Citations

Significance Pancreatic ductal adenocarcinoma (PDA) is the third leading of cause of cancer death in the United States and is predicted to be the second one by 2030. The tumor microenvironment is a major source of soluble mediators that influence tumor progression and hinder the success of therapeutic strategies. Using a genetically engineered mouse model and human cell-based systems, we identify galectin-1 (Gal1) as a critical soluble factor capable of regulating tumor–stroma crosstalk promoting proliferation, angiogenesis, and modulation of inflammatory responses, resulting in enhanced tumor development and metastasis. Our data provide an integrated view of the role of Gal1 in the PDA microenvironment and reinforce the high therapeutic value of Gal1 inhibition in PDA treatment.

Purpose: To investigate the influence of greater tuberosity healing on the functional outcomes of reverse shoulder arthroplasty (RSA) for the treatment of acute complex proximal humeral fractures (PHFs), and to investigate the influence of patient- and surgery-related factors in the healing of the greater tuberosity. Methods: Retrospective study including 41 consecutive PHFs treated using RSA with minimum 2-year follow-up. In all the cases, tuberosities were reattached with a standardized technique. All the patients were assessed at the last follow-up with constant score. Body mass index, surgery delay, comorbidities, polyethylene size, glenosphere size, overhanging of glenosphere, and scapular notch were recorded, and their influence in final constant score and in greater tuberosity healing was analyzed. Results: Mean final constant score was of 60.7 points (standard deviation (SD) = 9.9). Greater tuberosity healed in proper position in 68% of the cases. There were no significant differences in constant score between patients with (mean = 61; SD = 9.5) and without (mean = 61; SD = 11.3) the healing of greater tuberosity. All patients scored above 90° in forward elevation. Scapular notch was reported in 14.6% of the cases. Age significantly affected the constant score ( p = 0.008). Comorbidities significantly interfered with greater tuberosity healing ( p = 0.03). There was one reoperation after dislocation. Conclusion: In spite of expecting good functional outcome with low complication rate after RSA for acute PHFs, the influence of greater tuberosity healing on shoulder function could not be demonstrated. The presence of comorbidities, but not age or gender, negatively influenced the healing of the greater tuberosity.

Background: Strong evidence supports the role of both genetic and environmental factors in pediatric-onset multiple sclerosis (POMS) etiology. Objective: We comprehensively investigated the association between established major histocompatibility complex (MHC) and non-MHC adult multiple sclerosis (MS)-associated variants and susceptibility to POMS. Methods: Cases with onset <18 years ( n = 569) and controls ( n = 16,251) were included from the United States and Sweden. Adjusted logistic regression and meta-analyses were performed for individual risk variants and a weighted genetic risk score (wGRS) for non-MHC variants. Results were compared to adult MS cases ( n = 7588). Results: HLA–DRB1*15:01 was strongly associated with POMS (odds ratio (OR) meta = 2.95, p < 2.0 × 10 −16 ). Furthermore, 28 of 104 non-MHC variants studied (23%) were associated ( p < 0.05); POMS cases carried, on average, a higher burden of these 28 variants compared to adults (OR avg = 1.24 vs 1.13, respectively), though the difference was not significant. The wGRS was strongly associated with POMS (OR meta = 2.77, 95% confidence interval: 2.33, 3.32, p < 2.0 × 10 −16 ) and higher, on average, when compared to adult cases. Additional class III risk variants in the MHC region associated with POMS were revealed after accounting for HLA–DRB1*15:01 and HLA–A*02. Conclusion: Pediatric and adult MS share many genetic variants suggesting similar biological processes are present. MHC variants beyond HLA–DRB1*15:01 and HLA–A*02 are also associated with POMS.

Abstract Background: Endometrial cancer is highly curable when detected early, but clinical symptoms are often missed. Most cancers arise in women with abnormal postmenopausal bleeding (PMB). However, PMB is not specific for endometrial cancers. In previous reports, the prevalence of endometrial cancer in women with PMB was reported to range from 3-25%. Because of the importance for guiding clinical management and endometrial cancer risk prediction, we conducted a systematic review and meta-analysis to obtain precise prevalence estimates of endometrial cancer in women with PMB. Methods: A systematic review and meta-analysis summarized all peer-reviewed studies reporting endometrial cancer prevalence in women with PMB, published before Sept. 1, 2016. We calculated a pooled prevalence estimate and 95% confidence interval (CI) using a random-effects model, and quantified heterogeneity across studies using the I2 statistic. Subgroup meta-analyses were performed to investigate sources of variability according to selection criteria for endometrial thickness (ET) and hormone replacement therapy (HRT). We also stratified by study location to determine whether prevalence estimates varied by country or region if ≤5 studies included per country. Results: 105 studies were included, contributing data for 37,000 women with PMB and 3,028 with cancer from 34 countries. Overall, the pooled prevalence of endometrial cancer in women with PMB was 11% (95% CI 10-12%), with I2 =94.3%. Among studies that selected women with a minimum ET (≥ 4mm; n=14), the pooled prevalence of endometrial cancer was 17% (95% CI 14-20%) compared with studies that did not select for ET (10%, 95% CI 9-11%). In studies that excluded women using HRT (n=34), the pooled prevalence of endometrial cancer was 15% (95% CI 12-17%) compared with studies that did not exclude women using HRT (9%, 95% CI 8-10%). Stratification by study location revealed variation in prevalence estimates. For example, in the United States (n=9) and the United Kingdom (n=16), prevalence of endometrial cancer was 4% (95% CI 2-7%) and 5% (95% CI 4-6%), respectively, whereas in Italy (n=14), the prevalence was 11% (95% 8-14%). Regional differences were also observed, ranging from 8% (95% CI 3-14%) in South Central Asia (n=5) to 18% (95% CI 12-23%) in Southern Europe (n=11). Conclusions: The overall prevalence of endometrial cancer among unselected women with PMB is approximately 10% with substantial heterogeneity across studies. Marked geographic differences in the prevalence endometrial cancer were observed. Factors related to selection for ET and/or HRT use may partially contribute to this variability. Risk prediction models depend on precise prevalence estimates for accurate prediction and utility in clinical management. More research is needed to test the applicability of endometrial cancer risk prediction models in high-risk subgroups and in study populations from diverse geographic regions. Citation Format: Megan A. Clarke, Beverly J. Long, Arena Del Mar Morillo, Jamie N. Bakkum-Gamez, Nicolas Wentzensen. The prevalence of endometrial cancer in women with postmenopausal bleeding: a systematic review and meta-analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 275. doi:10.1158/1538-7445.AM2017-275

