Shallow whole-genome sequencing: a useful, easy to apply molecular technique for CNA detection on FFPE tumor tissue-a glioma-driven study.

Copy number alterations (CNAs) have increasingly become part of the diagnostic algorithm of glial tumors. Alterations such as homozygous deletion of CDKN2A/B, 7 +/ 10 - chromosome copy number changes or EGFR amplification are predictive of a poor prognosis. The codeletion of chromosome arms 1p and 19q, typically associated with oligodendroglioma, implies a more favorable prognosis. Detection of this codeletion by the current diagnostic standard, being fluorescence in situ hybridization (FISH), is sometimes however subject to technical and interpretation problems. In this study, we evaluated CNA detection by shallow whole-genome sequencing (sWGS) as an inexpensive, complementary molecular technique. A cohort of 36 glioma tissue samples, enriched with "difficult" and "ambiguous" cases, was analyzed by sWGS. sWGS results were compared with FISH assays of chromosomes 1p and 19q. In addition, CNAs relevant to glioblastoma diagnosis were explored. In 4/36 samples, EGFR (7p11.2) amplifications and homozygous loss of CDKN2A/B were identified by sWGS. Six out of 8 IDH-wild-type glioblastomas demonstrated a prognostic chromosome 7/chromosome 10 signature. In 11/36 samples, local interstitial and terminal 1p/19q alterations were detected by sWGS, implying that FISH's targeted nature might promote false arm-level extrapolations. In this cohort, differences in overall survival between patients with and without codeletion were better pronounced by the sequencing-based distinction (likelihood ratio of 7.48) in comparison to FISH groupings (likelihood ratio of 0.97 at diagnosis and 1.79 ± 0.62 at reobservation), suggesting sWGS is more accurate than FISH. We recognized adverse effects of tissue block age on FISH signals. In addition, we show how sWGS reveals relevant aberrations beyond the 1p/19q state, such as EGFR amplification, combined gain of chromosome 7 and loss of chromosome 10, and homozygous loss of CDKN2A/B. The findings presented by this study might stimulate implementation of sWGS as a complementary, easy to apply technique for copy number detection.

Intramuscular desmoplastic fibroblastoma: a case report of extreme rarities in extremities.

Soft tissue tumors are part of a wide and sometimes rare differential diagnostic landscape. Case description of these rare soft tissue masses helps the future differentiation and aids in preoperative multidisciplinary approach. Interpretation and staging, with the help of imaging, is key.

A Potential Role for Fructosamine-3-Kinase in Cataract Treatment.

Cataracts are the major cause of blindness worldwide, largely resulting from aging and diabetes mellitus. Advanced glycation end products (AGEs) have been identified as major contributors in cataract formation because they alter lens protein structure and stability and induce covalent cross-linking, aggregation, and insolubilization of lens crystallins. We investigated the potential of the deglycating enzyme fructosamine-3-kinase (FN3K) in the disruption of AGEs in cataractous lenses. Macroscopic changes of equine lenses were evaluated after ex vivo intravitreal FN3K injection. The mechanical properties of an equine lens pair were evaluated after treatment with saline and FN3K. AGE-type autofluorescence (AF) was measured to assess the time-dependent effects of FN3K on glycolaldehyde-induced AGE-modified porcine lens fragments and to evaluate its actions on intact lenses after in vivo intravitreal FN3K injection of murine eyes. A potential immune response after injection was evaluated by analysis of IL-2, TNFα, and IFNγ using an ELISA kit. Dose- and time-dependent AF kinetics were analyzed on pooled human lens fragments. Furthermore, AF measurements and a time-lapse of macroscopic changes were performed on intact cataractous human eye lenses after incubation with an FN3K solution. At last, AF measurements were performed on cataractous human eyes after crossover topical treatment with either saline- or FN3K-containing drops. While the lenses of the equine FN3K-treated eyes appeared to be clear, the saline-treated lenses had a yellowish-brown color. Following FN3K treatment, color restoration could be observed within 30 min. The extension rate of the equine FN3K-treated lens was more than twice the extension rate of the saline-treated lens. FN3K treatment induced significant time-dependent decreases in AGE-related AF values in the AGE-modified porcine lens fragments. Furthermore, in vivo intravitreal FN3K injection of murine eyes significantly reduced AF values of the lenses. Treatment did not provoke a systemic immune response in mice. AF kinetics of FN3K-treated cataractous human lens suspensions revealed dose- and time-dependent decreases. Incubation of cataractous human eye lenses with FN3K resulted in a macroscopic lighter color of the cortex and a decrease in AF values. At last, crossover topical treatment of intact human eyes revealed a decrease in AF values during FN3K treatment, while showing no notable changes with saline. Our study suggests, for the first time, a potential additional role of FN3K as an alternative treatment for AGE-related cataracts.

