Cellular response on Auger- and Beta-emitting nuclides: human embryonic stem cells (hESC) vs. keratinocytes.

PURPOSE: We studied the response of human embryonic stem cells (hESC) to the ß-emitter (131)I, which affects the entire cell and to the Auger electron emitter (125)I-deoxyuridine ((125)I-dU), primarily affecting the deoxyribonuleic acid (DNA). The effects were also studied in keratinocytes as a prototype for somatic cells. METHODS: HESC (H1) and human keratinocytes (HaCaT, human) were exposed to (125)I-dU (5 × 10(-5) - 5 MBq/ml) and (131)I-iodide (5 × 10(-5) - 12.5 MBq/ml) and apoptosis was measured by DNA-fragmentation. Cell morphology was studied by light microscopy and electron microscopy. Transcriptional profiling was done on the Agilent oligonucleotide microarray platform. RESULTS: Auger-process induced no apoptosis but a strong transcriptional response in hESC. In contrast, HaCaT cells showed a pronounced induction of apoptosis but only a moderate transcriptional response. Transcriptional response of hESC was similar after (125)I-dU and (131)I treatments, whereas HaCaT cells expressed a much more pronounced response to (125)I-dU than to (131)I. A striking radiation-induced down-regulation of pluripotency genes was observed in hESC whereas in keratinocytes the enriched gene annotations were related primarily to apoptosis, cell division and proliferation. CONCLUSIONS: Human embryonic stem cells respond to ionizing radiation by (125)I-dU and (131)I in a different way compared to keratinocytes. Transcriptional response and gene expression appear to facilitate an escape from programmed cell death by striking a new path which probably leads to cell differentiation.

Visual assessment of dopaminergic degeneration pattern in 123I-FP-CIT SPECT differentiates patients with atypical parkinsonian syndromes and idiopathic Parkinson's disease.

The aim of this study was to investigate whether visual assessment of (123)I-N-ω-fluoropropyl-2ß-carbomethoxy-3ß-(4-iodophenyl)nortropan ((123)I-FP-CIT) single photon emission computed tomography (SPECT) in addition to quantitative analyses can help to differentiate idiopathic Parkinson's disease (PD) from atypical parkinsonian syndromes (APS). From a consecutive series of patients examined with (123)I-FP-CIT SPECT (n = 190) over a three-year period we identified 165 patients with a clinical diagnosis of PD (n = 120) or APS (n = 45). (123)I-FP-CIT SPECT results were analysed visually and quantitatively and compared for PD and APS and for the subgroup of patients with early PD and APS (disease duration <5 years). According to predefined visual patterns of dopaminergic degeneration the results were graded as normal (grade 5) or abnormal (grade 1-4), distinguishing a posterior-anterior degeneration pattern ("egg shape") from a global and severe degeneration pattern ("burst striatum"). Visual assessment of (123)I-FP-CIT SPECT showed significant different dopaminergic degeneration patterns for PD and APS patients. A grade 1 ("burst striatum") degeneration pattern was predominantly associated with APS patients. In contrast to that, a grade 2 (egg shape) degeneration pattern was the characteristic finding in PD patients. In a subgroup of patients with early disease, visual assessment with identification of the burst striatum degeneration pattern provided 90% positive predictive value and 99% specificity for the diagnosis of APS. Quantitative analysis of striatal binding ratios failed to depict these different degeneration patterns in PD and APS patients. Visual assessment of the pattern of dopaminergic loss in (123)I-FP-CIT SPECT shows different patterns of dopaminergic degeneration for PD and APS patients. Therefore, it could provide valuable information to distinguish APS from PD patients, especially in early stages of disease. Within the first 5 years of disease, the occurrence of a burst striatum degeneration pattern has a high positive predictive value of APS.

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.

GATE based Monte Carlo simulation of planar scintigraphy to estimate the nodular dose in radioiodine therapy for autonomous thyroid adenoma.

