Citations

Abstract New approaches are needed to overcome intrinsic therapy resistance in glioblastoma (GBM). Because GBMs exhibit sexual dimorphism and are reported to express steroid hormone receptors, we reasoned that signaling through the androgen receptor (AR) could mediate therapy resistance in GBM, much as it does in AR-positive prostate and breast cancers. We found that nearly half of GBM cell lines, patient-derived xenografts (PDX), and human tumors expressed AR at the transcript and protein level—with expression levels overlapping those of primary prostate cancer. Analysis of gene expression datasets also revealed that AR expression is higher in GBM patient samples than normal brain tissue. Multiple clinical-grade antiandrogens slowed the growth of and radiosensitized AR-positive GBM cell lines and PDXs in vitro and in vivo. Antiandrogens blocked the ability of AR-positive GBM PDXs to engage adaptive transcriptional programs following radiation and slowed the repair of radiation-induced DNA damage. These results suggest that combining blood–brain barrier permeable antiandrogens with radiation may have promise for patients with AR-positive GBMs.

Abstract Introduction: Hematologic response (HR) particularly complete response (CR) is critical in patients (pts) with AL since it improves overall survival (OS) because of organ response (OrgR). Bor based therapies especially in combination with cyclophosphamide and dexamethasone (CyBorD) have shown to be an active regimen in AL. So far, there have been no comparative studies studying the effect of treatment with B-based regimens prior to SCT (Bor-SCT) versus SCT upfront or SCT preceded by non-Bor therapies (non-Bor-SCT). We present a retrospective analysis of data with an aim to compare the OS, OrgR and HR in the two cohorts. Methods: Charts were reviewed for the pts who underwent SCT for AL since 2004 until 2015 at Mayo Clinic in Arizona. HR and OrgR were determined using the consensus criteria from International Society of Amyloidosis.1 HR were noted at 3, 6 and 12 months from SCT. Results: Patients and disease characteristics: 63 pts were identified who underwent SCT for AL, of which 34 were in Bor-SCT and 29 were in the non-Bor-SCT cohort. Median age at diagnosis was 59.5 (range, 39 - 72) and 63 (range, 38 - 76) years and at SCT was 60 (range, 40 - 72) and 63 (range, 39 - 76) years for Bor-SCT and non-Bor-SCT, respectively. There were 13 (38%) females in Bor-SCT and 9 (31%) in non-Bor-SCT. Mean bone marrow involvement of plasma cells at diagnosis was 18% (SD±16.5) in Bor-SCT and 6.8% (SD±7.8) in non-Bor-SCT (p = 0.004). All pts had an ECOG performance score of better than 3 at the time of SCT. Fifteen (44%) pts had single organ involvement at diagnosis and 9 (26.5%) had 2-organ involvement in Bor-SCT. In non-Bor-SCT, 21 (72%) pts had single and 6 (21%) had 2-organ involvement (p = 0.04). More than 2 organs were involved in 10 (29%) pts in Bor-SCT and 2 (7%) in non-Bor-SCT. Heart was involved in 18 (53%) pts in Bor-SCT and 8 (28%) in non-Bor-SCT (p = 0.04) while kidney involvement was seen in 27 (79%) in Bor-SCT and 23 (79%) in non-Bor-SCT (p = 0.99). Median creatinine was not significantly different in the 2 groups at diagnosis or at the time of SCT. In Bor-SCT, no pts were on hemodialysis at the time of diagnosis or SCT. In non-Bor-SCT, 1 pt at diagnosis and 3 pts at SCT progressed to need hemodialysis. Lambda light chain was involved in 27 (82%) and 22 (76%) (p = 0.56) with a mean level of involved light chains being 59(SD±88.7) g/dL and 43.3 (SD±64.6) g/dL (p=0.4539) in Bor-SCT and non-Bor-SCT, respectively. Treatment: Thirty-one (91%) out of 34 pts in Bor-SCT group got treatment with CyBorD while 2 (6%) got Bor with dexamethasone and 1 (3%) got Bor with pegylated liposomal doxorubicin. In the non-Bor-SCT group, 20 (69%) out of 29 got no treatment, 4 (14%) got melphalan prednisone, 2 (7%) got dexamethasone alone, 1 (3%) got vincristine dexamethasone and 2 (7%) got lenalidomide dexamethasone prior to SCT. Transplant factors: Median time from diagnosis to SCT was 226.5 (range, 65 - 1108) days in Bor-SCT and 150.5 (48 - 1139) days in non-Bor-SCT (p=0.32). Full dose of melphalan (200 mg/m2) was used in 21 (62%) pts in Bor-SCT and 13 (34%) pts in non-Bor-SCT (p <0.001). Mean dose of cells used for SCT was 4.6 (SD±0.9) and 4.8 (SD±2.2) x 106/kg in Bor-SCT and non-Bor-SCT, respectively. Median time to neutrophil and platelet engraftment was 13 (range, 10 - 27) and 16 (range, 8 - 28) days in Bor-SCT while 11 (range, 7 - 16) and 13 (range, 10 - 25) days in non-Bor-SCT. Responses: HR at 3, 6 and 12 months from SCT and OrgR by the time of last follow up is described in table 1. Survival: Median OS was not reached in Bor-SCT as compared to 53.4 months in non-Bor-SCT (p =0.001), Figure 1. Conclusions: Our study suggests a benefit in HR, OrgR as well as OS by reduction of disease burden by Bor-based therapy prior to SCT. This benefit was observed despite a higher percentage of pts with cardiac involvement, more than 2 organ involvement and mean bone marrow plasma cells at diagnosis in Bor-SCT. Currently, it is not standard practice to use Bor-based therapy prior to SCT. A prospective study with larger number of pts would be required to confirm these findings. References: 1. Gertz MA et al. Definition of Organ Involvement and Treatment Response in Immunoglobulin Light Chain Amyloidosis (AL): A Consensus Opinion From the 10th International Symposium on Amyloid and Amyloidosis. Am J Hematol. 2005;79(4):319-328. Disclosures Dueck: Bayer: Honoraria. Mikhael:Abbvie, Celgene, Onyx, Sanofi: Research Funding. Bergsagel:Amgen, BMS, Novartis, Incyte: Consultancy; Novartis: Research Funding. Reeder:Novartis, Millennium, BMS and Celgene: Research Funding. Stewart:celgene: Consultancy. Fonseca:AMGEN: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Sanofi: Consultancy; Bayer: Consultancy; Millennium, a Takeda Company: Consultancy; Millennium, a Takeda Company: Consultancy; AMGEN: Consultancy; BMS: Consultancy; Celgene: Consultancy; Patent: Patents & Royalties: Prognostication of MM based on genetic categorization of FISH of the disease; Patent: Patents & Royalties: Prognostication of MM based on genetic categorization of FISH of the disease; Patent Pending: Patents & Royalties: The use of calcium isotopes as biomarkers for bone metabolisms; AMGEN: Consultancy; AMGEN: Consultancy; Patent: Patents & Royalties: Prognostication of MM based on genetic categorization of FISH of the disease; Patent Pending: Patents & Royalties: The use of calcium isotopes as biomarkers for bone metabolisms; Millennium, a Takeda Company: Consultancy; Sanofi: Consultancy; Janssen: Consultancy; Millennium, a Takeda Company: Consultancy; Patent: Patents & Royalties: Prognostication of MM based on genetic categorization of FISH of the disease; Patent Pending: Patents & Royalties: The use of calcium isotopes as biomarkers for bone metabolisms; Patent Pending: Patents & Royalties: The use of calcium isotopes as biomarkers for bone metabolisms; Celgene: Consultancy; BMS: Consultancy; Bayer: Consultancy; Novartis: Consultancy.