Assessment of the effect of therapy in a rat model of glioblastoma using [18F]FDG and [18F]FCho PET compared to contrast-enhanced MRI.

OBJECTIVE: We investigated the potential of [18F]fluorodeoxyglucose ([18F]FDG) and [18F]Fluoromethylcholine ([18F]FCho) PET, compared to contrast-enhanced MRI, for the early detection of treatment response in F98 glioblastoma (GB) rats. METHODS: When GB was confirmed on T2- and contrast-enhanced T1-weighted MRI, animals were randomized into a treatment group (n = 5) receiving MRI-guided 3D conformal arc micro-irradiation (20 Gy) with concomitant temozolomide, and a sham group (n = 5). Effect of treatment was evaluated by MRI and [18F]FDG PET on day 2, 5, 9 and 12 post-treatment and [18F]FCho PET on day 1, 6, 8 and 13 post-treatment. The metabolic tumor volume (MTV) was calculated using a semi-automatic thresholding method and the average tracer uptake within the MTV was converted to a standard uptake value (SUV). RESULTS: To detect treatment response, we found that for [18F]FDG PET (SUVmean x MTV) is superior to MTV only. Using (SUVmean x MTV), [18F]FDG PET detects treatment effect starting as soon as day 5 post-therapy, comparable to contrast-enhanced MRI. Importantly, [18F]FDG PET at delayed time intervals (240 min p.i.) was able to detect the treatment effect earlier, starting at day 2 post-irradiation. No significant differences were found at any time point for both the MTV and (SUVmean x MTV) of [18F]FCho PET. CONCLUSIONS: Both MRI and particularly delayed [18F]FDG PET were able to detect early treatment responses in GB rats, whereas, in this study this was not possible using [18F]FCho PET. Further comparative studies should corroborate these results and should also include (different) amino acid PET tracers.

Survival impact of incidental subventricular zone irradiation in IDH-wildtype glioblastoma.

BACKGROUND AND PURPOSE: The subventricular zone (SVZ) is an important niche for neural stem cells but probably also for brain tumor propagating cells, including the glioblastoma stem cell. The SVZ may become a target for radiation therapy in glioblastoma patients. However, reports studying the effect of irradiation of the SVZ on glioblastoma patient survival show conflicting results. We studied the correlation between incidental SVZ radiation dose and survival in a cohort of isocitrate dehydrogenase-wildtype (IDHwt) glioblastoma patients with inclusion of important survival prognosticators. PATIENTS AND METHODS: In this retrospective analysis, only adult patients with supratentorial IDHwt glioblastoma were included who were treated with temozolomide-based chemoradiotherapy after surgery. The SVZ was contoured on the radiotherapy planning imaging. Cox proportional regression overall survival (OS) analysis was used to study the correlation between SVZ dose and survival. Age, Karnofsky Performance Score, extent of resection and O6-methylguanine-methyl-DNA-transferase gene promoter (MGMTp) methylation were used as covariates in multivariate analysis. RESULTS: In total, 137 patients were included. Median OS was 13.3 months. The MGMTp methylation was present in 40% of cases. Ipsilateral SVZ (iSVZ) mean dose was 44.4 Gy and 27.2 Gy for the contralateral SVZ (cSVZ). Univariate survival analysis showed an inverse relationship between cSVZ mean dose and OS (HR 1.029 (1.003-1.057); p= .032). However, there was no correlation between cSVZ mean dose and OS in multivariate analysis. iSVZ dose did not correlate with survival. CONCLUSION: In this cohort of 137 IDHwt glioblastoma patients, iSVZ did not correlate with OS. Higher cSVZ dose was inversely correlated with OS in univariate survival analysis but lost its significance in multivariate analysis, including MGMTp-methylation. Hence, the correlation between SVZ radiation and glioblastoma patient survival remains unclear. Carefully designed prospective studies are needed to provide unequivocal results on this controversial topic.

