Peri-gestational risk factors for pediatric brain tumors in Neurofibromatosis Type 1

BackgroundIndividuals with Neurofibromatosis Type 1 (NF1) are strongly predisposed to developing pediatric brain tumors (PBTs), especially optic pathway gliomas (OPGs). Although developmental factors have been implicated in the origins of PBTs in both human and animal studies, associations between early-life factors and PBTs have not been evaluated in individuals with NF1. Our objective was to evaluate associations between peri-gestational characteristics and PBTs in this population.MethodsWe conducted a cross-sectional study, ascertaining questionnaire and medical record data for 606 individuals <18 years old who enrolled in the NF1 Patient Registry Initiative (NPRI) from 6/9/2011-6/29/2015. One hundred eighty-four individuals had reported PBT diagnoses, including 65 who were identified with OPG diagnoses. Cox proportional hazards regression was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between PBT and OPG diagnoses and peri-gestational characteristics (prematurity, birth weight, parental age, plurality, family history of NF1, assisted reproductive technology, maternal vitamin supplementation, and parental smoking).ResultsWe observed no significant associations between any of the assessed characteristics and PBTs overall or OPGs with the exception of birth weight. After controlling for potential confounding variables, we observed a significant positive association between birth weight quartile and OPGs with a HR of 3.32 (95% CI 1.39⿿7.94) for the fourth (⿥3915.5 g) compared to the first (⿤3020 g) quartile (p for trend = 0.001).ConclusionsConsistent with results for PBTs in the general population, these results suggest that higher birth weights increase OPG risk in individuals with NF1.     

Toxoplasma gondii infection/exposure and the risk of brain tumors: A systematic review and meta-analysis

BackgroundBrain tumors are among the most fatal cancers with substantial morbidity and mortality worldwide. Epidemiologic evidence suggests that infectious agents, especially, protozoan parasite Toxoplasma gondii could be a possible risk factor or contributor. Here, we performed a systematic review and meta-analysis to evaluate the possible association between T. gondii infection/exposure and risk of brain tumors.MethodsWe searched the PubMed, Embase, Scopus, and Web of Science collection databases from inception through 1st of December 2021. Pooled estimates of odds ratios (ORs) and 95% confidence intervals (CIs) were generated using random effects models. We did the subgroup analysis according to tumor types. Statistical tests for heterogeneity and sensitivity analyses were applied.ResultsA total of seven eligible studies comprising 2323 patients diagnosed with brain tumors and 5131 healthy controls were included in the meta-analysis. T. gondii infection/exposure prevalence was 24.2% (95%CI, 12.7%–41.2) in cases and 12.9% (95%CI, 7.0–22.6%) in control subjects. Pooled analysis showed an overall OR of 1.96 (95%CI, 1.37–2.80), indicating a significant increased risk of brain tumors associated with T. gondii infection/exposure. In subgroup analysis T. gondii infection/exposure was significantly associated with gliomas (OR: 1.64, 95%CI, 1.15–2.33), meningioma (OR: 2.30, 95%CI, 1.0–5.27) and other types of brain tumors (OR: 2.19, 95%CI, 1.02–4.71).ConclusionThis study provides suggestive evidence for an association between T. gondii infection/exposure and brain tumors. Our findings should be further confirmed by well-designed cohort studies with strict control of confounders. Moreover, we suggest that future studies also focus on the effect of T. gondii infection/exposure to the types of brain tumors.     

Joint SFMN/ANOCEF focus on 18F-FDOPA PET imaging in glioma: Current applications and perspectives