The recommended target dose in radioiodine therapy of solitary hyperfunctioning thyroid nodules is 300-400Gy and therefore higher than in other radiotherapies. This is due to the fact that an unknown, yet significant portion of the activity is stored in extranodular areas but is neglected in the calculatory dosimetry. We investigate the feasibility of determining the ratio of nodular and extranodular activity concentrations (uptakes) from post-therapeutically acquired planar scintigrams with Monte Carlo simulations in GATE. The geometry of a gamma camera with a high energy collimator was emulated in GATE (Version 5). A geometrical thyroid-neck phantom (GP) and the ICRP reference voxel phantoms "Adult Female" (AF, 16ml thyroid) and "Adult Male" (AM, 19ml thyroid) were used as source regions. Nodules of 1ml and 3ml volume were placed in the phantoms. For each phantom and each nodule 200 scintigraphic acquisitions were simulated. Uptake ratios of nodule and rest of thyroid ranging from 1 to 20 could be created by summation. Quantitative image analysis was performed by investigating the number of simulated counts in regions of interest (ROIs). ROIs were created by perpendicular projection of the phantom onto the camera plane to avoid a user dependant bias. The ratio of count densities in ROIs over the nodule and over the contralateral lobe, which should be least affected by nodular activity, was taken to be the best available measure for the uptake ratios. However, the predefined uptake ratios are underestimated by these count density ratios: For an uptake ratio of 20 the count ratios range from 4.5 (AF, 1ml nodule) to 15.3 (AM, 3ml nodule). Furthermore, the contralateral ROI is more strongly affected by nodular activity than expected: For an uptake ratio of 20 between nodule and rest of thyroid up to 29% of total counts in the ROI over the contralateral lobe are caused by decays in the nodule (AF 3 ml). In the case of the 1ml nodules this effect is smaller: 9-11% (AF) respectively 7-8% (AM). For each phantom, the dependency of count density ratios upon uptake ratios can be modeled well by both linear and quadratic regression (quadratic: r(2)>0.99), yielding sets of parameters which in reverse allow the computation of uptake ratios (and thus dose) from count density ratios. A single regression model obtained by fitting the data of all simulations simultaneously did not provide satisfactory results except for GP, while underestimating the true uptake ratios in AF and overestimating them in AM. The scintigraphic count density ratios depend upon the uptake ratios between nodule and rest of thyroid, upon their volumes, and their respective position in a non-trivial way. Further investigations are required to derive a comprehensive rule to calculate the uptake or dose ratios based on post-therapeutic scintigraphy.

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.

Follow-up on thyroidal uptake after radioiodine therapy: how robust is the peri-therapeutic dosimetry?

Radioiodine therapy (RIT) for benign thyroid diseases in Germany requires the patient to stay in a nuclear medicine therapy ward for at least 48 hours and the dose to the thyroid to be computed from activity measurements performed during that stay. A major part of the total dose will be delivered after the patient's discharge from the hospital and thus has to be predicted through extrapolation with the effective half-life measured peri-therapeutically. We performed repeated thyroid uptake measurements on patients up to five months post therapy to investigate post-therapeutic changes in their effective half-lives and examine the dosimetric consequences. 12 patients (4 m, 8 f; age 36 - 76 y; 4 Graves' disease, 4 toxic adenoma, 3 toxic goitre, 1 non-toxic goitre) underwent late uptake measurements (1 - 7 meas., 13 - 154 d post administration, median 54 d, performed with thyroid probe resp. whole body counter at lower activities). Doses calculated from late measurements were compared to those predicted at discharge; half-lives calculated from the late measurement closest to the median delay (54 d) were compared to those determined at time of discharge. A cross-calibration between activity calibrator, thyroid probe, and whole body counter over an activity range from 52 MBq down to 45 Bq revealed linearity to within 6%, which was considered sufficient. In 9 out of 12 patients the achieved dose was within the range predicted at discharge. Averaged deviation between achieved and predicted dose was 3.1±2.2% (median 2.5%, range 0.7% - 7.2%). Averaged deviation between post- and peri-therapeutic half-lives was 5.1±3.9% (median 3.5%, range 1.3% - 12.5%). For n=5 patients discharged after 3 days, averaged deviations were greater (dose 4.0%, half-life 5.6%) than for those patients (n=7) who stayed in the hospital for a minimum of 4 days (dose 2.5%, half-life 4.8%). Excretion of iodine from the thyroid remains practically unchanged for at least two months after RIT. The dosimetric procedure implemented in our institution warrants a robust prediction of the post-therapeutic half-life and thus the actual achieved dose.

Primary tumour size is a prognostic parameter in patients suffering from differentiated thyroid carcinoma with extrathyroidal growth: results of the MSDS trial.

