Institutionalization of reconstructive lymphedema surgery in Austria-Single center experience.

BACKGROUND: Lymphedema surgery was not widely known in Austria before the introduction of lymphovenous anastomosis (LVA) and vascularized lymph node transfer (VLNT) in 2014. This study shares the experience and process of establishing and institutionalizing lymphedema surgery service in Austria. METHODS: The purpose of introducing reconstructive lymphedema surgery in Austria was to improve lymphedema patients' quality of life and provide them surgical therapy as an adjuvant treatment to complete decongestive therapy. To initialize reconstructive lymphedema surgery in Austria, LVA and VLNT had to be presented and introduced, in the manner of branding and advertizing a new product. Surgeries were performed with quality control by standardized documentation, pre- and postoperatively. RESULTS: Aligned with branding and marketing, presentations were given externally and internally to share knowledge and experience of lymphedema surgery. Lymphedema surgery service was introduced as a new brand in the medical service in Austria. After several communications with the Austrian Health Insurance Fund and with the final application, LVA and VLNT were listed as novel surgical therapies in its 2020 reimbursement catalog. Since 2014, more than 300 lymphedema patients were consulted, and 102 reconstructive lymphedema surgeries were performed. Circumference reduction of extremities after surgery was between 20% and 43%, postoperatively. CONCLUSION: Acceptance of surgery in lymphedema patients varies among continents, hospitals, and surgeons. Evaluation of the requirement of the surgical setup and insurance conditions for lymphedema surgery is essential to establish lymphedema surgery, providing targeted marketing and branding to spread knowledge of the novel technique and grant patients access to therapeutic treatment of their chronic disease.

(18)F-DOPA PET/CT and MRI: description of 12 histologically-verified pheochromocytomas.

AIM: To describe the (18)F-fluorodihydro-xyphenylalanine ((18)F-DOPA), positron emission tomography (PET) and magnetic resonance imaging (MRI) appearance of pheochromocytomas, with a focus on the presence or absence of typical MRI features. MATERIALS AND METHODS: Eleven patients with histologically-verified pheochromocytoma [sporadic (n=9), multiple endocrine neoplasia (MEN) 2A syndrome (n=2)] were enrolled retrospectively. All patients underwent an MRI examination of the upper abdomen. Nine out of 11 patients underwent (18)F-DOPA PET/CT, and the remaining two patients underwent independent PET and computed tomography (CT) examinations. (18)F-DOPA-PET/CT examinations were considered positive when an increased tracer accumulation in the adrenal region, as shown on CT images, was observed. When an adrenal mass was detected on MRI, the T1 and T2 signal intensity and contrast enhancement pattern were recorded. Based on MR characteristics, the lesions were divided into typical and atypical. RESULTS: Ten out of 11 patients had one lesion, while one patient had two lesions. All pheochromocytomas were detected by both PET/CT and MRI. On (18)F-DOPA scans, all lesions showed an increased tracer accumulation, with a mean maximum standardized uptake value (SUVmax) of 13.7±5.75. Eight out of 12 pheochromocytomas exhibited typical MRI features, with intermediate signal intensity on T1-weighted images in-phase, absence of signal drop on T1-weighted images out-of-phase, high signal intensity on T2-weighted images, and clear contrast enhancement in the arterial phase. The remaining four lesions exhibited atypical MRI features, namely absence of one of the listed criteria. CONCLUSION: In the assessment of pheochromocytoma, the combination of (18)F-DOPA PET with MRI is superior to MRI-alone. (18)F-DOPA PET/MRI may yield a higher diagnostic confidence for the detection of pheochromocytoma than (18)F-DOPA PET/CT.

Are contrast media required for (68)Ga-DOTATOC PET/CT in patients with neuroendocrine tumours of the abdomen?

