Clinical, economic, and health-related quality of life burden associated with von Willebrand disease in adults and children: Systematic and targeted literature reviews.

INTRODUCTION: Debilitating clinical complications in von Willebrand disease (VWD) can affect health-related quality of life (HRQoL), increase healthcare costs and cause long-lasting consequences. However, the magnitude of these burdens needs to be more fully explored. AIM: To estimate the prevalence and burden of clinical complications, the impact on HRQoL and the economic burden associated with VWD. METHODS: Embase® , MEDLINE® , the Cochrane Library and conference proceedings were searched for studies on VWD evaluating clinical complications, HRQoL and cost and resource use. RESULTS: Among 16 studies assessing clinical complications in VWD, the most prevalent bleeding symptoms were menorrhagia (2%-95% [n = 7 studies]), epistaxis (12%-80% [n = 6]) and easy bruising (46%-65% [n = 2]). Among 17 studies evaluating HRQoL, the most common assessment scales were the generic SF-36 (n = 8 studies) and the EQ-5D (n = 2). Bleeding symptoms were associated with reduced QoL in six of seven studies, and of six studies evaluating treatment impact, four reported improvements in one or more HRQoL components. Among 25 studies on cost and resource use, key observations included higher post-surgery healthcare costs in VWD versus non-VWD patients (n = 1 study) and higher costs and resource use in VWD patients with bleeding complications versus those without (n = 1). CONCLUSION: Although limited, available evidence suggests that VWD patients experience a high burden of clinical complications, reduced QoL and high healthcare costs. Haemarthrosis is more common in severe VWD than is often assumed, and bleeds (including haemarthrosis) can reduce QoL. Research efforts to improve QoL and other outcomes should be prioritized.

Dynamic 18F-FET PET in suspected WHO grade II gliomas defines distinct biological subgroups with different clinical courses.

In suspected grade II gliomas, three distinct patterns of time-activity curves (TAC) on O-(2-[(18)F]fluoroethyl)-1-tyrosine ((18)F-FET) positron emission tomography (PET) have been delineated (i) increasing TAC homogeneously throughout the tumor, and decreasing TAC, (ii) either homogeneously throughout the tumor or (iii) only focally within otherwise increasing TAC patterns. Increasing TAC was associated with low-grade histology and decreasing TAC with high-grade histology. This prospective study analyzed whether these patterns correlate with distinct biological tumor subtypes and differential outcome. (18)F-FET PET-guided biopsies were used for stepwise histopathological evaluation. Molecular-genetic evaluation included O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation, isocitrate dehydrogenase (IDH1/2) mutational and 1p/19q codeletion status. Progression-free survival (PFS) was estimated with the Kaplan-Meier method. Prognostic factors were obtained from multivariate regression models. 98 adult patients were included. Homogeneous increasing, focal decreasing and homogeneous decreasing TAC were seen in 51, 19 and 28 patients. The corresponding 1-year (2-years) PFS were 92% (85%), 89% (51%) and 50% (28%; p = 0.002). IDH1/2 mutations were more frequent in tumors with homogeneous increasing (90%) and focal decreasing (79%) TAC, but were rare in those exhibiting homogeneous decreasing TAC (25%; p < 0.001). Overall, TAC patterns, IDH1/2 mutational and 1p/19q codeletion status were powerful and independent prognostic factors. Dynamic (18)F-FET PET might be an important and independent imaging biomarker for patients with suspected WHO grade II gliomas and offers perspectives for stratified diagnostic and therapeutic strategies. Tumors with focal decreasing TAC need highly targeted surgical interventions to avoid undergrading and undertreatment.

PET imaging for brain tumor diagnostics.

