Clinical Relevance of Computed Tomography Pulmonary Venography.

BACKGROUND: In clinical routine, the pulmonary contrast-enhanced chest computer tomography (CT) is usually focussed on the pulmonary arteries. The purpose of this pictorial essay is to raise the clinicians' awareness for the clinical relevance of CT pulmonary venography. CASE PRESENTATION: A pictorial case series illustrates the clinical consequences of different pulmonary venous pathologies on systemic, pulmonary and bronchial circulation. CONCLUSION: Computed tomography pulmonary venography must be considered before atrial septal defect (ASD) closure and pulmonary lobectomy. Computed tomography pulmonary venography should be considered for patients with right ventricular overload and pulmonary hypertension, as well as for patients with unclear recurrent pulmonary infections, progressive dyspnoea, pleural effusions, haemoptysis, and for patients with respiratory distress after lung-transplantation.

Improving external beam radiotherapy by combination with internal irradiation.

The efficacy of external beam radiotherapy (EBRT) is dose dependent, but the dose that can be applied to solid tumour lesions is limited by the sensitivity of the surrounding tissue. The combination of EBRT with systemically applied radioimmunotherapy (RIT) is a promising approach to increase efficacy of radiotherapy. Toxicities of both treatment modalities of this combination of internal and external radiotherapy (CIERT) are not additive, as different organs at risk are in target. However, advantages of both single treatments are combined, for example, precise high dose delivery to the bulk tumour via standard EBRT, which can be increased by addition of RIT, and potential targeting of micrometastases by RIT. Eventually, theragnostic radionuclide pairs can be used to predict uptake of the radiotherapeutic drug prior to and during therapy and find individual patients who may benefit from this treatment. This review aims to highlight the outcome of pre-clinical studies on CIERT and resultant questions for translation into the clinic. Few clinical data are available until now and reasons as well as challenges for clinical implementation are discussed.

Dosimetric measurements of (68)Ga-high affinity DOTATATE: twins in spirit - part III.

PURPOSE: 68Ga-labelled compounds are increasingly used for somatostatin-receptor scintigraphy because of their favourable biokinetic properties, a higher tumour-to-background contrast and higher diagnostic accuracy compared to the gamma-emitting tracer 111In-DTPA-octreotide. Recently, we have introduced the new tracer 68Ga-DOTA-3-iodo-Tyr3-Thr8-octreotide (68Ga-HA-DOTATATE). The present study demonstrates the biodistribution and radiation dosimetry of this tracer in humans. PATIENTS, METHODS: Seven men were enrolled in this analysis. Every patient underwent a 20 min dynamic PET scan after intravenous injection of about 114 ± 9 MBq of 68Ga-HA-DOTATATE. This was followed by two whole-body scans at 30 min p. i. and 120 min p. i. Blood radioactivity concentration was determined non-invasively from a ROI drawn over the aorta. Urine was collected until the time of the last scan. Liver, spleen, kidneys and urinary bladder wall were included in the dosimetric estimation that was carried out with the software package OLINDA 1.0. RESULTS: Physiological 68Ga-HA-DOTATATE uptake was observed in the pituitary gland, thyroid, salivary glands, liver, spleen, kidneys, urinary bladder, adrenals and intestine. Organs with the highest absorbed dose were spleen (0.26 ± 0.11 mSv/MBq), kidneys (0.14 ± 0.03 mSv/MBq) and liver (0.12 ± 0.02 mSv/MBq).The estimated effective dose was 0.024 ± 0.001 mSv/MBq. CONCLUSION: Our study demonstrates biokinetics and radiation exposure of the 68Ga-labelled tracer HA-DOTATATE to be comparable to other 68Ga-labelled SSR analogues in clinical use.

Modification of staging and treatment of head and neck cancer by FDG-PET/CT prior to radiotherapy.

