Development of hypothyroidism during long-term follow-up of patients with toxic nodular goitre after radioiodine therapy.

OBJECTIVE: To investigate the cure rate and incidence of hypothyroidism of radioiodine treatment with a calculated dose regimen and an intended thyroid dose of 150 Gy in patients with toxic nodular goitre during long-term follow-up. PATIENTS: A total of 265 consecutive patients with toxic nodular goitre were treated between March 2003 and August 2004 at our institute and followed up for a maximum of 8 years. Preliminary radioiodine testing with volumetric measurement of the thyroid by ultrasound as well as individual thyroidal radioiodine uptake and half-life measurements were performed before radioiodine therapy. The estimated radiation dose to the thyroid was 150 Gy. MEASUREMENTS: Follow-up controls with respect to success of therapy and development of hypothyroidism were performed 3 months, 1 and up to 8 years after radioiodine treatment. The relation of the achieved thyroid dose to the success rate of treatment and to the incidence of hypothyroidism was analysed. RESULTS: The cure rates were 85% at 3 months, 98% at 1 year and 98% at the end of follow-up. Above an achieved thyroid dose of more than 120 Gy, there was no significant association between the dose achieved in the thyroid and the cure rate on follow-up. The incidences of hypothyroidism at 3 months, at 1 year and at the end of follow-up were 32%, 55% and 73%, respectively. CONCLUSIONS: Radioiodine treatment with a calculated dose regimen is a highly effective treatment option in patients with toxic goitre with an overall success rate of 98%. However, radioiodine treatment with an intended thyroid dose of 150 Gy leads to a high incidence of hypothyroidism on long-term follow-up. This finding supports the suggestion that in future intended thyroid doses could be lowered in patients treated with a calculated dose regimen for toxic nodular goitre.

Exhalation of ¹³¹I after radioiodine therapy: measurements in exhaled air.

PURPOSE: A considerable amount of radioiodine is exhaled after radioiodine therapy leading to unwanted radiation exposure through inhalation. This study focused on the concentration of radioactivity exhaled and its chemical nature. METHODS: Air exhaled by 47 patients receiving (131)I-iodine for different thyroid diseases (toxic goitre n = 26, Graves' disease n = 13, thyroid cancer n = 8) was investigated with a portable constant air-flow sampler. Different chemical iodine species were collected separately (organic, elemental and aerosolic) up to 26 h after administration of the radioiodine capsule. The data approximated to a monoexponential time-activity curve when integrated over 100 h. The radioactivity in the filters was measured with a well counter at defined time points after administration. RESULTS: The radioactivity of (131)I in the exhaled air 1 h after administration ranged from 1 to 100 kBq/m(3). Two parameters (half-life of radioiodine exhalation and time-integrated activity over 100 h) were substantially higher in patients with cancer after near-total thyroidectomy (11.8 ± 2.1 h and 535 ± 140 kBq / m(3), respectively) than in patients with hyperfunctioning thyroid tissue due to toxic adenoma (7.6 ± 2.5 h and 115 ± 27 kBq / m(3), respectively) or Graves' disease (6.4 ± 3.6 h and 113 ± 38 kBq / m(3), respectively). The percentage of radioiodine in the exhaled air in relation to radioiodine administered to the patient was between 80 ppm and 150 ppm. The fraction of organically bound radioiodine (mean value) for all time points after administration was 94-99.9%. This percentage did not depend on the type of thyroid disease. CONCLUSION: The amount of exhaled radioiodine is small but by no means negligible on the first day after administration. This is the first study to provide experimental evidence on a systematic basis that radioiodine becomes exhalable in vivo, i.e. in the patient. The mechanism of organification of orally administered radioiodine remains to be investigated.

Positron emission tomography has a high negative predictive value for progression or early relapse for patients with residual disease after first-line chemotherapy in advanced-stage Hodgkin lymphoma.

