Dosimetry-guided radioiodine therapy of hyperthyroidism: long-term experience and implications for guidelines.

BACKGROUND: Long-term follow-up after radioactive iodine therapy (RIT) for Graves' disease and toxic thyroid autonomy is incompletely addressed by current guidelines. We retrospectively analyzed the clinical course of 1233 out of 1728 consecutive Graves' disease (n = 536) and thyroid autonomy (n = 1192) patients after dosimetry-guided RIT to optimize follow-up. METHODS: Patients were referred between 1990 and 2018; follow-up was monitored according to available electronic registers with medical reports, including autopsies from 9 hospitals and 10 residential care homes. RESULTS: In total, 495/1728 cases were censored because of incomplete 6-month follow-up data. The conversion rates to hypothyroidism in Graves' disease and different forms of thyroid autonomy can be deconvoluted into two follow-up periods: first year after RIT and afterward. The conversion rate in Graves' disease was significantly higher than that in all thyroid autonomy subgroups during the first year but almost identical afterwards. Thyroxine substitution started between 10 and 7900 days after RIT at thyroid stimulating hormone between 0.11 and 177 µU/ml. CONCLUSIONS: We advise earlier (2-3 weeks) first follow-up checks after RIT in all Graves' disease patients and thyroid autonomy under antithyroid drugs (ATD) and re-checks every 2-4 weeks until conversion to hypothyroidism during the first year. The first check in thyroid autonomy without ATD should be after 3-4 weeks with re-checks every 4-6 weeks. After 1 year, both groups can be re-checked every 4-6 months over the next 5 years. The success rate of RIT in thyroid autonomyincreases with age but the history of RIT is rapidly lost during follow-up.

Clinicopathological description of two cases with SQSTM1 gene mutation associated with frontotemporal dementia.

There is a strong genetic influence on the clinicopathological phenotypes associated with frontotemporal lobar degeneration (FTLD) and frontotemporal dementia (FTD). Intracellular deposition of TDP-43 is the phenotypical hallmark of a frequent subgroup of cases. Mutations in the sequestosome 1 (SQSTM1) gene have rarely been found in individuals with FTD. Here we provide a comprehensive clinicopathological description of two cases with a SQSTM1 mutation. The clinical phenotype of patient 1 (mutation p.Glu396*) was compatible with the behavioural variant (bv) of FTD. TDP-43 pathology was consistent with the features of type B of FTLD-TDP pathology. However, prominent neuronal granular cytoplasmic TDP-43 immunoreactivity and abundant oligodendroglial inclusions, proven by colocalization with the oligodendroglial-marker TPPP/p25, were also seen. The clinical phenotype of patient 2 was compatible with bvFTD associated with parkinsonism and bulbar symptoms in the later stage. Genetic testing of patient 2 identified a C9orf72 repeat expansion mutation together with a missense mutation (p.Arg212Cys) in SQSTM1. TDP-43 pathology was characterized by neuritic profiles compatible mostly with type A. In contrast to patient 1, p62 pathology was seen to a greater extent as TDP-43 immunoreactivity in neurons. Using an antibody that detects poly(GP) peptides produced via repeat associated non-ATG translation associated with expanded hexanucleotide repeat in the C9orf72 gene, we confirmed the presence of pathognomonic inclusions. The present study supports previous observations on amyotrophic lateral sclerosis (ALS) that SQSTM1 mutations consistently associate with TDP-43 pathology. The co-presence of C9orf72 mutation may influence the phenotype, thus finding one FTLD (or ALS) related mutation does not exclude the presence of further influential genetic alterations. Oligodendroglial TDP-43 pathology is considerable in some forms of FTLD-TDP, thus their evaluation might be considered to be included in classification systems.

Circulating retinol-binding protein 4 and metabolic syndrome in the elderly.

BACKGROUND: Retinol-binding protein (RBP) 4, a human adipokine that specifically binds to retinol, has been reported to provide a link between obesity and insulin resistance. Plasma RBP4 concentration may be under the influence of age and obesity, but only a few studies has investigated this link in elderly individuals. Consequently, we tested the correlation between RBP4 concentrations and type 2 diabetes/metabolic syndrome (MetS) components in a large population based cohort study (VITA) of elderly [1, 2]. Using a single birth cohort, this investigation could exclude the influence of age. METHODS: We evaluated the correlation of RBP4 with type 2 diabetes and MetS components including Body Mass Index (BMI), blood pressure, lipid parameters, fasting glucose insulin, homeostasis model assessment insulin resistance (HOMA-IR), and smoking in exclusively 75-76 year old participants (N = 232). RESULTS: In the present study, RBP4 concentrations were associated with type 2 diabetes and metabolic syndrome (MetS) components. Of all the individual components of metabolic syndrome that were associated with RBP4 concentrations, the correlations of RBP4 with serum triglycerides and a negative correlation with HDL were the strongest ones observed in our study cohort (p<0.0001). CONCLUSIONS: RBP4 plays a role in biological mechanisms that are responsible for insulin resistance and development of type 2 diabetes.