PURPOSE OF REVIEW: Brain tumors differ in histology, biology, prognosis and treatment options. Although structural magnetic resonance is still the gold standard for morphological tumor characterization, molecular imaging has gained an increasing importance in assessment of tumor activity and malignancy. RECENT FINDINGS: Amino acid PET is frequently used for surgery and biopsy planning as well as therapy monitoring in suspected primary brain tumors as well as metastatic lesions, whereas 18F-fluorodeoxyglucose (18F-FDG) remains the tracer of choice for evaluation of patients with primary central nervous system lymphoma. Application of somatostatin receptor ligands has improved tumor delineation in skull base meningioma and concurrently opened up new treatment possibilities in recurrent or surgically not assessable tumors.Recent development focuses on the implementation of hybrid PET/MRI as well as on the development of new tracers targeting tumor hypoxia, enzymes involved in neoplastic metabolic pathways and the combination of PET tracers with therapeutic agents. SUMMARY: Implementation of molecular imaging in the clinical routine continues to improve management in patients with brain tumors. However, more prospective large sample studies are needed to validate the additional informative value of PET.

In-vivo monitoring of erythropoietin treatment after myocardial infarction in mice with [68Ga]Annexin A5 and [¹8F]FDG PET.

BACKGROUND: Several studies substantiate the cardioprotective effects of erythropoietin (EPO). Our goal was to quantify the effects of EPO treatment on the early expression of the apoptosis marker phosphatidylserine as well as on the left ventricular volumes and function by means of small animal PET. METHODS AND RESULTS: Myocardial infarction (MI) was induced in C57BL/6 mice. Animals were assigned to saline or EPO groups and underwent Annexin PET (day 2) and gated FDG PET (days 6 and 30). Annexin uptake was significantly higher in the infarction than in remote myocardium, with no differences between treatment groups. Infarct size showed a slight decrease in the EPO group and a slight increase in the controls, which did not reach statistical significance. Follow-up analyses revealed a significant increase of end-diastolic and end-systolic volumes in the EPO group, in which a stable left ventricular ejection fraction (LVEF) was maintained. CONCLUSION: We find that deleterious effects of EPO can outweigh cardioprotective effects. The present EPO treatment did not significantly reduce apoptosis after MI, but seemingly provoked significant myocardial dilation while maintaining a stable LVEF. Molecular mechanisms of EPO treatment may need further elucidation to optimize therapy regimens.

[18F]fluoroethyltyrosine-positron emission tomography-based therapy monitoring after stereotactic iodine-125 brachytherapy in patients with recurrent high-grade glioma.

Therapy monitoring of glioma after stereotactic iodine-125 brachytherapy (SBT) remains challenging because posttherapeutic changes in magnetic resonance imaging can mimic tumor progression. We evaluated the prognostic value of serial [18F]fluoroethyltyrosine (FET)-positron emission tomographic (PET) scans for therapy monitoring of high-grade glioma (HGG) after SBT. Thirty-three patients with recurrent HGG were included. Serial FET-PET scans were performed prior to therapeutic intervention and at 3-month intervals during the first year after SBT. FET-PET evaluation was performed by both conventional data analysis and kinetic analysis. Prognostic factors were obtained from proportional hazard models. Median local progression-free survival (LPFS) was 11.1 months. Maximal standardized background uptake value (SUVmax/BG) and biologic tumor volume (BTV) differentiated accurately between therapeutic effects and local tumor progression at the 6-month and subsequent examinations. Increasing uptake kinetics at baseline (p < .05) and during follow-up (p < .01) were stringently associated with a longer LPFS. Early increase in FET uptake after SBT is not unequivocally associated with tumor progression; it might be induced by reactive changes and could easily lead to a misclassification of the tumor status (pseudoprogression). Six months after SBT (or later), however, increased SUVmax/BG and BTV values are associated with a worse prognosis. Multivariate analysis stresses the prognostic importance of dynamic studies.

Comparison of abdominal MRI with diffusion-weighted imaging to 68Ga-DOTATATE PET/CT in detection of neuroendocrine tumors of the pancreas.

