Introduction
The International Society of Paediatric Oncology (SIOP) protocols recommend preoperative chemotherapy appropriate for Wilms tumors (WTs) in children with renal tumors aged ≥6 months, ...reserving biopsy for “atypical” cases. The Children's Cancer and Leukaemia Group (CCLG) joined the SIOP‐WT‐2001 study but continued the national practice of biopsy at presentation.
Method
Retrospective study of concordance between locally reported renal tumor biopsies and central pathology review nephrectomy diagnoses of children enrolled by CCLG centers in the SIOP‐WT‐2001 study.
Results
Biopsy reports were available for 552/787 children with unilateral tumors. 36 of 552 (6.5%) were nondiagnostic: 2 normal tissue, 12 necrotic, 9 insufficient sample, and 13 indeterminate results (disproportionately non‐WTs). The sensitivity and specificity of biopsy to identify tumors that did not require SIOP empirical preoperative chemotherapy were 86.0% and 99.6%, respectively. 13 of 548 (2.4%) biopsy results were discordant with nephrectomy; non‐WTs other than renal cell carcinoma and clear cell sarcoma of the kidney (CCSK) were poorly recognized. In children aged 6‐119 months, 480 of 518 (91.6%) had WT or nephroblastomatosis. 5 of 518 (1%) had benign tumors, and only one diagnosed on biopsy. Biopsy results correctly changed clinical management in 25 of 518 (4.8%), including identifying 19 of 20 CCSKs, but would have led to overtreatment in 5 of 518 (1%) or undertreatment in 4 of 518 (0.8%). In children aged ≥10 years, biopsy correctly changed management in 5 of 19 (26%) cases with no discordance.
Conclusion
Biopsy is less effective at identifying non‐WTs than WTs and rarely changes management in younger children. Biopsy should be reserved in SIOP protocols for children ≥10 years and in younger children with clinical or radiological features inconsistent with WT.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The presence of diffuse anaplasia in Wilms tumours (DAWT) is associated with TP53 mutations and poor outcome. As patients receive intensified treatment, we sought to identify whether TP53 mutational ...status confers additional prognostic information.
We studied 40 patients with DAWT with anaplasia in the tissue from which DNA was extracted and analysed for TP53 mutations and 17p loss. The majority of cases were profiled by copy number (n = 32) and gene expression (n = 36) arrays. TP53 mutational status was correlated with patient event-free and overall survival, genomic copy number instability and gene expression profiling.
From the 40 cases, 22 (55%) had TP53 mutations (2 detected only after deep-sequencing), 20 of which also had 17p loss (91%); 18 (45%) cases had no detectable mutation but three had 17p loss. Tumours with TP53 mutations and/or 17p loss (n = 25) had an increased risk of recurrence as a first event (p = 0.03, hazard ratio (HR), 3.89; 95% confidence interval (CI), 1.26-16.0) and death (p = 0.04, HR, 4.95; 95% CI, 1.36-31.7) compared to tumours lacking TP53 abnormalities. DAWT carrying TP53 mutations showed increased copy number alterations compared to those with wild-type, suggesting a more unstable genome (p = 0.03). These tumours showed deregulation of genes associated with cell cycle and DNA repair biological processes.