Nuclear medicine: proof of principle for targeted drugs in diagnosis and therapy.

Delivering a drug to a specific target in the body is comparable to the "magic bullet principle" applied in Nuclear Medicine. If clinical medicine today found treatment options by targeting specific receptors, proteins or enzymes by "small-molecule drugs" it utilizes concepts that have been initially described by Nobel Laureate George von Hevesy as "tracer principle". This article is going to show that molecular imaging probes in Nuclear Medicine can be regarded as proof of principle of many of recent trends in diagnosis and therapy and offers exciting opportunities for further developments. Radioiodine therapy of benign and malignant thyroid disease has been established in Nuclear Medicine over six decades ago and is a fine example for using the same highly specific probe for diagnosis and treatment of a given disease. The use of radio labeled monoclonal antibodies against surface receptors of tumor cells (e.g. CEA) dominated diagnostic Nuclear Medicine in the eighties and sees a recent revival in lymphoma treatment radioimmunotherapy. Finally Nuclear Medicine has shown that it may advance drug development by visualizing its biodistribution and site of action. On the other hand some drugs like somatostatin analogues have been reinvented as diagnostic and therapeutic probes over a decade after their initial introduction as therapeutics. Molecular Imaging and targeted therapy are merging and potentiate their individual strength. Nuclear Medicine has ample experience in applying Molecular Imaging in clinical research and practice and has a bright future in this exciting field.

Risk factors for Alzheimer dementia in a community-based birth cohort at the age of 75 years.

BACKGROUND: Few prospective community-based cohort studies have so far concentrated specifically on the risk factors for Alzheimer dementia (AD) with onset after the age of 75 years. METHODS: We prospectively investigated a birth cohort of 585 nondemented inhabitants in the area on the East bank of the river Danube who were born between 1925 and 1926. They were investigated at the age of 75 years and followed up after 30 months. The follow-up was possible with 488 probands; 36 died, and 61 refused to participate. RESULTS: In multivariate analysis an elevated risk for late-onset AD could be found for (1) history of depressive episodes (OR = 2.09; 95% CI = 1.25-3.48); (2) the epsilon 4 allele of the APOE gene (OR = 1.86; 95% CI = 1.08-3.23); (3) lower serum level of folate (OR = 0.92; 95% CI = 0.87-0.98); (4) no chronic use of nonsteroidal anti-inflammatory drugs (OR = 0.40; 95% CI = 0.20-0.81), and (5) lower education (OR = 1.43; 95% CI = 1.03-2.00). CONCLUSIONS: Five risk factors for late-onset AD could be confirmed, which might be targets for preventive strategies.

Clinical chemistry reference values for 75-year-old apparently healthy persons.

BACKGROUND: Clinical chemistry reference values for elderly persons are sparse and mostly intermixed with those for younger subjects. To understand the links between metabolism and aging, it is paramount to differentiate between "normal" physiological processes in apparently healthy elderly subjects and metabolic changes due to long-lasting diseases. The Vienna Transdanube Aging (VITA) study, which began in 2000 and is continuing, will allow us to do just that, because more than 600 male and female volunteers aged exactly 75 years (to exclude any influence of the "aging" factor in this cohort) are participating in this study. METHODS: Extensive clinical, neurological, biochemical, psychological, genetic, and radiological analyses, with a special emphasis on consumption of medication and abuse of drugs, were performed on each of the probands. The multitude of data and questionnaires obtained made possible an a posteriori approach to select individuals fulfilling criteria for a reference sample group of apparently healthy 75-year-old subjects for our study. Specific analytes were quantified on automated clinical analyzers, while manual methods were used for hormonal analytes. All clinical chemistry analytes were evaluated using in-depth statistical analyses with SPSS for Windows. RESULTS: In all, reference intervals for 45 analytes could be established. These include routine parameters for the assessment of organ functions, as well as hormone concentrations and hematological appraisals. Because all patients were reevaluated after exactly 30 months in the course of this study, we had the opportunity to reassess their health status at the age of 77.5 years. This was very useful for validation of the first round data set. Data of the second round evaluation corroborate the reference limits of the baseline analysis and further confirm our inclusion and exclusion criteria. CONCLUSIONS: In summary, we have established a reliable set of reference data for hormonal, hematological, and clinical chemistry analytes for elderly subjects. These values will be very useful for our future attempts to correlate disease states and aging processes with metabolic factors.

