Epilepsy surgery in children under 3 years

PurposeResective epilepsy surgery in early childhood has become an important treatment option for selected infants and children with epilepsy. We describe experience and clinical outcomes of children under 3 years undergoing epilepsy surgery at Great Ormond Street Hospital (GOSH).MethodsAll children under 36 months of age who had resective surgery for the purpose of treating epilepsy within the GOSH epilepsy surgery programme were ascertained using a departmental database. Aetiology, post-operative seizure frequency, pre and post-operative cognitive function, long-term complications and re-operation rates were analysed by retrospective examination of clinical records.ResultsForty-two children were included in our cohort with a median age at surgery of 20 months (range 3–36 months). Surgical procedures comprised 25 functional hemispherectomies, two anatomical hemispherectomies, four multilobar resections, seven lobar resections and four focal resections. 7/42 (17%, 95% CI 8–31%) children underwent re-operation. 20/42 (48%, 95% CI 33–62%) children achieved seizure freedom. 18/42 (43%, 95% CI 29–58) demonstrated an improvement in seizure frequency and no children had an increase in seizure frequency. Post-operative complications included subsequent shunt procedure in 5/25 (20%, 95% CI 9–39%) children undergoing hemispherectomy. There were no mortalities. In 23 children pre- and post-operative DQ or IQ was determinable allowing longitudinal comparison. Five children had a decrease in DQ/IQ >15 and two children had an increase DQ/IQ >15.DiscussionEpilepsy surgery in children under 3 years of age offers suitable candidates a good chance of significantly improved seizure outcome which compares with rates in older cohorts.     

Sigma receptor binding of tetrabenazine series tracers targeting VMAT2 in rat pancreas

The vesicular monoamine transporter type II (VMAT2) is highly expressed in pancreatic β-cells and thus has been proposed to be a potential target for measuring β-cell mass (BCM) by molecular imaging. Several tracers based on the TBZ backbone, including 9-fluoropropyl-(+)-dihydrotetrabenazine ([¹⁸F]AV-133), have shown some promising results as potential biomarkers for BCM despite a relatively high background signal in the pancreas. In the present study, we explore the background binding characteristics of [¹⁸F]AV-133 in rat pancreas.

Methods

Pancreatic exocrine cells and islet cells were isolated and purified from Sprague-Dawley rats. Membrane homogenates, prepared from both pancreatic exocrine and islet cells as well as from brain striatum regions, were used for in vitro binding studies of [¹⁸F]AV-133 under a selective masking condition. 1,3-Di-o-tolylguanidine (DTG), displaying high and roughly equal affinity for both sigma-1 and sigma-2 receptors, was chosen at 5 μM concentration for the masking/blocking studies.

Results

[¹⁸F]AV-133 binding to rat striatum homogenates was not significantly altered by the presence of DTG. In contrast, [¹⁸F]AV-133 showed significant competition with DTG for binding sites in rat pancreatic exocrine homogenates as well as in rat islet cell homogenates. Importantly, in the presence of DTG, [¹⁸F]AV-133 showed a single high-affinity binding site on islet cell homogenates with a K_d value of 3.8 nM which is consistent with the affinity reported previously for VMAT2 sites in rat pancreas.

Conclusions

[¹⁸F]AV-133, in addition to a high-affinity VMAT2 binding site, binds with low affinity (but high capacity) to sigma components that are present in the rat pancreas. Identification of the cause of background binding of [¹⁸F]AV-133 to rat pancreatic tissue may lead to improved methods for quantification.     

Synthesis and application of 188Re-MN-16ET/Lipiodol in a hepatocellular carcinoma animal model