In the HD15 trial of the German Hodgkin Study Group, the negative predictive value (NPV) of positron emission tomography (PET) using [(18)F]-fluorodeoxyglucose in advanced-stage Hodgkin lymphoma (HL) was evaluated. A total of 817 patients were enrolled and randomly assigned to receive BEACOPP-based chemotherapy. After completion of chemotherapy, residual disease measuring more than or equal to 2.5 cm in diameter was assessed by PET in 311 patients. The NPV of PET was defined as the proportion of PET(-) patients without progression, relapse, or irradiation within 12 months after PET review panel. The progression-free survival was 96% for PET(-) patients (95% confidence interval [CI], 94%-99%) and 86% for PET(+) patients (95% CI, 78%-95%, P = .011). The NPV for PET in this analysis was 94% (95% CI, 91%-97%). Thus, consolidation radiotherapy can be omitted in PET(-) patients with residual disease without increasing the risk for progression or early relapse compared with patients in complete remission. The impact of this finding on the overall survival at 5 years must be awaited. Until then, response adapted therapy guided by PET for HL patients seems to be a promising approach that should be further evaluated in clinical trials. This trial is registered at http://isrctn.org study as #ISRCTN32443041.

PROLARA: prognosis-based lifetime attributable risk approximation for cancer from diagnostic radiation exposure.

PURPOSE: To evaluate the impact of the reduced life expectancy of patients (compared to a nonpatient group with the same age distribution) on their nominal risk of developing cancer from the diagnostic use of radiation. METHOD: We define a "prognosis-based lifetime attributable risk modifier" (PROLARM) as the ratio of the risks for nonpatients and patients, a dimensionless quantity which indicates how strongly the life-time attributable risk (LAR) is reduced due to a patient's prognosis. An approximation to this ratio can be given (named PROLARA) which depends only on the patient's age at exposure and his/her life expectancy, but is independent of the exact choice of values for the baseline risk of cancer incidence and the excess relative risk (ERR) from radiation exposure. PROLARM and PROLARA were computed for a cohort of 4,285 female patients with metastatic breast cancer, for whom all necessary input data were available. RESULTS: LAR of solid cancer was significantly decreased in these patients: PROLARM >20 for age at exposure < or = 65 years. For any reasonable choice of function for ERR, the approximation PROLARA gave a lower estimate of the reduction in risk. The risk for a patient from the above cohort, exposed at age 50 years, is decreased by a factor of 29 (PROLARM) and 27 (PROLARA). In other words, 50 mSv in a patient with metastatic breast cancer corresponds risk-wise to only 2 mSv in a nonpatient of the same age. CONCLUSION: A major proportion of the total dose from diagnostic medical exposures does not constitute an additional cancer risk due to the poorer prognosis of patients compared to nonpatients of same gender and age. Our new PROLARA concept allows an estimation of the reduction in risk for any pathology when the associated survival is known.

Dosimetry for 131I-MIBG therapies in metastatic neuroblastoma, phaeochromocytoma and paraganglioma.

PURPOSE: Radiation dosimetry is a basic requirement for targeted radionuclide therapies (TRT) which have become of increasing interest in nuclear medicine. Despite the significant role of the radiopharmaceutical (131)I-metaiodobenzylguanidine (MIBG) for the treatment of metastatic neuroblastoma, phaeochromocytoma and paraganglioma details for a reliable dosimetry are still sparse. This work presents our procedures, the dosimetric data and experiences with TRT using (131)I-MIBG. METHODS: A total of 21 patients were treated with (131)I-MIBG between 2004 and 2008 according to a clearly defined protocol. Whole-body absorbed doses were determined by a series of scintillation probe readings for all 21 cases. Tumour absorbed doses were calculated on the basis of quantitative imaging for an entity of 25 lesions investigated individually using the region of interest (ROI) technique based on five scans each. RESULTS: Typical whole-body absorbed doses are found in the region of 2 Gy (range: 1.0-2.9 Gy) whereas tumour absorbed doses in turn cover a span between 10 and 60 Gy. Nonetheless this variation of tumour absorbed doses is comparatively low. CONCLUSION: The trial protocol in use is a substantial advancement in terms of reliable dosimetry. A clearly defined modus operandi for MIBG therapies should involve precisely described dosimetric procedures, e.g. a minimum of 20 whole-body measurements using a calibrated counter and at least four gamma camera scans over the whole period of the inpatient stay should be carried out. Calculation of tumour volumes is accomplished best via evaluation of SPECT and CT images.

[18F]-Fluorodeoxyglucose-positron emission tomography for the assessment of histopathologic response and prognosis after completion of neoadjuvant chemoradiation in esophageal cancer.