Transient bone marrow edema syndrome of the knee: clinical and magnetic resonance imaging results at 5 years after core decompression.

PURPOSE: We report on 24 cases of transient bone marrow edema syndrome in 18 patients who underwent core decompression of the knee. METHODS: Diagnosis was made with the use of radiographs, magnetic resonance imaging (MRI), and core biopsy testing. Arthroscopic surgery and core decompression were carried out in all patients, and MRI was performed again, 5 years after surgery was performed. RESULTS: Medial and lateral femoral condyles were affected in 15 and 7 knees, respectively. In all, 6 patients presented with bilateral involvement of the knees (migrating transient bone marrow edema syndrome). Two of these patients had affections of the medial and lateral compartments within the same knee at different times, consistent with intra-articular regional bone marrow edema syndrome. Core biopsy specimens showed areas of bone marrow edema and vital trabeculae covered by osteoblasts and osteoid seams. Resolution of symptoms and normalization of MRI findings occurred in all patients within 12 weeks after surgery. CONCLUSIONS: Migrating bone marrow edema was found in a high percentage (33%) of patients at 5-year follow-up; however, all patients were clinically asymptomatic, and signal alterations on MRI had resolved completely. The high incidence of migrating bone marrow edema, the lack of osteonecrotic regions in our specimens, and the fact that none of these cases progressed to spontaneous osteonecrosis seem to further support the contention that bone marrow edema syndrome of the knee is a distinct entity. LEVEL OF EVIDENCE: Level II, diagnostic study; development of diagnostic criteria on the basis of consecutive patients and with universally applied reference gold standard.

Insulin-like growth factor 1, chromogranin A and prostate specific antigen serum levels in prostate cancer patients and controls.

OBJECTIVE: Insulin-like growth factor 1 (IGF-1) and chromogranin A (CGA) are currently discussed as supplemental serum markers for prostate cancer (PC) diagnosis. To address this issue we determined serum levels of IGF-1, CGA and PSA in men with newly diagnosed PC and controls. METHODS: A consecutive series of 156 men (median age: 67 yrs) with newly diagnosed, untreated PC and 271 controls (69 yrs) were recruited. The diagnosis of PC was made by transrectal ultrasound guided biopsies only. In controls, the presence of PC was excluded by digito-rectal examination, serum prostate specific antigen (PSA) levels by using age-specific reference values and-if indicated-by transrectal ultrasound guided 12-core biopsies. Serum levels of IGF-1, CGA and PSA were compared between cases and controls and correlated to histopathological findings and age. RESULTS: Serum PSA-levels were significantly higher in men with PC (49.6+/-13.9 ng/ml, mean+/-standard error of the mean; median: 7.0 ng/ml) than in controls (2.6+/-0.2 ng/ml; median: 1.3 ng/ml) (p<0.001). In contrast, serum levels of IGF-1 (PC: 166+/-6.1 ng/ml, median: 155 ng/ml; controls: 159+/-4.5 ng/ml, 153 ng/ml) and CGA (PC: 92+/-7.4 U/l, median: 67 U/l; controls: 117+/-12.0 U/l; median: 74 U/l) were identical in both groups (p>0.05). Serum levels of IGF-1 and CGA revealed no correlation to serum PSA, Gleason score and number of positive biopsy cores. In the PC-cohort all three serum markers did not correlate with age. In controls, PSA (p=0.018) and CGA (p<0.001) correlated positively and IGF-1 (p<0.001) negatively with age. CONCLUSION: Our data suggest that quantification of IGF-1 and CGA-serum levels provides no useful information in the diagnosis of PC.

Elevated levels of serum type I collagen C-telopeptide in patients with rapidly destructive osteoarthritis of the hip.

