Citations

Abstract Abstract 1516 Background: MM is generally considered incurable, but the rapid integration of IMiDs.. and proteasome inhibitors into systemic anticancer treatment (SAT) has resulted in clinically important improvements in response rates, disease control and overall survival. A number of factors — including age and comorbidities — influence selection of an initial SAT and whether autologous stem cell transplant (ASCT) is planned. A paucity of information exists on selection of specific SATs for patients in different age groups and resultant outcomes. We attempted to address this issue by aggregating and examining clinical information on individual patients receiving initial treatment for MM. Methods: US community-based MOs were recruited from a database of past participants in our CME activities to provide anonymous information on the presenting symptoms, diagnostic workup, treatment selection, side effects and clinical antitumor response for all patients in their practices with a new diagnosis of MM since January 1, 2008. Modest, per-patient honoraria were provided to each MO for this work. Results: From April 14 to July 9, 2010, 43 MOs entered a total of 276 cases of MM into a web-based data bank (minimum 1 case, maximum 14, median 6). 54% of the patients were men. The median age was 68, with 34% under age 65, 36% from 65 to 74 and 30% age 75 or older. 88% of patients had their tumors evaluated by FISH and/or metaphase cytogenetics. 73% of the evaluated specimens were considered to be “standard risk” and 27% were determined to be “poor risk.” 67% of patients were considered very or moderately symptomatic from the disease at the time treatment was initiated (Table 1), and similar fractions of patients presented with various levels of symptomology across the three age groups. 128 patients (46%) were deemed eligible for ASCT (maximum age 78), and 59 of these patients had already received ASCT after induction treatment. The median age of patients eligible for ASCT was 62, and the most common induction SATs for these patients were Rd or RD (29%), RVD (26%) and VD (23%). The median age of patients considered ineligible for transplant was 76.5, and the most common induction SATs were VD (22%) Rd or RD (21%) MPT (17%) and MPV (17%). Overall, these treatments resulted in CR and PR rates of 22% and 64% respectively, and “things went very well with expected or fewer toxicities” in 38% and minor or moderate toxicity in 44%. These outcomes are similar to what has been reported in published trial data from randomized Phase III studies of these regimens. No major differences were observed in reported levels of efficacy and side effects among the three age groups (Table 1). Conclusions: This unselected case series produced, in a rapid manner, useful information addressing a variety of clinical issues in newly diagnosed MM, including the impact of age and transplant status on treatment selection and outcomes. These data suggest that MOs are able to individualize SATs for older patients and match the short-term outcomes of the therapies they select for younger patients. This risk-benefit differential is of particular palliative importance as these data demonstrate that at diagnosis most patients present with tumor-related symptoms. Additional work of this kind is needed to better understand how physicians adjust doses and schedules of SATs to prevent and ameliorate toxicity, particularly in older patients. Disclosures: Lonial: Bristo-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium Pharmaceuticals Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Anderson:Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millenium Pharmaceuticals Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees; Onxy Pharmaceuticals Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees. Fonseca:Amgen Inc: Consultancy; Bristol-Myers Squibb: Consultancy; Celgene Corporation: Consultancy, Research Funding; Genzyme Corporation: Consultancy; Medtronic Inc: Consultancy; Otsuka Pharmaceutical Co Ltd: Consultancy; Onyx Pharmaceuticals: Research Funding.

