Long-term kidney function in children with Wilms tumour and constitutional WT1 pathogenic variant.

BACKGROUND: Wilms tumour (WT) survivors, especially patients with associated syndromes or genitourinary anomalies due to constitutional WT1 pathogenic variant, have increased risk of kidney failure. We describe the long-term kidney function in children with WT and WT1 pathogenic variant to inform the surgical strategy and oncological management of such complex children. METHODS: Retrospective analysis of patients with WT and constitutional WT1 pathogenic variant treated at a single centre between 1993 and 2016, reviewing genotype, phenotype, tumour histology, laterality, treatment, patient survival, and kidney outcome. RESULTS: We identified 25 patients (60% male, median age at diagnosis 14 months, range 4-74 months) with WT1 deletion (4), missense (2), nonsense (8), frameshift (7), or splice site (4) pathogenic variant. Thirteen (52%) had bilateral disease, 3 (12%) had WT-aniridia, 1 had incomplete Denys-Drash syndrome, 11 (44%) had genitourinary malformation, and 10 (40%) had no phenotypic anomalies. Patient survival was 100% and 3 patients were in remission after relapse at median follow-up of 9 years. Seven patients (28%) commenced chronic dialysis of which 3 were after bilateral nephrectomies. The overall kidney survival for this cohort as mean time to start of dialysis was 13.38 years (95% CI: 10.3-16.4), where 7 patients experienced kidney failure at a median of 5.6 years. All of these 7 patients were subsequently transplanted. In addition, 2 patients have stage III and stage IV chronic kidney disease and 12 patients have albuminuria and/or treatment with ACE inhibitors. Four patients (3 frameshift; 1 WT1 deletion) had normal blood pressure and kidney function without proteinuria at follow-up from 1.5 to 12 years. CONCLUSIONS: Despite the known high risk of kidney disease in patients with WT and constitutional WT1 pathogenic variant, nearly two-thirds of patients had sustained native kidney function, suggesting that nephron-sparing surgery (NSS) should be attempted when possible without compromising oncological risk. Larger international studies are needed for accurate assessment of WT1genotype-kidney function phenotype correlation.

The diagnostic accuracy and clinical utility of pediatric renal tumor biopsy: Report of the UK experience in the SIOP UK WT 2001 trial.

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.

Origin and Fate of Vanadium in the Hazeltine Creek Catchment following the 2014 Mount Polley Mine Tailings Spill in British Columbia, Canada.

Results from the analysis of aqueous and solid-phase V speciation within samples collected from the Hazeltine Creek catchment affected by the August 2014 Mount Polley mine tailings dam failure in British Columbia, Canada, are presented. Electron microprobe and X-ray absorption near-edge structure (XANES) analysis found that V is present as V3+ substituted into magnetite and V3+ and V4+ substituted into titanite, both of which occur in the spilled Mount Polley tailings. Secondary Fe oxyhydroxides forming in inflow waters and on creek beds have V K-edge XANES spectra exhibiting E1/2 positions and pre-edge features consistent with the presence of V5+ species, suggesting sorption of this species on these secondary phases. PHREEQC modeling suggests that the stream waters mostly contain V5+ and the inflow and pore waters contain a mixture of V3+ and V5+. These data, and stream, inflow, and pore water chemical data, suggest that dissolution of V(III)-bearing magnetite, V(III)- and V(IV)-bearing titanite, V(V)-bearing Fe(-Al-Si-Mn) oxhydroxides, and V-bearing Al(OH)3 and/or clay minerals may have occurred. In the circumneutral pH environment of Hazeltine Creek, elevated V concentrations are likely naturally attenuated by formation of V(V)-bearing secondary Fe oxyhydroxide, Al(OH)3, or clay mineral colloids, suggesting that the V is not bioavailable. A conceptual model describing the origin and fate of V in Hazeltine Creek that is applicable to other river systems is presented.

Nephrogenic rests in Wilms tumors treated with preoperative chemotherapy: The UK SIOP Wilms Tumor 2001 Trial experience.