PURPOSE: The aim of the study was to evaluate contrast-enhanced MRI, diffusion-weighted MRI (DW MRI), and (68)Ga-DOTATATE positron emission tomography (PET)/CT in the detection of intermediate to well-differentiated neuroendocrine tumors (NET) of the pancreas. METHODS: Eighteen patients with pathologically proven pancreatic NET who underwent MRI including DW MRI and PET/CT within 6 weeks of each other were included in this retrospective study. Two radiologists evaluated T2-weighted (T2w), T2w + DW MRI, T2w + contrast-enhanced T1-weighted (CE T1w) MR images, and PET/CT for NET detection. The sensitivity and level of diagnostic confidence were compared among modalities using McNemar's test and a Wilcoxon signed rank test. Apparent diffusion coefficients (ADC) of pancreatic NETs and normal pancreatic tissue were compared with Student's t test. RESULTS: Of the NETs, 8/23 (34.8 %) and 9/23 (39.1 %) were detected on T2w images by observers 1 and 2, respectively. Detection rates improved significantly by combining T2w images with DW MRI (observer 1: 14/23 = 61 %; observer 2: 15/23 = 65.2 %; p < 0.05) or CE T1w images (observer 1: 14/23 = 61 %; observer 2: 15/23 = 65.2 %; p < 0.05). Detection rates of pancreatic NET with PET/CT (both observers: 23/23 = 100 %) were statistically significantly higher than with MRI (p < 0.05). The mean ADC value of NET (1.02 ± 0.26 × 10(-3) mm(2)/s) was statistically significantly lower than that of normal pancreatic tissue (1.48 ± 0.39 × 10(-3) mm(2)/s). CONCLUSION: DW MRI is a valuable adjunct to T2w imaging and comparable to CE T1w imaging in pancreatic NET detection, quantitatively differentiating between NET and normal pancreatic tissue with ADC measurements. (68)Ga-DOTATATE PET/CT is more sensitive than MRI in the detection of pancreatic NET.

Atypical parkinsonism due to a D202N Gerstmann-Sträussler-Scheinker prion protein mutation: first in vivo diagnosed case.

BACKGROUND: Parkinsonism with dopa-sensitivity and a correlating DaTSCAN turned out to be due to a D202N mutation which is associated with the Gerstmann-Sträussler-Scheinker (GSS) disease. METHODS/RESULTS: We report a 51-year old female who presented with left-dominant parkinsonism and a positive DaTSCAN. She was diagnosed with idiopathic Parkinson's syndrome. Dopaminergic medication reduced her symptoms. In addition, punding-like behavior, deficits in organizing daily life and abnormal sleep behavior were reported. Neuropsychological testing, EEG, polysomnography as well as PET imaging with fluorodexyglucose (FDG), [F-18]-desmethoxyfallypride (DMFP), and [C-11]-6-OH-BTA-1 (PIB) were not diagnostic. Cerebral spinal fluid analysis revealed no 14-3-3 protein, but elevated neuron-specific enolase (NSE) and S100-beta and a very low phospho-tau/total-tau ratio. Analysis of the prion gene disclosed the rare D202N mutation. CONCLUSIONS: The D202N prion mutation has been associated with GSS pathology and up to now was only reported post mortem. Our patient is the very first case diagnosed in vivo.

Relationship between PSA kinetics and [18F]fluorocholine PET/CT detection rates of recurrence in patients with prostate cancer after total prostatectomy.

