Early- and advanced non-enzymatic glycation in diabetic vascular complications: the search for therapeutics

Cardiovascular disease is a common complication of diabetes and the leading cause of death among people with diabetes. Because of the huge premature morbidity and mortality associated with diabetes, prevention of vascular complications is a key issue. Although the exact mechanism by which vascular damage occurs in diabetes in not fully understood, numerous studies support the hypothesis of a causal relationship of non-enzymatic glycation with vascular complications. In this review, data which point to an important role of Amadori-modified glycated proteins and advanced glycation endproducts in vascular disease are surveyed. Because of the potential role of early- and advanced non-enzymatic glycation in vascular complications, we also described recent developments of pharmacological inhibitors that inhibit the formation of these glycated products or the biological consequences of glycation and thereby retard the development of vascular complications in diabetes

Feasibility of preoperative chemotherapy for locally advanced, operable colon cancer: The pilot phase of a randomised controlled trial

Summary: Background Preoperative (neoadjuvant) chemotherapy and radiotherapy are more eff ective than similar postoperative treatment for oesophageal, gastric, and rectal cancers, perhaps because of more eff ective micrometastasis eradication and reduced risk of incomplete excision and tumour cell shedding during surgery. The FOxTROT trial aims to investigate the feasibility, safety, and effi cacy of preoperative chemotherapy for colon cancer. Methods In the pilot stage of this randomised controlled trial, 150 patients with radiologically staged locally advanced (T3 with ≥5 mm invasion beyond the muscularis propria or T4) tumours from 35 UK centres were randomly assigned (2:1) to preoperative (three cycles of OxMdG [oxaliplatin 85 mg/m², l-folinic acid 175 mg, fl uorouracil 400 mg/m² bolus, then 2400 mg/m² by 46 h infusion] repeated at 2-weekly intervals followed by surgery and a further nine cycles of OxMdG) or standard postoperative chemotherapy (12 cycles of OxMdG). Patients with KRAS wild-type tumours were randomly assigned (1:1) to receive panitumumab (6 mg/kg; every 2 weeks with the fi rst 6 weeks of chemotherapy) or not. Treatment allocation was through a central randomisation service using a minimised randomisation procedure including age, radiological T and N stage, site of tumour, and presence of defunctioning colostomy as stratifi cation variables. Primary outcome measures of the pilot phase were feasibility, safety, and tolerance of preoperative therapy, and accuracy of radiological staging. Analysis was by intention to treat. This trial is registered, number ISRCTN 87163246. Findings 96% (95 of 99) of patients started and 89% (85 of 95) completed preoperative chemotherapy with grade 3–4 gastrointestinal toxicity in 7% (seven of 94) of patients. All 99 tumours in the preoperative group were resected, with no signifi cant diff erences in postoperative morbidity between the preoperative and control groups: 14% (14 of 99) versus 12% (six of 51) had complications prolonging hospital stay (p=0·81). 98% (50 of 51) of postoperative chemotherapy patients had T3 or more advanced tumours confi rmed at post-resection pathology compared with 91% (90 of 99) of patients following preoperative chemotherapy (p=0·10). Preoperative therapy resulted in signifi cant downstaging of TNM5 compared with the postoperative group (p=0·04), including two pathological complete responses, apical node involvement (1% [one of 98] vs 20% [ten of 50], p<0·0001), resection margin involvement (4% [ four of 99] vs 20% [ten of 50], p=0·002), and blinded centrally scored tumour regression grading: 31% (29 of 94) vs 2% (one of 46) moderate or greater regression (p=0·0001). Interpretation Preoperative chemotherapy for radiologically staged, locally advanced operable primary colon cancer is feasible with acceptable toxicity and perioperative morbidity. Proceeding to the phase 3 trial, to establish whether the encouraging pathological responses seen with preoperative therapy translates into improved long-term oncological outcome, is appropriate

Localized variation in ancestral admixture identifies pilocytic astrocytoma risk loci among Latino children.

