Lymphocyte function following radioiodine therapy in patients with thyroid carcinoma.

AIM: Since the nuclear disaster in Fukushima has raised great concern about the danger of radioactivity, we here addressed the question if the therapeutic use of iodine 131, the most frequently applied radionuclide, was harmful to immune function in patients. It was our aim to define for the first time in a clinical setting how radioiodine therapy alters anti-microbial immune responses. PATIENTS, METHODS: In 21 patients with thyroid carcinoma anti-microbial lymphocyte responses were assessed by lymphocyte transformation test and ELISpot - measuring lymphocyte proliferation and on a single cell level production of pro- and anti-inflammatory cytokines (interferon-γ and interleukin-10) - prior to therapy, at day 1 and day 7 post therapy. RESULTS: Proliferative lymphocyte responses and interferon-γ production after in vitro stimulation with microbial antigens were significantly (p < 0.05) increased at day 1 vs. pre therapy, and returned to pre therapy levels at day 7. On the contrary, at day 1 interleukin-10 production was significantly (p < 0.05) reduced. Thus, we observed a short-term increase in pro-inflammatory immune responses. However, T lymphocyte responses were in the range of healthy controls at all three time points. CONCLUSION: Thyroid carcinoma patients receiving radioiodine therapy do not display any sign of immunosuppression.

Diagnostic accuracy of noninvasive polymerase chain reaction testing for the determination of fetal rhesus C, c and E status in early pregnancy.

OBJECTIVE: The aim of the study was to determine the sensitivity, specificity and accuracy of noninvasive tests for the fetal rhesus CcEc (RHCE) alleles C, c and E in early pregnancy. DESIGN: A prospective clinical trial was carried out to evaluate diagnostic accuracy. SETTING: Women were recruited at four centres specialising in prenatal diagnosis. Peripheral blood and amniotic fluid samples were obtained and sent to a single laboratory for analysis. SAMPLE: A total of 233 tests (46 for C, 87 for c and 100 for E) were performed on 181 specimens obtained from pregnant women at weeks 12 to 28 (median week 16) of gestation. METHODS: Following automated extraction of fetal DNA from maternal plasma, two different real-time polymerase chain reaction (PCR) protocols were used for the detection of the C, c and E alleles of RHCE. The results of the PCR were compared with genotyping results for the amniotic fluid. MAIN OUTCOME MEASURES: Failure rate, sensitivity, specificity and accuracy were the main outcome measures. RESULTS: Unequivocal results were obtained for all specimens. With the first PCR protocol, the sensitivity was 100% for C, 38% for c and 59% for E. In contrast, with the second protocol, the sensitivity for C, c and E was 100%. The specificity for all assays was found to be between 99% and 100%. CONCLUSIONS: A highly accurate protocol has been identified for the detection of fetal RHCE alleles in maternal plasma in early pregnancy. This noninvasive approach can be considered as a useful test in the management of pregnancies with anti-c, anti-E or anti-C alloimmunisation.

[Impact of nuclear medicine imaging techniques for lymph node surgery]. / Bedeutung der nuklearmedizinischen Bildgebung für die Lymphknotenchirurgie.

Nuclear medicine imaging techniques allow the noninvasive in vivo visualization of cellular and subcellular molecular processes. In the context of lymph node surgery and patient management in uro-oncology, two molecular nuclear imaging techniques deserve special interest: positron emission tomography (PET) for staging, restaging, and follow-up, and preoperative identification and subsequent biopsy of the sentinel lymph node (the first lymph node in the lymphatic drainage system of the tumor). Both methods and their clinical potential are described in this review. Future trends in molecular imaging in uro-oncology are also discussed.

[Evil radioactivity. Subjective perception of radioactivity in patients with thyroid disease prior to treatment with radioiodine]. / Radioaktivität ist böse: Subjektive Konzepte von Radioaktivität bei Schilddrüsenpatienten vor einer möglichen Radioiodtherapie.