Abstract Abstract 1825 Poster Board I-851 Purpose Recent advances in understanding of the molecular alterations that occur at the genetic and epigenetic levels in Multiple Myeloma (MM) have led to major leaps in identifying molecular pathways that regulate progression and resistance to therapeutic agents. However, despite great scientific advances at the genomic level, studies to identify signaling pathways deregulated at the functional proteomic level in MM are limited. We have previously demonstrated that Citron Rho Interacting Kinase (CRIK) is overexpressed in primary multiple myeloma (MM) cells, as compared to the normal plasma cell counterpart, using an antibody-based protein microarray technique. We therefore sought to investigate the functional role of CRIK in MM cells. Methods We determined the protein expression level of 512 polypeptides in 12 samples of newly diagnosed patients with MM using high-throughput proteomic analysis with antibody-based protein microarray. Primary CD138+ sorted MM cells were obtained from the bone marrow of patients after informed consent. MM.1S, RPMI8226, and INA6 MM cell lines were used in this study. Protein expression has been studied by immunoblotting. Gene expression analysis has been assessed using the Affymetrix U133A platform. Lentivirus was used to knockdown CRIK in MM cell lines (MM.1S, RPMI8226, INA6). DNA synthesis, cell survival, cell cycle profiling and apoptosis were assessed by thymidine uptake, MTT, PI and Annexin/PI staining and flow cytometric analysis, respectively. Results Overexpression of CRIK has been confirmed in primary CD138+ tumor cells isolated from bone marrow of 12 patients with MM, as compared to normal plasma cells obtained from healthy donors. We found that CRIK-knockdown exerted an anti-proliferative and pro-apoptotic effect only in IL-6-dependent MM cell line INA6; in contrast, no effect on proliferation and survival was observed in MM1.S and RPMI8226. Indeed, INA6 CRIK-knockdown cells were characterized by a reduction in the proliferation rate, associated with decreased S-phase and G2/M phase cell cycle arrest. Moreover, induction of cytotoxicity was also demonstrated in CRIK knockdown cells compared to scramble probe transfected or non-transfected cells. We also showed that CRIK knockdown led to cytokinesis in INA6, indicating a possible mechanism for inhibition of proliferation of these cells. We next correlated CRIK gene expression level (CIT) with prognosis using previously published gene expression datasets and found that CRIK correlated with poor prognosis. Conclusion In this study, we show that MM cells express a high level of CRIK, and that inhibition of this protein leads to significant inhibition of proliferation and survival of IL-6 dependent MM cells. Moreover, CRIK protein expression correlated with poor survival in patients with MM. Disclosures Anderson: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ghobrial:Millennium: Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau.

Abstract Background: Patients on systemic therapy for cancer are at varying risk for venous thromboembolism (VTE) and its consequences. Thromboprophylaxis is recommended in hospitalized medical and surgical cancer patients, but most VTE occurs in ambulatory cancer patients where risk can be estimated with a validated score. However, the benefit of extended outpatient thromboprophylaxis is uncertain with heparins and has not been tested with direct oral anticoagulants. Methods: We conducted a double-blind, randomized, placebo-controlled, parallel-group, multicenter study in adult ambulatory patients with various cancers initiating a new systemic regimen and at increased risk for VTE (defined as Khorana score ≥ 2). Enrolled subjects were screened for deep-vein thrombosis (DVT) and if none found randomized 1:1 to rivaroxaban 10 mg once daily or placebo up to day 180. Subjects were screened with lower extremity ultrasounds every 8 weeks on