Distinguishing synchronous from metachronous manifestation of distant metastases: a prognostic feature in differentiated thyroid carcinoma.

AIM: Distant metastasis has a negative impact on survival in differentiated thyroid carcinoma (DTC). The timing of this manifestation, however, is of unknown prognostic relevance. The aim of this retrospective study was to investigate the potential significance of discriminating synchronous versus metachronous distant metastases (SDM vs. MDM) for the outcome of patients with DTC. METHODS: We retrospectively analyzed a consecutive cohort of n = 89 patients with distant metastases of DTC (43 with follicular, 46 with papillary DTC histology; mean age 52.6 ± 17.7 years) undergoing radioiodine treatment at our institution. All patients were treated with the same protocol consisting of ablative radioiodine therapy (RIT, 3.7 GBq) and one post-ablation treatment after 3 months (3.7-11.1 GBq). Further cycles of RIT were administered for recurrent, progressive or newly developed metastatic disease. We distinguished 2 types of distant metastases according to the time of manifestation: SDM (within ≤12 months after DTC diagnosis) and MDM (occurring >12 months after diagnosis). Tumor-related survival was analyzed using the Kaplan-Meier method. Uni- and multivariate analyses including the Cox proportional hazards model were performed with a significance level of p < 0.05. RESULTS: The mean follow-up period was 13.8 ± 1.2 years. SDM were present in 49 (55.1 %), MDM in 40 (44.9 %) patients. MDM were associated with shorter tumor-related survival (p = 0.002). 5-year and 10-year survival rates were 68.5 % and 34.8 % for MDM, and 84.3 % and 66.9 % for SDM, respectively. Within both age subgroups of <45 and ≥45 years, SDM were also linked with longer survival. No effect on tumor-related survival was found for the co-variables sex, lymph node metastases and histologic type. CONCLUSION: Distinguishing synchronous from metachronous manifestation of distant metastases may add an important prognostic feature to risk stratification in DTC, as proven metachronous appearance is associated with impaired survival.

The significance of bremsstrahlung SPECT/CT after yttrium-90 radioembolization treatment in the prediction of extrahepatic side effects.

Purpose Unwanted deposition of 90Y microspheres in organs other than the liver during radioembolization of liver tumours may cause severe side effects such as duodenal ulcer. The aim of this study was to evaluate the significance of posttherapy bremsstrahlung (BS) SPECT/CT images of the liver in comparison to planar and SPECT images in the prediction of radioembolization-induced extrahepatic side effects.Methods A total of 188 radioembolization procedures were performed in 123 patients (50 women, 73 men) over a 2-year period. Planar, whole-body and BS SPECT/CT imaging were performed 24 h after treatment as a part of therapy work-up.Any focally increased extrahepatic accumulation was evaluated as suspicious. Clinical follow-up and gastroduodenoscopy served as reference standards. The studies were reviewed to evaluate whether BS SPECT/CT imaging was of benefit.Results In the light of anatomic data obtained from SPECT/CT, apparent extrahepatic BS in 43% of planar and in 52% of SPECT images proved to be in the liver and hence false positive.The results of planar scintigraphy could not be analysed further since 12 images were not assessable due to high scatter artefacts. On the basis of the gastrointestinal (GI)complications and the results of gastroduodenoscopy, true positive,true-negative, false-positive and false-negative results of BS SPECT and SPECT/CT imaging in the prediction of GI ulcers were determined. The sensitivity, specificity, positive and negative predictive values and the accuracy of SPECT and SPECT/CT in the prediction of GI ulcers were 13%, 88%, 8%,92% and 82%, and 87%, 100%, 100%, 99% and 99%,respectively.Conclusion Despite the low quality of BS images, BSSPECT/CT can be used as a reliable method to confirm the safe distribution of 90Y microspheres and in the prediction of GI side effects.

The Marine-Lenhart syndrome revisited.

The coexistence of thyroid autonomy (Plummer's disease) and Graves' disease has been termed "Marine-Lenhart syndrome". During the last years, several papers have been published on the development of Graves' disease shortly after radioiodine therapy of Plummer's disease (autonomy). Especially in patients with elevated thyroid antibodies, the incidence of this event is significantly higher after radioiodine therapy of autonomy. A review of the literature dating back to 1911 is discussed in this paper. The original paper published by Marine and Lenhart comes to the conclusion that the two diseases are different expressions of one disease. Looking at the literature, we have to state now that the Marine-Lenhart syndrome has never existed: With Plummer we know now that Plummer's and Graves' disease are different diseases. They may develop in the same patient but independent from each other.

Pathological 99mTc-sestamibi myocardial perfusion scintigraphy is independently associated with emerging cardiac events in elderly patients with known or suspected coronary artery disease.