AIM: We assess the perspective of patients with thyroid disease towards radiation and radioactivity by means of a cultural-anthropological approach based on qualitative measures and quantitative scores. From the interviews with the patients we evaluate as to how much radioactivity is accepted as an abstract term or as a benefit within the medical context. PATIENTS, METHODS: 68 patients with autonomously functioning thyroid lesions (35 women, 33 men, 32-81 years) were included in this study. All patients were interviewed in an open dialogue with the principal investigator. Patients were asked to describe their attitude towards radioactivity in general and towards radioiodine therapy in particular. Patients were asked to use a scoring system (1 = positive, 5 = negative) to quantify their attitudes. RESULTS: The responses of all patients towards radioactivity in general were heterogeneous with most responses reflecting a negative perception. Many patients expressed their associated fears about atomic energy, malignant diseases and radioactive contamination. The scoring system reflected a mostly negative opinion base. However, patients became more positive once they assumed an immediate benefit of radioactivity for the treatment of their own disease (p = 0.01). CONCLUSIONS: Knowing about significant differences in patient's perception about radioactivity in general or in the clinical context may help to optimise and tailor the initial, pre-therapeutical interview towards the patient.

[Value of imaging for lymph node metastases from renal cell, bladder, prostate, penile, and testicular cancers]. / Wertigkeit der Bildgebung für die Lymphknotenmetastasierung beim Nierenzell-, Blasen-, Prostata- und Peniskarzinom sowie dem Hodentumor.

Computed tomography (CT) imaging is the standard method for the assessment of lymph node metastases in renal cell and testicular cancer. In bladder cancer and prostate cancer the results of CT are not convincing due to a large number of false-negative findings and the prognostic relevance of undetected metastases. For both entities recent studies revealed that MR lymphography using iron oxide particles allows the detection of small metastatic lymph nodes. For penile cancer reliable results for imaging of lymph node metastases do not exist. PET imaging using [(18)F]-fluorodeoxyglucose (FDG) is the modality of choice in therapy control of seminomas but has no defined value in other urological malignancies. PET with [(11)C] choline and [(11)C] acetate offers great potential in staging and restaging of prostate cancer. Further investigations are necessary to determine the role of these new methods.

Value of (124)I-PET/CT in staging of patients with differentiated thyroid cancer.

The aim of this study is to evaluate the clinical significance of (124)I positron emission tomography (PET) using a combined PET/CT tomograph in patients with differentiated thyroid carcinoma and to compare the PET/CT results with (131)I whole-body scintigraphy (WBS), dedicated PET and CT alone. Twelve thyroid cancer patients were referred for diagnostic workup and entered complete clinical evaluation, including histology, cytology, thyroglobulin level, ultrasonography, fluorine-18 fluorodeoxyglucose (FDG)-PET, FDG-PET/CT and CT. Lesion-based evaluation showed a lesion delectability of 56, 87 and 100% for CT, (124)I-PET, and combined (124)I-PET/CT imaging, respectively. Lesion delectability of (131)I-WBS was 83%. We conclude that (124)I-PET/CT imaging is a promising technique to improve treatment planning in thyroid cancer. It is particularly valuable in patients suffering from advanced differentiated thyroid cancer prior to radio-iodine therapy and in patients with suspected recurrence and potential metastatic disease.

FDG-PET/CT in re-staging of patients with lymphoma.

The aim of this study was to evaluate the clinical significance of combined fluorine-18 fluorodeoxyglucose positron emission tomography and computed tomography (FDG-PET/CT) in patients with lymphoma, and to compare the FDG-PET/CT staging results with those of FDG-PET and CT alone. Twenty-seven patients were studied. Each patient had clinical follow-up for >12 months and entered complete follow-up evaluation. Patient-based evaluation showed a sensitivity of 78% for CT alone, 86% for FDG-PET alone, 93% for CT and FDG-PET read side by side, and 93% for combined FDG-PET/CT imaging. Region-based evaluation showed a sensitivity for regional lymph node involvement of 61%, 78%, 91% and 96% respectively. FDG-PET/CT imaging is superior to CT alone ( P=0.02) and has additional benefit over FDG-PET alone due to exact anatomical localisation. We conclude that FDG-PET/CT imaging is accurate in re-staging lymphoma and offers advantages over separate FDG-PET and CT imaging.