PURPOSE: The aim of the present study was to identify prostate-specific antigen (PSA) threshold levels, as well as PSA velocity, progression rate and doubling time in relation to the detectability and localization of recurrent lesions with [(18)F]fluorocholine (FC) PET/CT in patients after radical prostatectomy. METHODS: The study group comprised 82 consecutive patients with biochemical relapse after radical prostatectomy. PSA levels measured at the time of imaging were correlated with the FC PET/CT detection rates in the entire group with PSA velocity (in 48 patients), with PSA doubling time (in 47 patients) and with PSA progression (in 29 patients). RESULTS: FC PET/CT detected recurrent lesions in 51 of the 82 patients (62%). The median PSA value was significantly higher in PET-positive than in PET-negative patients (4.3 ng/ml vs. 1.0 ng/ml; p < 0.01). The optimal PSA threshold from ROC analysis for the detection of recurrent prostate cancer lesions was 1.74 ng/ml (AUC 0.818, 82% sensitivity, 74% specificity). Significant differences between PET-positive and PET-negative patients were found for median PSA velocity (6.4 vs. 1.1 ng/ml per year; p < 0.01) and PSA progression (5.0 vs. 0.3 ng/ml per year, p < 0.01) with corresponding optimal thresholds of 1.27 ng/ml per year and 1.28 ng/ml per year, respectively. The PSA doubling time suggested a threshold of 3.2 months, but this just failed to reach statistical significance (p = 0.071). CONCLUSION: In a study cohort of patients with biochemical recurrence of prostate cancer after radical prostatectomy there emerged clear PSA thresholds for the presence of FC PET/CT-detectable lesions.

MRI-suspected low-grade glioma: is there a need to perform dynamic FET PET?

PURPOSE: Since differentiation between low-grade glioma (LGG) and high-grade glioma (HGG) remains challenging according to MRI criteria alone, we investigated the discriminative value of additional dynamic FET PET in patients with MRI-suspected LGG. METHODS: Included in this retrospective study were 127 patients with newly diagnosed MRI-suspected LGG and dynamic FET PET prior to histopathological assessment. FET PET lesions were visually classified as having reduced, normal, or increased tracer uptake. Maximal tumour uptake scaled to the mean background uptake (SUV(max)/BG), mean tumour uptake (SUV(mean)/BG), biological tumour volume and kinetics were evaluated and correlated with individual histopathological findings. RESULTS: Histopathological analysis revealed 71 patients with LGG, 47 patients with HGG (including 5 glioblastoma multiforme), 2 patients with low-grade ganglioglioma and 7 patients with non-neoplastic lesions. Of the 127 patients, 97 had lesions with increased FET uptake, of which 93 were neoplastic. Increased uptake was found in 49/71 LGG (69 %) and 42/47 HGG (89 %). None of the conventional uptake parameters differed significantly between the HGG and LGG groups. Kinetic analysis reliably identified HGG (sensitivity 95 %, specificity 72 %, PPV 74 %, NPV 95 %). Normal tracer uptake was observed in 19 patients (15 with LGG, 1 with HGG and 3 with non-neoplastic lesions) and reduced uptake in 11 patients (7 with LGG and 4 with HGG). CONCLUSION: Among the MRI-suspected LGG, kinetic but not conventional analysis of FET uptake enabled remarkably high sensitivity for detection of HGG. This held true even for lesions with low or diffuse tracer uptake. Lesions with reduced tracer uptake must be interpreted with caution, as they can also harbour HGG tissue.

Re-irradiation in recurrent malignant glioma: prognostic value of [18F]FET-PET.

The aim of the present study is to determine new positron emission tomography (PET) imaging-related factors predictive of progression-free survival as well as survival in patients with recurrent malignant glioma (MG) prior to and after re-irradiation. Fifty-six patients with recurrent MG who underwent re-irradiation treatment and pretherapeutic dynamic [(18)F]-fluoroethyl-L-tyrosine (FET)-PET scan were retrospectively analyzed. The prognostic value of different parameters, such as biological tumor volume, maximal tumor uptake (SUV(max)/BG), mean tumor uptake (SUV(mean)/BG), as well as uptake kinetics, was evaluated. [(18)F]FET uptake kinetics was classified according to a five-point rating as category G(1-2) (strongly/mainly increasing kinetics), G(3) (mixed 1:1), or G(4-5) (mainly/strongly decreasing kinetics). Patients within the pretherapeutic kinetic group G(4-5) had significantly worse survival than the other two groups (p = 0.01). Multivariate analysis revealed that histologic grade, Karnofsky Performance Score (KPS), and kinetic group were independent significant predictors for survival after re-irradiation. The uptake kinetics of [(18)F]FET-PET is an independent determinant of overall and to a lesser extent also progression-free survival. Thus, [(18)F]FET-PET kinetics may provide valuable additional prognostic information for treatment decisions.