BACKGROUND: Only few data are available regarding the prognostic impact of myocardial perfusion scintigraphy with (99m)Tc-sestamibi (MPS) regarding emerging cardiac events in elderly patients PURPOSE: To evaluate the prognostic value of MPS regarding emerging cardiac events in patients aged ≥70 years with known or suspected coronary artery disease (CAD). MATERIAL AND METHODS: One hundred and thirty-three patients (74.6 ± 3.7 years) who underwent exercise or pharmacological stress/rest MPS were included in this analysis. Semi-quantitative visual interpretation of MPS images was performed and Summed-Stress- (SSS), Summed-Difference- (SDS), and Summed-Rest Scores (SRS) were calculated. Multivariate logistic regression analyses were calculated for evaluation of the independent prognostic impact of MPS results and several cardiac-related patient characteristics with regard to emerging cardiac events. Kaplan-Meier survival- and log rank analyses were calculated for assessment of cardiac event-free survival. RESULTS: Pathological SSS (OR: 3.3), angina (OR: 2.7) and ischemic ECG (OR: 3.0) were independently associated with cardiac events. Patients with pathological SSS (p=0.005) and ischemic ECG (p=0.012) had a significantly lower incidence of cardiac event-free survival. CONCLUSION: Pathological MPS is independently associated with emerging cardiac events predicting a significantly lower incidence of cardiac event-free survival in patients aged ≥70 years.

Alternative therapeutic approaches in the treatment of primary and secondary dedifferentiated and medullary thyroid carcinoma.

The prognosis of patients with surgically unresectable differentiated thyroid tumors deteriorates significantly if radioiodine therapy is or becomes ineffective, considering the limited role of conventional chemotherapies in these patients. Several alternative approaches have been investigated for the treatment of patients with advanced thyroid malignancies in recent years. Among targeted therapies, tyrosine kinase inhibitors have resulted in the most encouraging responses and could soon be, along with redifferentiation therapy, the possible palliative strategies. Radiopeptide therapy, especially with beta emitter-labeled DOTANOC, which shows a great affinity to the somatostatin receptors expressed by thyroid tumor cells, might also be an attractive approach considering its comparatively low rate of side effects. However, the indication should be evaluated on individual basis. Medullary thyroid carcinoma shows a worse overall prognosis compared with the other differentiated thyroid tumors especially because of its natural resistance to radioiodine therapy. However, among possible palliative strategies, (131)I-meta-iodobenzylguanidine therapy is a noteworthy therapeutic approach in patients experiencing metastasized medullary thyroid carcinoma. In summary, recent developments in the treatment of patients with advanced thyroid malignancies have shown promising results, raising the hope for better outcomes in these patients in future.

Influence of 5-HTTLPR polymorphism on resting state perfusion in patients with major depression.

Neuroimaging studies in major depressive disorder (MDD) have indicated dysregulation in a network involving prefrontal cortex, subgenual cingulate and the amygdalae, which is known to be modulated by serotonin. The serotonergic system is the principal target for pharmacological treatment in MDD and the functional variable serotonin promoter polymorphism (5-HTTLPR) influences susceptibility, course and treatment response of MDD. Using data from a previously published sample of 89 MDD-patients, we examined post hoc the effect of 5-HTTLPR status on resting state perfusion, as measured with (99m)Tc-HMPAO-SPECT. MDD patients were stratified according to receptor polymorphism, both using a bi-allelic (group A: L/L vs. group B: S/S and S/L genotype) and a tri-allelic approach (Group A': LA/LA vs. Group B': non-LA/LA genotype). There were no significant differences between both subgroups regarding age, gender, severity of depression, medication, or treatment response (p > 0.1). Using the bi-allelic approach, Group B, compared to group A, revealed a significantly higher resting state perfusion in medial prefrontal cortex (p(voxel) (FWE) < 0.05). Additional ROI analyses showed relative overactivity of the amygdalae in group B (p(voxel) (FWE) < 0.05). Similar effects were observed in the tri-allelic approach. The opposite contrasts (Group A > Group B) revealed no significant effects. We demonstrate that in patients with MDD, 5-HTTLPR gene polymorphism modulates resting state perfusion in key structures of mood processing. While the clinical impact of these findings will need to be further investigated in larger cohort studies, the necessity to monitor and to account for individual 5-HTTLPR-status in future MDD imaging studies is highly recommended.

Impact of the Ki-67 proliferation index on response to peptide receptor radionuclide therapy.

