Caroline Van den Broecke

Meta-analysis of Neuroblastomas Reveals a Skewed ALK Mutation Spectrum in Tumors with MYCN Amplification

Purpose: Activating mutations of the anaplastic lymphoma kinase (ALK) were recently described in neuroblastoma. We carried out a meta-analysis of 709 neuroblastoma tumors to determine their frequency and mutation spectrum in relation to genomic and clinical parameters, and studied the prognostic significance of ALK copy number and expression. Experimental Design: The frequency and type of ALK mutations, copy number gain, and expression were analyzed in a new series of 254 neuroblastoma tumors. Data from 455 published cases were used for further in-depth analysis. Results: ALK mutations were present in 6.9% of 709 investigated tumors, and mutations were found in similar frequencies in favorable [International Neuroblastoma Staging System (INSS) 1, 2, and 4S; 5.7%] and unfavorable (INSS 3 and 4; 7.5%) neuroblastomas (P = 0.087). Two hotspot mutations, at positions R1275 and F1174, were observed (49% and 34.7% of the mutated cases, respectively). Interestingly, the F1174 mutations occurred in a high proportion of MYCN-amplified cases (P = 0.001), and this combined occurrence was associated with a particular poor outcome, suggesting a positive cooperative effect between both aberrations. Furthermore, the F1174L mutant was characterized by a higher degree of autophosphorylation and a more potent transforming capacity as compared with the R1275Q mutant. Chromosome 2p gains, including the ALK locus (91.8%), were associated with a significantly increased ALK expression, which was also correlated with poor survival. Conclusions: ALK mutations occur in equal frequencies across all genomic subtypes, but F1174L mutants are observed in a higher frequency of MYCN-amplified tumors and show increased transforming capacity as compared with the R1275Q mutants. Clin Cancer Res; 16(17); 4353–62. ©2010 AACR.

Salvage intensity-modulated radiotherapy for rising PSA after radical prostatectomy

INTRODUCTION The aim was to prospectively evaluate both acute and late toxicity and biochemical non-evidence of disease (bNED) in patients treated with salvage intensity-modulated radiotherapy (IMRT) +/- androgen deprivation (AD) for biochemical relapse after radical prostatectomy (RP). MATERIALS AND METHODS IMRT was prescribed to a mean prescription dose to the planning target volume (PTV) of 75 Gy to be delivered in 37 fractions of 2 Gy. In total, 135 patients were treated with IMRT. Median age was 64 years. Median PSA level was 0.8 ng/ml. AD was initiated in 94 patients. Indications were perineural invasion, seminal vesicle invasion or Gleason score > or = 8 at RP. (1) Acute toxicity (n = 135). All patients were available for this analysis. Acute toxicity was scored using an in-house developed scoring system. (2) Late toxicity (n = 68). Only patients with a follow-up of at least 18 months were considered for late toxicity analysis. The RILIT score was used to register gastro-intestinal (GI) toxicity. An in-house developed scale was used to register genito-urinary (GU) toxicity. (3) bNED (n = 87). For bNED, all AD-naive patients (n = 38) together with the AD-positive patients with a follow-up > or = 18 months (n = 49) were considered. Factors influencing the results of salvage treatment were analyzed. RESULTS (1) Acute toxicity (n = 135). No patient developed grade 3 GI toxicity. We observed grade 2 toxicity in 20 patients. Four patients developed grade 3 GU toxicity. (2) Late toxicity (n = 68). One patient developed grade 3 rectal blood loss. One patient developed grade 3 anal pain (anal fissure). We observed grade 2 GI toxicity in 9 patients. Two patients developed grade 3GU toxicity. Twenty-one patients developed grade 2 GU toxicity. We observed an urethral stricture in 5 patients. (3) bNED (n = 87). The 3- and 5-year bNED was 67%. Gleason score at RP, perineural invasion and capsular perforation were significant predictors for bNED. PSA before IMRT (<1.0 vs. 1.0 ng/ml) showed a trend in predicting bNED (p = 0.08). CONCLUSION IMRT to 75Gy+/-AD can be delivered with low levels of acute and late toxicity. In patients without perineural invasion and capsular invasion and with a Gleason score > or = 7 (3 + 4), IMRT offers very good 5-years bNED.

Endoscopic coagulation of choroid plexus hyperplasia

Hydrocephalus is a clinical disorder resulting from an imbalance between the production of CSF and its resorption, of which the latter is mostly a disadvantage. In rare cases of choroid plexus papilloma or carcinoma, hydrocephalus is due to an overproduction of CSF. Choroid plexus hyperplasia (CPH) is a distinct clinicopathological entity in which the enlarged choroid plexus produces large amounts of CSF. Historically, patients with CPH were treated by shunt procedures or by microsurgical removal of the choroid plexus, which is associated with a high complication rate. In this paper the authors show that endoscopic plexus coagulation can result in restoring the equilibrium of the intracranial fluid volumes, resulting in shunt independency. In this way, both the shunt-related complications and the bleeding risks of microsurgical plexectomy are avoided. In instances of hydrocephalus, thorough efforts should be made to demonstrate the underlying pathophysiology to choose the optimal treatment, of which shunt procedures should receive the least priority.

