Outcome following surgery for colorectal cancer: analysis by hospital after adjustment for case-mix and deprivation

Outcome, adjusted for case-mix and deprivation, in 3200 patients undergoing resection for colorectal cancer in 11 hospitals in Central Scotland between 1991 and 1994 was studied. There were significant differences among individual hospitals in the proportion of elderly (P<0.001) and deprived (P<0.0001) patients, the mode (P=0.007) and stage (P<0.0001) at presentation, and the proportion of patients who underwent apparently curative resection (P<0.001). There were no significant differences in postoperative mortality. Cancer-specific survival at 5 years following apparently curative resection varied from 59 to 76%; cancer-specific survival at 2 years following palliative resection varied from 22 to 44%. The corresponding hazard ratios, adjusted for the above prognostic factors, for patients undergoing apparently curative resection varied among hospitals from 0.58 to 1.32; and the ratios for palliative resection varied from 0.73 to 1.26. This study demonstrates that, after adjustment for variations in case-mix and deprivation, significant differences in outcome among hospitals following resection for colorectal cancer persist

High EMSY expression defines a BRCA‐like subgroup of high‐grade serous ovarian carcinoma with prolonged survival and hypersensitivity to platinum

Background Approximately half of high‐grade serous ovarian carcinomas (HGSOCs) demonstrate homologous recombination repair (HR) pathway defects, resulting in a distinct clinical phenotype comprising hypersensitivity to platinum, superior clinical outcome, and greater sensitivity to poly(adenosine diphosphate‐ribose) polymerase (PARP) inhibitors. EMSY, which is known to be amplified in breast and ovarian cancers, encodes a protein reported to bind and inactivate BRCA2. Thus, EMSY overexpression may mimic BRCA2 mutation, resulting in HR deficiency. However, to our knowledge, the phenotypic consequences of EMSY overexpression in HGSOC patients has not been explored. Methods Here we investigate the impact of EMSY expression on clinical outcome and sensitivity to platinum‐based chemotherapy using available data from transcriptomically characterized HGSOC cohorts. Results High EMSY expression was associated with better clinical outcome in a cohort of 265 patients with HGSOC from Edinburgh (overall survival multivariable hazard ratio, 0.58 [95% CI, 0.38‐0.88; P = .011] and progression‐free survival multivariable hazard ratio, 0.62 [95% CI, 0.40‐0.96; P = .030]). Superior outcome also was demonstrated in the Medical Research Council ICON7 clinical trial and multiple publicly available data sets. Patients within the Edinburgh cohort who had high EMSY expression were found to demonstrate greater rates of complete response to multiple platinum‐containing chemotherapy regimens (radiological complete response rate of 44.4% vs 12.5% at second exposure; P = .035) and corresponding prolonged time to disease progression (median, 151.5 days vs 60.5 days after third platinum exposure; P = .004). Conclusions Patients with HGSOCs demonstrating high EMSY expression appear to experience prolonged survival and greater platinum sensitivity, reminiscent of BRCA‐mutant cases. These data are consistent with the notion that EMSY overexpression may render HGSOCs HR deficient

A double shunt technique for the prevention of ischaemia of a congenital, solitary, pelvic kidney during abdominal aortic aneurysm repair: a case report

<p>Abstract</p> <p>Introduction</p> <p>Congenital solitary pelvic kidney is a rare condition, and its association with an abdominal aortic aneurysm is even more unusual. To the best of our knowledge, only two such cases have been reported in the literature to date.</p> <p>Case presentation</p> <p>We report the case of a 59-year-old Caucasian man with a congenital solitary pelvic kidney, who was found to have an abdominal aortic aneurysm 83 mm in diameter. Abdominal computed tomography angiography clearly identified two renal arteries, one originating from the aortic bifurcation. and the other from the proximal portion of the right common iliac artery. At surgery, renal ischaemia was prevented by introduction of an axillofemoral shunt (consisting of two femoral cannulas and a vent tube of extracorporeal circulation) from the right axillary to the right femoral artery, and a second Argyle shunt from the right common iliac artery to the origin of the left renal artery. A 20 mm Dacron tube graft was then implanted. Our patient's postoperative renal function was normal.</p> <p>Conclusion</p> <p>The renal preservation double shunt technique used in this case seems to be effective during abdominal aortic aneurysm repair.</p

A realistic pattern of fermion masses from a five-dimensional SO(10) model

We provide a unified description of fermion masses and mixing angles in the framework of a supersymmetric grand unified SO(10) model with anarchic Yukawa couplings of order unity. The space-time is five dimensional and the extra flat spatial dimension is compactified on the orbifold $S^1/(Z_2 \times Z_2')$, leading to Pati-Salam gauge symmetry on the boundary where Yukawa interactions are localised. The gauge symmetry breaking is completed by means of a rather economic scalar sector, avoiding the doublet-triplet splitting problem. The matter fields live in the bulk and their massless modes get exponential profiles, which naturally explain the mass hierarchy of the different fermion generations. Quarks and leptons properties are naturally reproduced by a mechanism, first proposed by Kitano and Li, that lifts the SO(10) degeneracy of bulk masses in terms of a single parameter. The model provides a realistic pattern of fermion masses and mixing angles for large values of $\tan\beta$. It favours normally ordered neutrino mass spectrum with the lightest neutrino mass below 0.01 eV and no preference for leptonic CP violating phases. The right handed neutrino mass spectrum is very hierarchical and does not allow for thermal leptogenesis. We analyse several variants of the basic framework and find that the results concerning the fermion spectrum are remarkably stable.Comment: 30 pages, 7 figures, 4 table

Evidence for the role of EPHX2 gene variants in anorexia nervosa.