We compared type I collagen degradation using serum cross-linking C-terminal telopeptide (ICTP) in 18 patients with rapidly destructive osteoarthrosis and in 20 patients with slowly progressive osteoarthrosis of the hip. The diagnosis was established by clinical examination and radiographic evaluation. Total hip arthroplasty was performed in all patients. Serum levels of ICTP, bone-specific alkaline phosphatase, osteocalcin and N-terminal propeptide were studied. Patients with rapidly destructive osteoarthrosis had higher mean (SD) serum ICTP levels than patients with slowly progressive osteoarthrosis [13.2 (5.6) versus 3.7 ng/ml (1.4), p=0.001] whereas no significant difference of all other markers was seen between the groups. Elevation of ICTP levels correlated significantly with decreased joint-space width assessed by radiographs of the hip (p=0.01). Our data suggest that rapidly destructive hip osteoarthrosis is associated with elevated serum ICTP levels, reflecting increased collagen type I degradation.

SPECT-CT for topographic mapping of sentinel lymph nodes prior to gamma probe-guided biopsy in head and neck squamous cell carcinoma.

INTRODUCTION: Lymphoscintigraphic planar imaging is a common procedure for sentinel lymph node imaging prior to lymph node biopsy, but fails to elucidate the specific lymphatic drainage. Composite functional/anatomical imaging (SPECT-CT) has the potential to enhance topographic orientation and diagnostic sensitivity of sentinel lymph node imaging, but has not yet been applied in the head and neck region. STUDY DESIGN: A total of 30 patients were investigated. Planar imaging was 5 min, 265 x 265, right and left lateral; 500 kilocounts (Kcts) and SPECT (GE Millenium VG Hawk Eye 6 degrees/30s. step, 128 x 128, slice thickness 4.42 mm). Scans were performed 60 min after intra-mucodermal injection of 0.1 ml of 20 MBq 99mTc nanocolloid in patients with squamous cell cancer of the head and neck. SPECT studies were analysed by filtered back projection (FBP: Hann (0.7) prefiltering, Butterworth (0.5) postfiltering) and reconstruction (OSEM: Post Filter Hamming (0.85), 2 Iterations) and independently viewed with the co-registered CT image (eNTEGRA Functional Anatomical Fusion Vers 2.0216). The results were validated by comparing the results of each method employed in all 30 cases and intraoperative gamma probe-guided sentinel lymph node biopsy with histological examination in 13 of these patients. RESULTS: The majority of patients had more than one sentinel node (mean 1.63, min. 0, max. 4). Seven out of the 30 studies demonstrated lymphatic flow to the contralateral side of the neck. Forty-nine sentinel nodes were identified by iteratively reconstructed SPECT-CT. Thirty-eight out of these 49 could be located in lymphoscintigraphic planar imaging, whereas only 24/49 were detected in filtered back projection, respectively. In 11 of the 30 cases, a clinically unpredictable pattern of lymphatic drainage was observed. No correlation was found between T stage or tumour location and the number of sentinel nodes detected. In one out of the 13 cases, in whom imaging was followed by intraoperative gamma probe-guided biopsy, no sentinel node could be detected with the probe in the proximity of the primary tumour, although the node was clearly discernible in the reconstructed SPECT-CT. CONCLUSION: Composite functional/anatomical imaging (SPECT-CT) is feasible for sentinel lymph node detection. It enhances topographic orientation and diagnostic sensitivity with more sentinel nodes being detectable than by planar lymphoscintigraphy alone. Planar imaging should be accompanied by iterative reconstructed SPECT-CT to identify lymph nodes adjacent to the primary lesion. Such nodes are easily overlooked by planar lymphoscintigraphy and intraoperative gamma probes, as the high activity at the injection site can obscure their detection.

Microvessel density is not crucial for scintigraphic visualization of brain tumors using 99mTc-MIBI.

Functional imaging of brain tumors assists biopsy localization, therapy monitoring, and differentiating tumor recurrence from radiation necrosis. Tumor vascularization is a strong prognostic predictor in solid tumors and also a key factor of tracer uptake. However, the relationship of brain tumor vascularization and functional imaging has not yet been investigated sufficiently so far. In the present study, we correlated histologically assessed microvessel density as an objective parameter for brain tumor vascularization with imaging data. Four male patients were studied. After 99mTc-MIBI scintigraphy, all patients had a MRI within 2 weeks. Histology showed microcystic astrocytoma, glioblastoma (n = 2), and anaplastic oligodendroglioma, respectively. Microvessel density was lowest in the microcystic astrocytoma, medium in the glioblastomas, and highest in the anaplastic oligodendroglioma. Scintigraphy visualized only the glioblastomas, but not the microcystic astrocytoma or oligodendroglioma. Our data showed no correlation between tumor microvessel density and 99mTc-MIBI scintigraphy. Thus, we conclude that scintigraphic visualization of brain tumors is not strictly dependent on tumor vascularization.