BACKGROUND: Nephrogenic rests (NRs) are abnormally persistent foci of embryonal cells, thought to be the precursor lesion of Wilms tumors (WTs). To date, their presence has not been systematically examined in WTs treated with preoperative chemotherapy. METHODS: A systematic analysis of the data on NRs in WTs treated with preoperative chemotherapy obtained from the UK cohort of the International Society of Pediatric Oncology (SIOP) WT 2001 Trial. The study was based on central pathology review of full sets of slides from pathological specimens, with a median of 28 slides reviewed per case. RESULTS: NRs were identified in 40% of unilateral WTs, including 25% perilobar nephrogenic rest (PLNR), 9% intralobar nephrogenic rest (ILNR), 5% both PLNR and ILNR, and 1% nephroblastomatosis, and in 93% of cases with bilateral lesions. ILNRs were associated with stromal histology and a younger age at diagnosis and found frequently in patients with congenital anomalies associated with WT1 mutation. PLNRs were found frequently in patients with overgrowth syndromes. CONCLUSIONS: The prevalence of NRs in WTs after preoperative chemotherapy observed in SIOP UK WT 2001 Trial is similar to the previously published data on NRs not treated with preoperative chemotherapy. Their epidemiology supports at least two pathways to Wilms tumorigenesis.

Anti-inflammatory loaded poly-lactic glycolic acid nanoparticle formulations to enhance myocardial gene transfer: an in-vitro assessment of a drug/gene combination therapeutic approach for direct injection.

BACKGROUND: Cardiac gene therapy for heart disease is a major translational research area with potential, yet problems with safe and efficient gene transfer into cardiac muscle remain unresolved. Existing methodology to increase vector uptake include modifying the viral vector, non-viral particle encapsulation and or delivery with device systems. These advanced methods have made improvements, however fail to address the key problem of inflammation in the myocardium, which is known to reduce vector uptake and contribute to immunogenic adverse events. Here we propose an alternative method to co-deliver anti-inflammatory drugs in a controlled release polymer with gene product to improve therapeutic effects. METHODS: A robust, double emulsion production process was developed to encapsulate drugs into nanoparticles. Briefly in this proof of concept study, aspirin and prednisolone anti-inflammatory drugs were encapsulated in various poly-lactic glycolic acid polymer (PLGA) formulations. The resultant particle systems were characterized, co-delivered with GFP plasmid, and evaluated in harvested myocytes in culture for uptake. RESULTS: High quality nanoparticles were harvested from multiple production runs, with an average 64 ± 10 mg yield. Four distinct particle drug system combinations were characterized and evaluated in vitro: PLGA(50:50) Aspirin, PLGA(65:35) Prednisolone, PLGA(65:35) Aspirin and PLGA(50:50) Prednisolone Particles consisted of spherical shape with a narrow size distribution 265 ± 104 nm as found in scanning electron microscopy imaging. Prednisolone particles regardless of PLGA type were found on average ≈ 100 nm smaller than the aspirin types. All four groups demonstrated high zeta potential stability and re-constitution testing prior to in vitro. In vitro results demonstrated co uptake of GFP plasmid (green) and drug loaded particles (red) in culture with no incidence of toxicity. CONCLUSIONS: Nano formulated anti-inflammatories in combination with standalone gene product therapy may offer a clinical solution to maximize cardiac gene therapy product effects while minimizing the risk of the host response in the inflammatory myocardial environment.

Hallmark discoveries in the biology of Wilms tumour.

The modern study of Wilms tumour was prompted nearly 50 years ago, when Alfred Knudson proposed the 'two-hit' model of tumour development. Since then, the efforts of researchers worldwide have substantially expanded our knowledge of Wilms tumour biology, including major advances in genetics - from cloning the first Wilms tumour gene to high-throughput studies that have revealed the genetic landscape of this tumour. These discoveries improve understanding of the embryonal origin of Wilms tumour, familial occurrences and associated syndromic conditions. Many efforts have been made to find and clinically apply prognostic biomarkers to Wilms tumour, for which outcomes are generally favourable, but treatment of some affected individuals remains challenging. Challenges are also posed by the intratumoural heterogeneity of biomarkers. Furthermore, preclinical models of Wilms tumour, from cell lines to organoid cultures, have evolved. Despite these many achievements, much still remains to be discovered: further molecular understanding of relapse in Wilms tumour and of the multiple origins of bilateral Wilms tumour are two examples of areas under active investigation. International collaboration, especially when large tumour series are required to obtain robust data, will help to answer some of the remaining unresolved questions.

