Identifying nonsmall-cell lung tumours bearing the T790M EGFR TKI resistance mutation using PET imaging.

Specific mutations significantly affect response to epidermal growth factor tyrosine kinase inhibitor (EGFR-TKI) treatment in lung cancer patients. Identifying patients with these mutations remains a major clinical challenge. EGFR T790M mutation, which conveys resistance to in the present study, [18 F]FEWZ was assessed in vitro to determine efficacy relative to the starting compound and in vivo to measure the biodistribution and specificity of binding to EGFR wild-type, L858R and T790M bearing tumours. [18 F]FEWZ is the first evidence of a radiolabeled third generation anilinopyrimidine-derived tyrosine kinase inhibitor targeting T790M mutation bearing tumours in vivo.

Understanding nanomedicine treatment in an aggressive spontaneous brain cancer model at the stage of early blood brain barrier disruption.

Personalised nanomedicine is an advancing field which has developed significant improvements for targeting therapeutics to aggressive cancer and with fewer side effects. The treatment of gliomas such as glioblastoma (or other brain tumours), with nanomedicine is complicated by a commonly poor accumulation of drugs in tumour tissue owing to the partially intact blood-brain barrier (BBB). Nonetheless, the BBB becomes compromised following surgical intervention, and gradually with disease progression. Increased vasculature permeability generated by a tumour, combined with decreased BBB integrity, offers a mechanism to enhance therapeutic outcomes. We monitored a spontaneous glioma tumour model in immunocompetent mice with ongoing T2-weighted and contrast-enhanced T1-weighted magnetic resonance imaging gradient echo and spin echo sequences to predict an optimal "leakiness" stage for nanomedicine injections. To ascertain the effectiveness of targeted nanomedicines in treating brain tumours, subsequent systemic administration of targeted hyperbranched polymers was then utislised, to deliver the therapeutic payload when both the tumour and brain vascularity had become sufficiently susceptible to allow drug accumulation. Treatment with either doxorubicin-loaded hyperbranched polymer, or the same nanomedicine targeted to an ephrin receptor (EphA2) using a bispecific antibody, resulted in uptake of chemotherapeutic doxorubicin in the tumour and in reduced tumour growth. Compared to vehicle and doxorubicin only, nanoparticle delivered doxorubicin resulted in increased tumour apoptosis, while averting cardiotoxicity. This suggests that polyethylene based (PEGylated)-nanoparticle delivered doxorubicin could provide a more efficient treatment in tumours with a disrupted BBB, and that treatment should commence immediately following detection of gadolinium permeability, with early detection and ongoing 'leakiness' monitoring in susceptible patients being a key factor.

Dopamine transporter neuroimaging accurately assesses the maturation of dopamine neurons in a preclinical model of Parkinson's disease.

BACKGROUND: Significant developments in stem cell therapy for Parkinson's disease (PD) have already been achieved; however, methods for reliable assessment of dopamine neuron maturation in vivo are lacking. Establishing the efficacy of new cellular therapies using non-invasive methodologies will be critical for future regulatory approval and application. The current study examines the utility of neuroimaging to characterise the in vivo maturation, innervation and functional dopamine release of transplanted human embryonic stem cell-derived midbrain dopaminergic neurons (hESC-mDAs) in a preclinical model of PD. METHODS: Female NIH RNu rats received a unilateral stereotaxic injection of 6-OHDA into the left medial forebrain bundle to create the PD lesion. hESC-mDA cell and sham transplantations were carried out 1 month post-lesion, with treated animals receiving approximately 4 × 105 cells per transplantation. Behavioural analysis, [18F]FBCTT and [18F]fallypride microPET/CT, was conducted at 1, 3 and 6 months post-transplantation and compared with histological characterisation at 6 months. RESULTS: PET imaging revealed transplant survival and maturation into functional dopaminergic neurons. [18F]FBCTT-PET/CT dopamine transporter (DAT) imaging demonstrated pre-synaptic restoration and [18F]fallypride-PET/CT indicated functional dopamine release, whilst amphetamine-induced rotation showed significant behavioural recovery. Moreover, histology revealed that the grafted cells matured differently in vivo producing high- and low-tyrosine hydroxylase (TH) expressing cohorts, and only [18F]FBCTT uptake was well correlated with differentiation. CONCLUSIONS: This study provides further evidence for the value of in vivo functional imaging for the assessment of cell therapies and highlights the utility of DAT imaging for the determination of early post-transplant cell maturation and differentiation of hESC-mDAs.

Quality indices in a cervicovaginal cytology service: before and after laboratory accreditation.

CONTEXT: Quality assurance practices contribute to the effectiveness of cervical screening and are formalized by participation in a laboratory accreditation program. OBJECTIVE: To identify changes in the quality indices of our cervicovaginal cytology service preceding and following laboratory accreditation by the College of American Pathologists in 2000. DESIGN: Cervicovaginal cytology quality indices for 2001 (postaccreditation) were compared with those of 1997 (preaccreditation). Performances in the College of American Pathologists Interlaboratory Comparison Program in Cervicovaginal Cytology (PAP) for the years 1999-2002 were analyzed. RESULTS: A comparison between data for 1997 and 2001 shows the following: (a) a higher inadequacy rate (1.3% vs 0.7%; P <.001) in 2001; (b) maintenance of a low atypical squamous cells of undetermined significance-squamous intraepithelial lesion ratio (0.79 and 0.76, respectively); (c) overall positive predictive values of positive cytology of 82% and 87%, respectively; (d) relatively few changes to the original cytologic diagnoses following review of significant cytohistologic discrepancies (4 cases and 2 cases, respectively); and (e) a higher subsequent positive yield of squamous intraepithelial lesions following atypical squamous cells of undetermined significance diagnoses in 2001 (41% vs 19%; P =.02). The performance of the laboratory and cytotechnologists in the PAP program showed maintenance of a high standard with almost no major discrepancies recorded. CONCLUSIONS: An increased awareness of quality-related issues and participation in intradepartmental consultation/diagnostic seminars, all part of the accreditation process, have very likely contributed to the modest improvements identified in the cytology service. Future challenges include increases in workload with the anticipated launch of Singapore's national cervical screening program and adaptation to the emerging cervical screening technologies.