BACKGROUND AND PURPOSE: Reliable tumor staging is a fundamental pre-requisite for efficient tumor therapy and further prognosis. The aim of this study was to compare head and neck cancer (HNC) staging before and after FDG-PET/CT, evaluating the stage modifications for radiotherapy (RT) planning. PATIENTS AND METHODS: A total of 102 patients with untreated primary HNC, who underwent conventional staging and staging including FDG-PET/CT before RT, were enrolled in this retrospective study. Blinded pre-FDG-PET/CT and post-FDG-PET/CT staging data were compared. The impact on patient management was tested by comparing the intention before and after FDG-PET/CT. RESULTS: Significant modifications of T, N, and M stage as well as clinical stage were detected after inclusion of FDG-PET/CT data (p = 0.002, 0.0006, 0.001, 0.03, respectively). Overall, the implementation of FDG-PET/CT led to modification of RT intention decision in 14 patients. CONCLUSIONS: FDG-PET/CT demonstrates essential influence on tumor staging in HNC patients scheduled for irradiation. Implementation of FDG-PET/CT in imaging protocol improves selection of candidates for curative and palliative RT and allows further optimization of treatment management and therapy intention.

Two or four hour [¹8F]FMISO-PET in HNSCC. When is the contrast best?

UNLABELLED: [¹8F]Fluoromisonidazole positron emission tomography (FMISO-PET) is a non invasive imaging technique that can assist detecting intra tumour regions of hypoxia. FMISO-PET evinces comparatively low signal-to-noise-ratio (SNR) and may be acquired dynamically or after different uptake times post injection (p.i.). The aim of this study was to identify, if static images acquired two hours (MISO2) or four hours (MISO4) p.i. reveal higher contrast. PATIENTS, METHODS: As part of a prospective trial, 23 patients with cancers of the head and neck underwent [¹8F]fluorodeoxyglucose (FDG) PET before and during curative radiochemotherapy. Additionally, FMISO-PET studies 2 h and 4 h p.i. were done before treatment and after a mean dose of 11Gy, 23 Gy and 57 Gy during RCT. After coregistration, a dedicated software was used to define the gross tumour volume (GTV) by FDG PET for the primary tumour. This volume was overlaid to the FMISO images and hypoxia within the GTV was determined. The contrast between hypoxia determined by MISO2 and by MISO4 was investigated and analysed with the Wilcoxon-matched-pairs test. RESULTS: Mean SUVmax in tumours of all examinations was 2.2 (stdev: 0.4, min: 1.3, max: 3.4) after 2 h and 2.4 (stdev: 0.7, min: 1.1, max: 4.4) after 4 h. In the neck musculature the mean SUVmax was 1.5 at both time points and the mean SUVmean decreased from 1.2 after 2 h to 1.1 after 4 h, respectively. These effects resulted in significantly rising contrast ratios from MISO2 to MISO4. The differently defined contrasts revealed significantly higher values for examinations 4 h p.i. (p < 0.002). CONCLUSION: Data acquisition of [¹8F]FMISO should be done 4 h p.i. to gather the optimal contrast, preferably allowing further analysis, e. g. hypoxic sub volume definition for therapy planning.

[Ventilation-perfusion-lungscintigraphy using PET and 68Ga-labeled radiopharmaceuticals]. / Ventilations-Perfusions-Lungenszintigraphie mit der PET und 68Ga-markierten Radiopharmaka.

AIM: Imaging of lung perfusion with positron emission tomography (PET) is already possible with 68Ga labeled denaturized albumin. The purpose of our study was to produce and test a 68Ga labeled aerosol (Galligas®) for ventilation and 68Ga labeled albumin particles (microspheres) for perfusion imaging with PET. PATIENTS, METHODS: Galligas was produced by simmering and burning generator eluted 68Ga solution (100 MBq/0.1 ml) in an ordinary technegas generator. Fifteen patients with suspicion on pulmonary embolism underwent PET/CT (Biograph 16) after inhalation of Galligas and application of 68Ga labeled microspheres. A low dose CT was acquired for attenuation correction (AC). Images were reconstructed with and without AC. The inhaled activity was calculated compared to the activity injected. RESULTS: Inhaled radioaerosol Galligas demonstrated typical distribution as known from 99mTc-labeled technegas with homogeneous distribution in lung without hilar deposits. Attenuation corrected images resulted in artefacts in the lung base. Therefore, non-corrected images were used for making the results. Three out of fifteen patients showed a deficient perfusion whereas ventilation was normal corresponding to pulmonary embolism. CONCLUSION: Lung scintigraphy with PET is feasible. Galligas is simple to produce (analogously to technegas). 68Ga labeled microspheres are available. The method is applicable to daily routine and rendered clinically relevant informations.

