224 research outputs found
Chronic allograft nephropathy
Chronic allograft nephropathy (CAN) is the leading cause of renal allograft loss in paediatric renal transplant recipients. CAN is the result of immunological and nonimmunological injury, including acute rejection episodes, hypoperfusion, ischaemia reperfusion, calcineurin toxicity, infection and recurrent disease. The development of CAN is often insidious and may be preceded by subclinical rejection in a well-functioning allograft. Classification of CAN is histological using the Banff classification of renal allograft pathology with classic findings of interstitial fibrosis, tubular atrophy, glomerulosclerosis, fibrointimal hyperplasia and arteriolar hyalinosis. Although improvement in immunosuppression has led to greater 1-year graft survival rates, chronic graft loss remains relatively unchanged and opportunistic infectious complications remain a problem. Protocol biopsy monitoring is not current practice in paediatric transplantation for CAN monitoring but may have a place if new treatment options become available. Newer immunosuppression regimens, closer monitoring of the renal allograft and management of subclinical rejection may lead to reduced immune injury leading to CAN in the paediatric population but must be weighed against the risk of increased immunosuppression and calcineurin inhibitor nephrotoxicity
Dexamethasone and supportive care with or without whole brain radiotherapy in treating patients with non-small cell lung cancer with brain metastases unsuitable for resection or stereotactic radiotherapy (QUARTZ): results from a phase 3, non-inferiority, randomised trial
Background
Whole brain radiotherapy (WBRT) and dexamethasone are widely used to treat brain metastases from
non-small cell lung cancer (NSCLC), although there have been no randomised clinical trials showing that WBRT
improves either quality of life or overall survival. Even after treatment with WBRT, the prognosis of this patient group
is poor. We aimed to establish whether WBRT could be omitted without a signifi cant eff ect on survival or quality of life.
Methods
The Quality of Life after Treatment for Brain Metastases (QUARTZ) study is a non-inferiority, phase 3
randomised trial done at 69 UK and three Australian centres. NSCLC patients with brain metastases unsuitable for
surgical resection or stereotactic radiotherapy were randomly assigned (1:1) to optimal supportive care (OSC)
including dexamethasone plus WBRT (20 Gy in five daily fractions) or OSC alone (including dexamethasone). The
dose of dexamethasone was determined by the patients’ symptoms and titrated downwards if symptoms improved.
Allocation to treatment group was done by a phone call from the hospital to the Medical Research Council Clinical
Trials Unit at University College London using a minimisation programme with a random element and stratifi cation
by centre, Karnofsky Performance Status (KPS), gender, status of brain metastases, and the status of primary lung
cancer. The primary outcome measure was quality-adjusted life-years (QALYs). QALYs were generated from overall
survival and patients’ weekly completion of the EQ-5D questionnaire. Treatment with OSC alone was considered noninferior
if it was no more than 7 QALY days worse than treatment with WBRT plus OSC, which required 534 patients
(80% power, 5% [one-sided] signifi cance level). Analysis was done by intention to treat for all randomly assigned
patients. The trial is registered with ISRCTN, number ISRCTN3826061.
Findings
Between March 2, 2007, and Aug 29, 2014, 538 patients were recruited from 69 UK and three Australian
centres, and were randomly assigned to receive either OSC plus WBRT (269) or OSC alone (269). Baseline characteristics
were balanced between groups, and the median age of participants was 66 years (range 38–85). Signifi cantly more
episodes of drowsiness, hair loss, nausea, and dry or itchy scalp were reported while patients were receiving WBRT,
although there was no evidence of a difference in the rate of serious adverse events between the two groups. There was
no evidence of a diff erence in overall survival (hazard ratio 1·06, 95% CI 0·90–1·26), overall quality of life, or
dexamethasone use between the two groups. The diff erence between the mean QALYs was 4·7 days (46·4 QALY days
for the OSC plus WBRT group vs 41·7 QALY days for the OSC group), with two-sided 90% CI of –12·7 to 3·3.
