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A case of ovarian teratoma which produced glial peritoneal deposits is described. Twelve other cases in the literature are tabulated. The age at presentation ranges from 22 months to 22 years (mean age 14·6 years). The primary tumour may be solid or cystic. The prognosis does not appear to be improved by radical surgery as opposed to simple excision but depends mainly on the maturity of the tissues of the primary tumour and the peritoneal deposits. Although the period of follow up is generally short, a survival time up to 26 years is recorded. In the fatal cases, there is rapid recurrence and metastatic spread. The pathogenesis of the glial deposits is discussed. [ABSTRACT FROM PUBLISHER]

[This corrects the article DOI: 10.1371/journal.pone.0091694.].

The development of a novel electrochemical methodology to generate carbon-11 carbon monoxide ([ 11 C]CO) from cyclotron-produced carbon-11 carbon dioxide ([ 11 C]CO 2 ) using Ni(cyclam) and Zn(cyclen) complexes is described. This methodology allows up to 10% yields of [ 11 C]CO from [ 11 C]CO 2 . Produced [ 11 C]CO was subsequently converted to [ 11 C]N-benzylbenzamide under mild conditions with a radiochemical purity (RCP) of >98%.

The glycerophospholipid phosphatidylcholine is the most abundant phospholipid species of eukaryotic membranes and essential for structural integrity and signaling function of cell membranes required for cancer cell growth. Inhibition of choline kinase alpha (CHKA), the first committed step to phosphatidylcholine synthesis, by the selective small-molecule ICL-CCIC-0019, potently suppressed growth of a panel of 60 cancer cell lines with median GI50 of 1.12 μM and inhibited tumor xenograft growth in mice. ICL-CCIC-0019 decreased phosphocholine levels and the fraction of labeled choline in lipids, and induced G1 arrest, endoplasmic reticulum stress and apoptosis. Changes in phosphocholine cellular levels following treatment could be detected non-invasively in tumor xenografts by [18F]-fluoromethyl-[1,2-2H4]-choline positron emission tomography. Herein, we reveal a previously unappreciated effect of choline metabolism on mitochondria function. Comparative metabolomics demonstrated that phosphatidylcholine pathway inhibition leads to a metabolically stressed phenotype analogous to mitochondria toxin treatment but without reactive oxygen species activation. Drug treatment decreased mitochondria function with associated reduction of citrate synthase expression and AMPK activation. Glucose and acetate uptake were increased in an attempt to overcome the metabolic stress. This study indicates that choline pathway pharmacological inhibition critically affects the metabolic function of the cell beyond reduced synthesis of phospholipids., Competing Interests: None.

Tumour response to therapy is assessed primarily in the clinic by monitoring reductions in tumour size. However, this approach lacks sensitivity since in many cases several weeks may elapse before there is evidence of tumour shrinkage. There is therefore a need to develop non-invasive imaging techniques for monitoring tumour treatment response in the clinic. Here, we assessed the pre-clinical utility of (18)F-ICMT-11 positron emission tomography--a method for detecting caspase 3/7 activation--in non-small cell lung cancer (NSCLC). (18)F-ICMT-11 uptake was compared to molecular biochemical measures of cell death in PC9 and A549 NSCLC cells following treatment with carboplatin in vitro and in vivo. Carboplatin-induced apoptosis in the ERCC1 low/mutant EGFR PC9 cells was characterised by time and dose-related increased caspase-3/7 activation, poly-ADP-ribose polymerase cleavage and Annexin V staining. 18F-ICMT-11 uptake was consequently increased up to 14-fold at 200 µM carboplatin compared to vehicle treated cells (P<0.01). In contrast, necrosis was the predominant death mechanism in ERCC1 high/wt EGFR A549 cells and no change in (18)F-ICMT-11 uptake was detected. In vivo, histological analysis of PC9 tumour xenografts indicated high pre-therapy necrosis. A 4.6-fold increase in cleaved caspase-3/7 was measured in non-necrotic regions of PC9 tumours at 48 h post carboplatin therapy. Average PET-derived tumour (18)F-ICMT-11 uptake was insensitive to changes in apoptosis in the presence of substantial pre-existing necrosis. PET-based voxel intensity sorting however, identified intra-tumoural regions of high (18)F-ICMT-11 uptake, enabling accurate assessment of apoptosis and therefore therapy response. In A549 tumours that lacked high pre-therapy necrosis, carboplatin induced growth inhibition that was only minimally associated with apoptosis and thus not detectable by (18)F-ICMT-11 PET.

Purpose: Induction of apoptosis in tumors is considered a desired goal of anticancer therapy. We investigated whether the dynamic temporal and spatial evolution of apoptosis in response to cytotoxic and mechanism-based therapeutics could be detected noninvasively by the caspase-3 radiotracer [(18)F]ICMT-11 and positron emission tomography (PET)., Experimental Design: The effects of a single dose of the alkylating agent cyclophosphamide (CPA or 4-hydroperoxycyclophosphamide), or the mechanism-based small molecule SMAC mimetic birinapant on caspase-3 activation was assessed in vitro and by [(18)F]ICMT-11-PET in mice bearing 38C13 B-cell lymphoma, HCT116 colon carcinoma, or MDA-MB-231 breast adenocarcinoma tumors. Ex vivo analysis of caspase-3 was compared to the in vivo PET imaging data., Results: Drug treatment increased the mean [(18)F]ICMT-11 tumor uptake with a peak at 24 hours for CPA (40 mg/kg; AUC40-60: 8.04 ± 1.33 and 16.05 ± 3.35 %ID/mL × min at baseline and 24 hours, respectively) and 6 hours for birinapant (15 mg/kg; AUC40-60: 20.29 ± 0.82 and 31.07 ± 5.66 %ID/mL × min, at baseline and 6 hours, respectively). Voxel-based spatiotemporal analysis of tumor-intrinsic heterogeneity suggested that discrete pockets of caspase-3 activation could be detected by [(18)F]ICMT-11. Increased tumor [(18)F]ICMT-11 uptake was associated with caspase-3 activation measured ex vivo, and early radiotracer uptake predicted apoptosis, distinct from the glucose metabolism with [(18)F]fluorodeoxyglucose-PET, which depicted continuous loss of cell viability., Conclusion: The proapoptotic effects of CPA and birinapant resulted in a time-dependent increase in [(18)F]ICMT-11 uptake detected by PET. [(18)F]ICMT-11-PET holds promise as a noninvasive pharmacodynamic biomarker of caspase-3-associated apoptosis in tumors.