study. Primary efficacy endpoint was a composite of objectively confirmed symptomatic or asymptomatic lower-extremity proximal DVT, symptomatic upper- or lower-extremity distal DVT, symptomatic or incidental pulmonary embolism and VTE-related death. ISTH-defined major bleeding was the primary safety endpoint. All endpoints were adjudicated by blinded independent committees. Analyses for efficacy endpoints were conducted for intent-to-treat (ITT) population (all randomized patients) for the up-to-day 180 observation period (primary) and the on-treatment period (supportive). Safety analyses were conducted for on-treatment period only for patients who received at least one dose of study drug. Results: Of 1,080 patients who provided consent, 49 (4.53%) had DVT on baseline screening and another 190 screen-failed due to other reasons. Of 841 randomized patients, 274 (32.6%) had pancreatic cancer; 698 (83%) were white and 428 (50.9%) were male. The primary efficacy endpoint occurred in 25 of 420 patients (5.95%) and 37 of 421 patients (8.79%) (HR, 0.66; 95% CI, 0.40 to 1.09; p=0.101) in the rivaroxaban and placebo groups respectively (number needed to treat, NNT=35) in the up-to-day 180 observation period (Figure 1A). Of all patients with VTE, 38.70% experienced events after discontinuing study drug. In a pre-specified analysis of all randomized patients during the on-treatment period, the primary endpoint occurred in 11 of 420 patients (2.62%) and 27 of 421 (6.41%) in rivaroxaban and placebo groups respectively (HR 0.40, 95% CI 0.20 to 0.80, p=0.007) (NNT=26) (Figure 1B). Major bleeding occurred in 8 of 405 (1.98%) in the rivaroxaban group and in 4 of 404 (0.99%) patients in the placebo group (hazard ratio, 1.96; 95% CI, 0.59 to 6.49; p=0.265) (number needed to harm, NNH=101). Clinically relevant non-major bleeding occurred in 2.72% and 1.98% of rivaroxaban and placebo groups, respectively (HR, 1.34; 95% CI, 0.54 to 3.32; p=0.53) (NNH=135). Adverse events were comparable between groups. For secondary efficacy endpoints, a pre-specified analysis of the composite of primary endpoint with addition of arterial and visceral thromboembolic events in the up-to-day 180 observation period showed significantly fewer events in rivaroxaban versus placebo group (6.90% versus 10.70% respectively; HR, 0.62; 95% CI: 0.39, 0.99; p=0.04). All-cause mortality occurred in 20.0% of patients in rivaroxaban group and 23.8% in placebo group (HR=0.83, 95% CI 0.62, 1.11; p=0.213). A pre-specified composite of the primary endpoint with all-cause mortality occurred in 23.1% of patients in rivaroxaban group and 29.5% in placebo group (HR 0.75; 95% CI 0.57 to 0.97; p=0.03) (Figure 1C). Conclusions: Rivaroxaban significantly reduced VTE and VTE-related death during the on-treatment period but not during the full study period; over one-third of events occurred post discontinuation of study drug. The incidence of major bleeding was low. The Khorana risk score cut-off of ≥2 identified cancer patients at high risk of thrombotic events both at baseline (4.53%) and during study (8.79% with additional 1.66% arterial events in placebo group). These results should inform future recommendations regarding thromboprophylaxis in at-risk ambulatory cancer patients. (Funded by Janssen; ClinicalTrials.gov number, NCT02555878) Figure 1 Figure 1. Disclosures Khorana: Parexel: Other: Personal fees and non-financial support for travel; Sanofi: Consultancy, Other: Personal fees and non-financial support for travel; Pfizer: Consultancy, Other: Personal fees and non-financial support for travel; Janssen: Consultancy, Other: Personal fees, Research Funding; TriSalus: Other: Personal fees; Halozyme: Other: Personal fees and non-financial support for travel; Seattle Genetics: Other: Personal fees and non-financial support for travel; AngioDynamics: Other: Personal fees and non-financial support for travel; LEO Pharma: Other: Personal fees and non-financial support for