Continuously increasing sensitivity over three generations of TSH receptor autoantibody assays.

Thyroid stimulating hormone (TSH) receptor (TSHR) antibodies (TRAb) are the hallmarks in serological diagnosis of Graves' disease (GD, autoimmune hyperthyroidism). In the 1980s, the first generation liquid-phase TRAb assay with detergent solubilized porcine TSHR was introduced into routine thyroid serology and proved to be highly specific for GD, albeit with moderate sensitivity. In the 1990 s, second generation solid-phase TRAb assays with immobilized porcine or recombinant human TSHR became available, and were clearly more sensitive for Graves' disease without loss of specificity. Recently, third generation TRAb assays have been developed, in which the human thyroid stimulating monoclonal antibody M22 replaces bovine TSH as the competing reagent for TRAb binding to TSHR. Again, an improvement in functional sensitivity was reported for this latest assay generation. To investigate the analytical (aas) and functional assay sensitivity (fas) over 3 generations of TRAb assays, pooled serum samples from patients with GD were measured 10-fold in different assay lots over a few months. The 20% inter-assay coefficients of variation (CV) were calculated and compared taking into account the different calibrations of the assay generations. The fas continuously increased from about 8 U/l of MRC B65/122 in liquid phase TRAb assays, to about 1.0 IU/l (NIBSC 90/672) in TSH based solid phase TRAb assays and to about 0.3 IU/l (NIBSC 90/672) in the M22 based TRAb assay finally. In conclusion, the fas of TRAb measurements has been improved continuously over the last 3 decades.

TSH receptor antibody (TRAb) assays based on the human monoclonal autoantibody M22 are more sensitive than bovine TSH based assays.

Measurements of TSH receptor autoantibodies (TRAb) using assays based on the human monoclonal TSH receptor autoantibody M22 or bovine TSH have been compared in 136 adult patients. They suffered from Graves' disease (GD, n=62), Hashimoto's thyroiditis (HT, n=26), or non-autoimmune hyperthyroidism (NAH, n=48) and were selected on the basis of undetectable, borderline or low TRAb levels (0.6-3 IU/l) as measured by TSH based TRAb assay (Dynotest TRAKhuman from BRAHMS). The time interval between initial diagnosis of GD and TRAb determination was high and ranged from 1 month to 3.5 years (median: 2.3 years). Using the kit manufacturer's cutoff values, 53/62 (85.5%) of the selected group of GD patients were TRAb positive (>0.4 IU/l) by M22 based TRAb ELISA (Medizym TRAb clone, Medipan) and 45/62 (72.6%) were TRAb positive (>1.5 IU/l) by TSH based TRAb assay. In the HT group, 9/26 (34.6%) sera were positive in the M22 based ELISA and all but one of these 9 were positive or borderline in the TSH based assay. ROC plot analysis of the GD group using the NAH group as reference showed that at 95% specificity, the bovine TSH based TRAb assay had a sensitivity of 62.9% (cutoff for positivity=1.64 IU/l) and the M22 based TRAb ELISA a sensitivity of 90.3% (cutoff for positivity=0.32 IU/l). Overall therefore, the M22 based Medizym TRAb clone assay is more sensitive than the bovine TSH based Dynotest TRAK human assay.

[Radiation exposure of patients during 68Ga-DOTATOC PET/CT examinations]. / Strahlenexposition der Patienten bei Untersuchungen mit 68Ga-DOTATOC am PET/CT.

