Prevention of activated brown adipose tissue on 18F-FDG-PET scans of young lymphoma patients: results of an ancillary study within the EuroNet-PHL-C2 trial.

Activated brown fat (aBAT) is known to affect the evaluation of 18F-FDG PET scans, especially in young patients. The aim of this study was to determine factors influencing the occurrence of aBAT, and to investigate the effectiveness of the two preventive measures, warming and beta-blocker (propranolol) administration. Five-hundred-twenty-eight 18F-FDG-PET scans of 241 EuroNet-PHL-C2 trial patients from 41 nuclear medicine departments in Germany and Czech Republic were screened for aBAT. The occurrence of aBAT was analyzed with patient characteristics (age, sex, body mass index, predisposition to aBAT), weather data at the day of 18F-FDG PET scanning as well as the preventive measures taken. Potentially important factors from univariate analyses were included into a logistic regression model. Warming as a preventive measure was used in 243 18F-FDG-PET scans, propranolol was administered in 36, warming and propranolol were combined in 84, and no preventive measures were taken in 165 scans. Whereas age, sex and body mass index had no clear impact, there was an individual predisposition to aBAT. Logistic regression model revealed that the frequency of aBAT mainly depends on the outside temperature (p = 0.005) and can be effectively reduced by warming (p = 0.004), the administration of unselective beta-blocker or the combination of both. Warming is a simple, cheap and non-invasive method to reduce the frequency of aBAT. However, the effect of warming decreases with increasing outside temperatures. Administration of propranolol seems to be equally effective and provides advantages whenever the positive effect of warming is compromised. The combination of both preventive measures could have an additive effect.

Whole-body [18F]-FDG-PET/MRI for staging of pediatric non-Hodgkin lymphoma: first results from a single-center evaluation.

AIM: In 2015, the revised International Pediatric Non-Hodgkin Lymphoma Staging System was published. It mentions [18F]-FDG-PET/MRI as the latest method to perform whole-body imaging. However, supporting data are pending. Our aim was to investigate the performance of whole-body [18F]-FDG-PET/MRI in pediatric non-Hodgkin lymphoma patients by using a limited number of MRI sequences. MATERIALS AND METHODS: Ten pediatric patients with histologically proven non-Hodgkin lymphoma underwent whole-body [18F]-FDG-PET/MRI at staging. The retrospective analysis included three steps: First, [18F]-FDG-PET and MR scans were evaluated separately by a nuclear medicine physician and a pediatric radiologist. Nineteen nodal and two extranodal regions as well as six organs were checked for involvement. Second, discrepant findings were reviewed together in order to reach consensus. Third, [18F]-FDG-PET/MRI findings were correlated with the results of other clinical investigations. RESULTS: Of the 190 lymph node regions evaluated, four were rated controversial. Consensus was reached by considering metabolic, functional and morphologic information combined. Concordantly, [18F]-FDG-PET and MRI detected Waldeyer's ring involvement in two patients whose Waldeyer's ring was negative on clinical assessment. In four patients MRI showed pleural effusion. However, in only two of them an increased glucose metabolism as a reliable sign of pleural involvement was detectable. In six patients [18F]-FDG-PET and MRI detected skeletal lesions although bone marrow biopsy was positive in only one of them. CONCLUSION: Despite the small number of cases evaluated, whole-body [18F]-FDG-PET turned out to be a valuable tool for staging of pediatric non-Hodgkin lymphoma.

Only strongly enhanced residual FDG uptake in early response PET (Deauville 5 or qPET ≥ 2) is prognostic in pediatric Hodgkin lymphoma: Results of the GPOH-HD2002 trial.