Cortical activation to auditory mismatch elicited by frequency deviant and complex novel sounds: a PET study.

The analysis of auditory deviant events outside the focus of attention is a fundamental capacity of human information processing and has been studied in experiments on Mismatch Negativity (MMN) and the P3a component in evoked potential research. However, generators contributing to these components are still under discussion. Here we assessed cortical blood flow to auditory stimulation in three conditions. Six healthy subjects were presented with standard tones, frequency deviant tones (MMN condition), and complex novel sounds (Novelty condition), while attention was directed to a nondemanding visual task. Analysis of the MMN condition contrasted with thestandard condition revealed blood flow changes in the left and right superior temporal gyrus, right superior temporal sulcus and left inferior frontal gyrus. Complex novel sounds contrasted with the standard condition activated the left superior temporal gyrus and the left inferior and middle frontal gyrus. A small subcortical activation emerged in the left parahippocampal gyrus and an extended activation was found covering the right superior temporal gyrus. Novel sounds activated the right inferior frontal gyrus when controlling for deviance probability. In contrast to previous studies our results indicate a left hemisphere contribution to a frontotemporal network of auditory deviance processing. Our results provide further evidence for a contribution of the frontal cortex to the processing of auditory deviance outside the focus of directed attention.

SPECT imaging with [123I]-beta-CIT in Parkinsonism: comparison of SPECT images obtained by a single-headed and a three-headed gamma camera.

Single photon emission computed tomography (SPECT) imaging of dopamine transporters by using the cocaine derivative [123I]-(1R)-2-beta-carbomethoxy-3-beta-(4-iodophenyl)-tropane ([123I]-beta-CIT) has been shown to be useful in patients with Parkinsonism. The aim of this study was to compare beta-CIT imaging with single-headed (SHS) and three-headed gamma camera systems (THS). In 17 patients with Parkinsonism, SPECT imaging with an SHS and a THS was performed 24 h after injection of 180 MBq of [123I]-beta-CIT. The SPECT studies were evaluated by visual assessment of the caudate nucleus (CN) and the putamen (PT) and the calculation of the striatal/cerebellar (S/C) ratios (with additional comparison to clinical symptoms measured by the Unified Parkinson's Disease Rating Scale (UPDRS)). The S/C ratios measured by the SHS and THS showed highly significant correlation (two-tailed P < 0.01) with Spearman correlation coefficients (SCCs) of 0.864 for the right side, 0.676 for the left side, and 0.761 for both sides. By the SHS, a sufficient visual differentiation between the CN and the PT could not be achieved. A significantly better distinction could be achieved by using the THS (Wilcoxon P<0.05). The S/C ratios of the THS only showed a significant (P < 0.05) SCC of -0.514 comparing to the UPDRS. Pathological alterations in the beta-CIT uptake pattern could be identified by using the SHS, but a significantly better differentiation of CN and the PT was possible by using the THS. The significant correlation of the S/C ratios measured by THS only emphasizes the value of THS in beta-CIT imaging.

Evaluation of scatter compensation methods by their effects on parameter estimation from SPECT projections.