National-scale geodatabase of catchment characteristics in the Philippines for river management applications.

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.

Molecular profiling reveals frequent gain of MYCN and anaplasia-specific loss of 4q and 14q in Wilms tumor.

Anaplasia in Wilms tumor, a distinctive histology characterized by abnormal mitoses, is associated with poor patient outcome. While anaplastic tumors frequently harbour TP53 mutations, little is otherwise known about their molecular biology. We have used array comparative genomic hybridization (aCGH) and cDNA microarray expression profiling to compare anaplastic and favorable histology Wilms tumors to determine their common and differentiating features. In addition to changes on 17p, consistent with TP53 deletion, recurrent anaplasia-specific genomic loss and under-expression were noted in several other regions, most strikingly 4q and 14q. Further aberrations, including gain of 1q and loss of 16q were common to both histologies. Focal gain of MYCN, initially detected by high resolution aCGH profiling in 6/61 anaplastic samples, was confirmed in a significant proportion of both tumor types by a genomic quantitative PCR survey of over 400 tumors. Overall, these results are consistent with a model where anaplasia, rather than forming an entirely distinct molecular entity, arises from the general continuum of Wilms tumor by the acquisition of additional genomic changes at multiple loci.

National-scale assessment of decadal river migration at critical bridge infrastructure in the Philippines.

River migration represents a geomorphic hazard at sites of critical bridge infrastructure, particularly in rivers where migration rates are high, as in the tropics. In the Philippines, where exposure to flooding and geomorphic risk are considerable, the recent expansion of infrastructural developments warrants quantification of river migration in the vicinity of bridge assets. We analysed publicly available bridge inventory data from the Philippines Department of Public Works and Highways (DPWH) to complete multi-temporal geospatial analysis using three decades worth of Landsat satellite imagery in Google Earth Engine (GEE). For 74 large bridges, we calculated similarity coefficients and quantified changes in width for the active river channel (defined as the wetted channel and unvegetated alluvial deposits) over decadal and engineering (30-year) timescales. Monitoring revealed the diversity of river planform adjustment at bridges in the Philippines (including channel migration, contraction, expansion and avulsion). The mean Jaccard index over decadal (0.65) and engineering (0.50) timescales indicated considerable planform adjustment throughout the national-scale inventory. However, planform adjustment and morphological behaviour varied between bridges. For bridges with substantial planform adjustment, maximum active channel contraction and expansion was equal to 25% of the active channel width over decadal timescales. This magnitude of lateral adjustment is sufficient to imply the need for bridge design to accommodate channel dynamism. For other bridges, the planform remained stable and changes in channel width were limited. Fundamental differences in channel characteristics and morphological behaviours emerged between different valley confinement settings, and between rivers with different channel patterns, indicating the importance of the local geomorphic setting. We recommend satellite remote sensing as a low-cost approach to monitor river planform adjustment with large-scale planimetric changes detectable in Landsat products; these approaches can be applied to other critical infrastructure adjacent to rivers (e.g. road, rail, pipelines) and extended elsewhere to other dynamic riverine settings.

Giant renal angiomyolipoma without fat density on CT scan: case report and review of the literature.

Giant renal angiomyolipomas have been reported, but typically have the pathognomonic finding of fat density on CT scan. We present the case of a 53-year-old male with a symptomatic, 35-cm, predominantly cystic renal mass without fat density on CT that on nephrectomy was found to be a fat-poor angiomyolipoma with predominantly epithelioid morphology weighing 17.9 kg. Giant renal angiomyolipoma without macroscopic fat density on CT scan is an exceedingly rare occurrence.