18F-FDOPA PET has demonstrated its additional value during the clinical course of glioma, at initial diagnosis, for treatment planning or follow-up. The aim of the current review was to summarize current applications of 18F-FDOPA PET in gliomas and constitute, as a perspective, a first step in harmonizing clinical practices in French centers. In France, the indication for 18F-FDOPA PET is restricted to the assessment of primary brain tumor recurrence. According to the literature, this indication could be expanded to primary diagnosis and, to a lesser extent, treatment monitoring. There is a real need to harmonize standard procedures among French centers. The objective is to increase the availability of data for this rare entity of glioma and to develop multi-parametric PET analyses (static, dynamic and textural), also known as radiomics, by using artificial intelligence algorithms. For this purpose, kinetics analysis with dynamic PET acquisition should be implemented in routine practice because it has demonstrated its additional value for initial diagnosis in gliomas. Therefore, this review proposes a workflow based on acquisition and reconstruction parameters that can be implemented in each center to increase the amount of standardized 18F-FDOPA PET data in neuro-oncology imaging in France. This would help in creating a national database and developing national multi-center studies that can respond to the challenge of using multi-parametric PET in glioma.     

Secondary brain tumors after cranial radiation therapy: A single-institution study

AimTo study the probability of developing secondary brain tumors after cranial radiotherapy.Background Patients treated with cranial radiotherapy are at risk for developing secondary brain tumors.Patients and methodsWe planned an institutional survey for secondary brain tumors in survivors after cranial irradiation and reviewed the 30-year duration data. Event analysis and cumulative proportion curves were performed to generally estimate the cumulative proportion of developing secondary brain tumors, cavernoma and meningioma at different periods of time.ResultsSecondary brain tumors occurred in 21% of cases: 10% were cavernomas, 6% were meningiomas, 3% were skull osteomas, and 1% were anaplastic astrocytoma. The cumulative proportion of developing secondary brain tumor was 6% at 10 years and 20% at 20 years, while the cumulative proportion for developing cavernomas and meningiomas was 16% and 7% at 20 years, respectively.ConclusionOur study shows that patients who received cranial irradiation were at risk of secondary brain tumors such as cavernomas and meningiomas. Thus, a meticulous follow-up of cancer survivors with history of cranial irradiation by an annual MRI scan is justifiable. This will help clinicians to detect secondary brain tumors early and make its management much easier.     

Robustness of post-reconstruction and direct kinetic parameter estimates under rigid head motion in dynamic brain PET imaging

ObjectiveDynamic PET imaging is extensively used in brain imaging to estimate parametric maps. Inter-frame motion can substantially disrupt the voxel-wise time-activity curves (TACs), leading to erroneous maps during kinetic modelling. Therefore, it is important to characterize the robustness of kinetic parameters under various motion and kinetic model related factors.MethodsFully 4D brain simulations ([¹⁵O]H₂O and [¹⁸F]FDG dynamic datasets) were performed using a variety of clinically observed motion patterns. Increasing levels of head motion were investigated as well as varying temporal frames of motion initiation. Kinetic parameter estimation was performed using both post-reconstruction kinetic analysis and direct 4D image reconstruction to assess bias from inter-frame emission blurring and emission/attenuation mismatch.ResultsKinetic parameter bias heavily depends on the time point of motion initiation. Motion initiated towards the end of the scan results in the most biased parameters. For the [¹⁸F]FDG data, k₄ is the more sensitive parameter to positional changes, while K₁ and blood volume were proven to be relatively robust to motion. Direct 4D image reconstruction appeared more sensitive to changes in TACs due to motion, with parameter bias spatially propagating and depending on the level of motion.ConclusionKinetic parameter bias highly depends upon the time frame at which motion occurred, with late frame motion-induced TAC discontinuities resulting in the least accurate parameters. This is of importance during prolonged data acquisition as is often the case in neuro-receptor imaging studies. In the absence of a motion correction, use of TOF information within 4D image reconstruction could limit the error propagation.     

Comparison of lymphokine-activated killer activities between thymocytes and splenocytes in rats with brain tumors

Summary We studied the lymphokine-activated killer (LAK) activity in splenocytes and thymocytes of rats with brain tumors chronologically from the early stage to the late stage, in order to clarify how much LAK activity would be developed at each stage. Simultaneously the natural killer (NK) activity in splenocytes, as one aspect of the host immunocompetence, was also determined. The splenic NK activity was significantly depressed in rats with brain tumors during the 2nd and 3rd weeks after tumor transplantation, as compared with normal controls. On the other hand, the splenocytes incubated with interleukin-2 showed the same killer activity in rats with brain tumors as in normal rats at all times. The LAK activity in thymocytes from rats with brain tumors was significantly higher than that of controls in the 1st and 2nd weeks and became equal to that of the controls during the 3rd week. The killer activity after incubation with interleukin-2 in thymocytes was superior to that in splenocytes throughout the experiment in both tumor-bearing rats and controls, which suggested that the precursor of LAK cells was not NK cells.     