OBJECTIVES: To determine the value of intravenous contrast medium in (68)Ga-DOTA-Phe(1)-Tyr(3)-octreotide - (68)Ga-DOTATOC - PET/CT for the detection of abdominal neuroendocrine tumours (NET). METHODS: In fifty-five patients with known or suspected NETs of the abdomen PET/CT was performed on a 64-row multi-detector hybrid system. For PET, 150 MBq of (68)Ga-DOTATOC were injected intravenously. Full-dose unenhanced, and arterial- and venous-phase contrast-enhanced CT images were obtained. Unenhanced and contrast-enhanced PET/CT images were evaluated separately for the presence of NETs on a per-region basis, by two separate teams with different experience levels. RESULTS: On unenhanced PET/CT, sensitivity and specificity ranged from 89.3% (junior team) to 92% (senior team), and 99.1% (junior team) to 99.2% (senior team), respectively. On contrast-enhanced PET/CT, sensitivity and specificity ranged from 92.3% (junior team) to 98.5% (senior team), and 99.4% (junior team) to 99.5% (senior team), respectively. These increases in sensitivity and specificity, due to the use of contrast-enhanced images, were statistically significant (P < 0.05). CONCLUSIONS: Intravenous contrast medium only moderately, aleit significantly, improves the sensitivity of (68)Ga-DOTATOC PET/CT for the detection of abdominal NETs, and hardly affects specificity. Thus, while contrast enhancement is justified to achieve maximum sensitivity, unenhanced images may be sufficient for routine PET/CT in NET patients. KEY POINTS: Contrast media moderately improve the sensitivity of (68)Ga-DOTATOC PET/CT for neuroendocrine tumours. Contrast media hardly affect the specificity of (68)Ga-DOTATOC PET/CT for neuroendocrine tumours. Unenhanced PET/CT is sufficient for routine imaging of patients with neuroendocrine tumours.

Functional imaging in head and neck squamous cell carcinoma: correlation of PET/CT and diffusion-weighted imaging at 3 Tesla.

PURPOSE: The purposes of this study were: (a) to prospectively assess the correlation between apparent diffusion coefficient (ADC) values and maximum standardized uptake values (SUVmax) in patients with head and neck squamous cell carcinomas (SCC); and (b) to assess ADC and SUVmax values in relation to different tumour grades and stages in our patient population. METHODS: The study group comprised 31 consecutive patients with biopsy-proven head and neck squamous cell carcinoma who were examined using a 3T MRI scanner with a 16-channel head and neck coil. In addition to routine sequences, axial (DWIBS) and sagittal (DW-EPI) diffusion-weighted sequences were obtained using b-values of 0 mm(2)/s and 800 mm(2)/s. The ADC maps were calculated automatically. The ADC values of the tumours were measured with three regions of interest (ROIs) of standard size, and an ROI covering the entire tumour. In all patients, contrast-enhanced, whole-body (18)F-FDG PET/CT was performed within 2 weeks of the MRI examination. SUVmax was measured for every tumour using a 3-D freehand ROI that covered the entire tumour. Two-way repeated measures ANOVA was used for group comparisons. The Spearman rank correlation test was performed for ADC values. RESULTS: Mean ADC values in the 31 SCC were 0.902 (± 0.134) with a ROI of standard size, and 0.928 (± 0.160) with the large ROI measurements on the axial DWIBS sequence. The ADC values of the tumours were significantly higher when measured with the sagittal DW-EPI sequence: 1.051 (± 0.211) and 1.082 (± 0.208). We observed no significant differences in ADC values and SUVmax between the various T stages or histological grades of the tumours. SUVmax values (26.5 ± 12) did not correlate with ADC values on DWIBS or EPI. CONCLUSION: There is no correlation between the FDG uptake and the ADC value in head and neck SCC. The three different tumour grades and four tumour stages present in our study population could not be differentiated based on ADC values or SUV.

Increased platelet aggregation and in vivo platelet activation after granulocyte colony-stimulating factor administration. A randomised controlled trial.

Granulocyte colony-stimulating factor (G-CSF) stimulates the bone marrow to produce granulocytes and stem cells and is widely used to accelerate neutrophil recovery after chemotherapy. Interestingly, specific G-CSF receptors have been demonstrated not only on myeloid cells, but also on platelets. Data on the effects of G-CSF on platelet function are limited and partly conflicting. The objective of this study was to determine the effect of G-CSF on platelet aggregation and in vivo platelet activation. Seventy-eight, healthy volunteers were enrolled into this randomised, placebo-controlled trial. Subjects received 5 µg/kg methionyl human granulocyte colony-stimulating factor (r-metHuG-CSF, filgrastim) or placebo subcutaneously for four days. We determined platelet aggregation with a whole blood impedance aggregometer with various, clinically relevant platelet agonists (adenosine diphosphate [ADP], collagen, arachidonic acid [AA], ristocetin and thrombin receptor activating peptide 6 [TRAP]). Filgrastim injection significantly enhanced ADP (+40%), collagen (+60%) and AA (+75%)-induced platelet aggregation (all p<0.01 as compared to placebo and p<0.001 as compared to baseline). In addition, G-CSF enhanced ristocetin-induced platelet aggregation (+18%) whereas TRAP-induced platelet aggregation decreased slightly (-14%) in response to filgrastim. While baseline aggregation with all agonists was only slightly but insignificantly higher in women than in men, this sex difference was enhanced by G-CSF treatment, and became most pronounced for ADP after five days (p<0.001). Enhanced platelet aggregation translated into a 75% increase in platelet activation as measured by circulating soluble P-selectin. G-CSF enhances platelet aggregation and activation in humans. This may put patients suffering from cardiovascular disease and cancer at risk for thrombotic events.