OBJECTIVE: To evaluate the potential of [(18)F]-fluorodeoxyglucose-positron emission tomography (FDG-PET) after the completion of neoadjuvant chemoradiation for the assessment of histopathologic response and prognosis in the multimodality treatment of patients with esophageal cancer. BACKGROUND: Combined chemoradiation with and without surgery are widely accepted treatment options for patients with locally advanced esophageal cancer. Evidence suggests that patients with response to chemoradiation have no additional benefit from surgery compared with definitive chemoradiation. However, there is still a great lack in noninvasive markers for response assessment in patients with esophageal cancer undergoing multimodality treatment. Interestingly, recent studies imply that FDG-PET significantly correlates with histopathologic response and survival in patients with esophageal cancer undergoing neoadjuvant chemotherapy followed by surgical resection. METHODS: Study patients were recruited from a prospective clinical observation trial on neoadjuvant chemoradiation for esophageal cancer between 1997 and 2006. The study included 119 (98 men, 21 women; median age, 59.4 years; squamous cell cancer: 66; adenocarcinoma: 53) patients with locally advanced esophageal cancer (cT2- 4, N(x), M(0)). All patients received neoadjuvant chemoradiation (cisplatin, 5-FU, 36 Gy) and subsequently underwent transthoracic en bloc esophagectomy. Histomorphologic regression was defined as major histopathologic response when resected specimens contained less than 10% vital residual tumor cells (major response: 47 patients [39.5%]; minor response: 72 patients [60.5%]). FDG-PET was performed before and 2 to 3 weeks after the end of chemoradiation with assessment of the intratumoral FDG-uptake (pretreatment standardized uptake value; post-treatment standardized uptake value; percentage change). These variables were correlated with histopathologic response and survival. RESULTS: Major histomorphologic response was confirmed as an important prognostic factor (P = 0.005; log-rank test). Neoadjuvant chemoradiation led to a significant reduction of intratumoral FDG-uptake (P = 0.0001). A nonsignificant association was seen between major responders and FDG-PET results (P = 0.056). However, the receiver operating characteristic analysis could not identify a standardized uptake value threshold with a relevant predictive value for histomorphologic response. No significant association between metabolic imaging and prognosis was found. CONCLUSION: FDG-PET seems not to be an imaging system that effectively characterizes the groups of major and minor response as well as survival in patients with esophageal cancer after multimodality treatment.

Mean and maximum standardized uptake values in [18F]FDG-PET for assessment of histopathological response in oesophageal squamous cell carcinoma or adenocarcinoma after radiochemotherapy.

PURPOSE: To evaluate the potential of [(18)F]fluorodeoxyglucose positron emission tomography (FDG-PET) for the assessment of histopathological response and survival after neoadjuvant radiochemotherapy in patients with oesophageal cancer. PATIENTS AND METHODS: In 2005 and 2006, 55 patients (43 men, 12 women; median age 60 years) with locally advanced oesophageal cancer (cT3-4 Nx M0; 24 with squamous cell carcinoma, 31 with adenocarcinoma) underwent transthoracic en bloc oesophagectomy after completion of treatment with cisplatin, 5-fluorouracil, and radiotherapy ad 36 Gy in a prospective clinical trial. Of the 55 patients, 21 (38%) were classified as histopathological responders (<10% vital residual tumour cells) and 34 (62%) as nonresponders. FDG-PET was performed before (PET 1) and 3-4 weeks after the end (PET 2) of radiochemotherapy with assessment of maximum and average standardized uptake values (SUV) for correlation with histopathological response and survival. RESULTS: Histopathological responders had a slightly higher baseline SUV than nonresponders (p<0.0001 between PET 1 and PET 2 for responders and nonresponders) and the decrease was more prominent in responders. Except for SUVmax in patients with squamous cell carcinoma neither baseline nor preoperative SUV nor percent SUV reduction correlated significantly with histopathological response. Histopathological responders had a 2-year overall survival of 91 +/- 9% and nonresponders a survival of 53 +/- 10% (p = 0.007). CONCLUSION: Our study does not support recent reports that FDG-PET predicts histopathological response and survival in patients with locally advanced oesophageal cancer treated by neoadjuvant radiochemotherapy.

[Should all patients with thyroid nodules > or = 1 cm undergo fine-needle aspiration biopsy?]. / Soll man alle Schilddrüsenknoten > or = 1 cm punktieren?