AIM: Investigation of the biodistribution and calculation of dosimetry of Ga-68-DOTATOC- for patients imaged in the routine clinical setting for diagnosis or exclusion of neuroendocrine tumours. PATIENTS, METHODS: Dynamic PET/CT-imaging (Biograph 16) was performed over 20 min in 14 patients (8 men, 6 women) after injection of (112+/-22) MBq 68Ga-DOTATOC followed by whole body 3D-acquisition (8 bed positions, 3 or 4 min each) 30 min p.i. and 120 min p.i.. Urinary tracer elimination was measured and blood activity was derived non-invasively from the blood pool of the heart. The relevant organs for dosimetry were spleen, kidneys, liver, adrenals, urinary bladder and pituitary gland. Dosimetry was performed using OLINDA/EXM 1.0 software and specific organ uptake was expressed as standardized uptake values (SUVs). RESULTS: Rapid physiological uptake of the radiotracer could be demonstrated in liver, spleen and kidneys, adrenals and pituitary gland (mean SUVs were 6, 20, 16, 10, and 4, respectively). Radiotracer elimination was exclusively via urine (16% of injected dose within 2h); no redistribution could be observed. The spleen and the kidneys received the highest radiation exposure (0.24 mSv/MBq, 0.22 mSv/MBq resp.), mean effective dose yielded 0.023 mSv/MBq. CONCLUSION: 68Ga-DOTATOC is used extensively for diagnosis of somatostatin receptor positive tumours because it has several advantages over the 111In-labelled ligand. The derived dosimetric values are lower than first approximations from the biological data of OctreoScan. The use of CT for transmission correction of the PET data delivers radiation exposure up to 1 mSv (low dose).

Retrospective analysis of radiation load during examination of cancer patients by (68)Ga-DOTATOC and (18)F-FDG positron emission tomography.

We present retrospective analysis of the results of examinations of 1,338 cancer patients by (68)Ga-DOTATOC and (18)F-FDG positron emission and computer-aided tomography. It was shown that complex devices for positron emission and computer-aided tomography provide more informative data than individual methods. The protocol for examination by methods of positron emission and computer-aided tomography in each case is determined by clinical requirements and risk of extra exposure of the patient.

[Radiation exposure in (90)Y-Zevalin therapy: results of a prospective multicentre trial]. / Strahlenexposition bei der (90)Y-Zevalin-Therapie: Ergebnisse einer prospektiven multizentrischen Studie.

UNLABELLED: AIM of this study was the assessment of the radiation exposure from preparation and application of (90)Y-Zevalin, the measurement of the dose rate at the patient, the exposure of family members as well as the determination of the activity concentration in urine of patients. METHODS: Overall data from 31 therapeutic administrations carried out in four institutions were evaluated. During preparation and application of (90)Y-Zevalin the finger exposures of radiochemists, technicians, and physicians were measured. The dose rate of the patient was measured immediately after radioimmunotherapy. In patients treated in a nuclear medicine therapy unit, urine was collected over a two day period and the corresponding activity was determined. Family members of outpatients were asked to wear a dosimeter over a seven day period. RESULTS: During the preparation we found a maximum skin dose of 6 mSv at the average, and during application of 3 mSv, respectively. After administration of (90)Y the dose rate was 0.4 +/- 0.1 microSv/h at 2 m distance. Urine measurements yielded a cumulated 24 h excretion of 3.9 +/- 1.4% and 4.4 +/- 1.4% within 48 h, respectively, that is equivalent to 43 +/- 18 and 50 +/- 20 MBq of (90)Y, respectively. Family members received a radiation exposure of 40 +/- 14 microSv over seven days. CONCLUSION: During preparation and application of (90)Y-Zevalin appropriate radiation shielding is necessary. For family members as well as nursing staff no additional special radiation protection measures beyond those being common for other nuclear medicine procedures are necessary.

[Where does subclinical hypothyroidism start? Implications for the definition of the upper reference limit for thyroid stimulating hormone]. / Wo beginnt die subklinische Hypothyreose? Implikationen zur Definition der oberen Referengrenze für Thyreotropin.