Psychometric qualities of the Dutch version of the Pediatric Inventory for Parents (PIP): a multi-center study.

OBJECTIVES: Diagnosis and treatment of childhood cancer are continuous stressors in the lives of the entire family involved. Disease-related tools for the assessment of parental stress and adaptation are scarce. For that reason, the Pediatric Inventory for Parents (PIP), a disease-related measure, was translated into Dutch and its psychometric qualities were determined to prove its value. METHODS: The PIP and three other measures (State-Trait Anxiety Inventory, General Health Questionnaire and Parenting Stress Index, Short Form) were administered to 174 parents of 107 children diagnosed with cancer in three university medical centers in the Netherlands. RESULTS: Internal consistency (Crohnbach's alpha=0.94 and 0.95) and test-retest reliability (Pearson's r between 0.67 and 0.87) of the Dutch PIP total scales are satisfactory. Validity was illustrated by a high correlation between PIP-scores and anxiety and general stress. Confirmatory factor analysis showed acceptable fit to the data for the original four-factor and the one-factor models; the four-factor model showed slightly better fit. CONCLUSION: The PIP can be used in clinical practice to assess disease-related parental stress. Further psychometric testing is highly recommended.

Understanding haemophilic arthropathy: an exploration of current open issues.

Haemophilic arthropathy is joint damage evolving from recurrent joint bleeds that occur in patients suffering from the clotting disorder haemophilia. Insight into the pathogenetic mechanism of this blood-induced arthropathy yields possible treatment targets and modalities useful to reduce this invalidating co-morbidity of haemophilia. Joint bleeding leads to initially independent adverse changes in both the synovial tissue and the articular cartilage. These subsequently influence each other: the synovial inflammatory changes enhancing cartilage damage and vice versa. Consequently, effective treatment strategies will have to affect both pathways.

Interleukin-10 protects against blood-induced joint damage.

Despite prophylactic treatment, haemophilia patients suffer from spontaneous joint bleeds, which lead to severe joint damage. Also after joint trauma, an intra-articular haemorrhage can add to joint damage over time. This study evaluated interleukin 10 (IL-10) in the search for possible interventions to prevent or limit the damaging effects of joint bleeds. Human articular cartilage tissue explants were cultured in the presence or absence of 50% v/v blood (or its cellular components) for 4 d (the expected blood load in vivo after a joint haemorrhage), followed by a recovery period of 12 d. Pharmacological dosages of IL-10 reached during treatment (1 or 10 ng/ml) were added. Additionally, cartilage and synovial tissue obtained from joints with end-stage haemophilic arthropathy (HA) were cultured in the presence of IL-10 (10 ng/ml). IL-10 protected cartilage from the damaging effects of blood exposure, measured by its effects on proteoglycan turnover. In addition, IL-10 beneficially influenced cartilage from patients with HA and reduced the production of the inflammatory cytokines IL-1beta and tumour necrosis factor-alpha by haemophilic synovial tissue. Taken together, although effects were obtained in vitro, IL-10 protects against blood-induced joint damage and might be further evaluated as candidate in treatment of tissue damaging effects of joint haemorrhages.

Post-treatment intellectual functioning in children treated for acute lymphoblastic leukaemia (ALL) with chemotherapy-only: a prospective, sibling-controlled study.