Hepatocellular carcinoma masquerading as a large renal mass with hepatic invasion.

Large masses are evaluated with imaging to assess primary origin and tumor spread. We present the unusual case of a 53-year-old male with a 17-cm right upper quadrant mass suspected to be renal or adrenal in origin based on radiographic findings. After surgical excision, the mass was subsequently discovered to be primary hepatocellular carcinoma with direct extension to the kidney and adrenal gland. A diagnosis of chronic hepatitis B was made postoperatively. Primary hepatocellular carcinoma with direct renal extension is an exceedingly rare occurrence based on our experience and review of the published literature.

Pediatric Tenosynovial Giant Cell Tumor of the Flexor Hallucis Longus Tendon Sheath: A Case Report.

CASE: An otherwise healthy 13-year-old girl presented with a firm nodule on the plantar right forefoot that was tender after cheerleading. Initial workup was unremarkable, but magnetic resonance imaging revealed a multilobulated mass surrounding the flexor hallucis longus tendon. Surgical resection revealed a tenosynovial mass without tendon infiltration. Pathologic examination was consistent with tenosynovial giant cell tumor. The patient resumed cheerleading and remained asymptomatic after 1 year. CONCLUSION: As far as we know, this is the first report of a tenosynovial giant cell tumor of the flexor hallucis longus in a pediatric patient; it illustrates the importance of considering this lesion when diagnosing a pediatric plantar mass.

The significance of lymphovascular invasion in transurethral resection of bladder tumour and cystectomy specimens on the survival of patients with urothelial bladder cancer.

OBJECTIVE: To test the hypothesis that patients with bladder cancer who had evidence of lymphovascular invasion (LVI) in their transurethral resection of bladder tumour (TURBT) and radical cystectomy (RC) specimens would have a worse prognosis and higher likelihood of clinical understaging, and to assess the effect of LVI discovered at RC on subsequent disease-related mortality, as the prognostic significance of LVI in TURBT or RC specimens of patients treated for urothelial carcinoma of the bladder is not completely established. PATIENTS AND METHODS: We retrospectively reviewed the records of 163 patients with urothelial carcinoma of the bladder seen at our institution, and who had TURBT (69) or RC (94) between 1995 and 2005. We compared patients with LVI on TURBT and/or RC specimens to a group of controls who did not have LVI on TURBT (34) or RC (32). RESULTS: Patients with LVI present in their TURBT specimen had a shorter disease-specific survival than those without LVI, with a 5-year survival of 33.6% vs 62.9% (log-rank test P = 0.027; hazard ratio 2.21). LVI at TURBT varied with clinical stage (P = 0.049). Patients with LVI and who were clinical stage I or II had lower survival than those without LVI (P = 0.049; hazard ratio 2.68). LVI did not affect survival among those with clinical stage III or IV (P = 0.29). There was a trend for patients with LVI at TURBT to be clinically understaged compared to those without LVI (75% vs 46%) but the difference was not significant (P = 0.086). Patients with LVI detected in their RC specimen were significantly more likely to have cancer recurrence than were those with no evidence of LVI (48% vs 19%, P = 0.006). For the RC group there was also a significant difference in survival distribution between patients with evidence of LVI vs those without (5-year survival 45.5% vs 78.4%, P = 0.017). Those with LVI were significantly more likely to die from the disease than those without LVI (P = 0.017; hazard ratio 2.92). CONCLUSIONS: Our findings suggest that LVI is a histological feature that might be associated with a poorer prognosis in patients with urothelial carcinoma of the bladder. The presence of LVI in TURBT specimens predicts shorter survival for patients with stage I or II disease. The presence of LVI in RC specimens predicts recurrence of disease and shorter survival. Further studies are needed to determine whether this group of patients would benefit from early RC and/or perioperative chemotherapy to improve clinical outcomes.

Perilobar nephrogenic rests are nonobligate molecular genetic precursor lesions of insulin-like growth factor-II-associated Wilms tumors.

