Recent genome-wide association studies identified 11 single nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk. We investigated these and 62 other SNPs for their prognostic ...relevance. Confirmed BC risk SNPs rs17468277 (CASP8), rs1982073 (TGFB1), rs2981582 (FGFR2), rs13281615 (8q24), rs3817198 (LSP1), rs889312 (MAP3K1), rs3803662 (TOX3), rs13387042 (2q35), rs4973768 (SLC4A7), rs6504950 (COX11) and rs10941679 (5p12) were genotyped for 25 853 BC patients with the available follow-up; 62 other SNPs, which have been suggested as BC risk SNPs by a GWAS or as candidate SNPs from individual studies, were genotyped for replication purposes in subsets of these patients. Cox proportional hazard models were used to test the association of these SNPs with overall survival (OS) and BC-specific survival (BCS). For the confirmed loci, we performed an accessory analysis of publicly available gene expression data and the prognosis in a different patient group. One of the 11 SNPs, rs3803662 (TOX3) and none of the 62 candidate/GWAS SNPs were associated with OS and/or BCS at P<0.01. The genotypic-specific survival for rs3803662 suggested a recessive mode of action hazard ratio (HR) of rare homozygous carriers=1.21; 95% CI: 1.09-1.35, P=0.0002 and HR=1.29; 95% CI: 1.12-1.47, P=0.0003 for OS and BCS, respectively. This association was seen similarly in all analyzed tumor subgroups defined by nodal status, tumor size, grade and estrogen receptor. Breast tumor expression of these genes was not associated with prognosis. With the exception of rs3803662 (TOX3), there was no evidence that any of the SNPs associated with BC susceptibility were associated with the BC survival. Survival may be influenced by a distinct set of germline variants from those influencing susceptibility.
The effect of anesthetic management (general anesthesia GA, conscious sedation, or local anesthesia) on functional outcome and the role of blood pressure management during endovascular treatment ...(EVT) for acute ischemic stroke is under debate. We aimed to determine whether hypotension during EVT under GA is associated with functional outcome at 90 days. We retrospectively collected data from patients with a proximal intracranial occlusion of the anterior circulation treated with EVT under GA. The primary outcome was the distribution on the modified Rankin Scale at 90 days. Hypotension was defined using two thresholds: a mean arterial pressure (MAP) of 70 mm Hg and a MAP 30% below baseline MAP. To quantify the extent and duration of hypotension, the area under the threshold (AUT) was calculated using both thresholds. Of the 366 patients included, procedural hypotension was observed in approximately half of them. The occurrence of hypotension was associated with poor functional outcome (MAP <70 mm Hg: adjusted common odds ratio acOR, 0.57; 95% confidence interval CI, 0.35-0.94; MAP decrease greater than or equal to30%: acOR, 0.76; 95% CI, 0.48-1.21). In addition, an association was found between the number of hypotensive periods and poor functional outcome (MAP <70 mm Hg: acOR, 0.85 per period increase; 95% CI, 0.73-0.99; MAP decrease greater than or equal to30%: acOR, 0.90 per period; 95% CI, 0.78-1.04). No association existed between AUT and functional outcome (MAP <70 mm Hg: acOR, 1.000 per 10 mm Hg*min increase; 95% CI, 0.998-1.001; MAP decrease greater than or equal to30%: acOR, 1.000 per 10 mm Hg*min; 95% CI, 0.999-1.000). Occurrence of procedural hypotension and an increase in number of procedural hypotensive periods were associated with poor functional outcome, whereas the extent and duration of hypotension were not. Randomized clinical trials are needed to confirm our hypothesis that hypotension during EVT under GA has detrimental effects.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Objective
We report longitudinal data from 144 type III SMA pediatric and adult patients treated with nusinersen as part of an international effort.
Methods
Patients were assessed using Hammersmith ...Functional Motor Scale Expanded (HFMSE), Revised Upper Limb Module (RULM), and 6‐Minute Walk Test (6MWT) with a mean follow‐up of 1.83 years after nusinersen treatment.
Results
Over 75% of the 144 patients had a 12‐month follow‐up. There was an increase in the mean scores from baseline to 12 months on both HFMSE (1.18 points, p = 0.004) and RULM scores (0.58 points, p = 0.014) but not on the 6MWT (mean difference = 6.65 m, p = 0.33).