Frequency and risk factors for meningioma in clinically healthy 75-year-old patients: results of the Transdanube Ageing Study (VITA).

BACKGROUND: The prevalence of clinically silent intracranial tumors in specific populations is poorly researched. It is known that, in advanced age groups, the number of clinically manifest meningiomas constitute a small proportion of the actual number of cases. The goals of the current study were to determine the frequency of asymptomatic patients with meningioma in advanced age and to identify risk factors for meningiomas in this population. METHODS: Between May 2000 and November 2002, 532 probands from a specifically defined geographic area of Vienna who were age 75 years underwent a magnetic resonance imaging scan of the brain and were evaluated for the presence of a space-occupying mass. All probands were examined clinically and neurologically as well as by a neuropsychiatrist. The patients' medical histories were carefully documented with regard to previous diseases, medication, and lifestyle, as were their laboratory reports. The collected data were correlated and similarities among subjects with meningioma were determined. RESULTS: Nine meningiomas that were unknown until the time of investigation were observed among the 318 women included in the trial (corresponding to a calculated prevalence of 2800/100,000 clinically silent meningiomas in 75-year-old women). No tumors were found among men. Associated clinical changes or deficits were not observed in any subject. Apart from advanced age and female gender, no other accepted or well known risk factors were observed in the tumor patients. CONCLUSIONS: Clinically quiescent meningiomas in the elderly female population were more common than was believed to be the case to date. Known and influenceable risk factors were found to be less important than age and gender. The high frequency of this lesion should be considered when deciding on the treatment of patients with incidentally discovered, clinically quiescent meningiomas.

Concomitant hyperparathyroidism and nonmedullary thyroid cancer, with a review of the literature.

PURPOSE: Primary hyperparathyroidism and concomitant thyroid cancer is a rare and complicated setting for diagnostic imaging. MATERIALS AND METHODS: The authors report the accidental finding of primary hyperparathyroidism in a patient with rapid enlargement of a thyroid nodule and the results of a literature review. RESULTS: Tl-201-Tc-99m subtraction scintigraphy correctly revealed the malignant nature of a large cold thyroid nodule and mediastinal parathyroid hyperplasia. In contrast, high-resolution ultrasound indicated a retrothyroidal hyperplastic parathyroid gland. Surgery followed the findings of the preoperative ultrasound and intraoperative biopsy, yet hyperparathyroid disease persisted. Repeated scintigraphy confirmed an ectopic parathyroid gland, which was resected from a paraesophageal location. Subsequently, hormone and calcium levels returned to normal and remained normal during a follow-up period of 3 years. A literature review revealed a prevalence of approximately 3% of nonmedullary thyroid cancer, which was found in patients operated on for primary hyperparathyroidism. Previous neck irradiation, especially in childhood, appears to be a risk factor for the development of both nonmedullary thyroid carcinoma and for primary hyperparathyroid disease. CONCLUSIONS: This case illustrates the need for clinical awareness of concomitant hyperparathyroidism and nonmedullary thyroid cancer and is substantiated with published case reviews. The preoperative scintigraphic localization of hyperfunctioning parathyroid tissue, although not advised as a routine procedure, may provide diagnostic information in addition to high-resolution ultrasound and intraoperative biopsy. In addition, scintigraphy can be useful even in the technically difficult setting of concomitant thyroid cancer.

Hypertrophic osteoarthropathy caused by PGE1 in a patient with congestive heart failure during cardiac rehabilitation.

Continuous chronic drug infusion with PGE1 via a portable pump and neuromuscular electrical stimulation (NMES) help to improve the quality of life in patients with severe chronic heart failure waiting for a donor heart, as both treatments can be performed at home. We report a 56-year-old woman suffering from severe chronic heart failure, who was referred for a cardiac rehabilitation program because of progressive muscle weakness and weight loss. Due to her underlying heart disease she was unable to perform voluntary exercise. NMES of both knee extensor muscles was started. Under simultaneous chronic drug infusion with PGE1 via a portable pump the patient developed clinical signs of hypertrophic osteoarthropathy, which prevented her from continuing the rehabilitation program. X-ray examinations and bone scans concurred with the diagnosis of secondary hypertrophic osteoarthropathy. After the PGE1 dose had been reduced, the clinical signs of the osteoarthropathy resolved and the patient was able to continue the rehabilitation program with no difficulty. This case report underlines the importance of being aware of the potential side effects of modern cardiac drugs in the complex treatment of patients waiting for a donor heart.