Three algorithms for scatter compensation in Tc-99m brain single-photon emission computed tomography (SPECT) were optimized and compared on the basis of the accuracy and precision with which lesion and background activity could be simultaneously estimated. These performance metrics are directly related to the clinically important tasks of activity quantitation and lesion detection, in contrast to measures based solely on the fidelity of image pixel values. The scatter compensation algorithms were (a) the Compton-window (CW) method with a 20% photopeak window, a 92-126 keV scatter window, and an optimized "k-factor," (b) the triple-energy window (TEW) method, with optimized widths of the photopeak window and the abutting scatter window, and (c) a general spectral (GS) method using seventeen 4 keV windows with optimized energy weights. Each method was optimized by minimizing the sum of the mean-squared errors (MSE) of the estimates of lesion and background activity concentrations. The accuracy and precision of activity estimates were then determined for lesions of different size, location, and contrast, as well as for a more complex Bayesian estimation task in which lesion size was also estimated. For the TEW and GS methods, parameters optimized for the estimation task differed significantly from those optimized for global normalized pixel MSE. For optimal estimation, the CW bias of activity estimates was larger and varied more (-2% to 22%) with lesion location and size than that of the other methods. The magnitude of the TEW bias was less than 7% across most conditions, although its precision was worse than that of CW estimates. The GS method performed best, with bias generally less than 4% and the lowest variance; its root-mean square (rms) estimation error was within a few percent of that achievable from primary photons alone. For brain SPECT, estimation performance with an optimized, energy-based, subtractive correction may approach that of an ideal scatter-rejection procedure.

Increased expression of endothelin-1 and inducible nitric oxide synthase isoform II in aging arteries in vivo: implications for atherosclerosis.

We here report that aging increases expression of endothelin-1 and NO synthases in the vasculature and kidney of normotensive rats in vivo. Expression of preproendothelin-1 mRNA was quantified by RT-PCR and in situ hybridization, and endothelin-1 protein was determined by radioimmunoassay/HPLC. Vascular mRNA expression of NO synthase isoforms II and III was analyzed by RT-PCR. In young animals, vascular endothelin-1 protein was differentially expressed (aorta < renal artery < carotid artery) and increased with aging in all vascular beds (P < 0.05). In the intact aorta of aged rats, mRNA expression of preproendothelin-1, "inducible" NO synthase II, and endothelial cell NO synthase III gene was up-regulated (P < 0.05). Moreover, preproendothelin-1 mRNA expression increased in glomeruli and tubulointerstitial cells (P < 0.05). To our knowledge this is the first study demonstrating local vascular up-regulation of the trophic factor endothelin under physiological conditions. Activation of vascular endothelin and NO synthases may be important, pressure-independent factors contributing to structural and functional abnormalities of age-dependent diseases, including atherosclerosis.

Results of a humanitarian otologic and audiologic project performed outside of the United States: lessons learned from the "Oye, Amigos!" project.

From 1989 to 1993, "Oye, Amigos!" a combined group of hearing health and other medical professionals performed 18 humanitarian medical and audiologic trips to Tepic, Nayarit, Mexico. The group saw 1500 patients, issued over 800 hearing aids, and performed 150 surgeries on 123 patients. Our tympanoplasty success rate, defined as an intact tympanic membrane, was 41% during the first 2 years of the project but increased to 74% during the last 3 years. Two hundred eighteen patients who were candidates for surgery did not return for care. We present the lessons learned from the surgical care and overall management of this project, and present suggestions to improve future projects.

The value of fluorine-18 fluorodeoxyglucose PET in patients with medullary thyroid cancer.