Anorexia nervosa (AN) and related eating disorders are complex, multifactorial neuropsychiatric conditions with likely rare and common genetic and environmental determinants. To identify genetic variants associated with AN, we pursued a series of sequencing and genotyping studies focusing on the coding regions and upstream sequence of 152 candidate genes in a total of 1205 AN cases and 1948 controls. We identified individual variant associations in the Estrogen Receptor-ß (ESR2) gene, as well as a set of rare and common variants in the Epoxide Hydrolase 2 (EPHX2) gene, in an initial sequencing study of 261 early-onset severe AN cases and 73 controls (P=0.0004). The association of EPHX2 variants was further delineated in: (1) a pooling-based replication study involving an additional 500 AN patients and 500 controls (replication set P=0.00000016); (2) single-locus studies in a cohort of 386 previously genotyped broadly defined AN cases and 295 female population controls from the Bogalusa Heart Study (BHS) and a cohort of 58 individuals with self-reported eating disturbances and 851 controls (combined smallest single locus P&lt;0.01). As EPHX2 is known to influence cholesterol metabolism, and AN is often associated with elevated cholesterol levels, we also investigated the association of EPHX2 variants and longitudinal body mass index (BMI) and cholesterol in BHS female and male subjects (N=229) and found evidence for a modifying effect of a subset of variants on the relationship between cholesterol and BMI (P&lt;0.01). These findings suggest a novel association of gene variants within EPHX2 to susceptibility to AN and provide a foundation for future study of this important yet poorly understood condition

Scaling laws near the conformal window of many-flavor QCD

We derive universal scaling laws for physical observables such as the critical temperature, the chiral condensate, and the pion decay constant as a function of the flavor number near the conformal window of many-flavor QCD in the chiral limit. We argue on general grounds that the associated critical exponents are all interrelated and can be determined from the critical exponent of the running gauge coupling at the Caswell-Banks-Zaks infrared fixed point. We illustrate our findings with the aid of nonperturbative functional Renormalization Group (RG) calculations and low-energy QCD models.Comment: 18 pages, 4 figures, references added and discussion expanded (matches JHEP version

The relationship between patient physiology and cancer-specific survival following curative resection of colorectal cancer

The impact of patient physiology on cancer-specific survival is poorly documented. Patient physiology predicted overall, cancer-specific (Physiology Score>30; HR 8.64 (95% CI 3.00–24.92); P=0.0005) and recurrence-free survival (Physiology Score >30; HR 7.44 (95% CI 1.99–27.73); P=0.003) independent of Dukes stage following potentially curative surgery for colorectal cancer. This independent negative association with survival is a novel observation

UGT1A1 sequence variants and bilirubin levels in early postnatal life: a quantitative approach

<p>Abstract</p> <p>Background</p> <p>Fundamental to definitively identifying neonates at risk of developing significant hyperbilirubinemia is a better understanding of the genetic factors associated with early bilirubin rise. Previous genetic studies have focused on the UGT1A1 gene, associating common variation in the coding or promoter regions with qualitative assessments of bilirubin (i.e. significantly elevated or not). These studies have had conflicting results and limited success. We chose to approach the problem by focusing on the quantitative (absolute) change in bilirubin levels early in post-natal life. We apply this approach to the UGT1A1 gene - exploring the contribution of both rare and common variants to early bilirubin changes.</p> <p>Methods</p> <p>We sequenced the exons, PBREM, 5'-, and 3'- regions of the UGT1A1 gene in 80 otherwise healthy term neonates who had repeat bilirubin levels measured within the first five days of life.</p> <p>Results</p> <p>Three novel coding variants were observed, but there was no clear relationship between rare coding variants and bilirubin rise. Adjusted linear regression models fit to evaluate the relationship between changing bilirubin levels and common UGT1A1variants found that among 39 neonates whose bilirubin was resampled within 33 hours, individuals homozygous for the mutant allele of a 3'UTR SNP had significantly smaller changes in bilirubin (P = 0.003) than individuals carrying the wild-type allele.</p> <p>Conclusions</p> <p>Collectively, rare UGT1A1 coding variants do not appear to play a prominent role in determining early bilirubin levels; however common variants in the 3' UTR of UGT1A1 may modulate the early bilirubin rise. A quantitative approach to evaluating early bilirubin kinetics provides a more robust framework in which to better understand the genetics of neonatal hyperbilirubinemia.</p