PURPOSE: In 2014, we published the qPET method to quantify fluorodeoxyglucose positron emission tomography (FDG-PET) responses. Analysis of the distribution of the quantified signals suggested that a clearly abnormal FDG-PET response corresponds to a visual Deauville score (vDS) of 5 and high qPET values ≥ 2. Evaluation in long-term outcome data is still pending. Therefore, we analyzed progression-free survival (PFS) by early FDG-PET response in a subset of the GPOH-HD2002 trial for pediatric Hodgkin lymphoma (PHL). PATIENTS/METHODS: Pairwise FDG-PET scans for initial staging and early response assessment after two cycles of chemotherapy were available in 93 PHL patients. vDS and qPET measurement were performed and related to PFS. RESULTS: Patients with a qPET value ≥ 2.0 or vDS of 5 had 5-year PFS rates of 44%, respectively 50%. Those with qPET values < 2.0 or vDS 1 to 4 had 5-year PFS rates of 90%, respectively 80%. The positive predictive value of FDG-PET response assessment increased from 18% (9%; 33%) using a qPET threshold of 0.95 (vDS ≤ 3) to 30% (13%; 54%) for a qPET threshold of 1.3 (vDS ≤ 4) and to 56% (23%; 85%) when the qPET threshold was ≥ 2.0 (vDS 5). The negative predictive values remained stable at ≥92% (CI: 82%; 98%). CONCLUSION: Only strongly enhanced residual FDG uptake in early response PET (vDS 5 or qPET ≥ 2, respectively) seems to be markedly prognostic in PHL when treatment according to the GPOH-HD-2002 protocol is given.

[Head and Neck Cancer in Pregnancy - Recommendations for Diagnosis and Therapy With Case Report]. / Kopf-Hals-Krebs in der Schwangerschaft ­ Empfehlungen zu Diagnostik und Therapie mit Fallbericht.

Objective: The diagnosis of cancer in pregnancy is rare, but might become more relevant even for head and neck cancer patients due to a shift of age of primipara towards the last third of reproductive years. Unsureness exists about the risk and benefit of diagnostic and therapeutic cancer modalities for the unborn and established recommendations are still missing. But, according to recent data, even multimodal therapeutic approaches (e. g. surgery, radiation, chemotherapy) seem possible in face of pregnancy and should be traded against the risk of prematurity. Material and Methods: Our findings are discussed on the basis of a case report of a pregnant woman with advanced carcinoma of the outer ear canal and therapy options are formulated. Results: Sufficient performed diagnostic modalities do not reach imperilling uterus dosages. A growing number of case reports und studies did not detect any developmental disadvantage of children of prenatal exposed mothers by radiation or chemotherapy, whereas long-term impairments of premature infants are proven. Conclusion: In cancer in pregnancy, an immediate start of well-established therapy modalities like surgery and/or cisplatin-based chemoradiation seems to be possible without unjustifiable risks for the unborn.

Simultaneous [18F]FDG-PET/MRI: Correlation of Apparent Diffusion Coefficient (ADC) and Standardized Uptake Value (SUV) in Primary and Recurrent Cervical Cancer.

OBJECTIVES: Previous non-simultaneous PET/MR studies have shown heterogeneous results about the correlation between standardized uptake values (SUVs) and apparent diffusion coefficients (ADCs). The aim of this study was to investigate correlations in patients with primary and recurrent tumors using a simultaneous PET/MRI system which could lead to a better understanding of tumor biology and might play a role in early response assessment. METHODS: We included 31 patients with histologically confirmed primary (n = 14) or recurrent cervical cancer (n = 17) who underwent simultaneous whole-body 18F-FDG-PET/MRI comprising DWI. Image analysis was performed by a radiologist and a nuclear physician who identified tumor margins and quantified ADC and SUV. Pearson correlations were calculated to investigate the association between ADC and SUV. RESULTS: 92 lesions were detected. We found a significant inverse correlation between SUVmax and ADCmin (r = -0.532, p = 0.05) in primary tumors as well as in primary metastases (r = -0.362, p = 0.05) and between SUVmean and ADCmin (r = -0.403, p = 0.03). In recurrent local tumors we found correlations for SUVmax and ADCmin (r = -0.747, p = 0.002) and SUVmean and ADCmin (r = -0.773, p = 0.001). Associations for recurrent metastases were not significant (p>0.05). CONCLUSIONS: Our study demonstrates the feasibility of fast and reliable measurement of SUV and ADC with simultaneous PET/MRI. In patients with cervical cancer we found significant inverse correlations for SUV and ADC which could play a major role for further tumor characterization and therapy decisions.