Structural and metabolic features of two different variants of multiple sclerosis: a PET/MRI study.

Multimodality imaging such as proton magnetic resonance spectroscopy (MRS) and positron emission tomography (PET) have provided information specific to the underlying mechanisms of many brain diseases, including multiple sclerosis (MS).

The optimal timing for imaging brain tumours and other brain lesions with 18F-labelled fluoromethylcholine: a dynamic positron emission tomography study.

PurposeTo determine the optimal timing for imaging brain tumours and other brain lesions with 18F-labelled fluoromethylcholine (18F-FCho) PET. Materials and methodsDynamic PET imaging with 18F-FCho (acquisition time of 28 min) was performed in 24 patients with space-occupying lesions in the brain. On the coregistered PET and MRI, lesion-to-normal tissue uptake ratios (LNRs) were calculated. Time–activity curves (TACs) were generated on the basis of the LNRs. Changes in LNR over time were calculated on the basis of the linear part of the TAC (last 22 min of the acquisition). ResultsTACs for 18F-FCho in gliomas of different grading showed that, after a rapid uptake phase, the mean increase in LNR was 1.07±0.93 for glioblastomas, −0.52±1.56 for anaplastic astrocytomas, 0.04±0.13 for grade 2 oligoastrocytomas and 0.37 in a case of a pilocytic astrocytoma. The average increase in LNR was 0.46 for a brain metastasis, 0.41±0.69 for radiation-induced mass lesions and 1.07 for a tumefactive demyelinating lesion. In contrast, TACs for 18F-FCho in meningiomas showed that, after a rapid uptake phase, the average change in LNR was −5.25±4.19 for typical meningiomas and −3.04 in a case of a mixed angiomatous and clear cell meningioma. ConclusionOn the basis of the TACs, PET imaging with 18F-FCho starting within minutes after the administration of the tracer is preferred for the detection of brain tumours and other brain lesions. If discrimination between meningioma and other brain tumours is of concern, both ‘early’ and ‘late’ PET imaging could be helpful.

The effect of duration and timing of systemic cyclosporine therapy on corneal allograft survival in a rat model

Abstract. Background: Systemic cyclosporine A (CsA) remains a valuable treatment option in the prevention of corneal graft rejection, but the question of timing and duration of this systemic therapy remains unresolved. The effect of a pre- and postoperative dosing schedule, related to the expected moment of rejection, was examined in a rat model. Methods: All AO (strain) recipients of PVG grafts were assigned to the following treatment groups: Group 1 (controls), groups 2–5 (a postoperative treatment regimen of CsA for 5, 10, 15 and 30 days respectively) and groups 6 and 7 (CsA preoperatively for 5 days and postoperatively for another 5 or 10 days respectively). Corneal allografts were clinically evaluated and blood CsA levels were measured at various time points. Results: Untreated controls rejected their allografts after 13 days. Regression analysis showed a strongly significant positive correlation between graft survival time and duration of cyclosporine therapy. There was no difference in graft survival between groups 3 (CsA 10 days) and 4 (CsA 15 days). A pre-operative dosing schedule of CsA followed by postoperative treatment had no advantage over a solely postoperative treatment regimen. The moment of rejection was characterized by a low to undetectable CsA concentration. Conclusion: The present study demonstrates a significant influence of the duration of systemic CsA administration on allograft survival time. However, preoperative administration of CsA does not seem to have an additional influence on graft survival, which is in line with the biological evidence of the mechanism of action of CsA on the efferent arm of graft rejection.

18F-fluoromethylcholine (FCho), 18F-fluoroethyltyrosine (FET), and 18F-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.

Loss of endoplasmic reticulum calcium pump expression in choroid plexus tumours.

Sarco/Endoplasmic Reticulum Calcium ATPase‐type calcium pumps (SERCA enzymes) control cell activation by sequestering calcium ions from the cytosol into the endoplasmic reticulum. Although endoplasmic reticulum calcium signalling plays an important role in the regulation of choroid plexus epithelial function, SERCA expression in the choroid plexus has not been investigated so far.

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

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.

Ectopic meningioma anterior to the lacrimal gland fossa

A 66-year-old man reported a slowly growing tumor on the lateral edge of his left upper eyelid. This lesion was hard but movable on palpation. A neoplasm of the lacrimal gland was suspected. CT showed a highly calcified lesion at the left upper eyelid. Resection of the tumor was performed, which was located just behind the orbital septum and in front of the lacrimal gland. Anatomopathologic investigation of the excised specimen with immunohistochemistry revealed a benign meningioma of a meningotheliomatous type, containing multiple bone elements. An ectopic orbital meningioma is rare, and this is the first case of a unique lateral localization of this lesion. Therefore, it should be included in the differential diagnosis of a lacrimal gland tumor.