Citations

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 Wireless motility capsule ( WMC ) findings are incompletely defined in suspected gastroparesis. We aimed to characterize regional WMC transit and contractility in relation to scintigraphy, etiology, and symptoms in patients undergoing gastric emptying testing. Methods A total of 209 patients with gastroparesis symptoms at NIDDK Gastroparesis Consortium centers underwent gastric scintigraphy and WMC s on separate days to measure regional transit and contractility. Validated questionnaires quantified symptoms. Key Results Solid scintigraphy and liquid scintigraphy were delayed in 68.8% and 34.8% of patients; WMC gastric emptying times ( GET ) were delayed in 40.3% and showed 52.8% agreement with scintigraphy; 15.5% and 33.5% had delayed small bowel ( SBTT ) and colon transit ( CTT ) times. Transit was delayed in ≥2 regions in 23.3%. Rapid transit was rarely observed. Diabetics had slower GET but more rapid SBTT versus idiopathics ( P ≤ .02). GET delays related to greater scintigraphic retention, slower SBTT , and fewer gastric contractions ( P ≤ .04). Overall gastroparesis symptoms and nausea/vomiting, early satiety/fullness, bloating/distention, and upper abdominal pain subscores showed no relation to WMC transit. Upper and lower abdominal pain scores ( P ≤ .03) were greater with increased colon contractions. Constipation correlated with slower CTT and higher colon contractions ( P = .03). Diarrhea scores were higher with delayed SBTT and CTT ( P ≤ .04). Conclusions & Inferences Wireless motility capsules define gastric emptying delays similar but not identical to scintigraphy that are more severe in diabetics and relate to reduced gastric contractility. Extragastric transit delays occur in >40% with suspected gastroparesis. Gastroparesis symptoms show little association with WMC profiles, although lower symptoms relate to small bowel or colon abnormalities.

Abstract Background: Comorbidities can affect survival of ovarian cancer patients by influencing treatment efficacy. However, little evidence exists on the association between individual concurrent comorbidities and prognosis in ovarian cancer patients. Methods: Among patients diagnosed with invasive ovarian carcinoma who participated in 23 studies included in the Ovarian Cancer Association Consortium, we explored associations between histories of endometriosis; asthma; depression; osteoporosis; and autoimmune, gallbladder, kidney, liver, and neurological diseases and overall and progression-free survival. Using Cox proportional hazards regression models adjusted for age at diagnosis, stage of disease, histology, and study site, we estimated pooled HRs and 95% confidence intervals to assess associations between each comorbidity and ovarian cancer outcomes. Results: None of the comorbidities were associated with ovarian cancer outcome in the overall sample nor in strata defined by histologic subtype, weight status, age at diagnosis, or stage of disease (local/regional vs. advanced). Conclusions: Histories of endometriosis; asthma; depression; osteoporosis; and autoimmune, gallbladder, kidney, liver, or neurologic diseases were not associated with ovarian cancer overall or progression-free survival. Impact: These previously diagnosed chronic diseases do not appear to affect ovarian cancer prognosis. Cancer Epidemiol Biomarkers Prev; 26(9); 1470–3. ©2017 AACR.

Abstract Hematopoietic cell transplantation (HCT) is an expensive, resource-intensive, and medically complicated modality for treatment of many hematologic disorders. A well-defined care coordination model through the continuum can help improve health care delivery for this high-cost, high-risk medical technology. In addition to the patients and their families, key stakeholders include not only the transplantation physicians and care teams (including subspecialists), but also hematologists/oncologists in private and academic-affiliated practices. Initial diagnosis and care, education regarding treatment options including HCT, timely referral to the transplantation center, and management of relapse and late medical or psychosocial complications after HCT are areas where the referring hematologists/oncologists play a significant role. Payers and advocacy and community organizations are additional stakeholders in this complex care continuum. In this article, we describe a care coordination framework for patients treated with HCT within the context of coordination issues in care delivery and stakeholders involved. We outline the challenges in implementing such a model and describe a simplified approach at the level of the individual practice or center. This article also highlights ongoing efforts from physicians, medical directors, payer representatives, and patient advocates to help raise awareness of and develop access to adequate tools and resources for the oncology community to deliver well-coordinated care to patients treated with HCT. Lastly, we set the stage for policy changes around appropriate reimbursement to cover all aspects of care coordination and generate successful buy-in from all stakeholders.