Intellectual functioning (verbal, performance and full-scale IQ) in 43 children treated for acute lymphoblastic leukaemia (ALL) with chemotherapy-only was evaluated in a nationwide, prospective, sibling-controlled study. Intellectual assessment was performed at diagnosis and repeated shortly after cessation of 2 years treatment, including intrathecal and systemic chemotherapy. Using hierarchical regression analysis, patients' and siblings' (n=27) scores were longitudinally analysed and compared to assess possible changes and differences over time. At both assessments, before and after treatment, the patients showed average scores on intelligence tests compared to population norms. Longitudinal analysis and cross-sectional comparisons revealed no significant differences between patients and controls. Young patients showed a small relative decline, albeit not significant, on performance-IQ compared to healthy siblings. Despite intensive and potentially neurotoxic treatment, no evident negative effects on intelligence were found. However, it cannot be precluded that younger patients are at risk for a small decline in PIQ.

Prognostic significance of dynamic 18F-FET PET in newly diagnosed astrocytic high-grade glioma.

UNLABELLED: Despite advances in diagnosis and the use of different therapeutic regimens in astrocytic high-grade glioma (HGG), the prognosis for patients remains grim. Additional pretherapeutic information is needed to tailor management. To gain additional prognostic information at primary diagnosis, we investigated the value of dynamic O-(2-(18)F-fluoroethyl)-L-tyrosine ((18)F-FET) PET. METHODS: We retrospectively evaluated 121 patients who had a primary diagnosis of astrocytic HGG (51 World Health Organization [WHO] grade III; 70 WHO IV) and underwent dynamic (18)F-FET PET before histopathologic assessment. We assessed static parameters (maximal and mean tumoral standardized uptake value corrected for mean background activity in the contralateral hemisphere [SUV(max)/BG and SUV(mean)/BG, respectively], biologic tumor volume) and dynamic time-activity curves, including minimal time to peak (TTP(min)). The prognostic influence of PET parameters and other clinical parameters on progression-free and overall survival was evaluated using uni- and multivariate Cox regression and Kaplan-Meier survival estimates. RESULTS: In the group overall, median progression-free survival and overall survival were 12.2 and 21.9 mo. SUV(max)/BG, SUV(mean)/BG, and biologic tumor volume were significantly higher in WHO IV than in WHO III gliomas; median TTP(min) was 12.5 min in both groups. On univariate analysis, the factors age, WHO grade, O6-methylguanine-DNA methyltransferase promoter methylation status, contrast enhancement, initial treatment, and TTP(min) showed prognostic significance, with WHO grade, O6-methylguanine-DNA methyltransferase status, age, and TTP(min) remaining significant in the multivariate analysis. WHO grade and TTP(min) reached a similar fit for the prognostic evaluation. The prognosis of WHO III astrocytoma with an early TTP(min) of 12.5 min or less did not differ significantly from that of glioblastoma. CONCLUSION: Early TTP(min) is associated with worse outcome in patients with newly diagnosed astrocytic HGG. In the preoperative setting, TTP(min) can be a valuable noninvasive prognostic marker with comparable significance to WHO grade. Additionally, TTP(min) can help identify highly aggressive WHO III astrocytoma tumors and may help in adjusting standard treatment toward an individualized, risk-adapted therapy regime.

Biological tumor volume in 18FET-PET before radiochemotherapy correlates with survival in GBM.

OBJECTIVE: The aim of this prospective longitudinal study was to identify static and dynamic O-(2-[(18)F]fluoroethyl)-L-tyrosine PET ((18)FET-PET)-derived imaging biomarkers in patients with glioblastoma (GBM). METHODS: Seventy-nine patients with newly diagnosed GBM were included; 42 patients underwent stereotactic biopsy (unresectable tumors) and 37 patients microsurgical tumor resection. All patients were scheduled to receive radiotherapy plus concomitant and adjuvant temozolomide (RCx/TMZ). (18)FET-PET evaluation using static and dynamic analysis was done before biopsy/resection, after resection, 4 to 6 weeks following RCx, and after 3 cycles of TMZ. Endpoints were survival and progression-free-survival. Prognostic factors were obtained from proportional hazards models. RESULTS: Biological tumor volume before RCx (BTV(preRCx)) was the most important (18)FET-PET-derived imaging biomarker and was independent of MGMT promoter methylation and clinical prognostic factors: patients with smaller BTV(preRCx) had significantly longer progression-free and overall survival (OS). (18)FET time-activity curves (TACs) before treatment and their changes after RCx were also related to outcome; patients with initially increasing TACs experienced longer OS. CONCLUSION: BTV(preRCx) and TAC represent important (18)FET-PET-derived imaging biomarkers in GBM. Increasing TACs are associated with prolonged OS. The BTV(preRCx) is a strong prognostic factor for progression-free survival and OS independent of the mode of surgery. Our data furthermore suggest that patients harboring resectable GBM might benefit from maximal PET-guided tumor resection.