Partial resection offers an overall survival benefit over biopsy in MGMT-unmethylated IDH-wildtype glioblastoma patients.

Background Isocitrate dehydrogenase (IDH)-wildtype glioblastoma patients with O6-methylguanine-DNA-methyltransferase (MGMT)-unmethylated tumors have the worst outcome of all glioblastoma patients. The overall survival (OS) benefit of partial resection of glioblastoma compared to biopsy only remains controversial specifically in relation to molecular factors. In this report, we analyzed the effect of incomplete resection on OS compared to biopsy only in a cohort of IDH-wildtype glioblastoma patients who were uniformly treated with temozolomide-based chemoradiotherapy (TMZ-CR) after surgery. Material & Methods A retrospective study was conducted including only glioblastoma patients who were treated with TMZ-CR after surgery from two centers. Surgical groups were defined as biopsy only, partial resection (PR) or gross total resection depending on the presence of contrast-enhancing tumor on postoperative imaging. IDH-mutation was determined using next generation sequencing technique and MGMT-methylation was analyzed with semi-quantitative methylation-specific polymerase chain reaction. Next to descriptive statistics, univariate and multivariate survival analyses were performed using Kaplan-Meier estimates and Cox regression models. Results In total, 159 patients were included. 37 patients underwent biopsy only and 73 partial resections. 99 patients (62.3%) harbored unmethylated tumors. Median OS for the whole patient group was 13.4 months. In the subgroup of patients with unmethylated tumors, PR yielded a median OS of 12.2 months vs 7.6 months for biopsy patients (P = 0.003). PR proved an independent beneficial prognostic factor in multivariate Cox regression model, together with age, Karnofsky Performance Score and MGMT-methylation. Conclusion In IDH-wildtype glioblastoma patients with MGMT-unmethylated tumors, treated with chemoradiotherapy after surgery, PR yields a significant OS benefit compared to biopsy.

Development of a Rat Model for Glioma-Related Epilepsy.

Seizures are common in patients with high-grade gliomas (30-60%) and approximately 15-30% of glioblastoma (GB) patients develop drug-resistant epilepsy. Reliable animal models are needed to develop adequate treatments for glioma-related epilepsy. Therefore, fifteen rats were inoculated with F98 GB cells (GB group) and four rats with vehicle only (control group) in the right entorhinal cortex. MRI was performed to visualize tumor presence. A subset of seven GB and two control rats were implanted with recording electrodes to determine the occurrence of epileptic seizures with video-EEG recording over multiple days. In a subset of rats, tumor size and expression of tumor markers were investigated with histology or mRNA in situ hybridization. Tumors were visible on MRI six days post-inoculation. Time-dependent changes in tumor morphology and size were visible on MRI. Epileptic seizures were detected in all GB rats monitored with video-EEG. Twenty-one days after inoculation, rats were euthanized based on signs of discomfort and pain. This study describes, for the first time, reproducible tumor growth and spontaneous seizures upon inoculation of F98 cells in the rat entorhinal cortex. The development of this new model of GB-related epilepsy may be valuable to design new therapies against tumor growth and associated epileptic seizures.

