Ribose supplementation alone or with elevated creatine does not preserve high energy nucleotides or cardiac function in the failing mouse heart

Background: Reduced levels of creatine and total adenine nucleotides (sum of ATP, ADP and AMP) are hallmarks of chronic heart failure and restoring these pools is predicted to be beneficial by maintaining the diseased heart in a more favourable energy state. Ribose supplementation is thought to support both salvage and re-synthesis of adenine nucleotides by bypassing the rate-limiting step. We therefore tested whether ribose would be beneficial in chronic heart failure in control mice and in mice with elevated myocardial creatine due to overexpression of the creatine transporter (CrT-OE). Methods and Results: Four groups were studied: sham; myocardial infarction (MI); MI+ribose; MI+CrT-OE+ribose. In a pilot study, ribose given in drinking water was bioavailable, resulting in a two-fold increase in myocardial ribose-5-phosphate levels. However, 8 weeks post-surgery, total adenine nucleotide (TAN) pool was decreased to a similar amount (8–14%) in all infarcted groups irrespective of the treatment received. All infarcted groups also presented with a similar and substantial degree of left ventricular (LV) dysfunction (3-fold reduction in ejection fraction) and LV hypertrophy (32–47% increased mass). Ejection fraction closely correlated with infarct size independently of treatment (r2 = 0.63, p<0.0001), but did not correlate with myocardial creatine or TAN levels. Conclusion: Elevating myocardial ribose and creatine levels failed to maintain TAN pool or improve post-infarction LV remodeling and function. This suggests that ribose is not rate-limiting for purine nucleotide biosynthesis in the chronically failing mouse heart and that alternative strategies to preserve TAN pool should be investigated

Preoperative radiotherapy combined with 5 days per week capecitabine chemotherapy in locally advanced rectal cancer

There is increasing evidence supporting the use of preoperative chemoradiotherapy in patients with locally advanced rectal cancer in an attempt to facilitate complete surgical resection with clear margins. We describe our experience of using a 5-day per week regime of preoperative capecitabine chemoradiotherapy. Between November 2004 and September 2006, 70 patients with MRI-defined locally advanced rectal cancer were selected for treatment. Capecitabine was given at a dose of 900 mg m−2 for 5 days per week combined with 45 Gy of radiotherapy in 25 doses. This regime was well tolerated with 89% of our patients receiving the full dose of chemotherapy and 96% receiving the full dose of radiotherapy. Ninety-three per cent proceeded to macroscopically complete surgical resection. The pathological complete response rate was 9.2% with a node-negative rate of 66%. A negative circumferential margin was achieved by 79% of the patients who underwent resection. Compared to studies using a 7-day per week capecitabine schedule, our results show increased compliance and less dose reductions with comparable pathological outcome

Patient-reported outcomes in PROSPECT trial (Alliance N1048) – FOLFOX is not a panacea

The PROSPECT was a randomized phase III trial that included patients with resectable rectal cancer (clinical stage cT2-3N+ or cT3N0). The trial aimed to test the hypothesis that pre-operative chemotherapy consisting of 6 cycles of FOLFOX given over a 12-week period, followed by total mesorectal excision (TME) surgery, was non-inferior to pre-operative long-course chemoradiotherapy (CRT). The primary endpoint of the study was disease-free survival (DFS), and patients were also monitored for other relevant oncological outcomes such and health-related quality of life (HRQoL) using patient-reported outcome (PRO) tools [1, 2]

Impact of compliance to chemoradiation on long-term outcomes in squamous cell carcinoma of the anus. Results of a post-hoc analysis from the randomized phase III ACT II trial

PURPOSE: Concurrent chemoradiation is standard-of-care for patients with squamous cell carcinoma of the anus (SCCA). Poor compliance to chemotherapy, radiotherapy treatment interruptions and unplanned breaks may impact adversely on long-term outcomes. METHODS: The ACT II trial recruited 940 patients with localized SCCA, and assigned patients to mitomycin (week 1) or cisplatin (weeks 1 and 5), with fluorouracil (weeks 1 & 5) and radiotherapy (50·4Gy in 28 fractions over 38 days). This post-hoc analysis examined the association between baseline factors (age, gender, site, T-stage and N-stage), and compliance to treatment (radiotherapy and chemotherapy), and their effects on loco-regional failure-free survival (LRFFS), progression-free survival (PFS) and overall survival (OS). Compliance was categorized into groups. Radiotherapy: 6 groups according to total dose (TD) and overall treatment time (OTT). Chemotherapy: 3 groups (A = per-protocol; B = dose reduction or delay; C = omitted). RESULTS: 931/940 patients were evaluable for radiotherapy and 936 for chemotherapy compliance. Baseline Glomerular filtration rate (GR) 42 days is associated with worse PFS and OS (HR:1.72 (95%CI:1.17-2.54), p=0.006). CONCLUSION: Poor compliance to chemotherapy and radiotherapy were associated with worse LRFFS, PFS and OS. Treatment interruptions should be minimized, and OTT and TD maintained