The prevalence of thyroid nodules > or = 1 cm is high in a previously iodine-deficient area. Under the hypothesis, that all patients with such nodules undergo fine-needle aspiration biopsy (FNAB) and that sensitivity and specificity of cytology are calculated with 85%, the positive predictive value of pathologic cytologic finding will reach 1.5% only according to Bayes-theorem. This is clinically unacceptable, as resection will be the consequence in all cases with suspect cytology. Even implementation of a second, independent test (e. g. moleculargenetic testing of thyreocytes, sensitivity to detect mutation 50%, specificity 95%) and application of sequential Bayes-theorem the positive predictive value of combined pathologic findings will increase to 13% only. Nevertheless, 58% out of all thyroid cancer remain undetected by such a sequential algorithm. As a consequence , pre-selection of thyroid nodules for FNAB is required to increase the pretest-probability to at least 5-10%. A combination of sonographic criteria and scintigraphy, even in patients with normal TSH-levels, is suited to selected thyroid nodules for FNAB.

Long-term effects of a multimodal behavioral intervention on myocardial perfusion--a randomized controlled trial.

BACKGROUND: Recent advances in drug therapy question as to the additional impact behavioral interventions may have on the prognosis of patients with clinically stable coronary heart disease (CHD). PURPOSE: The aim of the study was to evaluate the effects of a multimodal, behavioral intervention on myocardial perfusion (MP) and cardiac events, compared to standardized cardiologic care, in patients with stable CHD. METHODS: Seventy-seven CHD patients (age 54.2 +/- 6.9 years, male 87%) were randomly assigned to a behavioral intervention plus standardized cardiologic care (INT, n = 39) or standardized cardiologic care alone (CO, n = 38). MP was assessed by (201)Thallium MP-scintigrams (SPECT) at baseline, after 2, 3, and 7 years, respectively. Subsequent cardiac events (MI, PCI, CABG) were assessed using the cardiologists' charts. RESULTS: Sixty-five patients (84%) completed the study. In all patients, the course of MP was significantly better in INT analysis of variance (ANOVA group x time p = 0.001); this was also true for patients without subsequent PCI/CABG (ANOVA group x time p = 0.002). Incidence of cardiac events was significantly associated with INT (6 vs. 14; log rank test p = .047). CONCLUSION: The study suggests additional long-term benefits of a behavioral intervention on myocardial perfusion and cardiac events in patients with stable CHD compared to standardized cardiologic care only.

The prognostic impact of functional imaging with (123)I-mIBG in patients with stage 4 neuroblastoma >1 year of age on a high-risk treatment protocol: results of the German Neuroblastoma Trial NB97.

AIM/PURPOSE: (123)I-meta-iodobenzylguanidine ((123)I-mIBG) scintigraphy is well established for staging and evaluation of response in children with high-risk neuroblastoma but its prognostic value in highly intensive first-line treatment protocols is uncertain. The presence of any (123)I-mIBG positive tumour tissue was correlated with event-free survival (EFS) and overall survival (OS). PATIENTS AND METHODS: The prognostic impact of residual (123)I-mIBG uptake into the primary tumour and metastases for predicting outcome in 113 stage 4 neuroblastoma patients >1 year of the German Neuroblastoma Trial NB97 was assessed using a univariate log-rank test and multivariate Cox regression analysis. RESULTS: All patients had (123)I-mIBG positive disease at initial staging. After four courses of induction chemotherapy, 71% of patients were still (123)I-mIBG positive for the primary tumour and 61% for metastases. After six courses, 39% of patients had (123)I-mIBG uptake by the primary tumour and 45% residual (123)I-mIBG positive metastatic disease. The (123)I-mIBG status of the primary tumour site had no bearing on outcome. Residual (123)I-mIBG positive metastatic disease after four (3-y-EFS 25.7+/-5.3% versus 55.9+/-7.6%, p=0.009; 3-y-OS 49.8+/-6.1% versus 65.0+/-7.3%; p=0.021) and after six chemotherapy cycles (3-y-EFS 27.5+/-6.2% versus 47.4+/-6.4%, p=0.011; 3-y-OS 50.5+/-7.1% vs 60.0+/-6.4%, p=0.031) was associated with poor outcome. CONCLUSION: Functional imaging with (123)I-mIBG scintigraphy can identify poor responders with any persistent metastatic (123)I-mIBG uptake who are at a high risk of disease relapse. (123)I-mIBG response of the primary tumour site had no bearing on outcome.

Long-term follow-up of antithyroid peroxidase antibodies in patients with chronic autoimmune thyroiditis (Hashimoto's thyroiditis) treated with levothyroxine.