travel; Medscape/WebMD: Other: Personal fees and non-financial support for travel; Pharmacyclics: Other: Personal fees; PharmaCyte: Other: Personal fees; Bayer: Consultancy, Other: Personal fees and non-financial support for travel. Soff:Janssen: Research Funding; Amgen: Research Funding. Kakkar:Bayer AG: Consultancy, Research Funding; Boehringer Ingelheim: Consultancy; Daiichi Sankyo Europe: Consultancy; Janssen Pharmaceuticals: Consultancy; Pfizer: Consultancy; Sanofi S.A.: Consultancy; Verseon: Consultancy. Vadhan-Raj:AMAG Pharmaceuticals, Inc: Other: received funding from Amag to support clinical trial; Janssen: Consultancy, Research Funding. Riess:Janssen Scientific Affairs: Other: Travel reimbursement; Bayer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees. Wun:Eli Lilly, Inc.: Research Funding; Emmaus, Inc.: Membership on an entity's Board of Directors or advisory committees; Glycomimetics, Inc.: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Pfizer, Inc.: Membership on an entity's Board of Directors or advisory committees. Streiff:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Other: outcome adjudication committee; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Research Funding; Roche: Research Funding; Portola: Consultancy, Research Funding. Garcia:Shingoi: Consultancy; Portola: Research Funding; Pfizer: Consultancy; Janssen: Consultancy, Research Funding; Incyte: Research Funding; Daiichi Sankyo: Research Funding; Bristol Meyers Squibb: Consultancy; Boehringer Ingelheim: Consultancy; Retham Technologies LLC: Consultancy; Genzyme Corporation: Consultancy; Alexion: Consultancy. Liebman:Janssen (Johnson & Johnson): Other: steering committee of the CASSINI trial during the conduct of the study. Belani:Janssen: Consultancy. O'Reilly:3DMed, Agios, AlignMed, Amgen, Antengene, Aptus, ASLAN, Astellas, AstraZeneca, Bayer, BeiGene, Bioline, BMS, Boston Scientific, Bridgebio, CARsgen, Celgene, CASI, Cipla, CytomX, Daiichi, Debio, Delcath, Eisai, Exelixis, Genoscience, Gilead, Halozyme: Consultancy; Hengrui, Incyte, Inovio, Ipsen, Jazz, Janssen, Kyowa Kirin, LAM, Lilly, Loxo, Merck, Mina, NewLink Genetics, Novella, Onxeo, PCI Biotech, Pfizer, PharmaCyte, Pharmacyclics, Pieris, QED, RedHill, Sanofi, Servier, Silenseed, Sillajen, Sobi, Targovax: Consultancy; Janssen: Research Funding; Acta Biologica, Agios, Array, AstraZeneca, Bayer, BeiGene, BMS, CASI, Celgene, Exelixis, Genentech, Halozyme, Incyte, Lilly, MabVax, Novartis, OncoQuest, Polaris Puma, QED, and Roche: Research Funding; Tekmira, twoXAR, Vicus, Yakult, and Yiviva: Consultancy. Patel:Janssen Pharmaceuticals: Research Funding. Yimer:Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Speakers Bureau; AstraZeneca: Speakers Bureau; Epizyme: Equity Ownership; Clovis Oncology: Equity Ownership; Puma Biotechnology: Equity Ownership. Wildgoose:Janssen Scientific Affairs: Employment; Johnson & Johnson: Equity Ownership. Burton:Janssen Pharmaceuticals: Employment; Johnson & Johnson: Equity Ownership. Vijapurkar:Janssen Pharmaceuticals, Inc.: Employment; Johnson & Johnson: Equity Ownership. Kaul:Janssen Pharmaceuticals, Inc.: Employment; Johnson & Johnson: Equity Ownership. Eikelboom:AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Daiichi Sankyo, GlaxoSmithKline, Janssen, sanofi-aventis, and Eli Lilly: Honoraria, Research Funding; Heart and Stroke Foundation: Other: Personnel award. Bauer:Janssen: Consultancy. Kuderer:Celldex: Consultancy; Mylan: Consultancy, Other: Travel, Accommodations, Expenses; Myriad Genetics: Consultancy; Halozyme: Consultancy; Coherus Biosciences: Consultancy, Other: Travel, Accommodations, Expenses; Janssen Scientific Affairs, LLC: Consultancy, Other: Travel, Accommodations, Expenses; Pfizer: Consultancy; Bayer: Consultancy. Lyman:Halozyme; G1 Therapeutics; Coherus Biosciences: Consultancy; Generex Biotechnology: Membership on an entity's Board of Directors or advisory committees; Amgen: Other: Research support.