Radiosynthesis and evaluation of [11C]EMPA as a potential PET tracer for orexin 2 receptors

EMPA is a selective antagonist of orexin 2 (OX₂) receptors. Previous literature with [³H]-EMPA suggest that it may be used as an imaging agent for OX₂ receptors; however, brain penetration is known to be modest. To evaluate the potential of EMPA as a PET radiotracer in non-human primate (as a step to imaging in man), we radiolabeled EMPA with carbon-11. Radiosynthesis of [¹¹C]N-ethyl-2-(N-(6-methoxypyridin-3-yl)-2-methylphenylsulfonamido)-N-(pyridin-3-ylmethyl)acetamide ([¹¹C]EMPA), and evaluation as a potential PET tracer for OX₂ receptors is described. Synthesis of an appropriate non-radioactive O-desmethyl precursor was achieved from EMPA with sodium iodide and chlorotrimethylsilane. Selective O-methylation using [¹¹C]CH₃I in the presence of cesium carbonate in DMSO at room temp afforded [¹¹C]EMPA in 1.5–2.5% yield (non-decay corrected relative to trapped [¹¹C]CH₃I at EOS) with ?95% chemical and radiochemical purities. The total synthesis time was 34–36 min from EOB. Studies in rodent suggested that uptake in tissue was dominated by nonspecific binding. However, [¹¹C]EMPA also showed poor uptake in both rats and baboon as measured with PET imaging.     

Synthesis and evaluation of indolinyl- and indolylphenylacetylenes as PET imaging agents for beta-amyloid plaques

Two new phenylacetylene derivatives, 5-((4-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)phenyl)ethynyl)indoline 8 and 5-((4-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)phenyl)ethynyl)-1H-indole 14, targeting β-amyloid (Aβ) plaques have been prepared. In vitro binding carried out in tissue homogenates prepared from postmortem AD brains with [¹²⁵I]IMPY (6-iodo-2-(4′-dimethylamino-)phenyl-imidazo[1,2-a]pyridine) as the radioligand indicated good binding affinities (K_i = 4.0 and 1.5 nM for 8 and 14, respectively). Brain penetration of the corresponding radiofluorinated ligands, evaluated in the normal mice, showed good initial brain penetration (4.50 and 2.43% ID/g (injected dose/gram) for [¹⁸F]8 and [¹⁸F]14 at 2 min after injection) with moderate to low washout rates from the brain (1.71% ID/g at 2 h and 2.10% ID/g at 3 h, respectively). Autoradiography and homogenate binding studies demonstrated the high specific binding of [¹⁸F]14 to the Aβ plaques; however, [¹⁸F]8 showed low specific binding. These preliminary results identified that indolylphenylacetylene, 14, may be a good lead for further structural modification to develop a useful Aβ plaque imaging agent.     

Synthesis and evaluation of radiolabeled AGI-5198 analogues as candidate radiotracers for imaging mutant IDH1 expression in tumors