BACKGROUND: A number of studies show that the serum levels of antithyroid peroxidase antibodies (TPO-Ab) in patients with Hashimoto's thyroiditis decline during levothyroxine treatment, but do not provide quantitative data or report the fraction of patients in whom test for TPO-Ab became negative ("normalization percentage"). The objective of the present study was to provide this information. METHODS: This was a retrospective study of TPO-Ab concentrations in 36 women and 2 men (mean age 51 +/- 16 years; range 19-81 years) with Hashimoto's thyroiditis as defined by the following criteria: elevated plasma TPO-Ab and typical hypoechogenicity of the thyroid in high-resolution sonography at first presentation or during follow-up and low pertechnetate uptake in thyroid scintigraphy. When first studied 17 women and 1 man were not yet taking levothyroxine. The remaining 20 patients were receiving levothyroxine. At initial examination 18 patients had serum thyroid-stimulating hormone (TSH) concentrations above normal. Results of up to eight (mean = 5.8) measurements obtained over a mean period of 50 months while patients were receiving levothyroxine were analyzed. In addition, serum TSH, free triiodothyronine (fT3), and free thyroxine (fT4) were measured, and ultrasound of the neck was performed at each follow-up examination. RESULTS: In terms of TPO-Ab levels, 35 of 38 patients (92%) had a decrease, 2 patients had undulating levels, and 1 patient had an inverse hyperbolic increase in her TPO-Ab levels. In the 35 patients in whom there were decreasing TPO-Ab values, the mean of the first value was 4779 IU/mL with an SD of 4099 IU/mL. The mean decrease after 3 months was 8%, and after 1 year it was 45%. Five years after the first value, TPO-Ab levels were 1456 +/- 1219 IU/mL, a decrease of 70%. TPO-Ab levels became negative, < 100 IU/mL, in only six patients, a normalization percentage of 16%. There were no correlations between changes in thyroid volume and changes in TPO-Ab. CONCLUSION: Serum TPO-Ab levels decline in most patients with Hashimoto's thyroiditis who are taking levothyroxine, but after a mean of 50 months, TPO-Ab became negative in only a minority of patients.

Diethylstilbestrol (DES) labeled with Auger emitters: potential radiopharmaceutical for therapy of estrogen receptor-positive tumors and their metastases?

PURPOSE: Diethylstilbestrol (DES) is a well-known, non-steroidal estrogen with high affinity to the estrogen receptor (ER). Labeled DES would be a useful tool for therapy of ER-positive mammary carcinomas and their metastases. Particularly with Auger emitters, high cytotoxic potential combined with only slight side effects can be expected. MATERIALS AND METHODS: DES was labeled by a new method with higher yield and specific activity than former methods. Cytotoxic effects on MCF-7 (human, Caucasian, breast, adenocarcinoma) cells, were tested in relation to radioactivity concentration applied and location of decay. Different iodine isotopes ((123)I, (125)I, (131)I) bound to DES or in the form of iodide were compared with regard to induction of intracellular DNA (deoxyribonucleic acid) fragmentation, and decrease of viability. For this purpose the 'Cell Death Detection Enzyme-Linked ImmunoSorbent Assay (ELISA)' and the water soluble tetrazolium salt WST-1 were used. The radiation protective effects of the radical scavenger vitamin C were also tested. RESULTS: The experiments showed a significantly lower viability of cells exposed to the Auger emitters than those with the beta-emitter (131)I. All nuclides induced intracellular DNA fragments. The maximum amount of intracellular DNA fragments was different for all nuclides: (131)I-DES <(125)I-DES <(123)I-DES. With isotopes in the form of iodide, no increase of intracellular DNA fragmentation could be detected. Vitamin C reduced intracellular DNA fragmentation significantly, which points to an induction mechanism mainly via free radicals. CONCLUSIONS: Labeled DES is a promising compound with high cytotoxic potential for treatment of ER-positive mamma carcinomas and their metastases.

Yttrium-90 ibritumomab tiuxetan-induced complete remission in a patient with classical lymphocyte-rich Hodgkin's Lymphoma.