INTRODUCTION: Non-variceal upper gastrointestinal hemorrhage is traditionally managed with mechanical devices, thermal coagulation, or injection therapy. However, due to specific lesion characteristics, certain cases may not be easily or effectively managed by these methods, in which case either a novel therapy or repurposing of an existing technique could be considered. Here, we present a case of gastric antral vascular ectasia (GAVE) addressed with cryotherapy. CASE DESCRIPTION/METHODS: An 82 year old man with CAD s/p CABG, AS s/p AVR, symptomatic AVB s/p PPM, HTN, and BPH presented to his primary care provider Clinic with chronic, symptomatic, transfusion-dependent iron-deficiency anemia with a hemoglobin nadir of 6.7 g/dL from 12.2 g/dL four months prior. The patient also reported possible melena, though stool appearance was obscured by oral iron supplementation. He underwent diagnostic EGD, which identified severe GAVE with mild associated bleeding throughout the entire stomach. This was therapeutically managed with APC, but given the severity and diffuse nature of the GAVE (Figure 1), the patient was referred for cryotherapy. Medically, the patient was recommended to initiate PPI therapy and continue iron supplementation. Three sessions occurring at 1 month intervals were completed, followed by one session 3 months out. By the third session, the patient no longer required transfusional support to maintain appropriate hemoglobin levels. On endoscopic follow-up 6 months out (one year from initial EGD), the GAVE had improved in severity (Figure 2). DISCUSSION: The current treatment of GAVE primarily involves argon plasma coagulation, which is limited by its inability to treat large areas of mucosa in an efficient manner. However, data supporting the use of cryotherapy as a safe and effective treatment for GAVE are emerging. Patients with diffuse, extensive mucosal gastrointestinal lesions should be referred to a tertiary care center to assess cryotherapy candidacy.

INTRODUCTION: Epidermal metaplasia is a histological correlate to a white patch on the surface of a mucous membrane that cannot be rubbed off, known as leukoplakia. It is a common finding in oral mucosa, however rare in esophageal mucosa. Etiology of this condition in the esophagus is unclear, thought to be associated with esophageal tobacco and alcohol exposure or possibly an unusual response to chronic acid reflux. In contrast to oral leukoplakia there is a female predominance. Although generally asymptomatic, symptom presentation can include dysphagia. Endoscopic features include slightly elevated whitish surface, which can be translucent or cobblestone-like in appearance. The natural history is unknown though there is concern for an increased risk of squamous cell cancer. Due to paucity of published studies about this condition, we aim to report a case treated with endoscopic submucosal dissection (ESD). CASE DESCRIPTION/METHODS: A 64-year-old Caucasian man with a history of tobacco use and stable weight, presented to Gastroenterology clinic due to an 11-month history of solid food esophageal dysphagia. Physical examination was unremarkable. Upper endoscopy demonstrated white plaques at the gastroesophageal junction (Figure 1A and B). Biopsies obtained from this abnormality showed esophageal epidermoid metaplasia consistent with leukoplakia and mild patchy active chronic inflammation. GMS stain for fungal organisms was negative. An ESD procedure was planned, due to lesion size to ensure complete removal. Chromoscopy with methylene blue was used to mark the borders of the lesion and ESD was accomplished without adverse events (Figure 1C). Histologic examination confirmed hyperplastic squamous esophageal mucosa with marked hyperkeratosis without dysplasia and negative margins. During 2 year follow up, patient reported complete resolution of his dysphagia. DISCUSSION: The management strategy for esophageal leukoplakia is not well defined though reports suggest that endoscopic resection and surveillance are warranted. Here we represent a case where symptoms resolved and the lesion was completely removed by ESD.