PURPOSE: Perilobar nephrogenic rests (PLNRs) are abnormally persistent foci of embryonal immature blastema that have been associated with dysregulation at the 11p15 locus by genetic/epigenetic means and are thought to be precursor lesions of Wilms tumor. The precise genomic events are, however, largely unknown. EXPERIMENTAL DESIGN: We used array comparative genomic hybridization to analyze a series of 50 PLNRs and 25 corresponding Wilms tumors characterized for 11p15 genetic/epigenetic alterations and insulin-like growth factor-II expression. RESULTS: The genomic profiles of PLNRs could be subdivided into three categories: those with no copy number changes (22 of 50, 44%); those with single, whole chromosome alterations (8 of 50, 16%); and those with multiple gains/losses (20 of 50, 40%). The most frequent aberrations included 1p- (7 of 50, 14%) +18 (6 of 50, 12%), +13 (5 of 50, 10%), and +12 (3 of 50, 6%). For the majority (19 of 25, 76%) of cases, the rest harbored a subset of the copy number changes in the associated Wilms tumor. We identified a temporal order of genomic changes, which occur during the insulin-like growth factor-II/PLNR pathway of Wilms tumorigenesis, with large-scale chromosomal alterations such as 1p-, +12, +13, and +18 regarded as "early" events. In some of the cases (24%), the PLNRs harbored large-scale copy number changes not observed in the concurrent Wilms tumor, including +10p, +14q, and +18. CONCLUSIONS: These data suggest that although the evidence for PLNRs as precursors is compelling, not all lesions must necessarily undergo malignant transformation.

Historical evolution of transurethral resection at the University of Iowa: Alcock and Flocks.

PURPOSE: In 1935 Nathaniel G. Alcock proclaimed that transurethral resection of the prostate "...cannot be taught and can be learned only by hard, tedious experience." However, his resident assistant, Rubin H. Flocks, added basic science and anatomical knowledge to Alcock's surgical experience to create a body of work that even today provides insight into the complexities of transurethral prostatic resection. MATERIALS AND METHODS: Even as Alcock studied preoperative and postoperative urethrography images to provide demonstration of the enlarged prostate, he firmly believed in the learning curve of surgical proficiency. However, when Alcock and Flocks began studying autopsy material they were able to pinpoint distribution of the prostatic blood supply, and demonstrate techniques to control bleeding and perform transurethral resection in an organized fashion. Autopsy specimens also demonstrated the previously unrecognized correlation between incomplete resection and complicated wound healing. Flocks' further work with surgical illustrations demonstrated an optimal technique. RESULTS: In his 1932 report to the American Urological Association Alcock detailed not only his surgical success, but also his mortality rate related to resection and prostatic obstruction and its complications. In autopsy specimens with barium sulfate injections into prostatic blood vessels Flocks demonstrated that complete resection of prostate adenoma was possible and produced the desired outcome with good wound healing. CONCLUSIONS: The strong collaboration between Alcock and Flocks, particularly during the 1940s, culminated in a movie presentation of the prostatic resection technique as viewed from inside the bladder antegrade toward the prostate that remains a model for surgical practice today.

Somatic TP53 Mutations Are Detectable in Circulating Tumor DNA from Children with Anaplastic Wilms Tumors.

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.

Accurate prediction of BRCA1 and BRCA2 heterozygous genotype using expression profiling after induced DNA damage.