Pediatric Nodular Lymphocyte-predominant Hodgkin Lymphoma: Treatment Recommendations of the GPOH-HD Study Group.

Nodular lymphocyte-predominant Hodgkin lymphoma (nLPHL) is a very rare disease in childhood and adolescence. In Germany, about 15 newly diagnosed patients present with this disease annually; this number comprises less than 10% of all pediatric Hodgkin lymphoma cases. Since the EuroNet-PHL-LP1 trial for early stage nLPHL patients stopped recruiting in Germany in October 2014, the GPOH-HD writing committee reviewed the literature and decided to deliver treatment recommendations for childhood and adolescent nLPHL patients. These guidelines shall be applicable to young nLPHL patients in European countries that will no longer be able to participate in nLPHL trials for young patients. Therefore, the EuroNet-PHL-nLPHL-registry will be installed to provide quality assured central review of staging and response assessment for registered patients by the Central Review Board of EuroNet-PHL in Halle/Leipzig, Germany.

Initial clinical results of simultaneous 18F-FDG PET/MRI in comparison to 18F-FDG PET/CT in patients with head and neck cancer.

PURPOSE: The aim of this study was to evaluate the diagnostic capability of simultaneous (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/MRI compared to (18)F-FDG PET/CT as well as their single components in head and neck cancer patients. METHODS: In a prospective study 17 patients underwent (18)F-FDG PET/CT for staging or follow-up and an additional (18)F-FDG PET/MRI scan with whole-body imaging and dedicated examination of the neck. MRI, CT and PET images as well as PET/MRI and PET/CT examinations were evaluated independently and in a blinded fashion by two reader groups. Results were compared with the reference standard (final diagnosis determined in consensus using all available data including histology and follow-up). Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated. RESULTS: A total of 23 malignant tumours were found with the reference standard. PET/CT showed a sensitivity of 82.7%, a specificity of 87.3%, a PPV of 73.2% and a NPV of 92.4%. Corresponding values for PET/MRI were 80.5, 88.2, 75.6 and 92.5%. No statistically significant difference in diagnostic capability could be found between PET/CT and PET/MRI. Evaluation of the PET part from PET/CT revealed highest sensitivity of 95.7%, and MRI showed best specificity of 96.4%. There was a high inter-rater agreement in all modalities (Cohen's kappa 0.61-0.82). CONCLUSION: PET/MRI of patients with head and neck cancer yielded good diagnostic capability, similar to PET/CT. Further studies on larger cohorts to prove these first results seem justified.

The EuroNet paediatric hodgkin network - modern imaging data management for real time central review in multicentre trials.

Since 2007, children and adolescents with Hodgkin lymphomas are treated in the Europe-wide EuroNet-PHL trials. A real time central review process for stratification of the patients enhances quality control and efficient therapy management. This process includes reading of all cross-sectional-images. Since reference evaluation is time critical, a fast, easy to handle and safe data transfer is important. In addition, immediate and constant access to all the data has to be guaranteed in case of queries and for regulatory reasons. To meet the mentioned requirements the EuroNet Paediatric Hodgkin Data Network (funded by the European Union - Project Number: 2007108) was established between 2008 and 2011. A respective tailored data protection plan was formulated. The aim of this article is to describe the networks' mode of operation and the advantages for multi-centre trials that include centralized image review.

Estrogen deficiency aggravates insulin resistance and induces ß-cell loss and diabetes in female New Zealand obese mice.