IntroductionHepatocellular carcinoma is the most common form of primary hepatic carcinoma. A new N₂S₂ tetradentate ligand, N-[2-(triphenylmethyl)thioethyl]-3-aza-19-ethyloxycarbonyl-3-[2-(triphenylmethyl)thioethyl]octadecanoate (H₃MN-16ET), was introduced and labeled with ¹⁸⁸Re to create ¹⁸⁸Re-MN-16ET in the Lipiodol phase. The potential of ¹⁸⁸Re-MN-16ET/Lipiodol for hepatoma therapy was evaluated in a hepatocellular carcinoma animal model of Sprague–Dawley rats implanted with the N1S1 cell line.MethodsSynthesis of H₃MN-16ET was described, and characterization was identified by infrared, nuclear magnetic resonance and mass spectra. We compared the effects of transchelating agents (glucoheptonate or tartaric acid) and a reducing agent (stannous chloride) on the complexing of ¹⁸⁸Re-perrhenate and H₃MN-16ET. Twenty-four rats implanted with hepatoma were injected with 3.7 MBq/0.1 ml of ¹⁸⁸Re-MN-16ET/Lipiodol or ¹⁸⁸Re-MN-16ET via transcatheter arterial embolization. Biodistribution experiments and single-photon emission computed tomography imaging were performed to investigate tumor accumulation.ResultsH₃MN-16ET was proved to easily conjugate with the Re isotope and showed good solubility in Lipiodol. The radiochemical purity of ¹⁸⁸Re-MN-16ET/Lipiodol with 10 mg tartaric acid and stannous chloride was shown to be more than 90%. The major distribution sites of ¹⁸⁸Re-MN-16ET in Sprague–Dawley rats were hepatoma and the liver. However, the radioactivity at the tumor site postadministered with ¹⁸⁸Re-MN-16ET was quickly decreased from 9.15±0.23 (at 1 h) to 2.71%±0.18% of injected dose/g (at 48 h). The biodistribution and micro-single-photon emission computed tomography/computed tomography image data showed that ¹⁸⁸Re-MN-16ET/Lipiodol was selectively retained at the tumor site, with 11.55±1.44, 13.16±1.46 and 10.67%±0.95% of injected dose/g at 1, 24 and 48 h postinjection, respectively. The radioactivity in normal liver tissue was high but significantly lower than that of the tumors.ConclusionH₃MN-16ET is a suitable tetradentate ligand for ¹⁸⁸Re labeling. From the animal data, we suggest that ¹⁸⁸Re-MN-16ET/Lipiodol has the potential to be a therapeutic radiopharmaceutical for hepatoma treatment.     

The gene transfection efficiency of a folate–PEI600–cyclodextrin nanopolymer

The success of gene therapy relies on a safe and effective gene delivery system. In this communication, we describe the use of folate grafted PEI₆₀₀–CyD (H₁) as an effective polyplex-forming plasmid delivery agent with low toxicity. The structures of the polymer and polyplex were characterized, and the in vitro transfection efficiency, cytotoxicity, and in vivo transfection of H₁ were examined. We found that folate molecules were successfully grafted to PEI₆₀₀–CyD. At N/P ratios between 5 and 30, the resulting H₁/DNA polyplexes had diameters less than 120 nm and zeta potentials less than 10 mV. In various tumor cell lines examined (U138, U87, B16, and Lovo), the in vitro transfection efficiency of H₁ was more than 50%, which could be improved by the presence of fetal bovine serum or albumin. The cytotoxicity of H₁ was significantly less than high molecular weight PEI-25 kDa. Importantly, in vivo optical imaging showed that the efficiency of H₁-mediated transfection (50 μg luciferase plasmid (pLuc), N/P ratio = 20/1) was comparable to that of adenovirus-mediated luciferase transduction (1 × 10⁹ pfu) in melanoma-bearing mice, and it did not induce any toxicity in the tumor tissue. These results clearly show that H₁ is a safe and effective polyplex-forming agent for both in vitro and in vivo transfection of plasmid DNA and its application warrants further investigation.     

Impact of bilateral anterior cingulotomy on neurocognitive function in patients with intractable pain

Although the cingulate cortices are important with regard to neurocognitive functions, outcome studies usually fail to identify evident cognitive dysfunction following anterior cingulotomy. The aim of this study was to document any impairment of neurocognitive functions following anterior cingulotomy. Between September 2002 and April 2004, 10 patients underwent stereotactic bilateral anterior cingulotomy for intractable cancer pain. A neuropsychological assessment of each patient was performed 1 day prior to surgery and 1 week and 1 month post-operatively. Assessment of pain relief was evaluated with a short form of the McGill pain questionnaire. Six of the 10 patients achieved fair to good pain relief following the cingulotomy procedure. Most neurocognitive functions, including language, memory, motor, visual-constructional, and intellectual functions, remained unaffected. A decline in focused attention performance was identified at the early post-operative assessment. The results of this longitudinal evaluation will help to better define the risk-to-benefit profile of cingulotomy for intractable pain.