BACKGROUND: Radioimmunotherapeutics directed against CD20 have been established in several types of B-cell non-Hodgkin's lymphoma (NHL). Yttrium-90 (90Y) ibritumomab tiuxetan (Zevalin) is the only approved radio - immunoconstruct for NHL in the EU. The malignant Hodgkin's and Reed-Sternberg cells in classical Hodgkin's lymphoma (cHL) express CD20 infrequently. Thus, only very limited data of cHL patients treated with anti- CD20 immunoconstructs are available. To date, none of the patients treated with 90Y ibritumomab tiuxetan demonstrated any response. CASE REPORT: We report on a 78-year-old female patient suffering from a second systemic relapse of classical nodular lymphocyte-rich HL who experienced a complete remission (CR) after treatment with 90Y ibritumomab tiuxetan lasting over a period of 6 months. DISCUSSION: Treatment of patients with cHL with the anti-CD20 monoclonal antibody rituximab resulted in a response rate of 22%. 90Y ibritumomab tiuxetan demonstrated superiority compared with rituximab in a randomized phase III trial. HL represents a radiosensitive tumor responding to anti-CD30 or antiferritin radioimmunotherapy. Further HL patients have to be treated with 90Y ibritumomab tiuxetan to evaluate a potential benefit. CONCLUSION: Treatment with 90Y ibritumomab tiuxetan induced a clinically relevant CR in a patient with CD20-positive cHL. Thus, we will expand treatment of relapsed CD20-positive HL with 90Y ibritumomab tiuxetan at our institution.

Detection of primary choriocarcinoma in the mediastinum by F-18 FDG positron emission tomography.

A 31-year-old woman with a history of infection with human papilloma virus was found to have an elevated human chorionic gonadotropin level (beta-HCG) of more than 9000 IU/L in January 2006. The patient reported an irregular menstrual cycle. Extensive clinical work-up including gynecologic examinations with laparoscopy, hysteroscopy, and curettage were performed but no pathologic explanation of this elevated beta-HCG could be found. In the initial computed tomography (CT) of the abdomen and the thorax, a tumor could not be detected. Based on a clinical decision, chemotherapy with methotrexate in a dose of 1 mg/kg body weight was started. Four months after beginning of the chemotherapy the beta-HCG level dropped to 3048 IU/L. At this time a first F-18 FDG PET was performed and the findings were negative. After completion of 7 cycles of chemotherapy the beta-HCG level rose again. In a second F-18 FDG PET in August 2006 focal, intense and pathologic F-18 FDG accumulation with a SUV max. of 5.4 was seen in the mediastinum in the region of the thymus. At this time the beta-HCG level was 7000 IU/L. In a subsequent CT of the chest a retrosternal mass of 4 x 1.7 cm was detected with contrast enhancement. Resection of the tumor and thymus gland demonstrated a choriocarcinoma in part adjacent to the thymus and in part in the thymus. Postoperative beta-HCG levels dropped to 105 IU/L.

Treatment of refractory Hodgkin's lymphoma patients with an iodine-131-labeled murine anti-CD30 monoclonal antibody.

PURPOSE: Hodgkin's lymphoma (HL) has been demonstrated to be a good target for immunotherapy since lymphocyte activation markers such as CD30 are expressed in high numbers on the malignant cells. Thus, we developed a new radioimmunoconjugate consisting of the murine anti-CD30 monoclonal antibody (MAb) Ki-4 labeled with iodine-131 ((131)I). PATIENTS AND METHODS: The biodistribution of (131)I-Ki-4 was assessed via dosimetry after preinfusion of 5 mg native Ki-4 followed by 250 to 300 MBq (131)I-labeled Ki-4. Whole-body scintigraphy was performed 1 hour, 24 hours, 48 hours, 72 hours, and 6 days after the infusion. Dosimetry was calculated using the programs NucliDose ICON-IDL (version 5.0.2; Siemens, Erlanger, Germany) and MIRDOSE (version 3.1; Oak Ridge National Laboratories; Oak Ridge, TN). The therapeutic dose was given on day 8 after preinfusion of unlabeled Ki-4. RESULTS: We treated 22 patients with relapsed or refractory CD30-positive HL. Preinfusion of 5 mg native Ki-4 was sufficient to bind the soluble CD30. Imaging demonstrated localization of involved areas measuring 5 cm in diameter or more in four patients and 2.5 cm in one patient. Patients received total body doses of 0.035 Gy to 0.99 Gy. Acute toxicity was mild with grade 1 fatigue in 19 of 22 assessable patients. Seven patients experienced grade 4 degrees hematotoxicity 4 to 8 weeks after treatment. Response included one complete remission, five partial remissions, and three minor responses. CONCLUSION: Treatment with (131)I-Ki-4 is effective but can be associated with severe hematotoxicity.

Incidence of postradioiodine immunogenic hyperthyroidism/Graves' disease in relation to a temporary increase in thyrotropin receptor antibodies after radioiodine therapy for autonomous thyroid disease.