Recurrence pattern analysis after re-irradiation with bevacizumab in recurrent malignant glioma patients.

BACKGROUND: The aim of the present analysis was to evaluate the recurrence pattern in patients with recurrent malignant glioma after re-irradiation in combination with bevacizumab as there is limited data on how to optimally choose dose, fractionation and delineation margins. METHODS: Thirty-one patients with recurrent malignant glioma treated with re-irradiation and bevacizumab after previous chemoradiotherapy (concurrent temozolomide 75 mg/m(2)/d according to the EORTC/NCIC trial) and [(18) F]FET-PET and/or MRI confirmed recurrence were retrospectively analyzed. Bevacizumab was applied twice during fractionated re-irradiation (10 mg/kg, d1+d15, median 36 Gy, conventionally fractionated). Recurrence patterns were assessed by means of [(18) F]FET-PET and/or MRI. RESULTS: Median follow-up was 34.0 months for all patients [95%-CI, 27.7-40.3] and median post-recurrence survival 10.8 months [95%-CI, 9.2-12.4]. Concerning the recurrence patterns, 61.3% of these were located in-field (19 patients), 22.6% were marginal (7 patients) and 16.1% ex-field (5 patients). No influence on the recurrence pattern was observed according to sex, WHO grade, maintenance chemotherapy or MGMT methylation status whereas planning target volume (PTV) size had a significant influence on the recurrence pattern (p=0.032). PTV sizes>75 ml were associated with a higher in-field recurrence rate and lower median post-recurrence progression-free survival (8.5 vs. 4.9 months, p=0.016). CONCLUSIONS: After the administration of re-irradiation with bevacizumab the recurrence pattern seems to be mainly centrally located. The PTV size was the main predictor for a marginal/ex-field recurrence.

Prognostic factors for survival and radiation necrosis after stereotactic radiosurgery alone or in combination with whole brain radiation therapy for 1-3 cerebral metastases.

BACKGROUND: In the present study factors affecting survival and toxicity in cerebral metastasized patients treated with stereotactic radiosurgery (SRS) were analyzed with special focus on radiation necrosis. PATIENTS AND METHODS: 340 patients with 1-3 cerebral metastases having been treated with SRS were retrospectively analyzed. Radiation necrosis was diagnosed by MRI und PET imaging. Univariate and multivariate analysis using a Cox proportional hazards regression model and log-rank test were performed to determine the prognostic value of treatment-related and individual factors for outcome and SRS-related complications. RESULTS: Median overall survival was 282 days and median follow-up 721 days. 44% of patients received WBRT during the course of disease. Concerning univariate analysis a significant difference in overall survival was found for Karnofsky Performance Status (KPS ≤ 70: 122 days; KPS > 70: 342 days), for RPA (recursive partitioning analysis) class (RPA class I: 1800 days; RPA class II: 281 days; RPA class III: 130 days), irradiated volume (≤2.5 ml: 354 days; > 2.5 ml: 234 days), prescribed dose (≤18 Gy: 235 days; > 18 Gy: 351 days), gender (male: 235 days; female: 327 days) and whole brain radiotherapy (+WBRT: 341 days/-WBRT: 231 days). In multivariate analysis significance was confirmed for KPS, RPA class and gender. MRI and clinical symptoms suggested radiation necrosis in 21 patients after SRS +/- whole brain radiotherapy (WBRT). In five patients clinically relevant radiation necrosis was confirmed by PET imaging. CONCLUSIONS: SRS alone or in combination with WBRT represents a feasible option as initial treatment for patients with brain metastases; however a significant subset of patients may develop neurological complications. Performance status, RPA class and gender were identified to predict improved survival in cerebral metastasized patients.

