Phase 2 trial of sunitinib and gemcitabine in patients with sarcomatoid and/or poor-risk metastatic renal cell carcinoma. Michaelson MD,McKay RR,Werner L,Atkins MB,Van Allen EM,Olivier KM,Song J,Signoretti S,McDermott DF,Choueiri TK.Cancer. 2015 Oct 1;121(19):3435-43. [Epub 2015 Jun 8]. doi: 10.1002/cncr.29503.

Background

Sarcomatoid renal cell carcinoma (RCC) is associated with an aggressive biology and a poor prognosis. Poor-risk RCC is defined by clinical prognostic factors and demonstrates similarly aggressive behavior. No standard treatment exists for patients with sarcomatoid RCC, and treatment options for patients with poor-risk disease are of limited benefit. The objective of this study was to investigate the efficacy of antiangiogenic therapy in combination with cytotoxic chemotherapy in clinically aggressive RCC.

Whole-Genome Linkage and Association Scan in Primary,Nonsyndromic Vesicoureteric Reflux

Primary vesicoureteric reflux accounts for approximately 10% of kidney failure requiring dialysis or transplantation, and sibling studies suggest a large genetic component. Here, we report a whole-genome linkage and association scan in primary, nonsyndromic vesicoureteric reflux and reflux nephropathy. We used linkage and family-based association approaches to analyze 320 white families (661 affected individuals, generally from families with two affected siblings) from two populations (United Kingdom and Slovenian). We found modest evidence of linkage but no clear overlap with previous studies. We tested for but did not detect association with six candidate genes (AGTR2, HNF1B, PAX2, RET, ROBO2, and UPK3A). Family-based analysis detected associations with one single-nucleotide polymorphism (SNP) in the UK families, with three SNPs in the Slovenian families, and with three SNPs in the combined families. A case-control analysis detected associations with three additional SNPs. The results of this study, which is the largest to date investigating the genetics of reflux, suggest that major loci may not exist for this common renal tract malformation within European populations.Vesicoureteric reflux (VUR) is abnormal movement of urine from the bladder retrogradely through the vesicoureteric junctions into the upper urinary tract. This is a study of primary VUR, i.e., VUR that is not secondary to bladder outflow obstruction caused by neurogenic damage or urethral valves or part of a multiorgan syndrome. VUR is usually a benign condition but can be associated with transient kidney damage, acute inflammation from ascending pyelonephritis, or permanent damage as a consequence of scarring after infection and/or congenital kidney defects histologically comprising renal hypoplasia (too few nephrons) and/or renal dysplasia (incomplete differentiation).^1–3 These renal defects are grouped under the term reflux nephropathy (RN). In the United Kingdom, RN accounts for 12% of the approximately 40,000 adults and 7% of the 768 children who require renal transplantation and/or life-long dialysis.⁴Traditionally, the diagnosis of VUR has been based on cystography with radiodense or radioisotopic materials to visualize retrograde passage of urine. Williams et al.³ reviewed 15 cystography studies in well children: The largest study reported no VUR in 722 children, whereas some of the smaller studies reported much higher percentages of affected individuals. The true prevalence of (primary) VUR in children remains uncertain: 1% is probably conservative, and 10 to 20% is possible.³ Screening studies of first-degree relatives of individuals with VUR identifies reflux in one third to one half of siblings^5,6 and 65% of offspring.⁷ Futhermore, there is a high concordance of primary VUR in identical twins,⁸ and families have been identified with multiple generations affected by primary VUR and RN.⁹ Collectively, these studies suggest that there is a substantial genetic component to VUR.The first genome-wide linkage analysis for VUR, based on seven kindreds,⁹ provided preliminary evidence for a locus on chromosome 1 and also for genetic heterogeneity. In this study, multipoint parametric and nonparametric linkage analysis was undertaken; however, one of the markers defining the interval on chromosome 1, GATA176C01, was subsequently found to be on chromosome 2 (Ensembl release 55, July 2009), so this localization should be treated with caution. Subsequent studies using similar kindreds^10–12 have supported the notion that the condition is genetically heterogeneous. In the largest linkage study of VUR before this report, Kelly et al.¹³ performed a linkage genome scan of 609 individuals (283 affected individuals in 129 families) and detected six to seven regions with suggestive evidence of linkage,¹⁴ one of which at chromosome 2q37 attained genome-wide significance when analyzed in a phenotypically derived subset of the data. The high incidence in offspring of affected individuals and the large number of pedigrees consistent with autosomal dominant inheritance, albeit with reduced penetrance, is in keeping with a dominant model; however, recently, a locus was identified on 12p11-q13 using a recessive model.¹⁵Here we report on linkage and association analysis in affected sibling pairs from two populations. We used the Affymetrix NspI array to generate genome-wide data, adding in haplotype-tagging single-nucleotide polymorphisms (SNPs) to obtain full coverage for six candidate genes: AGTR2, HNF1B, PAX2, RET, ROBO2, and UPK3A.¹⁶     