PURPOSE: The role of the Ki-67 tumour proliferation index (PI) in predicting the efficacy of peptide receptor radionuclide therapy (PRRT) in gastroenteropancreatic tumours (GEP-NET) remains undetermined. This single-centre analysis focused on the potential therapeutic impact of this immunohistochemical parameter. METHODS: A total of 81 consecutive GEP-NET patients treated with (177)Lu-DOTA-octreotate (mean activity of 7.9 GBq per cycle, usually four treatment cycles at standard intervals of 3 months) were retrospectively analysed. Both an evaluable PI and tumour response (modified SWOG criteria) were required for patient inclusion. RESULTS: Response of tumours with a PI of ≤20% (partial response 40%, minor response 15%, stable disease 34%, progressive disease 11%) was comparable in all PI subsets, including those with a PI of 20%. However, G3 tumours (PI > 20%) showed progression in 71% of patients. CONCLUSION: Response to PRRT is consistent over the PI range of ≤20% (G1 + G2). Contrary to preliminary previous suggestions, a PI of 15% or 20% should not preclude candidates from somatostatin receptor-targeted radiotherapy.

The significance of 99mTc-MAA SPECT/CT liver perfusion imaging in treatment planning for 90Y-microsphere selective internal radiation treatment.

UNLABELLED: Selective internal radiation therapy (SIRT), a catheter-based liver-directed modality for treating primary and metastatic liver cancer, requires appropriate planning to maximize its therapeutic response and minimize its side effects. (99m)Tc-macroaggregated albumin (MAA) scanning should precede the therapy to detect any extrahepatic shunting to the lung or gastrointestinal tract. Our aim was to compare the ability of SPECT/CT with that of planar imaging and SPECT in the detection and localization of extrahepatic (99m)Tc-MAA accumulation and to evaluate the impact of SPECT/CT on SIRT treatment planning and its added value to angiography in this setting. METHODS: Ninety diagnostic hepatic angiograms with (99m)Tc-MAA were obtained for 76 patients with different types of cancer. All images were reviewed retrospectively for extrahepatic MAA deposition in the following order: planar, non-attenuation-corrected SPECT, and SPECT/CT. Review of angiograms and follow-up of patients with abdominal shunting served as reference standards. RESULTS: Extrahepatic accumulation was detected by planar imaging, SPECT, and SPECT/CT in 12%, 17%, and 42% of examinations, respectively. The sensitivity for detecting extrahepatic shunting with planar imaging, SPECT, and SPECT/CT was 32%, 41%, and 100%, respectively; specificity was 98%, 98%, and 93%, respectively. The respective positive predictive values were 92%, 93%, and 89%, and the respective negative predictive values were 71%, 73%, and 100%. The therapy plan was changed according to the results of planar imaging, SPECT, and SPECT/CT in 7.8%, 8.9%, and 29% of patients, respectively. CONCLUSION: In pre-SIRT planning, (99m)Tc-MAA SPECT/CT is valuable for identifying extrahepatic visceral sites at risk for postradioembolization complications.

The value of HMPAO SPECT in predicting treatment response to citalopram in patients with major depression.

Alterations of regional cerebral blood flow (rCBF) in prefrontal cortex and the anterior cingulate cortex are conspicuous imaging findings in patients with major depression (MD). While these rCBF changes have been suggested as functional disease markers, data in large patient samples examining treatment response prediction to antidepressant therapy are limited. This study examined the predictive value of Tc-99m-HMPAO-SPECT for subsequent treatment response to antidepressant therapy with citalopram in an unprecedented large collective of patients. Ninety-three patients with MD were examined with Tc-99m-HMPAO-SPECT twice, at the beginning of citalopram-treatment (T1) and after 4 weeks of treatment (T2). To determine the impact of rCBF changes associated with treatment response, the patient sample was divided into two subgroups: responders (44 patients) and non-responders (49 patients). A two-sample t-test was used to determine group-specific rCBF-differences. Age, gender and initial Hamilton Rating Scale for Depression (HRSD) were treated as regressors of no interest. The responder group revealed significant relative rCBF increases at T1 in a large region en-compassing predominantly prefrontal and temporal cortices as well as subgenual cingulate cortex. No relative rCBF decreases were detected in this group. The comparison between T1 and T2 revealed trends of rCBF decreases in inferior frontal gyrus and rCBF increases in premotor cortex in the responder group. Our data show that rCBF measurements with TC-99M-HMPAO-SPECT provide a predictor estimate for subsequent treatment response in depressed patients undergoing antidepressant therapy with citalopram. This effect is highly significant and, most notably, independent of the initial HRSD score.

Hemodynamic variables during stress testing can predict referral to early catheterization but failed to show a prognostic impact on emerging cardiac events in patients aged 70 years and older undergoing exercise (99m)Tc-sestamibi myocardial perfusion scintigraphy.