In several rodent strains such as the New Zealand Obese (NZO) mouse, the incidence of obesity-associated diabetes mellitus is much higher in males than in females. In the present study, we investigated the effects of ovariectomy on glucose homeostasis in female NZO mice in order to elucidate the mechanism of their diabetes resistance. NZO females were ovariectomized at the age of 4 weeks, received a high-fat diet and body weight, body fat, glucose and insulin tolerance were investigated in comparison to sham-operated mice. In a second experiment, operated mice were fed a carbohydrate-free diet up to the age of 19 weeks before they received the high-fat diet. In comparison with a sham-operated control group, ovariectomized female NZO mice exhibited similar body weights, a reduced glucose tolerance, developed significantly higher blood glucose levels, lost insulin producing ß-cells, which finally resulted in a diabetes prevalence of 73% at the age of 16 weeks vs. 25% in controls. Similar to male NZO mice, ovariectomized females presented a more severe insulin resistance in the insulin tolerance test than sham-operated controls. Furthermore, the more severe insulin resistance in ovariectomized mice preceded the development of diabetes and pancreatic insulin depletion that was caused by a dietary regimen of carbohydrate restriction and subsequent re-exposure. In summary our data demonstrate that estrogen protects NZO females from ß-cell loss and obesity-associated diabetes mellitus. This effect is due to a reduced insulin resistance and possibly also to a reduced sensitivity of ß-cells to glucolipotoxic conditions.

Evaluation of the prognostic meaning of C-reactive protein (CRP) in children and adolescents with classical Hodgkin's lymphoma (HL).

BACKGROUND: In adult cancer patients the negative predictive value of elevated CRP levels has been described for several malignancies. Only few studies have analyzed the prognostic role of CRP in children and adolescents with classical HL. In these studies elevated CRP levels correlate with the presence of classical risk factors and adverse outcome. PATIENTS AND METHODS: The prognostic role of CRP for patients with classical HL admitted to the GPOH-HD-2002 study was analyzed retrospectively. RESULTS: CRP levels were documented for 369 of 573 patients. Significant (p<0.05) increased median CRP levels were found in the presence of B-Symptoms (25.7 vs. 5.1 mg/l), extranodal involvement (21.5 vs. 7.5 mg/l), elevated erythrocyte sedimentation rate (ESR, 13.0 vs. 1.0 mg/l) and stage III/IV disease (15.5 vs. 5.3 mg/l). 83.9% of patients with elevated and 45.8% of patients with normal CRP had an ESR >30 mm/h. CONCLUSION: Elevated CRP levels were associated with classical risk factors of HL. CRP and ESR may reflect different biological processes. CRP was prognostic within early stage TG-1 patients treated with reduced treatment, but not within advanced stage TG-2+3.

[Role of FDG-PET in Staging and Therapy of Children with Hodgkin Lymphoma]. / Die Bedeutung des FDG-PET für die Stadieneinteilung und Therapie des Hodgkin-Lymphoms im Kindesalter.

The paediatric Hodgkin lymphoma treatment optimisation concepts aim at reduction of treatment intensity with preservation of the high cure rates. A negative interim FDG-PET result after 2 cycles of chemotherapy is associated with a good prognosis. In the current EuroNet-PHL-C1 study radiotherapy is being omitted, if interim PET becomes negative. In addition to the early interim PET after 2 cycles of chemotherapy, all patients undergo an initial PET investigation which is part of the staging processs and plays an essential role for the interpretation of the interim PET. Skeletal involvement can be detected by a typical FDG-PET uptake pattern with high sensitivity and specifity. Therefore, in the forthcoming EuroNet-PHL-C2 study bone marrow biopsy and bone scintigraphy will no longer be part of the staging algorithm.

Dissociation of lipotoxicity and glucotoxicity in a mouse model of obesity associated diabetes: role of forkhead box O1 (FOXO1) in glucose-induced beta cell failure.