INTRODUCTION: High-resolution manometry using the Chicago Classification is standard in the evaluation of esophageal motility. When the relaxation of the esophagogastric junction is impaired and achalasia excluded, esophagogastric junction outflow obstruction (EGJ-OO) is diagnosed and the esophageal body is essentially ignored. We sought to characterize the function of the esophageal body in consecutive patients with EGJ-OO. METHODS: Retrospective review of the esophageal manometry findings in consecutive patients where there was computer recognition of EGJ-OO collected over a 2-month period. In each case, the esophageal body was reviewed manually and results reported independent of the suggested computer diagnosis. RESULTS: 116 patients underwent manometry over a 2-month period and 30 (26%) were identified as having EGJ-OO. The indications for testing included chronic cough (n = 5), GERD (n = 8), dysphagia (n = 9) and esophageal evaluation associated with severe lung disease or transplantation (n = 8). The mean IRP was 20.8 (range 16-33.6) and did not vary depending on indication ( P = 0.381). Computer interpretation was EGJ-OO in all patients without mention of the esophageal body. After review, 11 (37%) had an additional esophageal diagnosis. In effective esophageal motility (IEM) was the most prevalent among them (IEM-8, achalasia-2, jackhammer esophagus-1; P = 0.020). The frequency of an additional esophageal diagnosis was significantly different between GERD (0%) and dysphagia (66%; P = 0.004), but not between other groups (i.e. 40% in cough and 37.5% in transplant group). An esophageal body diagnosis was significantly more likely in patients with IRP > 25 (80%) compared with those with IRP < 25 (28%; P = 0.028). CONCLUSION: 1-EGJ-OO is common in patients referred for esophageal manometry. 2-An additional esophageal body diagnosis is common in those with EGJ-OO.3-Esophageal diagnoses are more common in patients with dysphagia and in those with a very high IRP. The body of the esophagus is important in cases of EGJ-OO and should be reported independent of the computer-generated interpretation of the Chicago Classification.

INTRODUCTION: Volumetric laser endomicroscopy (VLE) is a high-resolution imaging modality used in Barrett’s esophagus (BE) surveillance. Established VLE scoring systems use a combination of features to guide BE dysplasia diagnosis but it remains unclear whether these features are sufficient to reach optimal VLE diagnostic performance. This study explores an exhaustive list of VLE features using one-to-one imaging to pathology correlation to develop optimal VLE diagnostic models for BE dysplasia. METHODS: In this prospective, multi-center (5 sites) study, patients with dysplastic BE underwent VLE with laser targeted regions of interest (ROIs), followed by standard surveillance endoscopy and biopsy directed to laser-marked sites. Histology was reviewed by two GI pathologists (MV, RO) who achieved a consensus diagnosis (gold-standard). ROIs were dysplastic if low-grade dysplasia (LGD), high-grade dysplasia (HGD) or intramucosal adenocarcinoma (IMC) was present. Two VLE experts (CLL, GJT) reviewed ROIs and corresponding endoscopic images to identify and define a set of VLE features associated with BE dysplasia. A multi-variable logistic regression model based on least absolute shrinkage and selection operator (LASSO) method was developed to determine the optimal diagnostic performance of these features. A decision tree model with high clinical usability also was developed to evaluate VLE diagnostic performance for real-time image interpretation. RESULTS: A total of 461 VLE ROIs with matching histology were obtained from 150 patients (Table 1). A final dataset of 55 neoplastic (LGD, 12; HGD, 24; IMC, 19) and 56 randomly selected non-dysplastic ROIs were reviewed. Twenty-eight VLE features were identified describing layering, signal intensity, surface topography, and glandular characteristics. LASSO logistic regression modeling identified 5 VLE features which when utilized optimized diagnostic performance with an area under the curve (AUC) for BE dysplasia of 0.95 (Figure 1). To improve clinical usability, a decision tree model was optimized to three levels with an AUC of 0.90 (Figure 2). CONCLUSION: This study represents the most comprehensive review of VLE features associated with BE dysplasia to date. The proposed high-performing diagnostic models suggest that VLE can be used efficiently and effectively to enhance BE surveillance by identifying ROIs for targeted biopsy. Further validation of the proposed VLE models will determine their clinical utility.