When the 12‐month HFMSE changes in the treated cohort were compared to an external cohort of untreated patients, in all untreated patients older than 7 years, the mean changes were always negative, while always positive in the treated ones. To reduce a selection bias, we also used a multivariable analysis. On the HFMSE scale, age, gender, baseline value, and functional status contributed significantly to the changes, while the number of SMN2 copies did not contribute. The effect of these variables was less obvious on the RULM and 6MWT.
Interpretation
Our results expand the available data on the effect of Nusinersen on type III patients, so far mostly limited to data from adult type III patients.
Rare variants in at least 10 genes, including BRCA1, BRCA2, PALB2, ATM, and CHEK2, are associated with increased risk of breast cancer; however, these variants, in combination with common variants ...identified through genome-wide association studies, explain only a fraction of the familial aggregation of the disease. To identify further susceptibility genes, we performed a two-stage whole-exome sequencing study. In the discovery stage, samples from 1528 breast cancer cases enriched for breast cancer susceptibility and 3733 geographically matched unaffected controls were sequenced. Using five different filtering and gene prioritization strategies, 198 genes were selected for further validation. These genes, and a panel of 32 known or suspected breast cancer susceptibility genes, were assessed in a validation set of 6211 cases and 6019 controls for their association with risk of breast cancer overall, and by estrogen receptor (ER) disease subtypes, using gene burden tests applied to loss-of-function and rare missense variants. Twenty genes showed nominal evidence of association (p-value < 0.05) with either overall or subtype-specific breast cancer. Our study had the statistical power to detect susceptibility genes with effect sizes similar to ATM, CHEK2, and PALB2, however, it was underpowered to identify genes in which susceptibility variants are rarer or confer smaller effect sizes. Larger sample sizes would be required in order to identify such genes.
There is increasing evidence that elevated body mass index (BMI) is associated with reduced survival for women with breast cancer. However, the underlying reasons remain unclear. We conducted a ...Mendelian randomization analysis to investigate a possible causal role of BMI in survival from breast cancer.
We used individual-level data from six large breast cancer case-cohorts including a total of 36 210 individuals (2475 events) of European ancestry. We created a BMI genetic risk score (GRS) based on genotypes at 94 known BMI-associated genetic variants. Association between the BMI genetic score and breast cancer survival was analysed by Cox regression for each study separately. Study-specific hazard ratios were pooled using fixed-effect meta-analysis.
BMI genetic score was found to be associated with reduced breast cancer-specific survival for estrogen receptor (ER)-positive cases hazard ratio (HR) = 1.11, per one-unit increment of GRS, 95% confidence interval (CI) 1.01-1.22, P = 0.03). We observed no association for ER-negative cases (HR = 1.00, per one-unit increment of GRS, 95% CI 0.89-1.13, P = 0.95).
Our findings suggest a causal effect of increased BMI on reduced breast cancer survival for ER-positive breast cancer. There is no evidence of a causal effect of higher BMI on survival for ER-negative breast cancer cases.
Survival after a diagnosis of breast cancer varies considerably between patients, and some of this variation may be because of germline genetic variation. We aimed to identify genetic markers ...associated with breast cancer-specific survival.
We conducted a large meta-analysis of studies in populations of European ancestry, including 37954 patients with 2900 deaths from breast cancer. Each study had been genotyped for between 200000 and 900000 single nucleotide polymorphisms (SNPs) across the genome; genotypes for nine million common variants were imputed using a common reference panel from the 1000 Genomes Project. We also carried out subtype-specific analyses based on 6881 estrogen receptor (ER)-negative patients (920 events) and 23059 ER-positive patients (1333 events). All statistical tests were two-sided.
We identified one new locus (rs2059614 at 11q24.2) associated with survival in ER-negative breast cancer cases (hazard ratio HR = 1.95, 95% confidence interval CI = 1.55 to 2.47, P = 1.91 x 10(-8)). Genotyping a subset of 2113 case patients, of which 300 were ER negative, provided supporting evidence for the quality of the imputation. The association in this set of case patients was stronger for the observed genotypes than for the imputed genotypes. A second locus (rs148760487 at 2q24.2) was associated at genome-wide statistical significance in initial analyses; the association was similar in ER-positive and ER-negative case patients. Here the results of genotyping suggested that the finding was less robust.