The early detection of metastases from medullary thyroid cancer (MTC) is important because the only curative therapy consists in surgical removal of all tumour tissue. There is no single sensitive diagnostic imaging modality for the localization of all metastases in patients with MTC. Therefore, in many cases several imaging modalities (e.g. ultrasonography, magnetic resonance imaging, computerized tomography and scintigraphy using pentavalent technetium-99m dimercaptosuccinic acid, thallium-201 chloride, indium-111 pentetreotide, anti-CEA antibodies or metaiodobenzylguanidine) must be performed consecutively in patients with elevated calcitonin levels until the tumour is localized. In this prospective study, we investigated the value of fluorine-18 fluorodeoxyglucose positron emission tomography ([18F]FDG PET) in the follow-up of patients with MTC. [18F]FDG PET examinations of the neck and the chest were performed in 20 patients with elevated calcitonin levels or sonographic abnormalities in the neck. Positive [18F]FDG findings were validated by histology, computerized tomography or selective venous catheterization. [18F]FDG PET detected tumour in 13/17 patients (nine cases were validated by histology, four by computerized tomography). Five patients showed completely negative PET scans (of these cases, one was true-negative and four false-negative). One patient with [18F]FDG accumulation in pulmonary lesions from silicosis and one patient with a neck lesion that was not subjected to histological validation had to be excluded. Considering all validated localizations, [18F]FDG PET detected 12/14 tumour manifestations in the neck, 6/7 mediastinal metastases, 2/2 pulmonary metastases and 2/2 bone metastases. In two patients with elevated calcitonin levels, no diagnostic modality was able to localize a tumour. The sensitivity of [18F]FDG PET in the follow-up of MTC was 76% (95% confidence interval 53%-94%); this is encouraging. [18F]FDG PET promises to be a valuable diagnostic method, especially for the detection of lymph node metastases, surgical resection of which can result in complete remission.

A possible role of the human cerebellum in conditioning of the jaw-opening reflex.

The role of the human cerebellum in classical conditioning of the jaw-opening reflex was investigated using positron emission tomography (PET) in healthy subjects. The jaw-opening reflex was elicited by electrical stimulation of the right corner of the mouth (unconditioned stimulus, US). The conditioned stimulus was a tone preceding the US and coterminating with the US. Changes of regional cerebral blood flow (rCBF) were correlated with the rate of conditioning per PET scan. Conditioning effects were present in one third of all subjects. In these subjects, a significant increase of rCBF in the ipsilateral, intermediate cerebellum was shown during ongoing conditioning. Thus, the intermediate cerebellum appears to be involved in classical conditioning of the jaw-opening reflex in humans.

[Relationship between thyroglobulin and reliability of thallium 201 scintigraphy in differentiated thyroid cancer]. / Beziehung zwischen Thyreoglobulin und der Treffsicherheit der Thallium-201-Szintigraphie differenzierter Schilddrüsenkarzinome.

AIM: Tumor scintigraphy with 201-TlCl is an established diagnostic method in the follow-up of differentiated thyroid cancer. We investigated the relationship between thyroglobulin (Tg) level and tumor detectability. SUBJECT AND METHODS: We analyzed the scans of 122 patients (66 patients with proven tumor). The patient population was divided into groups with Tg above (N = 33) and below (N = 33) 5 ng/ml under TSH suppression or above (N = 33) and below (N = 33) 50 ng/ml under TSH stimulation. Tumor detectability was compared by ROC-analysis (True-Positive-Fraction test, specificity 90%). RESULTS: There was no significant difference (sensitivity 75% versus 64%; p = 0.55) for patients above and below 5 ng/ml under TSH suppression and a just significant difference (sensitivity 80% versus 58%; p = 0.04) for patients above and below 50 ng/ml under TSH stimulation. In 18 patients from our sample with tumor, Tg under TSH suppression was negative, but 201-TlCl-scan was able to detect tumor in 12 patients. CONCLUSION: Our results demonstrate only a moderate dependence of tumor detectability on Tg level, probably without significant clinical relevance. Even in patients with slight Tg elevation 201-TlCl scintigraphy is justified.

Training-induced brain plasticity in aphasia.