Evaluating repetitive 18F-fluoroazomycin-arabinoside (18FAZA) PET in the setting of MRI guided adaptive radiotherapy in cervical cancer.

BACKGROUND: The aim of this pilot study was to assess tumour hypoxia in patients with cervical cancer before, during and after combined radio-chemotherapy and Magnetic Resonance Imaging (MRI) guided brachytherapy (BT) by use of the hypoxia Positron Emission Tomography (PET) tracer (18)F-fluoroazomycin-arabinoside ((18)FAZA ). MATERIAL AND METHODS: Fifteen consecutive patients with locally advanced cervical cancer referred for definitive radiotherapy (RT) were included in an approved clinical protocol. Stage distribution was 3 IB1, 1 IB2, 10 IIB, 1 IIIB, tumour volume was 55 cm(3) (+/- 67, SD). Dynamic and static (18)FAZA -PET scans were performed before, during and after external beam therapy (EBRT) and image guided BT +/- concomitant cisplatin. Dose was prescribed to the individual High Risk Clinical Target Volume (HR CTV) taking into account the dose volume constraints for adjacent organs at risk. RESULTS: Five patients had visually identifiable tumours on (18)FAZA -PET scans performed prior to radio-chemotherapy and four patients before brachytherapy. One of five (18)FAZA PET positive patients had incomplete remission three months after RT, one had regional recurrence. Four of ten (18)FAZA-PET negative patients developed distant metastases. The one patient with incomplete remission received 69 Gy (D90) in the HR CTV, whereas all other patients received mean 99 Gy (+/-12, SD). CONCLUSION: PET imaging with (18)FAZA is feasible in patients with cancer of the uterine cervix. However, its predictive and prognostic value remains to be clarified. This applies in particular for the additional value of (18)FAZA-PET compared to morphologic repetitive MRI within the setting of image guided high dose radiotherapy which may contribute to overcome hypoxia related radioresistance.

No immunological benefit of selenium in consecutive patients with autoimmune thyroiditis.

BACKGROUND: Recently it has been demonstrated that after selenium (Se) supplementation in autoimmune thyroiditis (AIT) patients, there was a significant decrease of thyroid peroxidase (TPO) autoantibody (TPOAb) levels. The aim of our study was to evaluate the immunological benefit of Se administration in unselected AIT patients and thus address the question whether Se administration should generally be recommended for AIT patients. METHODS: Thirty-six consecutive AIT patients (aged 19-85 years) were included in the present study. In addition to their levothyroxine (LT(4)) treatment, 18 patients received 200 microg (2.53 micromol) sodium selenite per day orally for the time span of 3 months, whereas 18 patients received placebo. All patients had measurement of thyroid hormones, thyrotropin (TSH), autoantibodies (thyroglobulin antibodies [TgAb] and TPOAb), Se levels, and intracellular cytokine detection in CD4(+) and CD8(+) T cells of peripheral blood mononuclear cells (PBMC) by flow cytometry before and after Se or placebo administration. RESULTS: No significant difference in the TPOAb levels was found after Se administration (524 +/- 452 vs. 505 +/- 464 IU/mL; p > 0.05). Furthermore, we found no significant differences in the CD4(+) or CD8(+) cytokine pattern (IFN-gamma, IL-2, IL-4, IL-5, IL-6, IL-10, IL-13, TNF-alpha, TNF-beta) in patients before and after Se administration, in patients before and after placebo administration and between Se group and placebo group before and after Se vs. placebo administration. CONCLUSION: We demonstrate that Se administration in our AIT patient's cohort does not induce significant immunological changes, either in terms of cytokine production patterns of peripheral T lymphocytes or of TPOAb levels. Our data suggest that AIT patients with moderate disease activity (in terms of TPOAb and cytokine production patterns) may not (equally) benefit as patients with high disease activity.

Calcitonin measurements for early detection of medullary thyroid carcinoma or its premalignant conditions in Hashimoto's thyroiditis.