This study provides evidence that TP53 mutational analysis improves risk stratification in DAWT. This requires validation in an independent cohort before clinical use as a biomarker.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Quantitative descriptions of stream network and river catchment characteristics provide valuable context for enabling geomorphologically-informed sustainable river management. For countries where ...high-quality topographic data are available, there are opportunities to enable open access availability of baseline products from systematic assessment of morphometric and topographic characteristics. In this study, we present a national-scale assessment of fundamental topographic characteristics of Philippine river systems. We applied a consistent workflow using TopoToolbox V2 to delineate stream networks and river catchments using a nationwide digital elevation model (DEM) acquired in 2013 and generated through airborne Interferometric Synthetic Aperture Radar (IfSAR). We assessed morphometric and topographic characteristics for 128 medium- to large-sized catchments (catchment area > 250 km2) and organised the results in a national-scale geodatabase. The dataset realises the potential of topographic data as part of river management applications, by enabling variations in hydromorphology to be characterised and contextualised. The dataset is used to reveal the diversity of stream networks and river catchments in the Philippines. Catchments have a continuum of shapes (Gravelius compactness coefficient ranges from 1.05 to 3.29) with drainage densities that range from 0.65 to 1.23 km/km2. Average catchment slope ranges from 3.1 to 28.1° and average stream slope varies by more than an order of magnitude from 0.004 to 0.107 m/m. Inter-catchment analyses show the distinctive topographic signatures of adjacent river catchments; examples from NW Luzon highlight topographic similarity between catchments whereas examples from Panay Island shown marked topographic differences. These contrasts underline the importance of using place-based analyses for sustainable river management applications. By designing an interactive ArcGIS web-application to display the national-scale geodatabase, we improve data accessibility and enable users to freely access, explore and download the data (https://glasgow-uni.maps.arcgis.com/apps/webappviewer/index.html?id=a88b9ca0919f4400881eab4a26370cee). The national-scale geodatabase provides a baseline understanding of fundamental topographic characteristics in support of varied geomorphological, hydrological and geohazard susceptibility applications.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Li-Fraumeni syndrome is caused by germline TP53 mutations and is clinically characterized by a predisposition to a range of cancers, most commonly sarcoma, brain tumours and leukemia. Pathogenic ...mosaic TP53 mutations have only rarely been described.
We describe a 2 years old child presenting with three separate cancers over a 6 month period; two soft tissue mesenchymal tumors and an aggressive metastatic neuroblastoma. As conventional testing of blood DNA by Sanger sequencing for mutations in TP53, ALK, and SDH was negative, whole exome sequencing of the blood DNA of the patient and both parents was performed to screen more widely for cancer predisposing mutations. In the patient's but not the parents' DNA we found a c.743 G>A, p.Arg248Gln (CCDS11118.1) TP53 mutation in 3-20% of sequencing reads, a level that would not generally be detectable by Sanger sequencing. Homozygosity for this mutation was detected in all tumor samples analyzed, and germline mosaicism was demonstrated by analysis of the child's newborn blood spot DNA. The occurrence of separate tumors derived from different germ layers suggests that this de novo mutation occurred early in embryogenesis, prior to gastrulation.
The case demonstrates pathogenic mosaicim, detected by next generation deep sequencing, that arose in the early stages of embryogenesis.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Mitigation of myocardial fibrosis by molecular cardiac surgery–mediated gene overexpression Katz, Michael G., MD, PhD; Brandon-Warner, Elizabeth, PhD; Fargnoli, Anthony S., PhD ...
Journal of thoracic and cardiovascular surgery/The Journal of thoracic and cardiovascular surgery/The journal of thoracic and cardiovascular surgery,
04/2016, Volume:
151, Issue:
4
Journal Article
Peer reviewed
Open access
Abstract Objective Heart failure is accompanied by up-regulation of transforming growth factor beta signaling, accumulation of collagen and dysregulation of sarcoplasmic reticulum calcium adenosine ...triphosphatase cardiac isoform 2a (SERCA2a). We examined the fibrotic response in small and large myocardial infarct, and the effect of overexpression of the SERCA2a gene. Methods Ischemic cardiomyopathy was induced via creation of large or small infarct in 26 sheep. Animals were divided into 4 groups: small infarct; large infarct with heart failure; gene-treated (large infarct with heart failure followed by adeno-associated viral vector, serotype 1.SERCA2a gene construct transfer by molecular cardiac surgery with recirculating delivery); and control. Results Heart failure was significantly less pronounced in the gene-treated and small-infarct groups than in the large-infarct group. Expression of transforming growth factor beta signaling components was significantly higher in the large-infarct group, compared with the small-infarct and gene-treated groups. Both the angiotensin II type 1 receptor and angiotensin II were significantly elevated in the small- and large-infarct groups, whereas gene treatment diminished this effect. Active fibrosis with de novo collagen synthesis was evident in the large-infarct group; the small-infarct and gene-treated groups showed less fibrosis, with a lower ratio of de novo to mature collagen. Conclusions The data presented provide evidence that progression of fibrosis is mediated through increased transforming growth factor beta and angiotensin II signaling, which is mitigated by increased SERCA2a gene expression.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Single-agent management of diabetes and ischemia reperfusion injury Williams, Richard D., BS; Denlinger, Chadrick E., MD
Journal of thoracic and cardiovascular surgery/The Journal of thoracic and cardiovascular surgery/The journal of thoracic and cardiovascular surgery,
03/2017, Volume:
153, Issue:
3
Journal Article
Peer reviewed
Open access
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Purpose: We performed a phase I clinical trial of adenovirus/prostate-specific antigen (PSA) vaccine in men with measurable metastatic
hormone-refractory disease.