Hypothesis It has been hypothesized that high fungiform papillae density may be a risk factor for developing the taste and pain alterations characteristic of burning mouth syndrome. Objective Evaluate whether fungiform papillae density, taste sensitivity, and mechanical pain sensitivity differ between burning mouth syndrome cases and controls. Study Design This case‐control study compared cases diagnosed with primary burning mouth syndrome with pain‐free controls. Methods Participants (17 female cases and 23 female controls) rated the intensity of sucrose, sodium chloride, citric acid, and quinine applied separately to each side of the anterior tongue and sampled whole mouth. Mechanical pain sensitivity was assessed separately for each side of the tongue using weighted pins. Digital photographs of participants' tongues were used to count fungiform papillae. Results Burning mouth syndrome cases had increased whole mouth taste intensity. Cases also had increased sensitivity to quinine on the anterior tongue, as well as increased mechanical pain sensitivity on the anterior tongue. Fungiform papillae density did not differ significantly between cases and controls. Fungiform papillae density on the left and right sides of the tongue were correlated in controls; however, there was no left/right side correlation in cases. Conclusion Cases had increased pain and taste perception on the anterior tongue. The lack of correlation between left and right fungiform papillae density in cases may be an indication of asymmetrical lingual innervation in these patients. Level of Evidence 3b. Laryngoscope , 128:841–846, 2018

Abstract Cancer has been considered a heterogeneous disease, which mainly arises from the accumulation of genetic mutations, leading to a loss of tumor suppressor genes, as well as to an activation of oncogenes. The epigenetic mechanisms, such as DNA and histone modifications, are processes that regulate gene expression, and an alteration of these can contribute to cancer progression. Methylation on histone 3 lysine 9 (H3K9), in particular di-methyl (H3K9me2), is mainly mediated by the nuclear histone lysine methyltransferase G9a. Preliminary data showed that G9a was overexpressed in aggressive and highly metastatic forms of cancer. However, to date, this pathway has remained unstudied in esophageal adenocarcinoma. Interestingly, epigenetic drugs, such as those that target G9a, have the potential to reverse the adverse effects acquired downstream from genetic mutations, which currently cannot be directly repaired or targeted. In the current study, we utilize BRD4770, an S-adenosylmethionine (SAM) mimetic inhibitor of G9a, to determine the benefits of inhibiting this pathway in the context of esophageal adenocarcinoma. We hypothesize that pharmacological targeting of G9a by BRD4770 inhibits esophageal adenocarcinoma cell growth. To examine G9a-mediated dimethyl histone H3K9 levels in esophageal adenocarcinoma, we performed immunohistochemistry on paraffin-embedded esophageal adenocarcinoma tissues with an H3K9me2 antibody. In order to confirm specificity of BRD4770 in regulating the dimethyl histone H3K9 levels, and thus trimethyl H3K9 levels, in esophageal adenocarcinoma, we treated human esophageal adenocarcinoma cells (SKGT-4) with different doses of BRD4770 at various time points for western blot analysis using antibodies against histone H3K9me2 and H3K9me3. Moreover, we found that treatment of SKGT-4 cells with BRD4770 significantly inhibits cell proliferation by MTS assay, as well as clonogenic survival. Therefore, to determine the mechanism(s) by which BRD4770 inhibits the growth of esophageal adenocarcinoma cells, we utilized Caspase-3, Senescence, and Autophagy Assays. Our data shows that inhibition of G9a by BRD4770 does not induce Caspase 3 activity, while it significantly increases senescence and autophagy. Combined, our results suggest that BRD4770 has an important pharmacological role in regulating methyl histone H3K9 levels that may lead to inhibition of esophageal adenocarcinoma cell growth via an increase in senescence and autophagy. Further studies are focused on in vivo models to understand these effects in more detail, however the fact that an anti-G9a drug antagonizes esophageal adenocarcinoma cell growth raises optimism for its potential in the treatment of this malignancy. Note: This abstract was not presented at the meeting. Citation Format: Mabel G. Perez-Oquendo, Gwen A. Lomberk, Raul A. Urrutia, Sarah Kossak, Navtej Buttar, Sounak Gupta. Treatment with the G9a antagonist, BRD4770, inhibits esophageal adenocarcinoma cell growth [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 LB-094. doi:10.1158/1538-7445.AM2017-LB-094