Intermittent versus continuous oxaliplatin and fluoropyrimidine combination chemotherapy for first-line treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial

Background: When cure is impossible, cancer treatment should focus on both length and quality of life. Maximisation of time without toxic effects could be one effective strategy to achieve both of these goals. The COIN trial assessed preplanned treatment holidays in advanced colorectal cancer to achieve this aim. Methods: COIN was a randomised controlled trial in patients with previously untreated advanced colorectal cancer. Patients received either continuous oxaliplatin and fluoropyrimidine combination (arm A), continuous chemotherapy plus cetuximab (arm B), or intermittent (arm C) chemotherapy. In arms A and B, treatment continued until development of progressive disease, cumulative toxic effects, or the patient chose to stop. In arm C, patients who had not progressed at their 12-week scan started a chemotherapy-free interval until evidence of disease progression, when the same treatment was restarted. Randomisation was done centrally (via telephone) by the MRC Clinical Trials Unit using minimisation. Treatment allocation was not masked. The comparison of arms A and B is described in a companion paper. Here, we compare arms A and C, with the primary objective of establishing whether overall survival on intermittent therapy was non-inferior to that on continuous therapy, with a predefined non-inferiority boundary of 1·162. Intention-to-treat (ITT) and per-protocol analyses were done. This trial is registered, ISRCTN27286448. Findings: 1630 patients were randomly assigned to treatment groups (815 to continuous and 815 to intermittent therapy). Median survival in the ITT population (n=815 in both groups) was 15·8 months (IQR 9·4—26·1) in arm A and 14·4 months (8·0—24·7) in arm C (hazard ratio [HR] 1·084, 80% CI 1·008—1·165). In the per-protocol population (arm A, n=467; arm C, n=511), median survival was 19·6 months (13·0—28·1) in arm A and 18·0 months (12·1—29·3) in arm C (HR 1·087, 0·986—1·198). The upper limits of CIs for HRs in both analyses were greater than the predefined non-inferiority boundary. Preplanned subgroup analyses in the per-protocol population showed that a raised baseline platelet count, defined as 400 000 per µL or higher (271 [28%] of 978 patients), was associated with poor survival with intermittent chemotherapy: the HR for comparison of arm C and arm A in patients with a normal platelet count was 0·96 (95% CI 0·80—1·15, p=0·66), versus 1·54 (1·17—2·03, p=0·0018) in patients with a raised platelet count (p=0·0027 for interaction). In the per-protocol population, more patients on continuous than on intermittent treatment had grade 3 or worse haematological toxic effects (72 [15%] vs 60 [12%]), whereas nausea and vomiting were more common on intermittent treatment (11 [2%] vs 43 [8%]). Grade 3 or worse peripheral neuropathy (126 [27%] vs 25 [5%]) and hand—foot syndrome (21 [4%] vs 15 [3%]) were more frequent on continuous than on intermittent treatment. Interpretation: Although this trial did not show non-inferiority of intermittent compared with continuous chemotherapy for advanced colorectal cancer in terms of overall survival, chemotherapy-free intervals remain a treatment option for some patients with advanced colorectal cancer, offering reduced time on chemotherapy, reduced cumulative toxic effects, and improved quality of life. Subgroup analyses suggest that patients with normal baseline platelet counts could gain the benefits of intermittent chemotherapy without detriment in survival, whereas those with raised baseline platelet counts have impaired survival and quality of life with intermittent chemotherapy and should not receive a treatment break.

The Structural and Molecular Biology of Type I Galactosemia: Enzymology of Galactose 1-phosphate Uridylyltransferase

Reduced galactose 1-phosphate uridylyltransferase (GAIT) activity is associated with the genetic disease type 1 galactosemia. This results in an increase in the cellular concentration of galactose 1-phosphate. The accumulation of this toxic metabolite, combined with aberrant glycoprotein and glycolipid biosynthesis, is likely to be the major factor in molecular pathology. The mechanism of GAIT was established through classical enzymological methods to be a substituted enzyme in which the reaction with UDP-glucose results in the formation of a covalent, UMP-histidine adduct in the active site. The uridylated enzyme can then react with galactose 1-phosphate to form UDP-galactose. The structure of the enzyme from Escherichia coli reveals a homodimer containing one zinc (II) and one iron (11) ion per subunit. This enzymological and structural knowledge provides the basis for understanding the biochemistry of this critical step in the Leloir pathway. However, a high-resolution crystal structure of human GAIT is required to assist greater understanding of the effects of disease-associated mutations. (C) 2011 IUBMB IUBMB Life, 63(9): 694-700, 2011

Proton pump inhibitors and histamine-2-receptor antagonists and pancreatic cancer risk: a nested case-control study

Background: The relationship between use of proton pump inhibitors (PPIs) and histamine-2-receptor antagonists (H₂RAs) and pancreatic cancer risk has yet to be examined. Data from a range of studies suggest biologically plausible mechanisms, whereby these drugs (or the conditions for which they are prescribed) may affect pancreatic cancer risk. The objective of this study was to investigate the relationship between use of PPIs/H₂RAs and pancreatic cancer risk.