It has long been a matter of debate whether recovery from aphasia after left perisylvian lesions is mediated by the preserved left hemispheric language zones or by the homologous right hemisphere regions. Using PET, we investigated the short-term changes in the cortical network involved in language comprehension during recovery from aphasia. In 12 consecutive measurements of regional cerebral blood flow (rCBF), four patients with Wernicke's aphasia, caused by a posterior left middle cerebral artery infarction, were tested with a language comprehension task. Comprehension was estimated directly after each scan with a modified version of the Token Test. In the interval between the scans, the patients participated in brief, intense language comprehension training. A significant improvement in performance was observed in all patients. We correlated changes in blood flow measured during the language comprehension task with the scores achieved in the Token Test. The regions which best correlated with the training-induced improvement in verbal comprehension were the posterior part of the right superior temporal gyrus and the left precuneus. This study supports the role of the right hemisphere in recovery from aphasia and demonstrates that the improvement in auditory comprehension induced by specific training is associated with functional brain reorganization.

Involvement of the human cerebellum during habituation of the acoustic startle response: a PET study.

The present study investigated the involvement of the human cerebellum in the habituation of the acoustic startle response using PET. The startle response was elicited in seven young, healthy subjects by a tone presented via headphones. Startle responses were recorded from the right sternocleidomastoid muscle. Regional cerebral blood flow (rCBF) was assessed in nine scans and one startle stimulus was applied during each scan. The reduction of size of the sternocleidomastoid muscle response was correlated with changes in rCBF during the ongoing process of startle response habituation. A significant decrease of rCBF was found in the medial cerebellum. These data are consistent with an involvement of the medial parts of the human cerebellum in non-associative learning as proposed by previous animal studies.

Technetium-99m-furifosmin in the follow-up of differentiated thyroid carcinoma.

UNLABELLED: Tumor scintigraphy with flow tracers, such as 201TI-chloride, has an established role in the follow-up of differentiated thyroid cancer. We investigated a new tracer, 99mTc-furifosmin (Technescan Q12, Mallinckrodt Diagnostika, Hennef, Germany), in patients with elevated thyroglobulin levels or sonographic suspicion of lymph node metastases or recurrent disease. METHODS: In a prospective study, we examined 20 patients with 99mTc-furifosmin. All patients underwent a 18F-fluorodeoxyglucose (FDG) PET scan of the neck and chest. Positive 99mTc-furifosmin findings were validated by biopsy, (131)I scan, CT or 18F-FDG PET examinations. RESULTS: In three patients with cervical lymph node metastases detected on a planar 99mTc-furifosmin scan, we found a rapid tracer accumulation in the tumor (maximum < 2 min) and a significant washout in 2 of 3 patients after 4 hr. The visual contrast and the tumor-to-nontumor ratio was rather poor (average 1.2:1). In 3 additional patients, 3 pulmonary and 2 mediastinal lymph node metastases were detected by the 99mTc-furifosmin SPECT scan. Two patients were true-negative, and in 13 of 18 patients, the tumor could be localized by 18F-FDG PET (10 cervical, 6 mediastinal, 4 pulmonary metastases, 1 bone metastasis); 5 patients were false-negative. In 3 of these false-negative cases we could not localize the tumor with other diagnostic methods. Two patients had a true-negative PET examination. CONCLUSION: The statistical analysis of our data on 99mTc-furifosmin reveals that the sensitivity and 95% confidence interval of 33% (11%-56%) on a patient-by-patient basis and of 34% (17%-57%) for the lesion-by-lesion analysis is significantly lower than the sensitivity and 95% confidence interval of 72% (50%-89%) on a patient-by-patient basis and of 91% (78%-100%) on lesion-by-lesion basis for 18F-FDG. The sensitivity of 99mTc-furifosmin appears to be poor, even for cervical and mediastinal tumor manifestations where the value of 201TI-chloride is established.

A method for approximating the density of maximum-likelihood and maximum a posteriori estimates under a Gaussian noise model.

The performance of maximum-likelihood (ML) and maximum a posteriori (MAP) estimates in non-linear problems at low data SNR is not well predicted by the Cramér-Rao or other lower bounds on variance. In order to better characterize the distribution of ML and MAP estimates under these conditions, we derive a point approximation to density values of the conditional distribution of such estimates. In an example problem, this approximate distribution captures the essential features of the distribution of ML estimates in the presence of Gaussian-distributed noise.