Fructosamine-3-Kinase as a Potential Treatment Option for Age-Related Macular Degeneration.

Age-related macular degeneration is the leading cause of blindness in the developed world. Since advanced glycation end products (AGEs) are implicated in the pathogenesis of AMD through various lines of evidence, we investigated the potential of fructosamine-3-kinase (FN3K) in the disruption of retinal AGEs, drusenoid material and drusenoid lesions in patients with AMD. AGE-type autofluorescence was measured to evaluate the effects of FN3K on glycolaldehyde-induced AGE-modified neural porcine retinas and unmodified human neural retinas. Eye pairs from cigarette-smoke- and air-exposed mice were treated and evaluated histologically. Automated optical image analysis of human tissue sections was performed to compare control- and FN3K-treated drusen and near-infrared (NIR) microspectroscopy was performed to examine biochemical differences. Optical coherence tomography (OCT) was used to evaluate the effect of FN3K on drusenoid deposits after treatment of post-mortem human eyes. FN3K treatment provoked a significant decrease (41%) of AGE-related autofluorescence in the AGE-modified porcine retinas. Furthermore, treatment of human neural retinas resulted in significant decreases of autofluorescence (-24%). FN3K-treated murine eyes showed less drusenoid material. Pairwise comparison of drusen on tissue sections revealed significant changes in color intensity after FN3K treatment. NIR microspectroscopy uncovered clear spectral differences in drusenoid material (Bruch's membrane) and drusen after FN3K treatment. Ex vivo treatment strongly reduced size of subretinal drusenoid lesions on OCT imaging (up to 83%). In conclusion, our study demonstrated for the first time a potential role of FN3K in the disruption of AGE-related retinal autofluorescence, drusenoid material and drusenoid lesions in patients with AMD.

Technical feasibility of [18F]FET and [18F]FAZA PET guided radiotherapy in a F98 glioblastoma rat model.

BACKGROUND: Glioblastoma (GB) is the most common primary malignant brain tumor. Standard medical treatment consists of a maximal safe surgical resection, subsequently radiation therapy (RT) and chemotherapy with temozolomide (TMZ). An accurate definition of the tumor volume is of utmost importance for guiding RT. In this project we investigated the feasibility and treatment response of subvolume boosting to a PET-defined tumor part. METHOD: F98 GB cells inoculated in the rat brain were imaged using T2- and contrast-enhanced T1-weighted (T1w) MRI. A dose of 20 Gy (5 × 5 mm2) was delivered to the target volume delineated based on T1w MRI for three treatment groups. Two of those treatment groups received an additional radiation boost of 5 Gy (1 × 1 mm2) delivered to the region either with maximum [18F]FET or [18F]FAZA PET tracer uptake, respectively. All therapy groups received intraperitoneal (IP) injections of TMZ. Finally, a control group received no RT and only control IP injections. The average, minimum and maximum dose, as well as the D90-, D50- and D2- values were calculated for nine rats using both RT plans. To evaluate response to therapy, follow-up tumor volumes were delineated based on T1w MRI. RESULTS: When comparing the dose volume histograms, a significant difference was found exclusively between the D2-values. A significant difference in tumor growth was only found between active therapy and sham therapy respectively, while no significant differences were found when comparing the three treatment groups. CONCLUSION: In this study we showed the feasibility of PET guided subvolume boosting of F98 glioblastoma in rats. No evidence was found for a beneficial effect regarding tumor response. However, improvements for dose targeting in rodents and studies investigating new targeted drugs for GB treatment are mandatory.

New fluoroethyl phenylalanine analogues as potential LAT1-targeting PET tracers for glioblastoma.