Assessment of cerebral dopamine D 2/3 formula-receptors in patients with bilateral vestibular failure.

BACKGROUND: Absence of peripheral vestibular input in bilateral vestibular failure (BVF) has been suggested to induce plastic reorganization in various brain regions. Among several neurotransmitters, dopamine is known to play a key role in cortico-striatal-sensorimotor processing. However, the role of dopamine in vestibular plasticity is scantly documented. OBJECTIVE: Assessment of D 2/3 formula-receptors in patients with BVF. METHODS: D 2/3 formula-receptor-PET using [18F]fallypride and MRI examinations were performed in 12 BVF-patients and 13 healthy controls. RESULTS: BVF-patients showed reduced D 2/3 formula-receptor availability (approximately 40%) in the temporo-parieto-occipital cortex bilaterally, including the multisensory vestibular cortex and visual motion-sensitive areas (MT/MST), as well as in the striatum and the right thalamus. Longer illness duration was associated with bilaterally lower D 2/3 formula-receptor availability in the middle/superior temporal gyrus (GTm/s). D 2/3 formula-receptor availability in the right GTm/s and bilateral insula decreased with severity of symptoms. BVF-patients with oscillopsia showed reduced D 2/3 formula-receptor availability in the right MT/MST and midbrain tectum. CONCLUSIONS: Reduced D 2/3 formula-receptor availability in multisensory vestibular cortical network areas and basal ganglia may indicate a receptor down-regulation due to the lack of peripheral vestibular input. The more pronounced decline in D 2/3 formula-receptor availability in the multisensory vestibular cortex in patients with prolonged illness suggests the occurrence of progressive changes in dopamine transmission.

Dynamic 18F-FET PET in newly diagnosed astrocytic low-grade glioma identifies high-risk patients.

UNLABELLED: Because the clinical course of low-grade gliomas in the individual adult patient varies considerably and is unpredictable, we investigated the prognostic value of dynamic (18)F-fluorethyltyrosine ((18)F-FET) PET in the early diagnosis of astrocytic low-grade glioma (World Health Organization grade II). METHODS: Fifty-nine patients with newly diagnosed low-grade glioma and dynamic (18)F-FET PET before histopathologic assessment were retrospectively investigated. (18)F-FET PET analysis comprised a qualitative visual classification of lesions; assessment of the semiquantitative parameters maximal, mean, and total standardized uptake value as ratio to background and biologic tumor volume; and dynamic analysis of intratumoral (18)F-FET uptake over time (increasing vs. decreasing time-activity curves). The correlation between PET parameters and progression-free survival, overall survival, and time to malignant transformation was investigated. RESULTS: (18)F-FET uptake greater than the background level was found in 34 of 59 tumors. Dynamic (18)F-FET uptake analysis was available for 30 of these 34 patients. Increasing and decreasing time-activity curves were found in 18 and 12 patients, respectively. Neither the qualitative factor presence or absence of (18)F-FET uptake nor any of the semiquantitative uptake parameters significantly influenced clinical outcome. In contrast, decreasing time-activity curves in the kinetic analysis were highly prognostic for shorter progression-free survival and time to malignant transformation (P < 0.001). CONCLUSION: Absence of (18)F-FET uptake in newly diagnosed astrocytic low-grade glioma does not generally indicate an indolent disease course. Among the (18)F-FET-positive gliomas, decreasing time-activity curves in dynamic (18)F-FET PET constitute an unfavorable prognostic factor in astrocytic low-grade glioma and, by identifying high-risk patients, may ease treatment decisions.