Experimental Design: Men with ...measurable metastatic disease received one vaccine injection. Toxicity, immune responses, changes in PSA doubling
times, and patient survival were assessed. Thirty-two patients with hormone-refractory metastatic prostate cancer were treated
with a single s.c. vaccine injection at one of three dose levels, either as an aqueous solution or suspended in a Gelfoam
matrix. All patients returned for physical and clinical chemistry examinations at regular intervals up to 12 months after
injections.
Results: The vaccine was deemed safe at all doses in both administration forms. There were no serious vaccine-related adverse events;
the most prevalent were localized erythema/ecchymoses and cold/flu-like symptoms. Anti-PSA antibodies were produced by 34%
of patients and anti-PSA T-cell responses were produced by 68%. PSA doubling time was increased in 48%, whereas 55% survived
longer than predicted by the Halabi nomogram.
Conclusions: The adenovirus/PSA vaccine was proven safe with no serious vaccine-related adverse events. The majority of vaccinated patients
produced anti-PSA T-cell responses and over half survived longer than predicted by nomogram. Although the latter data are
only derived from a small number of patients in this phase I trial, they are encouraging enough to pursue further studies.
(Clin Cancer Res 2009;15(23):7375–80)
BACKGROUND: Diffuse anaplastic Wilms tumor (DAWT) is a rare, high-risk subtype that is often missed on diagnostic needle biopsy. Somatic mutations in TP53 are associated with the development of ...anaplasia and with poorer survival, particularly in advanced-stage disease. Early identification of DAWT harboring TP53 abnormalities could improve risk stratification of initial therapy and monitoring for recurrence. METHODS: Droplet digital polymerase chain reaction (ddPCR) was used to evaluate 21 samples from 4 patients with DAWT. For each patient, we assessed TP53 status in frozen tumor, matched germline DNA, and circulating tumor DNA (ctDNA) from plasma, serum, and urine collected throughout treatment. RESULTS: Mutant TP53 was detectable in ctDNA from plasma and serum in all patients. We did not detect variant TP53 in the same volume (200 μl) of urine. One patient displayed heterogeneity of TP53 in the tumor despite both histological sections displaying anaplasia. Concentration of ctDNA from plasma/serum taken prenephrectomy varied significantly between patients, ranging from 0.44 (0.05-0.90) to 125.25 (109.75-140.25) copies/μl. We observed variation in ctDNA throughout treatment, and in all but one patient, ctDNA levels fell significantly following nephrectomy. CONCLUSION: We demonstrate for the first time that ddPCR is an effective method for detection of mutant TP53 in ctDNA from children with DAWT even when there is intratumoral somatic heterogeneity. This should be further explored in a larger cohort of patients, as early detection of circulating variant TP53 may have significant clinical impact on future risk stratification and surveillance.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The evolution of pediatric solid tumors is poorly understood. There is conflicting evidence of intra-tumor genetic homogeneity vs. heterogeneity (ITGH) in a small number of studies in pediatric solid ...tumors. A number of copy number aberrations (CNA) are proposed as prognostic biomarkers to stratify patients, for example 1q+ in Wilms tumor (WT); current clinical trials use only one sample per tumor to profile this genetic biomarker. We multisampled 20 WT cases and assessed genome-wide allele-specific CNA and loss of heterozygosity, and inferred tumor evolution, using Illumina CytoSNP12v2.1 arrays, a custom analysis pipeline, and the MEDICC algorithm. We found remarkable diversity of ITGH and evolutionary trajectories in WT. 1q+ is heterogeneous in the majority of tumors with this change, with variable evolutionary timing. We estimate that at least three samples per tumor are needed to detect >95% of cases with 1q+. In contrast, somatic 11p15 LOH is uniformly an early event in WT development. We find evidence of two separate tumor origins in unilateral disease with divergent histology, and in bilateral WT. We also show subclonal changes related to differential response to chemotherapy. Rational trial design to include biomarkers in risk stratification requires tumor multisampling and reliable delineation of ITGH and tumor evolution.