The use of O-(2-[18F]fluoroethyl)-L-tyrosine ([18F]FET) as a positron emission tomography (PET) tracer for brain tumor imaging might have some limitations because of the relatively low affinity for the L-type amino acid transporter 1 (LAT1). To assess the stereospecificity and evaluate the influence of aromatic ring modification of phenylalanine LAT1 targeting tracers, six different fluoroalkylated phenylalanine analogues were synthesized. After in vitro Ki determination, the most promising compound, 2-[18F]-2-fluoroethyl-L-phenylalanine (2-[18F]FELP), was selected for further evaluation and in vitro comparison with [18F]FET. Subsequently, 2-[18F]FELP was assessed in vivo and compared with [18F]FET and [18F]FDG in a F98 glioblastoma rat model. 2-[18F]FELP showed improved in vitro characteristics over [18F]FET, especially when the affinity and specificity for system L is concerned. Based on our results, 2-[18F]FELP is a promising new PET tracer for brain tumor imaging.

The Path Toward PET-Guided Radiation Therapy for Glioblastoma in Laboratory Animals: A Mini Review.

Glioblastoma is the most aggressive and malignant primary brain tumor in adults. Despite the current state-of-the-art treatment, which consists of maximal surgical resection followed by radiation therapy, concomitant, and adjuvant chemotherapy, progression remains rapid due to aggressive tumor characteristics. Several new therapeutic targets have been investigated using chemotherapeutics and targeted molecular drugs, however, the intrinsic resistance to induced cell death of brain cells impede the effectiveness of systemic therapies. Also, the unique immune environment of the central nervous system imposes challenges for immune-based therapeutics. Therefore, it is important to consider other approaches to treat these tumors. There is a well-known dose-response relationship for glioblastoma with increased survival with increasing doses, but this effect seems to cap around 60 Gy, due to increased toxicity to the normal brain. Currently, radiation treatment planning of glioblastoma patients relies on CT and MRI that does not visualize the heterogeneous nature of the tumor, and consequently, a homogenous dose is delivered to the entire tumor. Metabolic imaging, such as positron-emission tomography, allows to visualize the heterogeneous tumor environment. Using these metabolic imaging techniques, an approach called dose painting can be used to deliver a higher dose to the tumor regions with high malignancy and/or radiation resistance. Preclinical studies are required for evaluating the benefits of novel radiation treatment strategies, such as PET-based dose painting. The aim of this review is to give a brief overview of promising PET tracers that can be evaluated in laboratory animals to bridge the gap between PET-based dose painting in glioblastoma patients.

Elevated ΔNp63α Levels Facilitate Epidermal and Biliary Oncogenic Transformation.

Unlike its family member p53, TP63 is rarely mutated in human cancer. However, ΔNp63α protein levels are often elevated in tumors of epithelial origin, such as squamous cell carcinoma and cholangiocarcinoma. To study the oncogenic properties of ΔNp63α in vivo, we generated transgenic mice overexpressing ΔNp63α from the Rosa26 locus promoter controlled by keratin 5-Cre. We found that these mice spontaneously develop epidermal cysts and ectopic ΔNp63α expression in the bile duct epithelium that leads to dilatation of the intrahepatic biliary ducts, to hepatic cyst formation and bile duct adenoma. Moreover, when subjected to models of 7,12-dimethylbenz[a]anthracene-based carcinogenesis, tumor initiation was increased in ΔNp63α transgenic mice in a gene dosage-dependent manner although ΔNp63α overexpression did not alter the sensitivity to 7,12-dimethylbenz[a]anthracene-induced cytotoxicity in vivo. However, keratinocytes isolated from ΔNp63α transgenic mice displayed increased survival and delayed cellular senescence compared with wild-type keratinocytes, marked by decreased p16Ink4a and p19Arf expression. Taken together, we show that increased ΔNp63α protein levels facilitate oncogenic transformation in the epidermis as well as in the bile duct.

Copy number variation analysis and methylome profiling of a GNAQ-mutant primary meningeal melanocytic tumor and its liver metastasis.