OBJECTIVE: The Multicentre Study Differentiated Thyroid Cancer (MSDS) collective represents a well-defined group of patients with thyroid carcinomas with extrathyroidal extension. The aim of the present study was to evaluate the relationship of the primary tumour size with clinicopathological features as well as the outcome of patients with minimum and extensive extrathyroidal growth (pT3b- and pT4a-tumours; UICC 2002/2003, 6th ed). METHODS: The tumour diameter was available in 324 out of 351 MSDS patients (244 females, 80 males). Mean age of patients was 47.7±12.0 years (range, 20.1-69.8 years), and the median follow-up was 6.2 years. The relationship between primary tumour size and the following clinicopathological data was investigated: age, gender, histological tumour type (papillary thyroid carcinomas (PTC) versus follicular thyroid carcinomas (FTC)) and UICC/AJCC TNM classification. In addition, the correlation between primary tumour size and event-free and overall survival was assessed. RESULTS: The FTC of our series were significantly larger than PTC (3.46 vs 1.84 cm; P<0.001). Patients suffering from pT3b-tumours presented with significantly smaller tumour size than those with extensive extrathyroidal growth (pT4a-tumours) (1.9 vs 3.0 cm; P<0.01). All patients with distant metastases suffered from tumours >2 cm. Furthermore, event-free and overall survival were significantly correlated with increasing tumour size (P<0.05). Using multivariate analysis, a pT4a-category and a tumour diameter >2 cm remained independent predictors of survival. CONCLUSIONS: In patients suffering from differentiated thyroid carcinoma with extrathyroidal growth (pT3b and pT4a), the tumour size is an independent predictor of event-free and overall survival.

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.

Radioiodine therapy of benign thyroid disorders: what are the effective thyroidal half-life and uptake of 131I?

AIM: The use of radioiodine therapy is common in the treatment of benign thyroid disease. Council directive Euratom 97/43 requires that for all medical exposure of individuals for radiotherapeutic purposes exposures of target volumes should be individually planned. There are several strategies to accomplish this aim for radioiodine therapy including individual radioiodine uptake measurement and using either individual or mean effective radioiodine uptake and half-life. Although it is always simple to use standard activities, the effective thyroidal half-life and thyroidal uptake of I needs to be estimated individually to achieve optimal dosimetric results. We analyzed the radioiodine half-life and uptake in a large number of patients for use in a semi-individual calculation. METHODS: Patients presenting consecutively between 1 January 2006 and 31 December 2007 were included in the study. Inclusion criteria were the control of hyperthyroidism and withdrawal of antithyroid drugs 2 days before preliminary radioiodine testing and therapy. Patients were treated for Graves' disease (n=363), nontoxic goitre (n=50), toxic goitre (n=639), or toxic uninodular adenoma (n=365). The effective half-life and uptake of I were estimated by uptake measurements after 24 h and 5 days during the preliminary radioiodine test, and serial measurements over 5 days during therapy. RESULTS: The mean effective half-life of I measured during radioiodine therapy was 5.4 days in Graves' disease, 6.4 days in nontoxic goitre, 6.6 days in toxic goitre, and 5.7 days in toxic uninodular adenoma. The mean maximal uptake of I measured during radioiodine therapy was 64% in Graves' disease, 42% in nontoxic goitre, 38% in toxic goitre, and 31% in toxic uninodular adenoma. CONCLUSION: These actual values analyzed here might be used for a semi-individual calculation of therapeutic activity when an individual approach is not possible.

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.

[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.

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.

Radioiodine therapy for thyroid volume reduction of large goitres.

OBJECTIVE: To evaluate the effect of radioiodine therapy for volume reduction in large goitres. METHODS: A retrospective study was performed involving 88 patients treated between 2001 and 2007 with radioiodine for toxic or nontoxic goitres. The goitres were between 80 and 250 ml in volume (median 127 ml+/-38.57). Activities of I to be administered were calculated individually through radioiodine testing with uptake measurements over 5 days, the mean activity being 1721+/-440 MBq I (714-2395 MBq I), equivalent to a mean of 14+/-4.19 MBq I/g of thyroid tissue (6-24 MBq I/g of thyroid tissue). The designated dose was 150 Gy for the entire thyroid volume, and post-therapeutic dosimetry revealed a mean thyroid dose of 175+/-45.92 Gy (64-300 Gy). Control examinations were performed, including thyroid blood testing and thyroid ultrasound at 6 weeks and at 3, 6, 12, 24, 36, 48 and 72 months after radioiodine therapy. RESULTS: The mean volume reduction was 41.9% after 3 months and 65.9% after 1 year. Thyroid volume reduction was highly significant (P<0.001) in the first year after radioiodine therapy. No volume increase was observed in any patient during follow-up. Unfortunately, many patients were lost during follow-up (n = 84 after 3 months, n = 38 after 1 year). CONCLUSION: Radioiodine therapy is an effective treatment for both nontoxic and toxic goitres, resulting in a highly significant thyroid volume reduction of nearly 66% within 1 year.

[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.

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.

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.

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.

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.

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.

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.