Background: The role of diet in multiple sclerosis (MS) is largely uncharacterized, particularly as it pertains to pediatric-onset disease. Objective: To determine the association between dietary factors and MS in children. Methods: Pediatric MS patients and controls were recruited from 16 US centers (MS or clinically isolated syndrome onset before age 18, <4 years from symptom onset and at least 2 silent lesions on magnetic resonance imaging). The validated Block Kids Food Screener questionnaire was administered 2011–2016. Chi-squared test compared categorical variables, Kruskal–Wallis test compared continuous variables, and multivariable logistic regression analysis was performed. Results: In total, 312 cases and 456 controls were included (mean ages 15.1 and 14.4 years). In unadjusted analyses, there was no difference in intake of fats, proteins, carbohydrates, sugars, fruits, or vegetables. Dietary iron was lower in cases ( p = 0.04), and cases were more likely to consume below recommended guidelines of iron (77.2% of cases vs 62.9% of controls, p < 0.001). In multivariable analysis, iron consumption below recommended guidelines was associated with MS (odds ratio = 1.80, p < 0.01). Conclusion: Pediatric MS cases may be less likely to consume sufficient iron compared to controls, and this warrants broader study to characterize a temporal relationship. No other significant difference in intake of most dietary factors was found.

Objective Genome‐wide association studies (GWAS) have been successful at identifying associations with stroke and stroke subtypes, but have not yet identified any associations solely with small vessel stroke (SVS). SVS comprises one quarter of all ischemic stroke and is a major manifestation of cerebral small vessel disease, the primary cause of vascular cognitive impairment. Studies across neurological traits have shown that younger‐onset cases have an increased genetic burden. We leveraged this increased genetic burden by performing an age‐at‐onset informed GWAS meta‐analysis, including a large younger‐onset SVS population, to identify novel associations with stroke. Methods We used a three‐stage age‐at‐onset informed GWAS to identify novel genetic variants associated with stroke. On identifying a novel locus associated with SVS, we assessed its influence on other small vessel disease phenotypes, as well as on messenger RNA (mRNA) expression of nearby genes, and on DNA methylation of nearby CpG sites in whole blood and in the fetal brain. Results We identified an association with SVS in 4,203 cases and 50,728 controls on chromosome 16q24.2 (odds ratio [OR; 95% confidence interval {CI}] = 1.16 [1.10–1.22]; p = 3.2 × 10 −9 ). The lead single‐nucleotide polymorphism (rs12445022) was also associated with cerebral white matter hyperintensities (OR [95% CI] = 1.10 [1.05–1.16]; p = 5.3 × 10 −5 ; N = 3,670), but not intracerebral hemorrhage (OR [95% CI] = 0.97 [0.84–1.12]; p = 0.71; 1,545 cases, 1,481 controls). rs12445022 is associated with mRNA expression of ZCCHC14 in arterial tissues ( p = 9.4 × 10 −7 ) and DNA methylation at probe cg16596957 in whole blood ( p = 5.3 × 10 −6 ). Interpretation 16q24.2 is associated with SVS. Associations of the locus with expression of ZCCHC14 and DNA methylation suggest the locus acts through changes to regulatory elements. Ann Neurol 2017;81:383–394

AbstractObjectiveThe aim of this study was to examine the relative contributions of body mass index (BMI) and pubertal measures for risk and age of onset of pediatric MS.MethodsCase–control study of 254 (63% female) MS cases (onset<18 years of age) and 420 (49% female) controls conducted at 14 U.S. Pediatric MS Centers. Sex‐ and age‐stratified BMI percentiles were calculated using CDC growth charts from height and weight measured at enrollment for controls, and within 1 year of onset for MS cases. Sex‐stratified associations between MS risk and age at symptom onset with both BMI and pubertal factors were estimated controlling for race and ethnicity.ResultsOnly 11% of girls and 15% of boys were prepubertal (Tanner stage I) at MS onset. 80% of girls had onset of MS after menarche. BMI percentiles were higher in MS cases versus controls (girls: P < 0.001; boys: P = 0.018). BMI was associated with odds of MS in multivariate models in postpubertal girls (OR = 1.60, 95% confidence interval [CI]: 1.12, 2.27, P = 0.009) and boys (OR = 1.43, 95% CI: 1.08, 1.88, P = 0.011). In girls with MS onset after menarche, higher BMI was associated with younger age at first symptoms (P = 0.031). Younger menarche was associated with stronger effects of BMI through mediation and interaction analysis. In pubertal/postpubertal boys, 89% of whom were obese/overweight, earlier sexual maturity was associated with earlier onset of MS (P < 0.001).InterpretationHigher BMI in early adolescence is a risk factor for MS in girls and boys. Earlier age at sexual maturity contributes to earlier age at MS onset, particularly in association with obesity.