UNLABELLED: The upper limit of the TSH reference range is currently under discussion. In its recent guidelines, the National Academy of Clinical Biochemistry (NACB) recommended the use of approximately 2.5 mIU/L, rather than approximately 4 mIU/L, due to the fact that reference populations, on which the definition of the reference range is based, contain persons undergoing an initial phase of autoimmune thyroid disease. This will skew the upper reference limit of TSH. Ultrasonography, in addition to measurement of thyroid autoantibodies, should be used to exclude these persons. OBJECTIVE: The present study investigates whether the NACB recommendation also applies for a region of mild iodine deficiency. METHODS: According to NACB criteria, a reference population (713 persons) was defined out of a total study population of 1442. The TSH reference range was calculated in this reference group and in further subgroups by percentiles. The results were compared with the total study population and the NACB recommendation. All assays used were provided by BRAHMS Diagnostica AG, Hennigsdorf, Germany. RESULTS: As expected, all median TSH values, excluding the median of the group with a hypoechogenic thyroid were close to 1.2 mIU/L. The 97.5th percentile in the reference population was 3.35 mIU/L. However, there was no difference compared to the total study population. CONCLUSION: The upper reference limit for TSH based on a reference population according to NACB criteria came down to 3.35 mIU/L, but not to approximately 2.5 mIU/L. Interestingly, there is no difference compared to the total study population.

[Predictive value of thyrotropin receptor antibodies using the second generation TRAb human assay after radioiodine treatment in Graves' disease]. / Prädiktiver Wert der Thyreotropinrezeptor-Antikörper bei Bestimmung im TRAK-human-Assay der zweiten Generation nach Radioiodtherapie des Morbus Basedow.

UNLABELLED: The detection of TSH-receptor antibodies (TRAb) in patients with Graves' disease is routinely used in nuclear medicine laboratories. This determination has been possible for approximately 3 years with a second generation human TRAb assay. Studies showed that this TRAb determination is diagnostically more sensitive compared to established, porcine TRAb assays. OBJECTIVE: The aim of our study was to investigate, based on a ROC analysis, whether TRAb determination with the new, second generation assay allows a dependable statement about probability of occurrence of relapse after radioiodine therapy in patient suffering from Graves' disease. METHODS: 57 patients were examined with the DYNOtest TRAKhuman (BRAHMS Diagnostica AG, Hennigsdorf) directly before and six months after therapy with radioiodine (dose: 150 Gy). A ROC-analysis was performed to determine positive/negative predictive values depending on different cut-off values. RESULTS: Whereas 21/57 patients became eu- or hypothyroid after six months, 36/57 patients relapsed. Non-relapsed patients showed a significant lower median TRAb titer (4.2 IU/l vs. 19.2 IU/l; p <0.05) compared to relapsed patients. But the positive predictive value conducted 63 and 66, 62 and 66 as well as 63 and 69% (before and after therapy) linked with the cut-offs 1.0, 1.5, and 2.0 IU/l. So it was in areas also achieved by the first generation porcine radio receptor assay. CONCLUSION: An increased sensitivity is achieved undoubtedly with the new DYNOtest TRAKhuman in the diagnostic of Graves' disease. It is not held over the established radio receptor assay concerning the positive predictive value for relapsing patients.

[Recovery test or immunoradiometric measurement of anti-thyroglobulin autoantibodies for interpretation of thyroglobulin determination in the follow-up of different thyroid carcinoma]. / Wiederfindungstest oder immunradiometrische Bestimmung der Autoantikörper gegen Thyreoglobulin zur Interpretation der Thyreoglobulinbestimmung in der Nachsorge des differenzierten Schilddrüsenkarzinoms.

UNLABELLED: The determination of thyroglobulin (Tg) in the follow-up of differentiated thyroid carcinomas (DTC), is routinely used in nuclear medicine, although some problems, like a disturbed recovery-test (RT) or autoantibodies to thyroglobulin (TgAb), are well known. But it is a controversial issue in literature, whether the determination of TgAb should be performed beside or instead of the RT. OBJECTIVE: The study compares the clinical value of the determination of both TgAb and RT with sensitive assays. METHODS: 356 patients (pts) were investigated. The results were compared to the concentration of Tg in the sera of the pts. 288 pts stayed tumor-free, the remaining 68 pts showed a recurrence (local and/or metastatic) of their DTC. We measured Tg (with RT) using an immunoradiometric assay (Tg-IRMA; SELco Tg; Fa. Medipan Diagnostica GmbH) and TgAb using a direct assay (CentAK anti-Tg; also from Fa. Medipan). RESULTS: The prevalence of TgAb, and of disturbed RT respectively, in the whole population of DTC-pts was 7.6%, in the subgroup of tumor-free pts 6.6%, and in the remaining pts with tumor-recurrence 11.8%, respectively 2.0%, 1.7% and 2.9%. In a significantly higher percentage of pts with local/metastatic recurrence, both a positive TgAb (p < 0.001) and a disturbed RT (p < 0.05) were found. 7/68 pts with tumor-recurrence but Tg < 1 ng/ml showed positive TgAb, only 2/7 had a disturbed RT. In this group, no patient with Tg > 1 ng/ml demonstrated either positive TgAb or disturbed RT (p < 0.001 and p < 0.05). CONCLUSION: The determination of TgAb in the follow-up of DTC is necessary, because it supports a suspicion to tumor-recurrence in pts with negative Tg. Also the RT is of great value because of a possibly High dose hook-effect.