BACKGROUND: The aim of the study was to analyze retrospectively the incidence of postradioiodine immunogenic hyperthyroidism/Graves' disease in relation to a temporary increase in TSH-receptor antibodies without overt hyperthyroidism after radioiodine therapy for autonomous thyroid disease. PATIENTS AND METHODS: Between May 2000 and May 2003 all patients (n = 1,357) who had undergone radioiodine therapy for autonomous thyroid disease were retrospectively analyzed for development of postradioiodine immunogenic hyperthyroidism. On pretreatment evaluation 565 of 1,357 patients (41.6%) had unifocal autonomous thyroid disease (UFA), 693 of 1,357 patients (51.1%) had multifocal autonomous thyroid disease (MFA), and 99 of 1,357 patients (7.3%) had diffuse thyroid disease (DISS). Free triiodothyronine (FT(3)), free thyroxine (FT(4)), thyrotropin (TSH), and thyroid antibodies were measured. Ultrasound examinations and thyroid scintigraphy were performed before and after radioiodine therapy. A sensitive assay with the human TSH receptor as antigen was chosen for measurement of the TSH receptor antibody and the study was limited to analysis of data obtained since introduction of this assay. RESULTS: Fifteen of 1,357 patients (1.1%) (UFA, 8/565 = 1.4%; MFA, 6/693 = 0.9%; DISS 1/99 = 1.0%) developed postradioiodine hyperthyroidism between 1 and 13 months after radioiodine therapy with clinically overt hyperthyroidism and an elevation of TSH receptor antibodies. Patients with elevated thyroid peroxidase (TPO) antibodies before radioiodine therapy had an almost 10-fold (6/57 patients =10.5%) higher risk of developing postradioiodine immunogenic hyperthyroidism. Thirteen of 999 patients (1.3%) with antibody measurements after radioiodine therapy (UFA, 2/421 = 0.5%; MFA, 9/494 = 1.8%, DISS, 2/84 = 2.4%) had increased levels of TSH receptor antibodies and, to some extent, TPO antibodies without development of clinically overt hyperthyroidism. CONCLUSIONS: There is an estimated 1.1% risk of developing postradioiodine immunogenic hyperthyroidism/Graves' disease in patients undergoing radioiodine therapy for autonomous thyroid disease and this increases approximately 10-fold when TPO antibody levels are elevated before radioiodine therapy. Furthermore, there is an estimated 1.3% risk of a temporary increase of TSH receptor antibodies after radioiodine therapy for autonomous thyroid disease without development of clinically overt hyperthyroidism.

Cell death induced by 131 I in a differentiated thyroid carcinoma cell line in vitro: necrosis or apoptosis?

AIM: The apoptotic and necrotic dose-response of thyroid carcinoma cells following irradiation with I was evaluated. METHODS: In our in-vitro model, cells of well-differentiated papillary thyroid carcinoma (B-CPAP) were incubated with increasing activity concentrations of I for 2 days. Changes in cell viability and the extents of necrosis and apoptosis were evaluated both immediately and 2 days after irradiation. RESULTS: Viability of B-CPAP cells diminished with increasing I activity concentration. No apoptosis was detectable immediately after irradiation. Two days after irradiation significant apoptosis was found. The lowest I activity concentration at which apoptosis was detectable corresponds to about 1 MBq . ml. At higher activity concentrations a larger percentage of cells became apoptotic but the proportion decreased again at activity concentrations >10 MBq . ml. Likewise, necrosis was minimal at low activity concentrations and showed an exponential increase with rising I activity concentrations (>5-10 MBq . ml). Necrosis was already detectable immediately after irradiation and was the predominant form of cell death at high activity concentrations. CONCLUSION: The data suggest that the nature of the cytotoxic effect of I and whether it leads to apoptotic or necrotic cell death is dose-dependent. High I doses seem to produce mainly necrotic phenomena, whereas at low I activity concentrations apoptotic phenomena prevail. The predominance of delayed apoptosis could explain why radioiodine therapy at lower doses is often linked to delayed onset and possible continuation of thyroid volume reduction over some months and even up to a year.

Localization of 131I-labelled monoclonal antibody ERIC1 in a subcutaneous xenograft model of neuroblastoma in SCID mice.

