Gastrointestinal perforation in metastatic colorectal cancer patients with peritoneal metastases receiving bevacizumab

Published online: May 7, 2015Aim: To investigate the safety and efficacy of adding bevacizumab to first-line chemotherapy in metastatic colorectal cancer patients with peritoneal disease. Methods: We compared rates of gastrointestinal perforation in patients with metastatic colorectal cancer and peritoneal disease receiving first-line chemotherapy with and without bevacizumab in three distinct cohorts: (1) the AGITG MAX trial (Phase III randomised clinical trial comparing capecitabine vs capecitabine and bevacizumab vs capecitabine, bevacizumab and mitomycinC); (2) the prospective Treatment of Recurrent and Advanced Colorectal Cancer (TRACC) registry (any first-line regimen ± bevacizumab); and (3) two cancer centres in New South Wales, Australia [Macarthur Cancer Therapy Centre and Liverpool Cancer Therapy Centre (NSWCC) from January 2005 to Decenber 2012, (any first-line regimen ± bevacizumab). For the AGITG MAX trial capecitabine was compared to the other two arms (capecitabine/bevacizumab and capecitabine/bevacizumab/mitomycinC). In the AGITG MAX trial and the TRACC registry rates of gastrointestinal perforation were also collected in patients who did not have peritoneal metastases. Secondary endpoints included progression-free survival, chemotherapy duration, and overall survival. Time-to-event outcomes were estimated using the Kaplan-Meier method and compared using the log-rank test. Results: Eighty-four MAX, 179 TRACC and 69 NSWCC patients had peritoneal disease. There were no gastrointestinal perforations recorded in either the MAX subgroup or the NSWCC cohorts. Of the patients without peritoneal disease in the MAX trial, 4/300 (1.3%) in the bevacizumab arms had gastrointestinal perforations compared to 1/123 (0.8%) in the capecitabine alone arm. In the TRACC registry 3/126 (2.4%) patients who had received bevacizumab had a gastrointestinal perforation compared to 1/53 (1.9%) in the chemotherapy alone arm. In a further analysis of patients without peritoneal metastases in the TRACC registry, the rate of gastrointestinal perforations was 9/369 (2.4%) in the chemotherapy/bevacizumab group and 5/177 (2.8%) in the chemotherapy alone group. The addition of bevacizumab to chemotherapy was associated with improved progression-free survival in all three cohorts: MAX 6.9 m vs 4.9 m, HR = 0.64 (95%CI: 0.42-1.02); P = 0.063; TRACC 9.1 m vs 5.5 m, HR = 0.61 (95%CI: 0.37-0.86); P = 0.009; NSWCC 8.7 m vs 6.8 m, HR = 0.75 (95%CI: 0.43-1.32); P = 0.32. Chemotherapy duration was similar across the groups. Conclusion: Patients with peritoneal disease do not appear to have an increased risk of gastrointestinal perforations when receiving first-line therapy with bevacizumab compared to systemic therapy alone.Aflah Roohullah, Hui-Li Wong, Katrin M Sjoquist, Peter Gibbs, Kathryn Field, Ben Tran, Jeremy Shapiro, Joe Mckendrick, Desmond Yip, Louise Nott, Val Gebski, Weng Ng, Wei Chua, Timothy Price, Niall Tebbutt, Lorraine Chantril

Computerised interpretation of fetal heart rate during labour (INFANT) : a randomised controlled trial

Background: Continuous electronic fetal heart-rate monitoring is widely used during labour, and computerised interpretation could increase its usefulness. We aimed to establish whether the addition of decision-support software to assist in the interpretation of cardiotocographs affected the number of poor neonatal outcomes. Methods: In this unmasked randomised controlled trial, we recruited women in labour aged 16 years or older having continuous electronic fetal monitoring, with a singleton or twin pregnancy, and at 35 weeks' gestation or more at 24 maternity units in the UK and Ireland. They were randomly assigned (1:1) to decision support with the INFANT system or no decision support via a computer-generated stratified block randomisation schedule. The primary outcomes were poor neonatal outcome (intrapartum stillbirth or early neonatal death excluding lethal congenital anomalies, or neonatal encephalopathy, admission to the neonatal unit within 24 h for >= 48 h with evidence of feeding difficulties, respiratory illness, or encephalopathy with evidence of compromise at birth), and developmental assessment at age 2 years in a subset of surviving children. Analyses were done by intention to treat. This trial is completed and is registered with the ISRCTN Registry, number 98680152. Findings: Between Jan 6, 2010, and Aug 31, 2013, 47 062 women were randomly assigned (23 515 in the decision-support group and 23 547 in the no-decision-support group) and 46 042 were analysed (22 987 in the decision-support group and 23 055 in the no-decision-support group). We noted no difference in the incidence of poor neonatal outcome between the groups-172 (0.7%) babies in the decision-support group compared with 171 (0.7%) babies in the no-decision-support group (adjusted risk ratio 1.01, 95% CI 0.82-1.25). At 2 years, no significant differences were noted in terms of developmental assessment. Interpretation: Use of computerised interpretation of cardiotocographs in women who have continuous electronic fetal monitoring in labour does not improve clinical outcomes for mothers or babies

Driving fiber diameters to the limit: nanoparticle-induced diameter reductions in electrospun photoactive composite nanofibers for organic photovoltaics

Electrospun photoactive nanofibers hold significant potential for enhanced photon absorption and charge transport in organic photovoltaics. However, electrospinning conjugated polymers with fiber diameters comparable to exciton diffusion lengths for efficient dissociation, is difficult. Previously, spinning sub-100 nm poly(3-hexylthiophene) (P3HT) fibers has required the auxiliary polymer, poly(ethylene oxide) (PEO), and large antisolvent additions. Therefore, its success differs considerably across donor polymers, due to variable antisolvent addition limits before precipitation. Herein, plasmonic nanoparticle infusion into P3HT nanofibers is used to modulate viscosity and deliver a novel and unrivaled strategy to achieve reduced fiber diameters. Following PEO removal, the fibers measure 55 nm in diameter, 30% lower than any previous report – providing the shortest exciton diffusion pathways to the heterojunction upon electron acceptor infiltration. The nanoparticle-containing nanofibers present a 58% enhancement over their pristine thin-film counterparts. ~17% is ascribed to plasmonic effects, demonstrated in thin-films, and the remainder to along-fiber polymer chain alignment, introduced by electrospinning. The anisotropy of light absorbed when polarized parallel versus perpendicular to the fibers increases from 0.88 to 0.62, suggesting the diameter reduction improves the alignment, resulting in greater electrospinning-induced enhancements. Controlled by the electrospinning behavior of PEO, our platform may be adapted to contemporary donor-acceptor systems

Severe combined hyperlipidaemia and retinal lipid infiltration in a patient with Type 2 diabetes mellitus

Severe combined hyperlipidaemia has occasionally been associated with infiltration of tissues in addition to arteries and the skin. We report a woman with Type 2 diabetes mellitus (DM) and severe combined hyperlipidaemia who developed retinal lipid infiltration, resulting in blindness. A 61-year-old woman with a 15-year history of Type 2 DM was admitted following a two-week history of progressive visual loss. Examination identified lipid infiltration into the retina. Phenotypically she had severe combined hyperlipidaemia with elevated IDL cholesterol and a broad beta band on lipoprotein electrophoresis, raising the possibility of familial dysbetalipoproteinaemia. However, gene sequencing analysis indicated that the patient was homozygous for the E3/E3 allele of the ApoE gene with no mutations detected in either the coding region or intron-exon boundaries. Her lipid profile improved following dietary therapy and gemfibrozil treatment, but this had little effect on either her fundal appearances or her visual acuity. Type 2 DM plays a vital role both in allowing expression of severe combined hyperlipoproteinaemia, in addition to serving as a risk factor for complications such as tissue infiltration

The effect of different dosing regimens of motesanib on the gallbladder: a randomized phase 1b study in patients with advanced solid tumors

Extent: 11 p.BACKGROUND: Gallbladder toxicity, including cholecystitis, has been reported with motesanib, an orally administered small-molecule antagonist of VEGFRs 1, 2 and 3; PDGFR; and Kit. We assessed effects of motesanib on gallbladder size and function. METHODS: Patients with advanced metastatic solid tumors ineligible for or progressing on standard-of-care therapies with no history of cholecystitis or biliary disease were randomized 2:1:1 to receive motesanib 125 mg once daily (Arm A); 75 mg twice daily (BID), 14-days-on/7-days-off (Arm B); or 75 mg BID, 5-days-on/2-days-off (Arm C). Primary endpoints were mean change from baseline in gallbladder size (volume by ultrasound; independent review) and function (ejection fraction by CCK-HIDA; investigator assessment). RESULTS: Forty-nine patients received ≥1 dose of motesanib (Arms A/B/C, n = 25/12/12). Across all patients, gallbladder volume increased by a mean 22.2 cc (from 38.6 cc at baseline) and ejection fraction decreased by a mean 19.2% (from 61.3% at baseline) during treatment. Changes were similar across arms and appeared reversible after treatment discontinuation. Three patients had cholecystitis (grades 1, 2, 3, n = 1 each) that resolved after treatment discontinuation, one patient developed grade 3 acute cholecystitis requiring cholecystectomy, and two patients had other notable grade 1 gallbladder disorders (gallbladder wall thickening, gallbladder dysfunction) (all in Arm A). Two patients developed de novo gallstones during treatment. Twelve patients had right upper quadrant pain (Arms A/B/C, n = 8/1/3). The incidence of biliary “sludge” in Arms A/B/C was 39%/36%/27%. CONCLUSION: Motesanib treatment was associated with increased gallbladder volume, decreased ejection fraction, biliary sludge, gallstone formation, and infrequent cholecystitis. Trial registration: ClinicalTrials.gov NCT00448786Lee S. Rosen, Lara Lipton, Timothy J. Price, Neil D. Belman, Ralph V. Boccia, Herbert I. Hurwitz, Joe J. Stephenson Jr., Lori J. Wirth, Sheryl McCoy, Yong-jiang Hei, Cheng-Pang Hsu and Niall C. Tebbut

Dibutyl phthalate exposure alters T-cell subsets in blood from allergen-sensitized volunteers

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Feasibility and design of a trial regarding the optimal mode of delivery for preterm birth: the CASSAVA multiple methods study

BACKGROUND: Around 60,000 babies are born preterm (prior to 37 weeks' gestation) each year in the UK. There is little evidence on the optimal birth mode (vaginal or caesarean section). OBJECTIVE: The overall aim of the CASSAVA project was to determine if a trial to define the optimal mode of preterm birth could be carried out and, if so, determine what sort of trial could be conducted and how it could best be performed. We aimed to determine the specific groups of preterm women and babies for whom there are uncertainties about the best planned mode of birth, and if there would be willingness to recruit to, and participate in, a randomised trial to address some, but not all, of these uncertainties. This project was conducted in response to a Heath Technology Assessment programme commissioning call (17/22 'Mode of delivery for preterm infants'). METHODS: We conducted clinician and patient surveys (n = 224 and n = 379, respectively) to identify current practice and opinion, and a consensus survey and Delphi workshop (n = 76 and n = 22 participants, respectively) to inform the design of a hypothetical clinical trial. The protocol for this clinical trial/vignette was used in telephone interviews with clinicians (n = 24) and in focus groups with potential participants (n = 13). RESULTS: Planned sample size and data saturation was achieved for all groups except for focus groups with participants, as this had to be curtailed because of the COVID-19 pandemic and data saturation was not achieved. There was broad agreement from parents and health-care professionals that a trial is needed. The clinician survey demonstrated a variety of practice and opinion. The parent survey suggested that women and their families generally preferred vaginal birth at later gestations and caesarean section for preterm infants. The interactive workshop and Delphi consensus process confirmed the need for more evidence (hence the case for a trial) and provided rich information on what a future trial should entail. It was agreed that any trial should address the areas with most uncertainty, including the management of women at 26-32 weeks' gestation, with either spontaneous preterm labour (cephalic presentation) or where preterm birth was medically indicated. Clear themes around the challenges inherent in conducting any trial emerged, including the concept of equipoise itself. Specific issues were as follows: different clinicians and participants would be in equipoise for each clinical scenario, effective conduct of the trial would require appropriate resources and expertise within the hospital conducting the trial, potential participants would welcome information on the trial well before the onset of labour and minority ethnic groups would require tailored approaches. CONCLUSION: Given the lack of evidence and the variation of practice and opinion in this area, and having listened to clinicians and potential participants, we conclude that a trial should be conducted and the outlined challenges resolved. FUTURE WORK: The CASSAVA project could be used to inform the design of a randomised trial and indicates how such a trial could be carried out. Any future trial would benefit from a pilot with qualitative input and a study within a trial to inform optimal recruitment. LIMITATIONS: Certainty that a trial could be conducted can be determined only when it is attempted. TRIAL REGISTRATION: Current Controlled Trials ISRCTN12295730. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 61. See the NIHR Journals Library website for further project information