The aim of the present study was to evaluate the prognostic value of hemodynamic variables during ergometric stress testing for (99m)Tc-sestamibi myocardial perfusion scintigraphy (MPS) as compared to several patient-related variables and MPS results with regard to referral to early coronary angiography (<3 months after MPS; CA) as well as cardiac event (CE) free survival in a study population aged > or =70 years. About 90 patients aged > or =70 years (74.5 +/- 3.6 years) who underwent ergometric stress/rest MPS were included in this study. About 19 hemodynamic variables during stress testing were assessed. Semiquantitative visual interpretation of MPS images were performed and Summed-Stress-(SSS), Summed-Difference-, and Summed-Rest-Scores were calculated. Emerging CE comprised myocardial revascularization and -infarction as well as cardiac-related death. Multivariate logistic regression analyses were performed for evaluation of independent prognostic impact of hemodynamic-, MPS- and clinical-variables with regard to referral to early catheterization as well as emerging CE. Kaplan-Meier survival- and log rank analyses were calculated for assessment of CE free survival. History of CAD (Odds ratio; OR: 99.3), low rest heart rate (OR: 14.9) and low peak systolic blood pressure (OR: 15.4) during ergometric stress testing as well as pathological SSS (OR: 48.4) were significantly associated with referral to CA. History of ischemic ECG (OR: 4.7) and pathological SSS (OR: 3.7) independently predicted emerging CE and were associated with a lower CE free survival. In patients aged > or =70 years, CA is independently predicted by clinical variables, pathological results of MPS and hemodynamic variables. In contrast, hemodynamic response to stress testing failed to show any predictive impact on emerging CE.

Subclinical hyperthyroidism seems not to have a significant impact on systemic anticoagulation in patients with coumarin therapy.

There is little data regarding the impact of subclinical hyperthyroidism on coagulation metabolism in patients undergoing systemic anticoagulation therapy with coumarin derivates. In this retrospective analysis we studied 233 patients with benign thyroid disorders receiving therapeutic iodine-131, as well as concomitant systemic anticoagulation therapy (subclinical hyperthyroidism: n = 178; overt hyperthyroidism: n = 15; euthyroidism: n = 40). Multivariate regression analyses were performed in the total study population as well as in the subgroup of patients with subclinical hyperthyroidism to identify the possible impact of several variables on anticoagulation therapy, large enough to push the International Normalized Ratio (INR) level out of the therapeutic range (INR <2.0 or >3.0). Therapy with antibiotics or nitrates was significantly associated with INR-values >3.0 in the total population, while ACE inhibitors were associated with lower incidence of INR-values <2.0. In patients with subclinical hyperthyroidism, therapy with antibiotics was predictive of INR-values >3.0, whereas therapy with thyroid suppressive drugs or TSH-values <0.1 mU/l was associated with INR-values <2.0. Moreover, in a subgroup of 40 patients with the positive history of both subclinical hyperthyroidism and euthyroidism intraindividual comparison with regard to the possible impact on anticoagulation therapy was performed which failed to show any significant differences in INR-values between the two thyroid metabolic conditions. In conclusion, subclinical hyperthyroidism seems to have no significant impact on coagulation metabolism in patients receiving anticoagulation therapy.

Dose selection for radioiodine therapy of borderline hyperthyroid patients according to thyroid uptake of 99mTc-pertechnetate: applicability to unifocal thyroid autonomy?

PURPOSE: The aim of this study was to evaluate the feasibility of applying a previously described dose strategy based on (99m)Tc-pertechnetate thyroid uptake under thyrotropin suppression (TcTU(s)) to radioiodine therapy for unifocal thyroid autonomy. METHODS: A total of 425 consecutive patients (302 females, 123 males; age 63.1+/-10.3 years) with unifocal thyroid autonomy were treated at three different centres with (131)I, using Marinelli's formula for calculation of three different absorbed dose schedules: 100-300 Gy to the total thyroid volume according to the pre-treatment TcTU(s) (n=146), 300 Gy to the nodule volume (n=137) and 400 Gy to the nodule volume (n=142). RESULTS: Successful elimination of functional thyroid autonomy with either euthyroidism or hypothyroidism occurred at a mean of 12 months after radioiodine therapy in 94.5% of patients receiving 100-300 Gy to the thyroid volume, in 89.8% of patients receiving 300 Gy to the nodule volume and in 94.4% receiving 400 Gy to the nodule volume. Reduction in thyroid volume was highest for the 100-300 Gy per thyroid and 400 Gy per nodule strategies (36+/-19% and 38+/-20%, respectively) and significantly lower for the 300 Gy per nodule strategy (28+/-16%; p<0.01). CONCLUSION: A dose strategy based on the TcTU(s) can be used independently of the scintigraphic pattern of functional autonomous tissue in the thyroid.