PURPOSE: To evaluate a novel strategy of immunolocalization of human neuroblastoma by targeting the neural cell adhesion molecule (NCAM), which is over-expressed on neuroblastoma. METHODS: NCAM expression on the cell surface of established neuroblastoma cells was shown by flow cytometry. A SCID mouse model using IMR5-75 neuroblastoma cells to induce subcutaneous tumour growth was established. 131I was used to label monoclonal NCAM specific ERIC1 antibodies generating the 131I-ERIC1 antibody, which showed a high affinity to NCAM also after labelling (KD=9 x 10(-8) mol . l(-1)). RESULTS: Measurement of organ-specific radioactivity showed low organ-specific uptake (5.33%ID/g (percent of injected dose per gram of tissue) after 72 h), which continuously decreased over the 96 h investigation period, demonstrating clearance of radioactivity. In contrast, tumours accumulated radioactivity continuously up to a peak of 42.07%ID/g at the 96 h time point (31.07%ID/g at 72 h). This specific uptake could be blocked by application of unlabelled ERIC1 antibodies. Measurement of blood specific radioactivity revealed a characteristic clearance over the first 72 h. With 37 Gy, tumour-specific radioactivity reached therapeutic doses after 96 h. CONCLUSIONS: These results indicate that 131I-labelled ERIC1 has the ability to probe NCAM-expressing tumour cells in vivo with high efficiency and is a promising reagent for the diagnosis and treatment of NCAM-positive human tumours, especially for neuroblastoma.

False-positive uptake of I-131 in a laryngocele mimicking thyroid remnant after thyroidectomy for papillary thyroid carcinoma.

A 66-year-old woman underwent total thyroidectomy for papillary thyroid carcinoma stage pT4 followed by radioiodine therapy with 3.7 GBq (100 mCi) iodine-131. Radioiodine therapy revealed intense radioiodine uptake of the neck, which was interpreted as thyroid remnant tissue. Follow-up whole-body scans with iodine-131 in hypothyroidism 3 months and 1 year after radioiodine therapy revealed focal uptake in the neck. Computed tomography and gadolinium-enhanced MRI of the neck demonstrated an ovoid lesion in the larynx without gadolinium enhancement. Neither thyroid remnant tissue nor enlarged cervical lymph nodes could be demonstrated either on CT or on MRI. Further examination of the patient in the ear, nose and throat department confirmed the finding of a laryngocele and biopsies demonstrated benign tissue. Follow-up whole-body scans with iodine-131 in hypothyroidism 3 years and after injection of rhTSH 5 years after radioiodine therapy reproduced the focal uptake in the neck. After initial radioiodine therapy thyroglobulin levels were never measurable, not at any of the whole-body scans in hypothyroidism, after rhTSH, or at intermediate follow-up examinations under TSH-suppressive levothyroxine therapy. The patient declined definitive operative revision of the laryngocele and is in good health 8 years after the diagnosis of papillary thyroid carcinoma.

Incidental multifocal papillary microcarcinomas of the thyroid: is subtotal thyroidectomy combined with radioiodine ablation enough?

BACKGROUND: The extent of thyroid resection and the necessity of lymph node dissection has become an issue of controversy in patients with incidental multifocal papillary microcarcinoma. METHOD: Between 1993 and 2001 a total of 4120 patients underwent surgery for thyroid diseases: 142 patients showed papillary thyroid cancer of < or = 1 cm, multifocal microcarcinomas were found in 22 patients (15.5%). Twenty patients (17 women, three men, aged 26-71 years) met the inclusion criterion of having pre- and intraoperatively no indication of malignancy (incidentaloma). A limited surgical procedure ranging from bilateral subtotal (n=15), ipsilateral total, contralateral subtotal (n=4) to bilateral total (n=1) thyroidectomy without lymph node dissection was performed. The mean volume of thyroid remnants was 4.3 ml. RESULTS: In 16/20 (80%) patients, the thyroid remnant was ablated by the first dose of 131I, using 3.7 GBq 131I in 15 patients and 1.85 GBq 131I in one patient. Three patients received a second, and one patient a third radioiodine ablation. All 20 patients remained free from relapse or metastasis, documented by negative 131I whole-body scintigraphy and unmeasurable thyroglobulin levels after thyroid hormone withdrawal in hypothyroidism. One patient died 7 years after the diagnosis of thyroid cancer from primary lung cancer. Median follow-up was 65 months (range, 24-120 months). CONCLUSION: Subtotal thyroidectomy followed by radioiodine therapy without completion thyroidectomy and lymphadenectomy is a possible option in incidental multifocal microcarcinomas.