The measurement of basal serum calcitonin (CT) in patients with evidence of Hashimoto's thyroiditis (HT) has been proposed in a recent study demonstrating an increased prevalence of elevated basal and stimulated CT. The aim of this study was to evaluate the frequency and relevance of elevated CT levels in HT. The basal sera CT were measured in 568 consecutive HT patients using a chemiluminescent immuno-assay. Whenever the serum CT was > 10 pg/ml, a pentagastrin (PG) stimulation test was performed. Two patients with abnormal/pathological PG tests were identified. Total thyroidectomy and lymph node dissection revealed for the first patient medullary thyroid carcinoma (MTC) and for the second patient C cell hyperplasia (CCH), together with papillary thyroid carcinoma. Our data showed a low prevalence of MTC and its premalignant condition CCH in HT patients; nevertheless, the patient with MTC presented lymph node metastasis. The fact that both cases presented without evidence of nodular thyroid disease highlights the persistent diagnostic dilemma of CT screening programs.

[18F]FETO for adrenocortical PET imaging: a pilot study in healthy volunteers.

PURPOSE: Functional imaging of the adrenal cortex by means of PET may play an important clinical role. Recently, we presented the synthesis and first evaluation of a novel 11beta-hydroxylase inhibitor, [(18)F]FETO, in rats displaying high tracer accumulation in the adrenals. In this study, we aimed to investigate for the first time the potency of [(18)F]FETO as a PET tracer for the adrenal cortex in humans. METHODS: An average preparation yielded 1-2 GBq of [(18)F]FETO ready to use. Ten healthy volunteers aged 24-57 years (five male and five female) were included in the study. After i.v. administration of 365 MBq [(18)F]FETO (246-391 MBq), dynamic images were acquired in 2D standard mode in 14 frames over 45 min. Afterwards, whole-body scanning was performed. In addition to visual interpretation, semi-quantitative analysis using standardised uptake values (SUVs) was conducted. RESULTS: [(18)F]FETO distribution was similar in all scanned volunteers. Visually, pronounced accumulation of [(18)F]FETO was found in the adrenals, whereas moderate uptake was observed-at least in some of the subjects-for liver, renal calices, gallbladder, stomach walls and pancreas. Kidney and bowels showed only faint uptake. Median SUVs for the right and left adrenal glands were 15.6 (10.0-28.6) and 15.7 (10.3-35.9), respectively. The reference tissue (liver) displayed a median SUV of 2.5 (2.2-4.6). CONCLUSION: [(18)F]FETO is a valuable tracer for adrenocortical PET imaging, combining the longer half-life of( 18)F with a high 11beta-hydroxylase selectivity. In accordance with our findings in rats, FETO PET revealed very high accumulation in the adrenal glands in healthy volunteers.

T lymphocyte cytokine production patterns in hashimoto patients with elevated calcitonin levels and their relationship to tumor initiation.

The aim of the study was to evaluate the possible changes in CD4+ and CD8+ T-cell cytokine production patterns in Hashimoto's thyroiditis (HT) with elevated calcitonin (CT). Fourteen consecutive patients with verified HT were included in the present study. Patients were divided into two groups. Group I: 7 HT patients with elevated CT levels (>10 pg/ml); Group II: 7 HT patients with CT levels <10 pg/ml). All patients underwent intracellular cytokine detection in CD4+ and CD8+ T-cells of peripheral blood mononuclear cells (PBMC) by flow cytometry. Patients with elevated CT levels (group I) had significantly higher percentages of CD8+ cells producing IFN-gamma compared to healthy donors. A detailed analysis of cytokine production patterns revealed that this was accompanied by an increased frequency of single IFN-gamma positive cells, i.e., cells not expressing most of the other cytokines tested. Similarly, patients in group I also showed higher percentages of CD8+ TNF-alpha positive cells than healthy donors. In this case, cells co-expressing TNF-alpha and IFN-gamma were found at significantly higher frequencies. No increase in Th1 type cytokines, such as IFN-gamma or TNF-alpha, was detectable in CD4+ T-cells. In contrast, CD4+ T-cells from group I patients showed significantly higher percentages of cells producing Th2 cytokines, such as IL-4 or IL-13. The lack of increased Th1 cytokine production accompanied by an increased Th2 cytokine production seems to be a special feature of HT patients with elevated CT levels that may reflect a pathogenetic mechanism for tumor initiation.

Relation of anti-TPO autoantibody titre and T-lymphocyte cytokine production patterns in Hashimoto's thyroiditis.