Abstract The MHC class I Ag presentation pathway in melanoma cells has a well-established role in immune-mediated destruction of tumors. However, the clinical significance of the MHC class II Ag presentation pathway in melanoma cells is less clear. In Ag-presenting cells, IFN-γ–inducible lysosomal thiol reductase (GILT) is critical for MHC class II–restricted presentation of multiple melanoma Ags. Although not expressed in benign melanocytes of nevi, GILT and MHC class II expression is induced in malignant melanocytes in a portion of melanoma specimens. Analysis of The Cancer Genome Atlas cutaneous melanoma data set showed that high GILT mRNA expression was associated with improved overall survival. Expression of IFN-γ, TNF-α, and IL-1β was positively associated with GILT expression in melanoma specimens. These cytokines were capable of inducing GILT expression in human melanoma cells in vitro. GILT protein expression in melanocytes was induced in halo nevi, which are nevi undergoing immune-mediated regression, and is consistent with the association of GILT expression with improved survival in melanoma. To explore potential mechanisms of GILT’s association with patient outcome, we investigated pathways related to GILT function and expression. In contrast to healthy skin specimens, in which the MHC class II pathway was nearly uniformly expressed and intact, there was substantial variation in the MHC class II pathway in the The Cancer Genome Atlas melanoma specimens. Both an active and intact MHC class II pathway were associated with improved overall survival in melanoma. These studies support a role for GILT and the MHC class II Ag presentation pathway in melanoma outcome.

Abstract Background Gastric electrical stimulation (GES) for treating gastroparesis symptoms is controversial. Methods We studied 319 idiopathic or diabetic gastroparesis symptom patients from the Gastroparesis Clinical Research Consortium (GpCRC) observational studies: 238 without GES and 81 with GES. We assessed the effects of GES using change in GCSI total score and nausea/vomiting subscales between baseline and 48 weeks. We used propensity score methods to control for imbalances in patient characteristics between comparison groups. Key Results GES patients were clinically worse (40% severe vs. 18% for non‐GES; P < .001); worse PAGI‐QOL (2.2. vs. 2.6; P = .003); and worse GCSI total scores (3.5 vs. 2.8; P < .001). We observed improvements in 48‐week GCSI total scores for GES vs. non‐GES: improvement by ≥ 1‐point (RR = 1.63; 95% CI = (1.14, 2.33); P = .01) and change from enrollment (difference = −0.5 (−0.8, −0.3); P < .001). When adjusting for patient characteristics, symptom scores were smaller and not statistically significant: improvement by ≥ 1‐point (RR = 1.29 (0.88, 1.90); P = .20) and change from the enrollment (difference = −0.3 (−0.6, 0.0); P = .07). Of the individual items, the nausea improved by ≥ 1 point (RR = 1.31 (1.03, 1.67); P = .04). Patients with GCSI score ≥ 3.0 tended to improve more than those with score < 3.0. (Adjusted P = 0.02). Conclusions and Inferences This multicenter study of gastroparesis patients found significant improvements in gastroparesis symptoms among GES patients. Accounting for imbalances in patient characteristics, only nausea remained significant. Patients with greater symptoms at baseline improved more after GES. A much larger sample of patients is needed to fully evaluate symptomatic responses and to identify patients likely to respond to GES.

Abstract We previously identified five single nucleotide polymorphisms (SNPs) at four susceptibility loci for diffuse large B-cell lymphoma (DLBCL) in individuals of European ancestry through a large genome-wide association study (GWAS). To further elucidate genetic susceptibility to DLBCL, we sought to validate two loci at 3q13.33 and 3p24.1 that were suggestive in the original GWAS with additional genotyping. In the meta-analysis (5662 cases and 9237 controls) of the four original GWAS discovery scans and three replication studies, the 3q13.33 locus (rs9831894; minor allele frequency [MAF] = 0.40) was associated with DLBCL risk [odds ratio (OR) = 0.83, P = 3.62 × 10−13]. rs9831894 is in linkage disequilibrium (LD) with additional variants that are part of a super-enhancer that physically interacts with promoters of CD86 and ILDR1. In the meta-analysis (5510 cases and 12 817 controls) of the four GWAS discovery scans and four replication studies, the 3p24.1 locus (rs6773363; MAF = 0.45) was also associated with DLBCL risk (OR = 1.20, P = 2.31 × 10−12). This SNP is 29 426-bp upstream of the nearest gene EOMES and in LD with additional SNPs that are part of a highly lineage-specific and tumor-acquired super-enhancer that shows long-range interaction with AZI2 promoter. These loci provide additional evidence for the role of immune function in the etiology of DLBCL, the most common lymphoma subtype.