Interpretation
Although the primary outcome measure result includes the prespecifi ed non-inferiority margin, the
combination of the small diff erence in QALYs and the absence of a diff erence in survival and quality of life between
the two groups suggests that WBRT provides little additional clinically signifi cant benefi t for this patient group
On Planetary Companions to the MACHO-98-BLG-35 Microlens Star
We present observations of microlensing event MACHO-98-BLG-35 which reached a
peak magnification factor of almost 80. These observations by the Microlensing
Planet Search (MPS) and the MOA Collaborations place strong constraints on the
possible planetary system of the lens star and show intriguing evidence for a
low mass planet with a mass fraction . A giant planet with is excluded from 95%
of the region between 0.4 and 2.5 from the lens star, where is the
Einstein ring radius of the lens. This exclusion region is more extensive than
the generic "lensing zone" which is . For smaller mass planets,
we can exclude 57% of the "lensing zone" for and 14% of
the lensing zone for . The mass fraction corresponds to an Earth mass planet for a lensing star of mass \sim
0.3 \msun. A number of similar events will provide statistically significant
constraints on the prevalence of Earth mass planets. In order to put our limits
in more familiar terms, we have compared our results to those expected for a
Solar System clone averaging over possible lens system distances and
orientations. We find that such a system is ruled out at the 90% confidence
level. A copy of the Solar System with Jupiter replaced by a second Saturn mass
planet can be ruled out at 70% confidence. Our low mass planetary signal (few
Earth masses to Neptune mass) is significant at the confidence
level. If this planetary interpretation is correct, the MACHO-98-BLG-35 lens
system constitutes the first detection of a low mass planet orbiting an
ordinary star without gas giant planets.Comment: ApJ, April 1, 2000; 27 pages including 8 color postscript figure
PATCH - Prostate adenocarcinoma: transcutaneous hormones. A randomised comparison evaluating cardiovascular morbidity and mortality of transdermal oestradiol versus luteinising hormone-releasing hormone agonists in advanced prostate cancer
Ultra-low DNA input into whole genome methylation assays and detection of oncogenic methylation and copy number variants in circulating tumour DNA
Background: Abnormal CpG methylation in cancer is ubiquitous and generally detected in tumour specimens using a variety of techniques at a resolution encompassing single CpG loci to genome wide coverage. Analysis of samples with very low DNA inputs, such as formalin fixed (FFPE) biopsy specimens from clinical trials or circulating tumour DNA is challenging at the genome-wide level because of lack of available input. We present the results of low input experiments into the Illumina Infinium HD methylation assay on FFPE specimens and ctDNA samples. Methods: For all experiments, the Infinium HD assay for methylation was used. In total, forty-eight FFPE specimens were used at varying concentrations (lowest input 50 ng); eighteen blood derived specimens (lowest input 10 ng) and six matched ctDNA input (lowest input 10 ng)/fresh tumour specimens (lowest input 250 ng) were processed. Downstream analysis was performed in R/Bioconductor for quality control metrics and differential methylation analysis as well as copy number calls. Results: Correlation coefficients for CpG methylation were high at the probe level averaged R2 = 0.99 for blood derived samples and R2 > 0.96 for the FFPE samples. When matched ctDNA/fresh tumour samples were compared, R2 > 0.91 between the two. Results of differential methylation analysis did not vary significantly by DNA input in either the blood or FFPE groups. There were differences seen in the ctDNA group as compared to their paired tumour sample, possibly because of enrichment for tumour material without contaminating normal. Copy number variants observed in the tumour were generally also seen in the paired ctDNA sample with good concordance via DQ plot. Conclusions: The Illumina Infinium HD methylation assay can robustly detect methylation across a range of sample types, including ctDNA, down to an input of 10 ng. It can also reliably detect oncogenic methylation changes and copy number variants in ctDNA. These findings demonstrate that these samples can now be accessed by methylation array technology, allowing analysis of these important sample types
Prevalence, Characteristics, and Prognostic Significance of HFE Gene Mutations in Type 2 Diabetes: The Fremantle Diabetes Study
OBJECTIVE—To examine the relationship between iron status, hereditary hemochromatosis (HFE) gene mutations, and clinical features and outcomes of type 2 diabetes in a well-characterized representative sample of community-based patients
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