AIMS/HYPOTHESIS: Carbohydrate-free diet prevents hyperglycaemia and beta cell destruction in the New Zealand Obese (NZO) mouse model. Here we have used a sequential dietary regimen to dissociate the effects of obesity and hyperglycaemia on beta cell function and integrity, and to study glucose-induced alterations of key transcription factors over 16 days. METHODS: Mice were rendered obese by feeding a carbohydrate-free diet for 18 weeks. Thereafter, a carbohydrate-containing diet was given. Plasma glucose, plasma insulin and total pancreatic insulin were determined, and forkhead box O1 protein (FOXO1) phosphorylation and the transcription factors pancreatic and duodenal homeobox 1 (PDX1), NK6 homeobox 1 protein (NKX6.1) and v-maf musculoaponeurotic fibrosarcoma oncogene family, protein A (avian) (MAFA) were monitored by immunohistochemistry for 16 days. RESULTS: Dietary carbohydrates produced a rapid and continuous increase in plasma glucose in NZO mice between day 2 and 16 after the dietary challenge. Hyperglycaemia caused a dramatic dephosphorylation of FOXO1 at day 2, followed by a progressive depletion of insulin stores. The loss of beta cells was triggered by apoptosis (detectable at day 8), associated with reduction of crucial transcription factors (PDX1, NKX6.1 and MAFA). Incubation of isolated islets from carbohydrate-restricted NZO mice or MIN6 cells with palmitate and glucose for 48 h resulted in a dephosphorylation of FOXO1 and thymoma viral proto-oncogene 1 (AKT) without changing the protein levels of both proteins. CONCLUSIONS/INTERPRETATION: The dietary regimen dissociates the effects of obesity (lipotoxicity) from those of hyperglycaemia (glucotoxicity) in NZO mice. Obese NZO mice are unable to compensate for the carbohydrate challenge by increasing insulin secretion or synthesising adequate amounts of insulin. In response to the hyperglycaemia, FOXO1 is dephosphorylated, leading to reduced levels of beta cell-specific transcription factors and to apoptosis of the cells.

[Procedure guidelines for whole-body 18F-FDG PET and PET/CT in children with malignant diseases]. / Empfehlungen zur Durchführung der Ganzkörper-18F-FDG-PET und -PET/CT bei Kindern mit onkologischen Erkrankungen. Anpassung der EANM-Guideline an aktuelle Gegebenheiten in Deutschland.

The purpose of these guidelines is to offer the nuclear medicine and the appropriate interdisciplinary team a framework for performing and reporting positron emission tomography (PET) and the combination with computed tomography (PET/CT) in children with malignant diseases mainly using the radiopharmaceutical 18F-fluorodeoxy-glucose (FDG). These guidelines are based on the recent guidelines of the Paediatric Committee of the European Association of Nuclear Medicine (EANM) (57) and have been translated and adapted to the current conditions in Germany. The adaptation of CT-parameters using PET/CT in children is covered in a more detailed way than in the EANM guideline taking into account that in Germany already a good portion of PET examinations is performed using an integrated PET/CT-scanner. Furthermore, a CT-scan without adoption of the CT acquisition parameters would result in a not tolerably high radiation exposition of the child. There are excellent guidelines for FDG PET and PET/CT in oncology published by the German Society of Nuclear Medicine (Deutsche Gesellschaft für Nuklearmedizin, DGN) (42) and EANM (4). These guidelines aim at providing additional information on issues particularly relevant to PET and PET/CT imaging in children. These guidelines should be taken in the context of local and national current standards of quality and rules.

Whole-body MRI for primary evaluation of malignant disease in children.

OBJECTIVE: The aim of this study was to compare diagnostic accuracy of whole-body (WB) MRI to a combined reference standard of conventional cross-sectional imaging methods and FDG-PET in the detection of malignant disease spread in children. MATERIALS AND METHODS: 24 children (age between 5 and 18 years) with malignant diseases (mainly Hodgkin's lymphoma and different types of sarcoma) initially examined with conventional cross-sectional imaging methods (ultrasound, computed tomography, or magnetic resonance imaging) were examined prospectively with whole-body MRI (1.5T) and FDG-PET. Studies were read by two nuclear medicine physicians (FDG-PET) and two radiologists (WB-MRI) independently in a blinded manner and each study type was evaluated in consensus. The reference standard was defined as pathological lesions detected in the same location both in FDG-PET and another conventional cross-sectional imaging method. RESULTS: Overall 190 lesions were detected by WB-MRI and 155 lesion were found by FDG-PET. 106 lesions fulfilled the criteria of the reference standard (42 osseous and 64 extraosseous lesions) from which 102 were detected by WB-MRI (sensitivity of 96%). All bone lesions were detected and extra-skeletal lesions were identified with a sensitivity of 93.8%. Overall 88 lesions detected by WB-MRI were not part of the reference standard from which 33 were lesions of the peripheral skeleton not imaged by conventional cross-sectional imaging studies. 4 lesions of the reference standard were not identified by WB-MRI which were all lymph nodes. CONCLUSION: WB-MRI is a radiation free imaging technique with high sensitivity for the detection of malignant disease spread in particular beneficial for children. In patients with suspected bone lesions it should be considered for initial disease evaluation prior to specific and regional imaging methods to reduce the overall number of imaging examinations and radiation exposure.