This is currently the largest study investigating genetic variation associated with breast cancer survival. Our results have potential clinical implications, as they confirm that germline genotype can provide prognostic information in addition to standard tumor prognostic factors.
Adherence to national and international clinical practice guidelines is suboptimal throughout Europe. The European Association of Urology Guidelines Office project “IMAGINE” (IMpact Assessment of ...Guidelines Implementation and Education) has been developed to measure baseline adherence to urological guideline recommendations across Europe and to identify issues that drive nonadherence.
Congenital anomalies of the kidney and urinary tract (CAKUT) are the predominant cause of chronic kidney disease (CKD) and the need for kidney replacement therapy (KRT) in children. Although more ...than 60 genes are known to cause CAKUT if mutated, genetic etiology is detected, on average, in only 16% of unselected CAKUT cases, making genetic testing unproductive.
Whole exome sequencing (WES) was performed in 100 patients with CAKUT diagnosed in the first 1000 days of life with CKD stages 1 to 5D/T. Variants in 58 established CAKUT-associated genes were extracted, classified according to the American College of Medical Genetics and Genomics guidelines, and their translational value was assessed.
In 25% of these mostly sporadic patients with CAKUT, a rare likely pathogenic or pathogenic variant was identified in 1 or 2 of 15 CAKUT-associated genes, including GATA3, HNF1B, LIFR, PAX2, SALL1, and TBC1D1. Of the 27 variants detected, 52% were loss-of-function and 18.5% de novo variants. The diagnostic yield was significantly higher in patients requiring KRT before 3 years of age (43%, odds ratio 2.95) and in patients with extrarenal features (41%, odds ratio 3.5) compared with patients lacking these criteria. Considering that all affected genes were previously associated with extrarenal complications, including treatable conditions, such as diabetes, hyperuricemia, hypomagnesemia, and hypoparathyroidism, the genetic diagnosis allowed preventive measures and/or early treatment in 25% of patients.
WES offers significant advantages for the diagnosis and management of patients with CAKUT diagnosed before 3 years of age, especially in patients who require KRT or have extrarenal anomalies.
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Aim
Literature on nationwide long‐term permanent stoma rates after rectal cancer resection in the minimally invasive era is scarce. The aim of this population‐based study was to provide more insight ...into the permanent stoma rate with interhospital variability (IHV) depending on surgical technique, with pelvic sepsis, unplanned reinterventions and readmissions as secondary outcomes.
Method
Patients who underwent open or minimally invasive resection of rectal cancer (lower border below the sigmoid take‐off) in 67 Dutch centres in 2016 were included in this cross‐sectional cohort study.
Results
Among 2530 patients, 1470 underwent a restorative resection (58%), 356 a Hartmann's procedure (14%, IHV 0%–42%) and 704 an abdominoperineal resection (28%, IHV 3%–60%). Median follow‐up was 51 months. The overall permanent stoma rate at last follow‐up was 50% (IHV 13%–79%) and the unintentional permanent stoma rate, permanent stoma after a restorative procedure or an unplanned Hartmann's procedure, was 11% (IHV 0%–29%). A total of 2165 patients (86%) underwent a minimally invasive resection: 1760 conventional (81%), 170 transanal (8%) and 235 robot‐assisted (11%). An anastomosis was created in 59%, 80% and 66%, with corresponding unintentional permanent stoma rates of 12%, 24% and 14% (p = 0.001), respectively. When corrected for age, American Society of Anesthesiologists classification, cTNM, distance to the anorectal junction and neoadjuvant (chemo)radiotherapy, the minimally invasive technique was not associated with an unintended permanent stoma (p = 0.071) after a restorative procedure.
Conclusion
A remarkable IHV in the permanent stoma rate after rectal cancer resection was found. No beneficial influence of transanal or robot‐assisted laparoscopy on the unintentional permanent stoma rate was found, although this might be caused by the surgical learning curve. A reduction in IHV and improving preoperative counselling for decision‐making for restorative procedures are required.
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