A 21-year-old man with systemic-onset juvenile rheumatoid arthritis, cough and progressive dyspnea

Primary or nonobstructive, endogenous lipoid pneumonia is a rare clinical entity usually associated with an underlying systemic disease. The present report describes a case involving a 21-year-old man with systemic-onset juvenile rheumatoid arthritis who developed primary endogenous lipoid pneumonia. Multiple treatment regimens were attempted; however, definitive management was only achieved through double-lung transplantation.     

Mutagenicity and oxidative damage induced by an organic extract of the particulate emissions from a simulation of the deepwater horizon surface oil burns

Emissions from oil fires associated with the “Deepwater Horizon” explosion and oil discharge that began on April 20, 2010 in the Gulf of Mexico were analyzed chemically to only a limited extent at the time but were shown to induce oxidative damage in vitro and in mice. To extend this work, we burned oil floating on sea water and performed extensive chemical analyses of the emissions (Gullett et al., Marine Pollut Bull, in press, 2017 ). Here, we examine the ability of a dichloromethane extract of the particulate material with an aerodynamic size ≤ 2.5 µm (PM_2.5) from those emissions to induce oxidative damage in human lung cells in vitro and mutagenicity in 6 strains of Salmonella. The extract had a percentage of extractable organic material (EOM) of 7.0% and increased expression of the heme oxygenase (HMOX1) gene in BEAS‐2B cells after exposure for 4 hr at 20 µg of EOM/ml. However, the extract did not alter mitochondrial respiration rate as measured by extracellular flux analysis. The extract was most mutagenic in TA100 +S9, indicative of a role for polycyclic aromatic hydrocarbons (PAHs), reflective of the high concentrations of PAHs in the emissions (1 g/kg of oil consumed). The extract had a mutagenicity emission factor of 1.8 ± 0.1 × 10⁵ revertants/megajoule_thermal in TA98 +S9, which was greater than that of diesel exhaust and within an order of magnitude of open burning of wood and plastic. Thus, organics from PM_2.5 of burning oil can induce oxidative responses in human airway epithelial cells and are highly mutagenic. Environ. Mol. Mutagen. 58:162–171, 2017. © 2017 Wiley Periodicals, Inc.     

Craniosynostosis: diagnostic value of three-dimensional CT reconstruction

Three-dimensional computed tomography (CT) has an important role in determining the presence and extent of congenital and acquired craniofacial deformities. The authors compared the sensitivity and specificity of three-dimensional CT in the detection and characterization of craniosynostosis with that of planar CT and skull radiography. Eighty-two patients with isolated and syndromal synostoses were imaged with CT and three-dimensional CT, and 42 with skull radiography. Three-dimensional CT scan processing was performed by shaded-surface reconstruction, volumetric, and depth-coded methods. Two trained observers read each scan series in a blinded fashion. Diagnostic utility of the images was determined with receiver operating characteristic analysis. The observers ranked three-dimensional shaded images higher than the other types, with three-dimensional volumetric images second and three-dimensional surface images ranked third. Results of this study demonstrate that three-dimensional shaded-surface reconstruction from CT scans is superior to conventional plain radiographs and CT scans in diagnosing craniosynostosis.