BackgroundPilocytic astrocytoma (PA) is the most common pediatric brain tumor. PA has at least a 50% higher incidence in populations of European ancestry compared to other ancestral groups, which may be due in part to genetic differences.MethodsWe first compared the global proportions of European, African, and Amerindian ancestries in 301 PA cases and 1185 controls of self-identified Latino ethnicity from the California Biobank. We then conducted admixture mapping analysis to assess PA risk with local ancestry.ResultsWe found PA cases had a significantly higher proportion of global European ancestry than controls (case median = 0.55, control median = 0.51, P value = 3.5x10-3). Admixture mapping identified 13 SNPs in the 6q14.3 region (SNX14) contributing to risk, as well as three other peaks approaching significance on chromosomes 7, 10 and 13. Downstream fine mapping in these regions revealed several SNPs potentially contributing to childhood PA risk.ConclusionsThere is a significant difference in genomic ancestry associated with Latino PA risk and several genomic loci potentially mediating this risk

A validation of carbon fiber imaging couch top modeling in two radiation therapy treatment planning systems: Philips Pinnacle³ and BrainLAB iPlan RT Dose

<p>Abstract</p> <p>Background</p> <p>Carbon fiber (CF) is now the material of choice for radiation therapy couch tops. Initial designs included side metal bars for rigidity; however, with the advent of IGRT, involving on board imaging, new thicker CF couch tops without metal bars have been developed. The new design allows for excellent imaging at the expense of potentially unacceptable dose attenuation and perturbation.</p> <p>Objectives</p> <p>We set out to model the BrainLAB imaging couch top (ICT) in Philips Pinnacle³ treatment planning system (TPS), to validate the already modeled ICT in BrainLAB iPlan RT Dose treatment planning system and to compute the magnitude of the loss in skin sparing.</p> <p>Results</p> <p>Using CF density of 0.55 g/cm³ and foam density of 0.03 g/cm³, we demonstrated an excellent agreement between measured dose and Pinnacle³ TPS computed dose using 6 MV beam. The agreement was within 1% for all gantry angle measured except for 120^o, which was 1.8%. The measured and iPlan RT Dose TPS computed dose agreed to within 1% for all gantry angles and field sizes measured except for 100^o where the agreement was 1.4% for 10 cm × 10 cm field size. Predicted attenuation through the couch by iPlan RT Dose TPS (3.4% - 9.5%) and Pinnacle³ TPS (2% - 6.6%) were within the same magnitude and similar to previously reported in the literature. Pinnacle³ TPS estimated an 8% to 20% increase in skin dose with increase in field size. With the introduction of the CF couch top, it estimated an increase in skin dose by approximately 46 - 90%. The clinical impact of omitting the couch in treatment planning will be dependent on the beam arrangement, the percentage of the beams intersecting the couch and their angles of incidence.</p> <p>Conclusion</p> <p>We have successfully modeled the ICT in Pinnacle³ TPS and validated the modeled ICT in iPlan RT Dose. It is recommended that the ICT be included in treatment planning for all treatments that involve posteriors beams. There is a significant increase in skin dose that is dependent on the percentage of the beam passing through the couch and the angle of incidence.</p

Two years experience with quality assurance protocol for patient related Rapid Arc treatment plan verification using a two dimensional ionization chamber array

<p>Abstract</p> <p>Purpose</p> <p>To verify the dose distribution and number of monitor units (MU) for dynamic treatment techniques like volumetric modulated single arc radiation therapy - Rapid Arc - each patient treatment plan has to be verified prior to the first treatment. The purpose of this study was to develop a patient related treatment plan verification protocol using a two dimensional ionization chamber array (MatriXX, IBA, Schwarzenbruck, Germany).</p> <p>Method</p> <p>Measurements were done to determine the dependence between response of 2D ionization chamber array, beam direction, and field size. Also the reproducibility of the measurements was checked. For the patient related verifications the original patient Rapid Arc treatment plan was projected on CT dataset of the MatriXX and the dose distribution was calculated. After irradiation of the Rapid Arc verification plans measured and calculated 2D dose distributions were compared using the gamma evaluation method implemented in the measuring software OmniPro (version 1.5, IBA, Schwarzenbruck, Germany).</p> <p>Results</p> <p>The dependence between response of 2D ionization chamber array, field size and beam direction has shown a passing rate of 99% for field sizes between 7 cm × 7 cm and 24 cm × 24 cm for measurements of single arc. For smaller and larger field sizes than 7 cm × 7 cm and 24 cm × 24 cm the passing rate was less than 99%. The reproducibility was within a passing rate of 99% and 100%. The accuracy of the whole process including the uncertainty of the measuring system, treatment planning system, linear accelerator and isocentric laser system in the treatment room was acceptable for treatment plan verification using gamma criteria of 3% and 3 mm, 2D global gamma index.</p> <p>Conclusion</p> <p>It was possible to verify the 2D dose distribution and MU of Rapid Arc treatment plans using the MatriXX. The use of the MatriXX for Rapid Arc treatment plan verification in clinical routine is reasonable. The passing rate should be 99% than the verification protocol is able to detect clinically significant errors.</p