Mutations in the metabolic enzyme isocitrate dehydrogenase 1 (IDH1) are commonly found in gliomas. AGI-5198, a potent and selective inhibitor of the mutant IDH1 enzyme, was radiolabeled with radioiodine and fluorine-18. These radiotracers were evaluated as potential probes for imaging mutant IDH1 expression in tumors with positron emission tomography (PET). Radioiodination of AGI-5198 was achieved using a tin precursor in 79?±?6% yield (n?=?9), and ¹⁸F-labeling was accomplished by the Ugi reaction in a decay-corrected radiochemical yield of 2.6?±?1.6% (n?=?5). The inhibitory potency of the analogous nonradioactive compounds against mutant IDH1 (IDH1-R132H) was determined in enzymatic assays. Cell uptake studies using radiolabeled AGI-5198 analogues revealed somewhat higher uptake in IDH1-mutated cells than that in wild-type IDH1 cells. The radiolabeled compounds displayed favorable tissue distribution characteristics in vivo, and good initial uptake in IDH1-mutated tumor xenografts; however, tumor uptake decreased with time. Radioiodinated AGI-5198 exhibited higher tumor-to-background ratios compared with ¹⁸F-labeled AGI-5198; unfortunately, similar results were observed in wild-type IDH1 tumor xenografts as well, indicating lack of selectivity for mutant IDH1 for this tracer. These results suggest that AGI-5198 analogues are not a promising platform for radiotracer development. Nonetheless, insights gained from this study may help in design and optimization of novel chemical scaffolds for developing radiotracers for imaging the mutant IDH1 enzyme.     

Radionuclide labeling and evaluation of candidate radioligands for PET imaging of histone deacetylase in the brain

Histone deacetylases (HDACs) regulate gene expression by inducing conformational changes in chromatin. Ever since the discovery of a naturally occurring HDAC inhibitor, trichostatin A (TSA) stimulated the recent development of suberoylanilide (SAHA, Zolinza®), HDAC has become an important molecular target for drug development. This has created the need to develop specific in vivo radioligands to study epigenetic regulation and HDAC engagement for drug development for diseases including cancer and psychiatric disorders. 6-([¹⁸F]Fluoroacetamido)-1-hexanoicanilide ([¹⁸F]FAHA) was recently developed as a HDAC substrate and shows moderate blood–brain barrier (BBB) permeability and specific signal (by metabolic trapping/or deacetylation) but rapid metabolism. Here, we report the radiosynthesis of two carbon-11 labeled candidate radiotracers (substrate- and inhibitor-based radioligand) for HDAC and their evaluation in non-human primate brain. PET studies showed very low brain uptake and rapid metabolism of both labeled compounds but revealed a surprising enhancement of brain penetration by F for H substitution when comparing one of these to [¹⁸F]FAHA. Further structural refinement is needed for the development of brain-penetrant, metabolically stable HDAC radiotracers and to understand the role of fluorine substitution on brain penetration.     

Assessment of 18FDG PET for diagnosis of pancreatic tumors

The paper examines the informational value of positron emission tomography (PET) using 18FDG in the diagnosis of malignant of neoplasms of the pancreas and in the estimation of the extent of a metastatic involvement. Forty-four patients (26 males and 18 females whose age ranged from 28 to 60 years) with histologically verified cancer of the pancreas were examined. The study was conducted in the whole body mode on an Ecat Exact 47 positron emission tomograph following 70-90 minutes of administration of 18FDG, 370-420 MBk. To assess the findings, the differential accumulation ratio (DAR) of formation/liver was calculated. The mean DAR in patients with benign and malignant pancreatic tumors was 1.17 +/- 0.064 and 4.90 +/- 0.3 (p < 0.05). There was a false positive case in a patient with an exacerbation of chronic pancreatitis in the study. A relationship was observed between the level of tumor tissue 18FDG capture and the degree of malignancy. PET scanning in the whole body mode estimates the extent of a tumorous process. The authors' data show that the liver was most commonly involved in a metastatic process (96.6%). Hence, 18FDG PET is a highly informative technique in the diagnosis of malignant pancreatic tumors and in the estimation of the extent of a metastatic process and permits a differential diagnosis between benign and malignant tumors.     