Caution is required in the implementation of 90-day mortality indicators for radiotherapy in a curative setting: A retrospective population-based analysis of over 16,000 episodes

Background: 90-day mortality (90DM) has been proposed as a clinical indicator in radiotherapy delivered in a curative setting. No large scale assessment has been made. Its value in allowing robust comparisons between centres and facilitating service improvement is unknown. Methods: All radiotherapy treatments delivered in a curative setting over seven years were extracted from the local electronic health record and linked to cancer registry data. 90DM rates were assessed and factors associated with this outcome were investigated using logistic regression. Cause of death was identified retrospectively further characterising the cause of 90DM. Results: Overall 90DM was 1.25%. Levels varied widely with diagnosis (0.20%-5.45%). Age (OR 1.066, 1.043-1.073), year of treatment (OR 0.900, 0.841-0.969) and diagnosis were significantly associated with 90DM on multi-variable logistic regression. Cause of death varied with diagnosis; 50.0% post-operative in rectal cancer, 40.4% treatment-related in head and neck cancer, 59.4% disease progression in lung cancer. Conclusion: Despite the drive to report centre level comparative outcomes, this study demonstrates that 90DM cannot be adopted routinely as a clinical indicator due to significant population heterogeneity and low event rates. Further national investigation is needed to develop a meaningful robust indicator that delivers appropriate comparisons and drive improvements in care

Changes in creatine transporter function during cardiac maturation in the rat

<p>Abstract</p> <p>Background</p> <p>It is well established that the immature myocardium preferentially utilises non-oxidative energy-generating pathways. It exhibits low energy-transfer capacity via the creatine kinase (CK) shuttle, reflected in phosphocreatine (PCr), total creatine and CK levels that are much lower than those of adult myocardium. The mechanisms leading to gradually increasing energy transfer capacity during maturation are poorly understood. Creatine is not synthesised in the heart, but taken up exclusively by the action of the creatine transporter protein (CrT). To determine whether this transporter is ontogenically regulated, the present study serially examined CrT gene expression pattern, together with creatine uptake kinetics and resulting myocardial creatine levels, in rats over the first 80 days of age.</p> <p>Results</p> <p>Rats were studied during the late prenatal period (-2 days before birth) and 7, 13, 21, 33, 50 and 80 days after birth. Activity of cardiac citrate synthase, creatine kinase and its isoenzymes as well as lactate dehydrogenase (LDH) and its isoenzymes demonstrated the well-described shift from anaerobic towards aerobic metabolism. mRNA levels of CrT in the foetal rat hearts, as determined by real-time PCR, were about 30% of the mRNA levels in the adult rat heart and gradually increased during development. Creatine uptake in isolated perfused rat hearts increased significantly from 3.0 nmol/min/gww at 13 days old to 4.9 nmol/min/gww in 80 day old rats. Accordingly, total creatine content in hearts, measured by HPLC, increased steadily during maturation (30 nmol/mg protein (-2 days) vs 87 nmol/mg protein (80 days)), and correlated closely with CrT gene expression.</p> <p>Conclusions</p> <p>The maturation-dependant alterations of CK and LDH isoenzyme activities and of mitochondrial oxidative capacity were paralleled by a progressive increase of CrT expression, creatine uptake kinetics and creatine content in the heart.</p

Evaluating the repeatability and set-up sensitivity of a large field of view distortion phantom and software for magnetic resonance-only radiotherapy

Background and purpose: Magnetic Resonance (MR)-only radiotherapy requires geometrically accurate MR images over the full scanner Field of View (FoV). This study aimed to investigate the repeatability of distortion measurements made using a commercial large FoV phantom and analysis software and the sensitivity of these measurements to small set-up errors. Materials and methods: Geometric distortion was measured using a commercial phantom and software with 2D and 3D acquisition sequences on three different MR scanners. Two sets of repeatability measurements were made: three scans acquired without moving the phantom between scans (single set-up) and five scans acquired with the phantom re-set up in between each scan (repeated set-up). The set-up sensitivity was assessed by scanning the phantom with an intentional 1 mm lateral offset and independently an intentional 1° rotation. Results: The mean standard deviation of distortion for all phantom markers for the repeated set-up scans was for all scanners and sequences. For the lateral offset scan of the markers agreed within two standard deviations of the mean of the repeated set-up scan (median of all scanners and sequences, range 78%–93%). For the 1° rotation scan, 80% of markers agreed within two standard deviations of the mean (range 69%–93%). Conclusions: Geometric distortion measurements using a commercial phantom and associated software appear repeatable, although with some sensitivity to set-up errors. This suggests the phantom and software are appropriate for commissioning a MR-only radiotherapy workflow