decrease in the size and number of hepatic metastatic lesions. The patient achieved and still maintains an optimal quality of life. CONCLUSION: To the best of our knowledge, this is the first report of a multidisciplinary approach including peptide receptor radionuclide therapy with 90Y-DOTATOC and 177Lu-DOTATATE, which proved to be effective in improving clinical outcome in a case of metastatic endocrine carcinoma of the pancreas in conjunction with ectopic Cushing syndrome. In this unusual case, the patient has one of the longest durations of survival in this setting described in the literature.

Comparison between remnant and red-marrow absorbed dose in thyroid cancer patients submitted to 131I ablative therapy after rh-TSH stimulation versus hypothyroidism induced by L-thyroxine withdrawal.

OBJECTIVE: In thyroidectomized patients, increased levels of thyroid stimulating hormone (TSH) are necessary to maximize I uptake. Traditionally, this has been achieved by withdrawing L-thyroxine (L-T4) for 4-6 weeks, inducing hypothyroidism in patients. The availability of a genetically engineered version of the recombinant human TSH (rh-TSH) provides an alternative tool to enhance the TSH serum level without inducing hypothyroidism. In this paper the I remnant and red-marrow doses calculated in differentiated thyroid cancer (DTC) patients pre-treated with rh-TSH are compared to those calculated in patients in hypothyroidism induced by L-T4 withdrawal. METHODS: Forty-six DTC patients, submitted to I ablative therapy, were randomly divided in group A (pre-treated with rh-TSH) and group B (treated after L-T4 withdrawal for 30 days). The red-marrow absorbed dose per unit administered activity and the remnant cumulated activity per unit administered activity were calculated for both groups. RESULTS: The red-marrow dose in 17 rh-TSH treated patients is 0.06+/-0.02 mGy.MBq; that in 14 hypothyroid patients is 0.09+/-0.03 mGy.MBq (two-tailed unpaired t-test P=0.003). The remnant cumulated activity per unit administered activity in 10 rh-TSH treated patients is 0.9+/-0.8 h; that calculated in 21 hypothyroid patients is 1.55+/-1.05 h (two-tailed unpaired t-test P=0.063). This last result is mainly due to the difference between the maximum uptake (U) in rh-TSH (U=0.01+/-0.01) and hypothyroid patients (U=0.03+/-0.02) (two-tailed unpaired t-test P=0.019). CONCLUSION: The rh-TSH pre-treated patients seem to have a lower uptake compared to those in hypothyroidism induced by L-T4 withdrawal. On the other hand their red-marrow absorbed dose seems to be lower.

In vivo and in vitro detection of dopamine d2 receptors in uveal melanomas.

Scintigraphy with radiolabeled benzamides was used in melanoma patients. Studies with a newer benzamide called 123I-epidepride, a high-affinity D2 receptor (D2R) antagonist, showed high sensitivity in D2R-positive pituitary adenomas. We evaluated the presence of D2R in patients with uveal melanomas in vivo with 123I-epidepride, and in vitro in melanomas, using immunohistochemistry (IHC) and 125I-epidepride autoradiography. We studied the in vivo tumor-to-background (TB) ratios in six patients with posterior uveal melanoma (one previously enucleated). IHC was performed in 3 of 6 tumors after enucleation and in another 20 uveal melanomas, 7 metastatic lymph nodes from skin melanoma, and 2 normal specimens. 125I-epidepride autoradiography was performed in 10 uveal melanomas (3 of which were studied in vivo), 7 metastases, and 2 normal samples. Radioligand uptake was present in the affected eye of 5 patients with uveal melanoma (TB = 3.1-6.1) and absent in the operated one (TB = 1). Eight uveal tumors were positive at IHC (35%), 14 weakly positive (61%), and 1 negative (4%). Two metastases were positive (29%), 2 weakly positive (29%), and 3 negative (42%). Two uveal tumors were positive at autoradiography (20%), 7 had nonspecific binding (70%), and 1 was negative (10%). One metastasis was positive (14%), while 6 were negative (86%). 123I-epidepride scintigraphy in uveal melanomas seems promising for sensitivity and image quality. D2R was demonstrated in a significant proportion of the melanomas, although 123I-epidepride uptake might also be nonspecific and unrelated to D2R binding. Although further studies on larger series are needed, 123I-epidepride could represent a future tool to study the expression of D2R in other classes of neuroendocrine tumors.

Assessment of tumor-associated trypsin inhibitor (TATI) as a marker of renal function.

BACKGROUND: Low molecular weight (LMW) proteins have been proposed for renal function assessment. This study aimed to ascertain the usefulness of tumor-associated trypsin inhibitor (TATI), a LMW protein (6.200 d), as a glomerular filtration rate (GFR) marker. The results were compared with those of beta2-microglobulin and of creatinine (Cr). METHODS: Renal handling of TATI labelled with 125I was first studied in rats. Then, in 198 patients, serum TATI levels and GFR (99mTc-DTPA clearance, bladder cumulative method) were determined. To evaluate urine excretion, the fractional TATI clearance was determined in 63 patients. RESULTS: In rats, total body scan showed a large amount of radioactivity in the kidneys, but not in other organs. The duration of radioactivity demonstrated a peak-time of 11 min. In human beings, the relationship between TATI and GFR was similar to that of beta2-microglobulin and Cr. The increase in TATI with declining renal function was statistically significant, vs. patients with GFR > 100 mL/min, already in the group with GFR 80-100 mL/min (p < 0.05, Bonferroni-Dunn test). The beta2-microglobulin increase was significant in the group with GFR 60-80 mL/min and of Cr in the group with GFR 40-60 mL/min. In patients with renal failure (GFR < 20 mL/min) TATI increased, vs. patients with GFR > 100 mL/min, 13x, beta2-microglobulin 8x and Cr 5x. Urinary excretion of TATI, expressed as fractional clearance, was very low increasing when GFR fell < 40 mL/min. CONCLUSIONS: The kidney plays an important role in the handling of TATI. When GFR fell, the increase in blood levels of TATI was sooner and higher than that of beta2-microglobulin and CR. Consequently, TATI can be added to the group of renal function markers.