We report here a radiosynthesis for the D(2/3) agonist (+)-4-([3-(11)C]propyl)-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-ol (3-[(11)C]-(+)-PHNO) labelled at the terminal carbon of the N-propyl chain. The protocol is based on (11)C-methylation of an N-acetyl precursor. This initial step is followed by a reduction with LiAlH(4) to give ([3-(11)C]-(+)-PHNO). We first applied the method for the synthesis of a model compound, N-3-([(11)C]propyl)-1,2,3,4-tetrahydroisoquinoline, which we obtained in 77-97% analytical radiochemical yield (n=6) in 20 min. Similarly, we prepared ([3-(11)C]-(+)-PHNO) in 55-60% analytical radiochemical yield (n=5) using a one-pot procedure. We have also been able to implement the complete process on a semi-automated module. This platform delivered purified and formulated [3-(11)C]PHNO with an average radiochemical yield of 9% (n=13, range 2-30%, non-decay corrected), a radiochemical purity >95%, and a specific radioactivity of 26.8-81.1 GBq/μmol in a total time of 63-65 min., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Introduction: Isatin-5-sulfonamide ([(18)F]ICMT-11) is a sub-nanomolar inhibitor of caspase-3 previously evaluated as an apoptosis imaging agent. Herein, an alternative radiosynthesis of [(18)F]ICMT-11 with increased purity and specific activity is presented. Finally, a GMP-applicable automated radiosynthesis of [(18)F]ICMT-11 is described., Methods: The preparation of [(18)F]ICMT-11 was evaluated under a variety of reaction conditions, including reaction solvent, by employing alternative phase transfer catalysts and under different deprotection conditions. Following initial investigations, the process was transferred onto a fully automated GE FASTlab synthesis platform for further development and optimisation., Results: The synthesis of [(18)F]ICMT-11 was successfully validated under GMP conditions, resulting in a yield of 4.6 ± 0.4 GBq with a radiochemical purity of >98% at EOS and a specific activity of 685 ± 237 GBq/μmol within 90 min. Quality control was carried out in accordance with the European Pharmacopoeia and demonstrated that [(18)F]ICMT-11 can be consistently manufactured on the FASTlab to meet specifications., Conclusions: A simplified methodology for the synthesis of the apoptosis imaging agent, [(18)F]ICMT-11, has been achieved by the S(N)2 displacement of a tosylate leaving group with [(18)F]fluoride ion. This results in an increased purity and specific activity over the original copper catalysed "Click" synthetic stratagem reaction involving 2-[(18)F]fluoroethylazide with an alkyne precursor and is now suitable for routine clinical application., (Copyright © 2012 Elsevier Inc. All rights reserved.)

The capacity to evade apoptosis has been defined as one of the hallmarks of cancer and, thus, effective anti-cancer therapy often induces apoptosis. A biomarker for imaging apoptosis could assist in monitoring the efficacy of a wide range of current and future therapeutics. Despite the potential, there are limited clinical examples of the use of positron emission tomography for imaging of apoptosis. [(18)F]ICMT-11 is a novel reagent designed to non-invasively image caspase-3 activation and, hence, drug-induced apoptosis. Radiochemistry development of [(18)F]ICMT-11 has been undertaken to improve specific radioactivity, reduce content of stable impurities, reduce synthesis time and enable automation for manufacture of multi-patient dose. Due to the promising mechanistic and safety profile of [(18)F]ICMT-11, the radiotracer is transitioning to clinical development and has been selected as a candidate radiotracer by the QuIC-ConCePT consortium for further evaluation in preclinical models and humans. A successful outcome will allow use of the radiotracer as qualified method for evaluating the pharmaceutical industry's next generation therapeutics., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Microreactors incorporating thin film resistive heating elements for continuous flow organic synthesis are presented. Internal thermal conditions were monitored in real time using reflectance spectra of temperature sensitive thermochromic liquid crystals (TLC) in a collateral microfluidic network. To demonstrate the precise temperature control provided by this method, the thermal optimisation of the Reimer-Tiemann formylation of beta-naphthol was performed under hydrodynamic pumping regimes.

A microfluidic procedure for the controlled production of cadmium sulfide nanoparticles is described.

Monolithic nanoreactors for the safe and expedient continuous synthesis of products requiring unstable intermediates were fabricated and tested by the synthesis of azo dyes under hydrodynamic pumping regimes.

An unique case of solitary metastasis to the region of the tricuspid valve is described. The mechanisms of formation and symptomatology of cardiac neoplasms are discussed. Tumour spread in this case was probably embolic.