Methods: A nested case – control study was conducted within the UK general practice research database (GPRD). Cases had a diagnosis of exocrine pancreatic cancer and controls were matched to cases on general practice site, sex and year of birth. Exposure to PPIs and to H₂RAs since entry into GPRD until 2 years before the diagnosis date (corresponding date in controls) and in the 5 years before the diagnosis date were separately assessed. Conditional logistic regression analyses were used to generate odds ratios (ORs) and 95% confidence intervals (CIs) associated with PPI or H₂RA use compared with nonuse.

Results: Ever use of PPIs since entry into the GPRD (excluding the 2 years prior to diagnosis) was not associated with risk of pancreatic cancer; OR (95% CI) 1.02 (0.85 – 1.22). Neither the dose nor the duration of PPI or H₂RA use was associated with pancreatic cancer risk. No consistent patterns of association were seen when cumulative exposure (dose and duration) to these drugs was examined separately or together.

Conclusion: PPI/H₂RA use, in a UK population, was not associated with pancreatic cancer risk.

ISOLATION AND PARTIAL SEQUENCING OF A PANCREATIC POLYPEPTIDE-LIKE NEUROPEPTIDE FROM THE LIVER FLUKE, FASCIOLA-HEPATICA

1. A pancreatic polypeptide (PP)-immunoreactive neuropeptide has been isolated and partially sequenced from the liver fluke, Fasciola hepatica.

Detection of short lived radioisotopes as a fast diagnostic for intense laser-solid interactions

As a diagnostic of high-intensity laser interactions (> 10(19) W cm(-2)), the detection of radioactive isotopes is regularly used for the characterization of proton, neutron, ion, and photon beams. This involves sample removal from the interaction chamber and time consuming post shot analysis using NaI coincidence counting or Ge detectors. This letter describes the use of in situ detectors to measure laser-driven (p,n) reactions in Al-27 as an almost real-time diagnostic for proton acceleration. The produced Si-27 isotope decays with a 4.16 s half-life by the predominantly beta+ emission, producing a strong 511 keV annihilation peak. (c) 2006 American Institute of Physics.

Visuomotor transformation for interception:catching while fixating

Catching a ball involves a dynamic transformation of visual information about ball motion into motor commands for moving the hand to the right place at the right time. We previously formulated a neural model for this transformation to account for the consistent leftward movement biases observed in our catching experiments. According to the model, these biases arise within the representation of target motion as well as within the transformation from a gaze-centered to a body-centered movement command. Here, we examine the validity of the latter aspect of our model in a catching task involving gaze fixation. Gaze fixation should systematically influence biases in catching movements, because in the model movement commands are only generated in the direction perpendicular to the gaze direction. Twelve participants caught balls while gazing at a fixation point positioned either straight ahead or 14 degrees to the right. Four participants were excluded because they could not adequately maintain fixation. We again observed a consistent leftward movement bias, but the catching movements were unaffected by fixation direction. This result refutes our proposal that the leftward bias partly arises within the visuomotor transformation, and suggests instead that the bias predominantly arises within the early representation of target motion, specifically through an imbalance in the represented radial and azimuthal target motion.

Mimicking the colourful wing scale structure of the Papilio blumei butterfly

The brightest and most vivid colours in nature arise from the interaction of light with surfaces that exhibit periodic structure on the micro- and nanoscale. In the wings of butterflies, for example, a combination of multilayer interference, optical gratings, photonic crystals and other optical structures gives rise to complex colour mixing. Although the physics of structural colours is well understood, it remains a challenge to create artificial replicas of natural photonic structures(1-3). Here we use a combination of layer deposition techniques, including colloidal self-assembly, sputtering and atomic layer deposition, to fabricate photonic structures that mimic the colour mixing effect found on the wings of the Indonesian butterfly Papilio blumei. We also show that a conceptual variation to the natural structure leads to enhanced optical properties. Our approach offers improved efficiency, versatility and scalability compared with previous approaches(4-6).

Quantitative detection of DNA by autocatalytic enlargement of hybridized gold nanoprobes

Quantitative detection of specific viral DNA has become a pressing issue for the earlier clinical diagnosis of viral infectious diseases. Therefore, in this paper, we report a simple, sensitive, and inexpensive quantitative approach for DNA detection based on the autocatalytic Au deposition of gold nanoprobes via the surface reduction of AuCl4- to Au0 on their surface in the presence of ascorbic acid (AA) and cetyltrimethylammonium bromide (CTAB). On this basis, signal enhancements in the absorbance intensity and kinetic behavior of gold enlargement in the aqueous phase have been well investigated and explained for the selection of analytical parameters. To achieve high sensitivity, magnetic particles conjugated with capture probes (PMPs) were employed for the collection of gold nanoprobes. After denaturated by ion a pH 11 solution, the amplified signals of gold nanoprobes, which is proportional to the concentration of the target DNA, could easily be confirmed by a UV-vis scanning spectrophotometer. Limit of detection could be obtained as low as 1.0 fM by this simple method.