Primary meningeal melanocytic tumors have genetic similarities with uveal melanomas, including GNAQ or GNA11 mutations. While BAP1 mutations and loss of chromosome 3 have adverse prognostic meaning in uveal melanoma, genetic alterations associated with metastasis have not been investigated in primary meningeal melanocytic tumors. We describe a 43-year-old female with a GNAQ-mutated, BAP1-wt melanocytic tumor originating in the parietal brain region and liver metastases 4years after initial diagnosis. After repeated surgery and chemotherapy she was treated with the immunomodulatory agent ipilimumab. Tissue from the primary and recurrent intracranial tumor (histologically originally diagnosed as intermediate-grade melanocytoma resp. melanoma) and from the liver metastasis was investigated for genome-wide copy number variations and DNA methylation profile. Complete loss of 10p and 19p, partial loss of 16p and a small deletion on 10q were only present in the liver metastasis and not in the intracranial tumors. The DNA methylation profiles of the intracranial tumors and the liver metastasis resembled those of meningeal melanocytomas. In conclusion, in this report we show that a distant metastasis of a meningeal melanocytic tumor has a similar methylation profile as the primary tumor and suggest that particular copy number variations may be associated with metastatic behavior.

18F-FCho PET and MRI for the prediction of response in glioblastoma patients according to the RANO criteria.

PURPOSE: In this study, we investigated fluorine-18 fluoromethylcholine (F-FCho) PET and contrast-enhanced MRI for predicting therapy response in glioblastoma (GB) patients according to the Response Assessment in Neuro-Oncology criteria. Our second aim was to investigate which imaging modality enabled prediction of treatment response first. MATERIALS AND METHODS: Eleven GB patients who underwent no surgery or debulking only and received concomitant radiation therapy (RT) and temozolomide were included. The gold standard Response Assessment in Neuro-Oncology criteria were applied 6 months after RT to define responders and nonresponders. F-FCho PET and MRI were performed before RT, during RT (week 2, 4, and 6), and 1 month after RT. The contrast-enhancing tumor volume on T1-weighted MRI (GdTV) and the metabolic tumor volume (MTV) were calculated. GdTV, standardized uptake value (SUV)mean, SUVmax, MTV, MTV×SUVmean, and percentage change of these variables between all time-points were assessed to differentiate responders from nonresponders. RESULTS: Absolute SUV values did not predict response. MTV must be taken into account. F-FCho PET could predict response with a 100% sensitivity and specificity using MTV×SUVmean 1 month after RT. A decrease in GdTV between week 2 and 6, week 4 and 6 during RT and week 2 during RT, and 1 month after RT of at least 31%, at least 18%, and at least 53% predicted response with a sensitivity and specificity of 100%. As such, the parameter that predicts therapy response first is MR derived, namely, GdTV. CONCLUSION: Our data indicate that both F-FCho PET and contrast-enhanced T1-weighted MRI can predict response early in GB patients treated with RT and temozolomide.

Correction: Kinetic Modeling and Graphical Analysis of 18F-Fluoromethylcholine (FCho), 18F-Fluoroethyltyrosine (FET) and 18F-Fluorodeoxyglucose (FDG) PET for the Fiscrimination between High-Grade Glioma and Radiation Necrosis in Rats.

[This corrects the article DOI: 10.1371/journal.pone.0161845.].

Long term outcome and side effects in patients receiving low-dose I125 brachytherapy: a retrospective analysis

ABSTRACT Objectives: To retrospectively evaluate the disease free survival (DFS), disease specific survival (DSS),overall survival (OS) and side effects in patients who received low-dose rate (LDR) brachytherapy with I125 stranded seeds. Materials and methods: Between july 2003 and august 2012, 274 patients with organ confined prostate cancer were treated with permanent I125 brachytherapy. The median follow-up, age and pretreatment prostate specific antigen (iPSA) was 84 months (12-120), 67 years (50-83) and 7.8 ng/mL (1.14-38), respectively. Median Gleason score was 6 (3-9). 219 patients (80%) had stage cT1c, 42 patients (15.3%) had stage cT2a, 3 (1.1%) had stage cT2b and 3 (1.1%) had stage cT2c. The median D90 was 154.3 Gy (102.7-190.2). Results: DSS was 98.5%.OS was 93.5%. 13 patients (4.7%) developed systemic disease, 7 patients (2.55%) had local progression. In 139 low risk patients, the 5 year biochemical freedom from failure rate (BFFF) was 85% and 9 patients (6.4%) developed clinical progression. In the intermediate risk group, the 5 year BFFF rate was 70% and 5 patients (7.1%) developed clinical progression. Median nPSA in patients with biochemical relapse was 1.58 ng/mL (0.21 – 10.46), median nPSA in patients in remission was 0.51 ng/mL (0.01 – 8.5). Patients attaining a low PSA nadir had a significant higher BFFF (p<0.05). Median D90 in patients with biochemical relapse was 87.2 Gy (51 – 143,1). Patients receiving a high D90 had a significant higher BFFF (p<0.05). Conclusion: In a well selected patient population, LDR brachytherapy offers excellent outcomes. Reaching a low PSA nadir and attaining high D90 values are significant predictors for a higher DFS.

Kinetic Modeling and Graphical Analysis of 18F-Fluoromethylcholine (FCho), 18F-Fluoroethyltyrosine (FET) and 18F-Fluorodeoxyglucose (FDG) PET for the Fiscrimination between High-Grade Glioma and Radiation Necrosis in Rats.

BACKGROUND: Discrimination between glioblastoma (GB) and radiation necrosis (RN) post-irradiation remains challenging but has a large impact on further treatment and prognosis. In this study, the uptake mechanisms of 18F-fluorodeoxyglucose (18F-FDG), 18F-fluoroethyltyrosine (18F-FET) and 18F-fluoromethylcholine (18F-FCho) positron emission tomography (PET) tracers were investigated in a F98 GB and RN rat model applying kinetic modeling (KM) and graphical analysis (GA) to clarify our previous results. METHODS: Dynamic 18F-FDG (GB n = 6 and RN n = 5), 18F-FET (GB n = 5 and RN n = 5) and 18F-FCho PET (GB n = 5 and RN n = 5) were acquired with continuous arterial blood sampling. Arterial input function (AIF) corrections, KM and GA were performed. RESULTS: The influx rate (Ki) of 18F-FDG uptake described by a 2-compartmental model (CM) or using Patlak GA, showed more trapping (k3) in GB (0.07 min-1) compared to RN (0.04 min-1) (p = 0.017). K1 of 18F-FET was significantly higher in GB (0.06 ml/ccm/min) compared to RN (0.02 ml/ccm/min), quantified using a 1-CM and Logan GA (p = 0.036). 18F-FCho was rapidly oxidized complicating data interpretation. Using a 1-CM and Logan GA no clear differences were found to discriminate GB from RN. CONCLUSIONS: Based on our results we concluded that using KM and GA both 18F-FDG and 18F-FET were able to discriminate GB from RN. Using a 2-CM model more trapping of 18F-FDG was found in GB compared to RN. Secondly, the influx of 18F-FET was higher in GB compared to RN using a 1-CM model. Important correlations were found between SUV and kinetic or graphical measures for 18F-FDG and 18F-FET. 18F-FCho PET did not allow discrimination between GB and RN.

Long term outcome and side effects in patients receiving low-dose I125 brachytherapy: a retrospective analysis.