•There is remarkable diversity of intratumor genetic heterogeneity and evolutionary trajectories.•Gain of 1q is frequently heterogeneous and shows variable evolutionary timing.•11p15 CNNLOH is consistently an early event in Wilms tumorigenesis.•Rational biomarker-based treatment stratification in Wilms tumors requires multisampling.We have shown that Wilms tumor (WT), the commonest pediatric kidney cancer, shows a range of evolutionary trajectories. We also found that gain of the long arm of chromosome 1 (1q+) may occur both early or late in the evolution of WT. 1q+ is associated with a poorer outcome and is proposed for use in choosing patients for more intensive treatment, but we show that in order to detect it reliably, future trials require testing for this biomarker in multiple samples per tumor.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background The sarcoplasmic reticulum calcium ATPase (SERCA2a) is an important molecular regulator of contractile dysfunction in heart failure. Gene transfer of SERCA2a mediated by molecular cardiac ...surgery with recirculating delivery (MCARD) is a novel and clinically translatable strategy. Methods Ischemic heart failure was induced by ligation of OM1 and OM2 in 14 sheep. Seven sheep underwent MCARD-mediated AAV1-SERCA2a delivery 4 weeks after myocardial infarction, and seven sheep served as untreated controls. Magnetic resonance imaging—based mechanoenergetic studies were performed at baseline, 3 weeks, and 12 weeks after infarction. Myocyte apoptosis was quantified by Tdt-mediated nick-end labeling assay. Myocyte cross-sectional area and caspase-8 and caspase-9 activity was measured with imaging software, specific fluorogenic peptides, and immunohistochemistry. Results MCARD-mediated AAV1-SERCA2a gene delivery resulted in robust cardiac-specific SERCA2a expression and stable improvements in global and regional contractility. There were significantly higher stroke volume index, left ventricular fractional thickening, and ejection fraction at 12 weeks in the MCARD group than in the control group (30 ± 3 vs 21 ± 2 mL/m2 ; 12% ± 5% vs 3% ± 3%; and 43 ± 4 vs 32 ± 4, respectively, all p < 0.05). Apoptotic myocytes were observed more frequently in the control group than in the MCARD-SERCA2a group (0.57.2 ± 0.16 AU vs 0.32.4 ± 0.08 AU, p < 0.05). MCARD-SERCA2a also resulted in decreased caspase-8 and caspase-9 expression and decreased myocyte area in the border zone of transgenic sheep compared with control sheep (14.6% ± 1.2% vs 2.9% ± 0.7%; 18.2% ± 1.9% vs 8.6% ± 1.4%; and 102.1 ± 3.8 μm2 vs 88.1 ± 3.6 μm2 , all p < 0.05). Conclusions MCARD-mediated SERCA2a delivery results in robust cardiac specific gene expression, improved contractility, and a decrease in both myocyte apoptosis and myocyte hypertrophy.
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