Endothelium-derived agents in pericyte function/dysfunction

The major components of blood vessels are the vascular endothelium and its supporting smooth muscle. Significant strides have been made in the understanding of the cellular and molecular biology of these two cell types and in particular their interactions have been the subject of much interest and debate over the past two decades. The vascular endothelium is now known to profoundly influence the synthetic and motor functions of the underlying smooth muscle and participate in the pathogenesis of all the major vascular disorders. Similarly, the vascular smooth muscle has important effects on the overlying endothelium, and any disruption in the cellular physiology of either cell type can result in dysfunction with important effects on blood flow and vascular permeability The majority of this accumulated knowledge relates to the vascular cells of the macrocirculation. Pericytes are the supporting cells of the microvasculature and a body of evidence is now available to show that similar regulatory mechanisms and vessel-wall cross-talk exists between these cells and the microvascular endothelium. Nowhere are these interactions more important than in the retinal microcirculation where autoregulation is vital for the maintenance of smooth and uninterrrupted blood flow. This review focuses on the interactions between retinal microvascular endothelial cells and their associated pericytes and examines the role of the endothelial cell and the pericyte in the pathogenesis of disease.

Retinal vascular geometry predicts incident renal dysfunction in young people with type 1 diabetes

OBJECTIVE - To examine the relationship between retinal vascular geometry parameters and development of incident renal dysfunction in young people with type 1 diabetes. RESEARCH DESIGN AND METHODS - This was a prospective cohort study of 511 adolescents with type 1 diabetes of at least 2 years duration, with normal albumin excretion rate (AER) and no retinopathy at baseline while attending an Australian tertiary-care hospital. AER was quantified using three overnight, timed urine specimen collections and early renal dysfunction was defined as AER >7.5 µg/min. Retinal vascular geometry (including length-to-diameter ratio [LDR] and simple tortuosity [ST]) was quantified from baseline retinal photographs. Generalized estimating equations were used to examine the relationship between incident renal dysfunction and baseline venular LDR and ST, adjusting for age, diabetes duration, glycated hemoglobin (A1C), blood pressure (BP), BMI, and cholesterol. RESULTS - Diabetes duration at baseline was 4.8 (IQR 3.3-7.5) years. After amedian 3.7 (2.3-5.7) years follow-up, 34% of participants developed incident renal dysfunction. In multivariate analysis, higher retinal venular LDR (odds ratio 1.7, 95% CI 1.2-2.4; quartile 4 vs. 1-3) and lower venular ST (1.6, 1.1-2.2; quartile 1 vs. 2-4) predicted incident renal dysfunction. CONCLUSIONS - Retinal venular geometry independently predicted incident renal dysfunction in young people with type 1 diabetes. These noninvasive retinal measures may help to elucidate early mechanistic pathways for microvascular complications. Retinal venular geometry may be a useful tool to identify individuals at high risk of renal disease early in the course of diabetes. © 2012 by the American Diabetes Association.

Drugs affecting the renin-angiotensin system and survival from cancer: a population based study of breast, colorectal and prostate cancer patient cohorts

Background: Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) are commonly prescribed to the growing number of cancer patients (more than two million in the UK alone) often to treat hypertension. However, increased fatal cancer in ARB users in a randomized trial and increased breast cancer recurrence rates in ACEI users in a recent observational study have raised concerns about their safety in cancer patients. We investigated whether ACEI or ARB use after breast, colorectal or prostate cancer diagnosis was associated with increased risk of cancer-specific mortality.

Methods: Population-based cohorts of 9,814 breast, 4,762 colorectal and 6,339 prostate cancer patients newly diagnosed from 1998 to 2006 were identified in the UK Clinical Practice Research Datalink and confirmed by cancer registry linkage. Cancer-specific and all-cause mortality were identified from Office of National Statistics mortality data in 2011 (allowing up to 13 years of follow-up). A nested case–control analysis was conducted to compare ACEI/ARB use (from general practitioner prescription records) in cancer patients dying from cancer with up to five controls (not dying from cancer). Conditional logistic regression estimated the risk of cancer-specific, and all-cause, death in ACEI/ARB users compared with non-users.

Results: The main analysis included 1,435 breast, 1,511 colorectal and 1,184 prostate cancer-specific deaths (and 7,106 breast, 7,291 colorectal and 5,849 prostate cancer controls). There was no increase in cancer-specific mortality in patients using ARBs after diagnosis of breast (adjusted odds ratio (OR) = 1.06 95% confidence interval (CI) 0.84, 1.35), colorectal (adjusted OR = 0.82 95% CI 0.64, 1.07) or prostate cancer (adjusted OR = 0.79 95% CI 0.61, 1.03). There was also no evidence of increases in cancer-specific mortality with ACEI use for breast (adjusted OR = 1.06 95% CI 0.89, 1.27), colorectal (adjusted OR = 0.78 95% CI 0.66, 0.92) or prostate cancer (adjusted OR = 0.78 95% CI 0.66, 0.92).

Conclusions: Overall, we found no evidence of increased risks of cancer-specific mortality in breast, colorectal or prostate cancer patients who used ACEI or ARBs after diagnosis. These results provide some reassurance that these medications are safe in patients diagnosed with these cancers.

Keywords: Colorectal cancer; Breast cancer; Prostate cancer; Mortality; Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers