Summary Background Cisplatin and gemcitabine is the standard first-line chemotherapy regimen for patients with advanced biliary tract cancer; expression of VEGF and its receptors is associated with ...adverse outcomes. We aimed to assess the effect of the addition of cediranib (an oral inhibitor of VEGF receptor 1, 2, and 3) to cisplatin and gemcitabine on progression-free survival. Methods In this multicentre, placebo-controlled, randomised phase 2 study, we recruited patients aged 18 years or older with histologically confirmed or cytologically confirmed advanced biliary tract cancer from hepatobiliary oncology referral centres in the UK. Patients were eligible if they had an ECOG performance status of 0–1 and an estimated life expectancy of longer than 3 months. Patients were given first-line cisplatin and gemcitabine chemotherapy (25 mg/m2 cisplatin and 1000 mg/m2 gemcitabine on days 1 and 8 every 21 days, for up to eight cycles) with either 20 mg oral cediranib or placebo once a day until disease progression. We randomly assigned patients (1:1) with a minimisation algorithm, incorporating the stratification factors: extent of disease, primary disease site, previous treatment, ECOG performance status, and centre. The primary endpoint was progression-free survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov , number NCT00939848 , and was closed on Sept 30, 2014; results of the final analysis for the primary endpoint are presented. Findings Between April 5, 2011, and Sept 28, 2012, we enrolled 124 patients (62 in each group). With a median follow-up of 12·2 months (IQR 7·3–18·5), median progression-free survival was 8·0 months (95% CI 6·5–9·3) in the cediranib group and 7·4 months (5·7–8·5) in the placebo group (HR 0·93, 80% CI 0·74–1·19, 95% CI 0·65–1·35; p=0·72). Patients who received cediranib had more grade 3–4 toxic effects than did patients who received placebo: hypertension (23 37% vs 13 21%; p=0·05), diarrhoea (eight 13% vs two 3%; p=0·05); platelet count decreased (ten 16% vs four 6%; p=0·09), white blood cell decreased (15 24% vs seven 11%; p=0·06) and fatigue (16 24% vs seven 11%; p=0·04). Interpretation Cediranib did not improve the progression-free survival of patients with advanced biliary tract cancer in combination with cisplatin and gemcitabine, which remains the standard of care. Although patients in the cediranib group had more adverse events, we recorded no unexpected toxic effects. The role of VEGF inhibition in addition to chemotherapy for patients with advanced biliary tract cancer remains investigational. Funding Cancer Research UK and AstraZeneca Pharmaceuticals.
Summary Background Guidelines for anal cancer recommend assessment of response at 6–12 weeks after starting treatment. Using data from the ACT II trial, we determined the optimum timepoint to assess ...clinical tumour response after chemoradiotherapy. Methods The previously reported ACT II trial was a phase 3 randomised trial of patients of any age with newly diagnosed, histologically confirmed, squamous cell carcinoma of the anus without metastatic disease from 59 centres in the UK. We randomly assigned patients (by minimisation) to receive either intravenous mitomycin (one dose of 12 mg/m2 on day 1) or intravenous cisplatin (one dose of 60 mg/m2 on days 1 and 29), with intravenous fluorouracil (one dose of 1000 mg/m2 per day on days 1–4 and 29–32) and radiotherapy (50·4 Gy in 28 daily fractions); and also did a second randomisation after initial therapy to maintenance chemotherapy (fluorouracil and cisplatin) or no maintenance chemotherapy. The primary outcome was complete clinical response (the absence of primary and nodal tumour by clinical examination), in addition to overall survival and progression-free survival from time of randomisation. In this post-hoc analysis, we analysed complete clinical response at three timepoints: 11 weeks from the start of chemoradiotherapy (assessment 1), 18 weeks from the start of chemoradiotherapy (assessment 2), and 26 weeks from the start of chemoradiotherapy (assessment 3) as well as the overall and progression-free survival estimates of patients with complete clinical response or without complete clinical response at each assessment. We analysed both the overall trial population and a subgroup of patients who had attended each of the three assessments by modified intention-to-treat. This study is registered at controlled-trials.com , ISRCTN 26715889. Findings We enrolled 940 patients from June 4, 2001, until Dec 16, 2008. Complete clinical response was achieved in 492 (52%) of 940 patients at assessment 1 (11 weeks), 665 (71%) of patients at assessment 2 (18 weeks), and 730 (78%) of patients at assessment 3 (26 weeks). 691 patients attended all three assessments and in this subgroup, complete clinical response was reported in 441 (64%) patients at assessment 1, 556 (80%) at assessment 2, and 590 (85%) at assessments 3. 151 (72%) of the 209 patients who had not had a complete clinical response at assessment 1 had a complete clinical response by assessment 3. In the overall trial population of 940 patients, 5 year overall survival in patients who had a clinical response at assessments 1, 2, 3 was 83% (95% CI 79–86), 84% (81–87), and 87% (84–89), respectively and was 72% (66–78), 59% (49–67), and 46% (37–55) for patients who did not have a complete clinical response at assessments 1, 2, 3, respectively. In the subgroup of 691 patients, 5 year overall survival in patients who had a clinical response at assessment 1, 2, 3 was 85% (81–88), 86% (82–88), and 87% (84–90), respectively, and was 75% (68–80), 61% (50–70), and 48% (36–58) for patients who did not have a complete clinical response at assessment 1, 2, 3, respectively. Similarly, progression-free survival in both the overall trial population and the subgroup was longer in patients who had a complete clinical response, compared with patients who did not have a complete clinical response, at all three assessments. Interpretation Many patients who do not have a complete clinical response when assessed at 11 weeks after commencing chemoradiotherapy do in fact respond by 26 weeks, and the earlier assessment could lead to some patients having unnecessary surgery. Our data suggests that the optimum time for assessment of complete clinical response after chemoradiotherapy for patients with squamous cell carcinoma of the anus is 26 weeks from starting chemoradiotherapy. We suggest that guidelines should be revised to indicate that later assessment is acceptable. Funding Cancer Research UK.
Replication timing of the human genome Woodfine, Kathryn; Fiegler, Heike; Beare, David M. ...
Human molecular genetics,
01/2004, Letnik:
13, Številka:
2
Journal Article
Recenzirano
Odprti dostop
We have developed a directly quantitative method utilizing genomic clone DNA microarrays to assess the replication timing of sequences during the S phase of the cell cycle. The genomic resolution of ...the replication timing measurements is limited only by the genomic clone size and density. We demonstrate the power of this approach by constructing a genome-wide map of replication timing in human lymphoblastoid cells using an array with clones spaced at 1 Mb intervals and a high-resolution replication timing map of 22q with an array utilizing overlapping sequencing tile path clones. We show a positive correlation, both genome-wide and at a high resolution, between replication timing and a range of genome parameters including GC content, gene density and transcriptional activity.
Objective To explore the association between brain maturation, injury, and volumes at term-equivalent age with 2-year development in moderate and late preterm children. Study design Moderate and late ...preterm infants were recruited at birth and assessed at age 2 years using the Bayley Scales of Infant and Toddler Development, Third Edition. Brain magnetic resonance imaging (MRI) was performed at term-equivalent age and qualitatively assessed for brain maturation (myelination of the posterior limb of the internal capsule and gyral folding) and injury. Brain volumes were measured using advanced segmentation techniques. The associations between brain MRI measures with developmental outcomes were explored using linear regression analyses. Results A total of 197 children underwent MRI and assessed using the Bayley Scales of Infant and Toddler Development, Third Edition. Larger total brain tissue volumes were associated with higher cognitive and language scores (adjusted coefficients per 10% increase in brain size; 95% CI of 3.2 0.4, 5.6 and 5.6 2.4, 8.8, respectively). Similar relationships were documented for white matter volumes with cognitive and language scores, multiple cerebral structures with language scores, and cerebellar volumes with motor scores. Larger cerebellar volumes were independently associated with better language and motor scores, after adjustment for other perinatal factors. There was little evidence of relationships between myelination of the posterior limb of the internal capsule, gyral folding, or injury with 2-year development. Conclusions Larger total brain tissue, white matter, and cerebellar volumes at term-equivalent age are associated with better neurodevelopment in moderate and late preterm children. Brain volumes may be an important marker for neurodevelopmental deficits described in moderate and late preterm children.
DNA sequence variants in specific genes or regions of the human
genome are responsible for a variety of phenotypes such as disease risk or
variable drug response. These variants can be investigated
...directly, or through their non-random associations with neighbouring markers
(called linkage disequilibrium (LD)). Here we
report measurement of LD along the complete sequence of human chromosome 22.
Duplicate genotyping and analysis of 1,504 markers in Centre d'Etude du
Polymorphisme Humain (CEPH) reference families at a median spacing of
15 kilobases (kb) reveals a highly variable pattern of LD along the
chromosome, in which extensive regions of nearly complete LD up to
804 kb in length are interspersed with regions of little or no
detectable LD. The LD patterns are replicated in a panel of unrelated UK
Caucasians. There is a strong correlation between high LD and low recombination
frequency in the extant genetic map, suggesting that historical and
contemporary recombination rates are similar. This study demonstrates the
feasibility of developing genome-wide maps of LD.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Objective To evaluate the long-term cardiovascular effects of extremely preterm birth in a cohort of adolescents followed prospectively, who were largely free from intrauterine growth restriction. ...Study design Central blood pressures, aortic and cardiac dimensions, left ventricle (LV) function, pulse wave velocity, augmentation index, and microvascular reactive hyperemia were measured in 18-year-old subjects born extremely preterm at <28 weeks' gestation (n = 109) and term-born controls (n = 81). Results Compared with controls, preterm adolescents had higher systolic (124 ± 13 vs 118 ± 10 mm Hg, P = .002) and diastolic (72 ± 8 vs 67 ± 7 mm Hg, P < .001) blood pressures, but lower ascending aortic z-scores (0.13 ± 0.89 vs 0.42 ± 0.78, P = .02), LV diastolic (48.5 ± 4 vs 50.3 ± 4.5 mm, P = .007) and systolic (30.2 ± 3.5 vs 31.9 ± 4.0 mm, P = .003) diameters, and a reduced LV mass (130 ± 34 vs 145 ± 41 g, P = .01) and mass index (75 ± 14 vs 81 ± 16 g/m2 , P = .02). However, LV relative wall thickness, LV function, pulse wave velocity, augmentation index, and microvascular reactive hyperemia were similar. Within the ex-preterm group, there were no significant relationships between birthweight z-scores and any cardiovascular measures, once the latter were adjusted for current body size. Conclusions Extremely preterm birth had relatively minor cardiovascular effects in late-adolescence, with increased blood pressures, decreased LV, and aortic size, but preserved LV function, macrovascular properties, and microvascular function. In utero growth was not independently related to cardiovascular function within the ex-preterm cohort.
Objectives To determine if nephrolithiasis-associated atherosclerosis has pediatric origins and to consider possible association between kidney stones and atherosclerosis-related proteins. Study ...design We matched children aged 12-17 years with kidney stones and without kidney stones. Carotid artery intima-media thickness (cIMT) was measured by ultrasound. Participants' urine was investigated by enzyme-linked immunosorbent assay for the atherosclerosis-related proteins fibronectin 1, macrophage scavenger receptor 1, osteopontin, and vascular cell adhesion molecule 1 levels, and normalized to urine creatinine levels. Results Subjects with nephrolithiasis had higher cIMT in the right common carotid artery and overall mean measurement. Urine osteopontin and fibronectin 1 were significant predictors of cIMT. Conclusions We have provided initial preliminary evidence that nephrolithiasis-associated atherosclerosis has pediatric origins and performed studies that begin to identify potential reasons for the association of nephrolithiasis and vascular disease.
Toxoplasmosis may be transferred by organ transplantation. The most common clinical presentation is with multisystem disease, although isolated ocular toxoplasmosis has been described. Many centers ...have suggested that universal use of co‐trimoxazole prophylaxis obviates the need for specific Toxoplasma testing. We report a case of donor‐acquired ocular toxoplasmosis after liver transplantation despite co‐trimoxazole prophylaxis. The diagnosis was confirmed by Toxoplasma polymerase chain reaction assay in conjunction with seroconversion. The fact that the infection was donor acquired was confirmed by serological mismatch and the absence of sporozoite‐specific antigen antibody in the recipient.
Chromosome 6 is a metacentric chromosome that constitutes about 6% of the human genome. The finished sequence comprises 166,880,988 base pairs, representing the largest chromosome sequenced so far. ...The entire sequence has been subjected to high-quality manual annotation, resulting in the evidence-supported identification of 1,557 genes and 633 pseudogenes. Here we report that at least 96% of the protein-coding genes have been identified, as assessed by multi-species comparative sequence analysis, and provide evidence for the presence of further, otherwise unsupported exons/genes. Among these are genes directly implicated in cancer, schizophrenia, autoimmunity and many other diseases. Chromosome 6 harbours the largest transfer RNA gene cluster in the genome; we show that this cluster co-localizes with a region of high transcriptional activity. Within the essential immune loci of the major histocompatibility complex, we find HLA-B to be the most polymorphic gene on chromosome 6 and in the human genome.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
To describe the prevalence, incidence, and progression of retinopathy and to report associations with demographic, clinical, and biochemical variables in people with diabetes in Southern Malawi.
...Prospective cohort study.
Subjects were systematically sampled from 2 primary care diabetes clinics.
We performed the first prospective cohort study of diabetic retinopathy from Sub-Saharan Africa over 24 months. Visual acuity, glycemic control, blood pressure, human immunodeficiency virus (HIV) status, urine albumin-to-creatinine ratio, hemoglobin, and lipids were assessed. Retinopathy was graded at an accredited reading center using modified Wisconsin grading of 4-field mydriatic photographs.
Incidence of sight-threatening retinopathy and progression of retinopathy by 2 steps on the Liverpool Diabetic Eye Study Scale.
A total of 357 subjects were recruited to the 24-month cohort study. At baseline, 13.4% of subjects were HIV positive and 15.1% were anemic. The 2-year incidence of sight-threatening diabetic retinopathy (STDR) for subjects with level 10 (no retinopathy), level 20 (background), and level 30 (preproliferative) retinopathy at baseline was 2.7% (95% confidence interval CI, 0.1–5.3), 27.3% (95% CI, 16.4–38.2), and 25.0% (95% CI, 0–67.4), respectively. In a multivariate logistic analysis, 2-step progression of diabetic retinopathy was associated with glycosylated hemoglobin (odds ratio OR, 1.27; 95% CI, 1.12–1.45), baseline grade of retinopathy (OR, 1.39; 95% CI, 1.02–1.91), and HIV infection (OR, 0.16; 95% CI, 0.03–0.78). At 2 years, 17 subjects (5.8%) lost ≥15 letters.
Incidence of STDR was approximately 3 times that reported in recent European studies. The negative association of HIV infection with retinopathy progression is a new finding.
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