OBJECTIVES: To retrospectively evaluate the disease free survival (DFS),disease specific survival (DSS),overall survival (OS) and side effects in patients who received low-dose rate (LDR) brachytherapy with I125 stranded seeds. MATERIALS AND METHODS: Between july 2003 and august 2012, 274 patients with organ confined prostate cancer were treated with permanent I125 brachytherapy. The median follow-up, age and pretreatment prostate specific antigen (iPSA) was 84 months (12-120), 67 years (50-83) and 7.8 ng/mL (1.14-38), respectively. Median Gleason score was 6 (3-9). 219 patients (80%) had stage cT1c, 42 patients (15.3%) had stage cT2a, 3 (1.1%) had stage cT2b and 3 (1.1%) had stage cT2c. The median D90 was 154.3 Gy (102.7-190.2). RESULTS: DSS was 98.5%.OS was 93.5%. 13 patients (4.7%) developed systemic disease, 7 patients (2.55%) had local progression. In 139 low risk patients, the 5 year biochemical freedom from failure rate (BFFF) was 85% and 9 patients (6.4%) developed clinical progression. In the intermediate risk group, the 5 year BFFF rate was 70% and 5 patients (7.1%) developed clinical progression. Median nPSA in patients with biochemical relapse was 1.58 ng/mL (0.21 - 10.46), median nPSA in patients in remission was 0.51 ng/mL (0.01 - 8.5). Patients attaining a low PSA nadir had a significant higher BFFF (p<0.05). Median D90 in patients with biochemical relapse was 87.2 Gy (51 - 143,1). Patients receiving a high D90 had a significant higher BFFF (p<0.05). CONCLUSION: In a well selected patient population, LDR brachytherapy offers excelente outcomes. Reaching a low PSA nadir and attaining high D90 values are significant predictors for a higher DFS.

(18)F-fluoromethylcholine (FCho), (18)F-fluoroethyltyrosine (FET), and (18)F-fluorodeoxyglucose (FDG) for the discrimination between high-grade glioma and radiation necrosis in rats: a PET study.

INTRODUCTION: Discrimination between (high-grade) brain tumor recurrence and radiation necrosis (RN) remains a diagnostic challenge because both entities have similar imaging characteristics on conventional magnetic resonance imaging (MRI). Metabolic imaging, such as positron emission tomography (PET) could overcome this diagnostic dilemma. In this study, we investigated the potential of 2-[(18)F]-fluoro-2-deoxy-D-glucose ((18)F-FDG), O-(2-[(18)F]-fluoroethyl)-L-tyrosine ((18)F-FET), and [(18)F]-Fluoromethyl-dimethyl-2-hydroxyethylammonium ((18)F-fluoromethylcholine, (18)F-FCho) PET in discriminating high-grade tumor from RN. METHODS: We developed a glioblastoma (GB) rat model by inoculating F98 GB cells into the right frontal region. Induction of RN was achieved by irradiating the right frontal region with 60 Gy using three arcs with a beam aperture of 3×3 mm (n=3). Dynamic PET imaging with (18)F-FDG, (18)F-FET, and (18)F-FCho, as well as (18)F-FDG PET at a delayed time interval (240 min postinjection), was acquired. RESULTS: MRI revealed contrast-enhancing tumors at 15 days after inoculation (n=4) and contrast-enhancing RN lesions 5-6 months postirradiation (n=3). On (18)F-FDG PET, the mean lesion-to-normal ratio (LNRmean) was significantly higher in GB than in RN (p=0.034). The difference in the LNRmean between tumors and RN was higher on the late (18)F-FDG PET images than on the PET images reconstructed from the last time frame of the dynamic acquisition (this is at a conventional time interval). LNRs obtained from (18)F-FCho PET were not significantly different between GB and RN (p=1.000). On (18)F-FET PET, the LNRmean was significantly higher in GB compared to RN (p=0.034). CONCLUSIONS: Unlike (18)F-FCho, (18)F-FDG and (18)F-FET PET were effective in discriminating GB from RN. Interestingly, in the case of (18)F-FDG, delayed PET seems particularly useful. ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE: Our results suggest that (delayed) (18)F-FDG and (18)F-FET PET can be used to discriminate GB (recurrence) from RN. Confirmation of these results in clinical studies is needed.