OBJECTIVE: Cytokines produced by cytotoxic T cells or autoantibodies lead to thyroid cell damage and/or cell death in Hashimoto's thyroiditis (HT). Anti-TPO autoantibodies (TPOAb) are the most frequently represented autoantibodies in the sera of patients with HT. Data describing the quantitative correlation between TPOAb titre and cytokine pattern are missing so far. To our knowledge this is the first study systematically evaluating the correlation of possible parameters of disease activity such as changes in CD4 and CD8 T-cell cytokine production and of TPOAb titre. METHODS: Twenty-four consecutive patients (aged 29-58) with verified HT under levothyroxine therapy were included in the present study. The patients were divided into two groups. Group I: 12 HT patients with a high TPOAb titre (> 1000 U/ml), group II: 12 HT patients with a low TPOAb titre (< 100 U/ml). All patients underwent intracellular cytokine detection in CD4 and CD8 T cells of peripheral blood mononuclear cells (PBMC) by flow cytometry. Twelve healthy volunteers matched in sex and age consisted the control group (group III). RESULTS: T cells from patients with a high TPOAb titre (group I) had significantly higher percentages of cells producing IFN-gamma compared to healthy donors (group III). A detailed analysis of cytokine production patterns revealed that this was accompanied by an increased frequency of single IFN-gamma positive cells, i.e. cells not expressing other cytokines tested, such as IL-2, IL-4, IL-5, IL-6, IL-10, IL-13 or TNF-beta. Similarly, patients in group I also showed higher percentages of TNF-alpha positive cells than healthy donors (group III). In this case, cells expressing TNF-alpha alone as well as cells coexpressing TNF-alpha and IFN-gamma were found at significantly higher frequencies. On the other hand, cytokine production patterns of patients with a low TPOAb titre (group II) showed significant difference neither to patients of group I nor to healthy donors (group III). CONCLUSION: Taken together, we were able for the first time to demonstrate that high TPOAb titre correlates with increased frequencies of T cells producing Th/Tc1 cytokines, probably responsible for thyroid cell damage and/or death in Hashimoto's thyroiditis.

T-lymphocyte cytokine production patterns in nonimmune severe hypothyroid state and after thyroid hormone replacement therapy.

The influence of thyroid hormones on the immune system is controversial. We analyzed the cytokine expression pattern of T lymphocytes in patients with severe nonimmune hypothyroidism in order to establish the role of thyroid hormones on the immune system. The study comprised 7 patients (1 male and 6 females) 20 to 76 years of age (mean age, 53 years), without signs of chronic thyroiditis, verified by histology and laboratory data. The patients were studied 5 weeks after total thyroidectomy. Peripheral blood mononuclear cell (PBMC) cultures and intracellular cytokine detection by flow cytometry before and after thyroid hormone replacement therapy were performed (free thyroxine [FT4] 0.030 +/- 0.034 ng/dL, versus FT4: 2.16 +/- 0.68 ng/dL). The control group consisted of 7 healthy subjects (FT4: 1.20 +/- 0.21 ng/dL). We found no significant differences in the cytokine pattern (interferon [IFN]-gamma, IL-2, interleukin [IL]-4, IL-5, IL-6, IL-10, IL-13, tumor necrosis factor [TNF]-alpha, TNF-beta) of CD4+ and CD8+ between the matched groups (hypothyroid subjects versus controls, levothyroxine treated subjects versus controls). Our data show no change in the type 1/type 2 balance of peripheral CD4+ and CD8+ T lymphocytes from patients with nonimmune hypothyroidism. According to our results, the hypothyreotic state does not contribute to the reported changes in cytokine production patterns in Hashimoto's thyroiditis.

Platelet kinetics and scintigraphic imaging in thrombocytopenic malaria patients.

Thrombocytopenia is a common occurrence in acute malaria. It is attributed, among other factors, to excessive splenic platelet pooling and a shortened platelet lifespan. The aim of our study was to evaluate the platelet kinetics and sequestration site by isotopic studies in uncomplicated malaria-induced thrombocytopenia. Seven thrombocytopenic malaria patients (74,000+/-36,000 platelets/ micro l) were included in the study. Autologous (111)In-labeled platelet scintigraphy was performed up to 96 hours (h) post injection (p.i.) to evaluate the platelet sequestration site. Late sequestration for the spleen (S) and the liver (L) was analyzed according to the following activity ratios: S (spleen count on the last day of the platelet lifespan / spleen count at 30 min) and L (liver count on the last day of the platelet lifespan / liver count at 30 min). Additionally, platelet survival studies were performed. A normal late sequestration (S: 0.95+/-0.06 and L: 1.04+/-0.08; normal values, S and L: 1+/-0.2.) was observed in all of our patients. The platelet lifespan was reduced (1 to 4 days; normal range, 7-9 days), recovery was normal (mean, 63+/-6%; normal range, 55-75%), and the turnover rate was enhanced (mean, 95,000+/-80,000/ micro l/day; normal value, 35,000+/-4,500/ micro l/ day). According to the results of scintigraphy, the sequestration site by uncomplicated malaria-induced thrombocytopenia appears to be non-splenic and/or hepatic, yet diffuse.