Determination of Regional Rates of Cerebral Protein Synthesis Adjusted for Regional Differences in Recycling of Leucine Derived from Protein Degradation into the Precursor Pool in Conscious Adult Rats

The quantitative autoradiographic L-[1-14C]leucine method for the determination of regional rates of cerebral protein synthesis in vivo takes into account recycling of unlabeled leucine derived from protein degradation into the precursor pool for protein synthesis. We have evaluated the degree of recycling by measuring the ratio of the apparent steady-state leucine specific activity in the precursor amino acid pool (tRNA-bound leucine) to that in the arterial plasma. In the whole brain of the conscious rat this ratio (lambda WB) equals 0.58. The equivalent ratio for leucine in the acid-soluble pool in whole brain (psi WB) is 0.49. A first-degree polynomial equation for lambda WB as a function of psi WB was fitted from paired determinations. To determine the degree of recycling in local regions of the brain, we have measured in individual brain regions (i) psi i and calculated lambda i assuming that the fitted equation also applies to these localized regions. Our results indicate that the degree of recycling into the precursor pool does vary regionally; lambda i in the individual regions varies from 0.62 in the hypoglossal nucleus to 0.50 in the globus pallidus. Local rates of protein synthesis were then determined by the autoradiographic technique with regional corrections for recycling of unlabeled leucine. Rates of leucine incorporation into protein averaged 6.1 nmol/g of tissue/min in the brain as a whole, with the rates in gray matter about twice those in white matter.     

In vivo comparison of N-11CH3 vs O-11CH3 radiolabeled microtubule targeted PET ligands

Altered dynamics of microtubules (MT) are implicated in the pathophysiology of a number of brain diseases. Therefore, radiolabeled MT targeted ligands that can penetrate the blood brain barrier (BBB) may offer a direct and sensitive approach for diagnosis, and assessing the clinical potential of MT targeted therapeutics using PET imaging. We recently reported two BBB penetrating radioligands, [¹¹C]MPC-6827 and [¹¹C]HD-800 as specific PET ligands for imaging MTs in brain. The major metabolic pathway of the above molecules is anticipated to be via the initial labeling site, O-methyl, compared to the N-methyl group. Herein, we report the radiosynthesis of N-¹¹CH₃-MPC-6827 and N-¹¹CH₃-HD-800 and a comparison of their in vivo binding with the corresponding O-¹¹CH₃ analogues using microPET imaging and biodistribution methods. Both O-¹¹CH₃ and N-¹¹CH₃ labeled MT tracers exhibit high specific binding and brain. The N-¹¹CH₃ labeled PET ligands demonstrated similar in vivo binding characteristics compared with the corresponding O-¹¹CH₃ labeled tracers, [¹¹C]MPC-6827 and [¹¹C]HD-800 respectively.     

Polyaminen and brain injury

Summary The cerebral ODC/polyamine system is disturbed by brain injury. The main modifications are important increases in ODC activity and putrescine concentration, with minor variations in spermidine and spermine concentrations. A great diversity of stimuli such as cerebral ischemia or overstimulation of the central nervous system by chemical or non-chemical agents can induce polyamine disturbances. Both the contribution of polyamines to the brain damage and their involvement in the repair mechanisms triggered after brain insults have been proposed.     

Radiosynthesis of [thiocarbonyl-11C]disulfiram and its first PET study in mice

[Thiocarbonyl-¹¹C]disulfiram ([¹¹C]DSF) was synthesized via iodine oxidation of [¹¹C]diethylcarbamodithioic acid ([¹¹C]DETC), which was prepared from [¹¹C]carbon disulfide and diethylamine. The decay-corrected isolated radiochemical yield (RCY) of [¹¹C]DSF was greatly affected by the addition of unlabeled carbon disulfide. In the presence of carbon disulfide, the RCY was increased up to 22% with low molar activity (A_m, 0.27 GBq/μmol). On the other hand, [¹¹C]DSF was obtained in 0.4% RCY with a high A_m value (95 GBq/μmol) in the absence of carbon disulfide. The radiochemical purity of [¹¹C]DSF was always >98%. The first PET study on [¹¹C]DSF was performed in mice. A high uptake of radioactivity was observed in the liver, kidneys, and gallbladder. The uptake level and distribution pattern in mice were not significantly affected by the A_m value of the [¹¹C]DSF sample used. In vivo metabolite analysis showed the rapid decomposition of [¹¹C]DSF in mouse plasma.     