[FDG-PET in Hodgkin lymphoma]. / FDG-PET beim Hodgkin-Lymphom.

The high negative predictive value of FDG-PET in therapy control of Hodgkin lymphoma is proven by the data acquired up to now. Thus, the analysis of the HD15 trial has shown that consolidation radiotherapy might be omitted in PET negative patients after effective chemotherapy. Further response adapted therapy guided by PET seems to be a promising approach in reducing the toxicity for patients undergoing chemotherapy. The criteria used for the PET interpretation have been standardized by the German study groups for Hodgkin lymphoma patients and will be reevaluated in the current studies.

[Myocardial perfusion scintigraphy 2006 in Germany. Results of the query and current status]. / Myokardperfusionsszintigraphie 2006 in Deutschland Ergebnisse der Erhebung und Standortbestimmung.

AIM: This second survey was to deliver further information on myocardial perfusion scintigraphy (MPS) in Germany in 2006. METHOD: 351 questionnaires were evaluated: 207 private practices (PP), 117 hospitals (HO), 27 from university hospitals (UH). RESULTS: MPS of 106 331 patients were reported, 85% were investigated with (99m)Tc-perfusion tracers. 74% [2005 = 72%] were performed in PP, 17% [2005 = 15%] in HO and 9% [2005 = 13%] in UH. PP, which participated in 2005 and 2006, demonstrated an increase by 3,9% (HO 0%, UH - 13,0%). The type of stress was pharmacological in 27% [2005 = 22%]; 54% adenosine (of these 29% with exercise), 37% dipyridamole (of these 56% with exercise), and 9% dobutamine. Gated SPECT was performed in 42% [2005 = 36%] of all rest- and in 39% [2005 = 32%] of all stress MPS. An attenuation correction was used by 69 [2005 = 78] institutions. 40% of all MPS were performed in patients suspected to have CAD. 24% of all institutions reported changes in the use of MPS by competing methods. CONCLUSION: There is a small increase of MPS between 2005 and 2006 despite competing methods. Gated SPECT has experienced more acceptance. Suspicion of CAD is an important indication of MPS. In order to tap the full potential of MPS a gated SPECT should be performed routinely.

Guidelines for 18F-FDG PET and PET-CT imaging in paediatric oncology.

OBJECTIVE: The purpose of these guidelines is to offer to the nuclear medicine team a framework that could prove helpful in daily practice. These guidelines contain information related to the indications, acquisition, processing and interpretation of (18)F-fluorodeoxyglucose positron emission tomography ((18)F-FDG PET) in paediatric oncology. The Oncology Committee of the European Association of Nuclear Medicine (EANM) has published excellent procedure guidelines on tumour imaging with (18)F-FDG PET (Bombardieri et al., Eur J Nucl Med Mol Imaging 30:BP115-24, 2003). These guidelines, published by the EANM Paediatric Committee, do not intend to compete with the existing guidelines, but rather aim at providing additional information on issues particularly relevant to PET imaging of children with cancer. CONCLUSION: The guidelines summarize the views of the Paediatric Committee of the European Association of Nuclear Medicine. They should be taken in the context of "good practice" of nuclear medicine and of any national rules, which may apply to nuclear medicine examinations. The recommendations of these guidelines cannot be applied to all patients in all practice settings. The guidelines should not be deemed inclusive of all proper procedures or exclusive of other procedures reasonably directed to obtaining the same results.