A high-sensitivity enzyme-linked immunosorbent assay for serum thyroglobulin.

A sensitive enzyme-linked immunosorbent assay (ELISA) for measuring serum thyroglobulin (Tg) is described. The assay has a functional sensitivity of 0.03 ng/mL and values obtained in sera from patients with treated differentiated thyroid cancer (DTC; n = 24, 17 of whom showed some evidence of recurrence) and from healthy blood donors (n = 48) were in agreement with those obtained by Tg immunoradiometric assay (IRMA) (functional sensitivity = 0.6 ng/ml) (r = 0.99 and 0.98 for the two groups, respectively). The Tg levels measured by ELISA in 47 of the healthy blood donor sera ranged from 2.3 to 139 ng/ml with 1 serum giving a value of 0.03 ng/mL. The mean +/- standard deviation (SD) Tg concentration for the healthy blood donors was 20.3+/-23 ng/mL. Studies with a recovery test suggest that Tg measurements by ELISA were not always reliable when Tg autoantibodies were present. Analysis of samples from 167 patients treated successfully for DTC (papillary carcinoma, 94; follicular carcinoma, 73) showed that 139 were negative for Tg autoantibodies and of these 106 (76%) had Tg levels measurable by ELISA (0.03 ng/mL or greater). In contrast, only 7 (5%) of these 139 sera had Tg levels measurable by IRMA (0.6 ng/mL or greater). It is possible that this ability to measure Tg simply and easily in most treated DTC patients will have significant advantages for patient care. In particular, the Tg level after initial ablative treatment will usually be measurable rather than undetectable. Furthermore, any increases in serum Tg levels which may herald relapse will be detectable earlier.

[Prevalence of goiter and iodine deficiency in Saxony is less than previously assumed. A study 6 years after discontinuation of general iodization of table salt]. / Strumaprävalenz und Joddefizit in Sachsen geringer als bisher angenommen. Eine Untersuchung sechs Jahre nach Abschaffung der generellen Speisesalzjodierung.

BACKGROUND: Germany is a known area of goitre endemicity. In East Germany (former German Democratic Republic), iodization of pre-packed table salt was introduced in 1985 and was only abolished after German reunification in 1990. Public awareness campaigns have concentrated on the use of iodized salt in the products of bakers and butchers as well as canned and frozen food since. Reports in the literature give figures of goitre prevalence (13 to 69%) inconsistent with each other and with our own clinical experience (about 30%). METHOD: We undertook a prospective cross-sectional study with a non randomly selected population (craftsmen and -women) covering Saxony in 1996, 1,129 and 1,594 adults were examined in 1996 and 1997, respectively, using a questionnaire, ultrasound, and measurement of urinary iodine excretion (1996 only). RESULTS: We found the following (mean) results in men/women in 1996: thyroid volume 23.0 +/- 1.3/17.1 +/- 1.5 ml, prevalence of goitre 32.1/31.3%, prevalence of thyroid nodules 21.1/23.0%, urinary iodine excretion (per creatinine) 86.4 +/- 1.3/104 +/- 24.1 nmol/mmol (97.1 +/- 1.4/117 +/- 27.1 micrograms/g). In 1997 the results were as follows: thyroid volume 20.9 +/- 1.2/15.7 +/- 2.1 ml, prevalence of goitre 25.6/23.6%, prevalence of thyroid nodules 16.4/19.8%. CONCLUSION: Whilst goitre and iodine deficiency are still endemic in Saxony, both have been improving despite the abolition of general table salt iodization.