68Ga labeled Erlotinib: A novel PET probe for imaging EGFR over-expressing tumors

Molecular imaging using radiolabeled Tyrosine Kinase Inhibitors (TKI) is a promising strategy for detection and staging of EGFR-positive cancers. A novel analogue of one such TKI, Erlotinib has been developed for PET imaging by derivatizing the parent Erlotinib molecule for conjugation with the bifunctional chelator p-SCN-Bn-NOTA towards radiolabeling with ⁶⁸Ga. NOTA-Erlotinib conjugate was synthesized and characterized by NMR and ESI-MS techniques. The conjugate was radiolabeled with ⁶⁸Ga in 95 ± 2% yield, as evidenced by HPLC characterization. The log P value of ⁶⁸Ga-NOTA-Erlotinib was – (0.6 ± 0.1). The ⁶⁸Ga-NOTA-Erlotinib conjugate was characterized using its ^natGa-NOTA-Erlotinib surrogate. Cell viability studies showed that the NOTA-Erlotinib conjugate retained the biological efficacy of the parent Erlotinib molecule. Further, ⁶⁸Ga-NOTA-Erlotinib exhibited an uptake of 9.8 ± 0.4% in A431 cells which was inhibited by 55.1 ± 0.2% on addition of cold Erlotinib (10 µg) confirming the specificity of the radioconjugate for EGFR expressing cells. In the biodistribution studies carried out in tumor bearing SCID mice, ⁶⁸Ga-NOTA-Erlotinib conjugate showed moderate tumor accumulation (1.5 ± 0.1% ID/g at 30 min p.i.; 0.7 ± 0.2% ID/g at 1 h p.i.). Hepatobiliary clearance of the radioconjugate was observed. The ⁶⁸Ga-NOTA-Erlotinib conjugate was found to have high in vivo stability as determined by the metabolite analysis study using urine sample of the Swiss mice injected with the preparation. The overall properties of ⁶⁸Ga-NOTA-Erlotinib are promising and merit further exploration. To the best of our knowledge, this is the first report on the design of a ⁶⁸Ga labeled Erlotinib for PET imaging of EGFR and opens avenues for the successful development of ⁶⁸Ga labeled TKI for imaging of EGFR over-expressing tumors.     

Facile synthesis of SSR180575 and discovery of 7-chloro-N,N,5-trimethyl-4-oxo-3(6-[18F]fluoropyridin-2-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide,a potent pyridazinoindole ligand for PET imaging of TSPO in cancer

A novel synthesis of the translocator protein (TSPO) ligand 7-chloro-N,N,5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide (SSR180575, 3) was achieved in four steps from commercially available starting materials. Focused structure–activity relationship development about the pyridazinoindole ring at the N3 position led to the discovery of 7-chloro-N,N,5-trimethyl-4-oxo-3(6-fluoropyridin-2-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide (14), a novel ligand of comparable affinity. Radiolabeling with fluorine-18 (¹⁸F) yielded 7-chloro-N,N,5-trimethyl-4-oxo-3(6-[¹⁸F]fluoropyridin-2-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide ([¹⁸F]-14) in high radiochemical yield and specific activity. In vivo studies of [¹⁸F]-14 revealed this agent as a promising probe for molecular imaging of glioma.     

The French experience of PSMA PET for the diagnosis of biological recurrence of prostate cancer

PSMA PET can only be performed in France in the context of a temporary authorization for use (ATU) granted by the ANSM only in the event of biological recurrence of prostate cancers with a normal or equivocal Fucyclovine or Choline PET scan. We present the experience of the Léon Bérard cancer centre and report on the experience of 3 other French centres that have published their results obtained within the framework of this ATU. Despite the absence of histological comparison of our results, the evidence of suspicious lesions on PSMA PET examination may induce changes in patient management in almost 2/3 of the patients. This is consistent with the already abundant results in the literature, which show a clear superiority of PSMA PET over Choline PET for the diagnosis of biological recurrence of prostate cancer.