PURPOSE: In this study, the differential gene expression changes following radiation-induced DNA damage in healthy cells from BRCA1/BRCA1 mutation carriers have been compared with controls using high-density microarray technology. We aimed to establish if BRCA1/BRCA2 mutation carriers could be distinguished from noncarriers based on expression profiling of normal cells. EXPERIMENTAL DESIGN: Short-term primary fibroblast cultures were established from skin biopsies from 10 BRCA1 and 10 BRCA2 mutation carriers and 10 controls, all of whom had previously had breast cancer. The cells were subjected to 15 Gy ionizing irradiation to induce DNA damage. RNA was extracted from all cell cultures, preirradiation and at 1 hour postirradiation. For expression profiling, 15 K spotted cDNA microarrays manufactured by the Cancer Research UK DNA Microarray Facility were used. Statistical feature selection was used with a support vector machine (SVM) classifier to determine the best feature set for predicting BRCA1 or BRCA2 heterozygous genotype. To investigate prediction accuracy, a nonprobabilistic classifier (SVM) and a probabilistic Gaussian process classifier were used. RESULTS: In the task of distinguishing BRCA1 and BRCA2 mutation carriers from noncarriers and from each other following radiation-induced DNA damage, the SVM achieved 90%, and the Gaussian process classifier achieved 100% accuracy. This effect could not be achieved without irradiation. In addition, the SVM identified a set of BRCA genotype predictor genes. CONCLUSIONS: We conclude that after irradiation-induced DNA damage, BRCA1 and BRCA2 mutation carrier cells have a distinctive expression phenotype, and this may have a future role in predicting genotypes, with application to clinical detection and classification of mutations.

Maximizing clinical information obtained by CT.

CT scanning is an integral part of the urologist's practice today. It is the most commonly used imaging modality and the one with which urologists are most familiar. CT urography, CT angiography, and 3D reconstruction enable the urologist to perform comprehensive evaluations of patients who have different urologic diseases, using a single imaging modality. It is thus prudent that urologists become familiar with CT applications, to maximize the clinical information available from them.

Meta-analysis and pooled re-analysis of copy number changes in colorectal cancer detected by comparative genomic hybridization.

BACKGROUND: Comparative genomic hybridization (CGH) provides an insight into chromosomal changes associated with colorectal cancer (CRC) development. However, a problem with many studies is the limited cohort size, making the significance of some findings unclear. MATERIALS AND METHODS: To derive a better insight into the chromosomal changes associated with CRC, we performed a meta-analysis and pooled re-analysis of published metaphase CGH data. RESULTS: In addition to recurrent alterations, gains of 20 13q, 8q and 7p and loss of 18, 17p, 8p and 4p, pooling identified less frequent, but significant changes, including gain of 1q and 3, and losses from 6q, 9p and 21q. CONCLUSION: These additional alterations may be characteristic of some tumors and thus have relevance to CRC biology. Meta-analysis not only has the potential to detect novel changes, present at low frequency in several independent studies, but can provide greater reliability for their detection than single studies alone.

Induction and regulation of tumor necrosis factor-related apoptosis-inducing ligand/Apo-2 ligand-mediated apoptosis in renal cell carcinoma.

The lack of effective therapy for disseminated renal cell carcinoma (RCC) has stimulated the search for novel treatments including immunotherapeutic strategies. However, poor therapeutic responses and marked toxicity associated with immunological agents has limited their use. The tumor necrosis factor family member tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/Apo-2 ligand induces apoptosis in a variety of tumor cell types, while having little cytotoxic activity against normal cells. In this study the activation and regulation of TRAIL-induced apoptosis and TRAIL receptor expression in human RCC cell lines and pathologic specimens was examined. TRAIL induced caspase-mediated apoptotic death of RCC cells with variable sensitivities among the cell lines tested. Compared with TRAIL-sensitive RCC cell lines (A-498, ACHN, and 769-P), the TRAIL-resistant RCC cell line (786-O) expressed lesser amounts of the death-inducing TRAIL receptors, and greater amounts of survivin, an inhibitor of apoptosis. Incubation of 786-O with actinomycin D increased the expression of the death-inducing TRAIL receptors and, concomitantly, decreased the intracellular levels of survivin, resulting in TRAIL-induced apoptotic death. The link between survivin and TRAIL regulation was confirmed when an increase in TRAIL resistance was observed after overexpression of survivin in the TRAIL-sensitive, survivin-negative RCC line A-498. These findings, along with our observation that TRAIL receptors are expressed in RCC tumor tissue, suggest that TRAIL may be useful as a therapeutic agent for RCC and that survivin may partially regulate TRAIL-induced cell death.