Objective Antireflux surgery can be proposed in patients with GORD, especially when proton pump inhibitor (PPI) use leads to incomplete symptom improvement. However, to date, international consensus guidelines on the clinical criteria and additional technical examinations used in patient selection for antireflux surgery are lacking. We aimed at generating key recommendations in the selection of patients for antireflux surgery. Design We included 35 international experts (gastroenterologists, surgeons and physiologists) in a Delphi process and developed 37 statements that were revised by the Consensus Group, to start the Delphi process. Three voting rounds followed where each statement was presented with the evidence summary. The panel indicated the degree of agreement for the statement. When 80% of the Consensus Group agreed (A+/A) with a statement, this was defined as consensus. All votes were mutually anonymous. Results Patients with heartburn with a satisfactory response to PPIs, patients with a hiatal hernia (HH), patients with oesophagitis Los Angeles (LA) grade B or higher and patients with Barrett’s oesophagus are good candidates for antireflux surgery. An endoscopy prior to antireflux surgery is mandatory and a barium swallow should be performed in patients with suspicion of a HH or short oesophagus. Oesophageal manometry is mandatory to rule out major motility disorders. Finally, oesophageal pH (±impedance) monitoring of PPI is mandatory to select patients for antireflux surgery, if endoscopy is negative for unequivocal reflux oesophagitis. Conclusion With the ICARUS guidelines, we generated key recommendations for selection of patients for antireflux surgery.

Background:Mutations in isocitrate dehydrogenase 1 (IDH1) occur in ∼4% of patients with myelodysplastic syndrome (MDS) and have been linked with increased transformation to acute myeloid leukemia (AML). Ivosidenib (IVO; AG‐120) is an oral, potent, targeted inhibitor of the mutant IDH1 protein (mIDH1) that is approved for the treatment of adults with mIDH1 relapsed or refractory (R/R) AML. Through inhibition of mIDH1, IVO suppresses production of the oncometabolite 2‐hydroxyglutarate, leading to clinical responses via differentiation of malignant cells.Aims:To report safety and efficacy data from patients with R/R MDS enrolled in the first‐in‐human, phase 1, dose escalation and expansion study of IVO in patients with mIDH1 advanced hematologic malignancies (NCT02074839).Methods:This ongoing study is evaluating the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and clinical activity of IVO. Enrollment was completed on May 8, 2017. In dose escalation, patients received single‐agent IVO orally (dose range, 200–1200 mg daily) in 28‐day cycles. The MTD was not reached and 500 mg QD was selected as the dose for expansion. The overall response rate (ORR) for MDS was defined as complete remission (CR) + partial remission + marrow CR (mCR) according to International Working Group 2006 criteria for MDS. Exploratory biomarker assessments included baseline co‐occurring mutations (next‐generation sequencing panel for hematologic malignancies) and mIDH1 variant allele frequency (VAF) in bone marrow mononuclear cells (BEAMing Digital PCR; lower limit of detection for mIDH1, 0.02–0.04%).Results:Baseline characteristics of the 12 patients with R/R MDS who received 500 mg IVO once daily were: 9 men/3 women; median age 72.5 years (range 52–78), and 42% were ≥75 years of age; median number of prior therapies 1 (range 1–3). As of Nov 2, 2018, 3 of 12 (25.0%) patients remained on treatment; 9 (75.0%) had discontinued (one for allogeneic stem cell transplantation). Median duration of exposure to IVO was 11.4 months (range 3.3–42.5). Adverse events (AEs) of any grade, irrespective of causality, occurring in ≥20% of the 12 patients were diarrhea, fatigue, back pain, rash (n = 4 each, 33.3%), anemia, urinary tract infection, decreased appetite, hypokalemia, arthralgia, dyspnea, pruritus, and hypotension (n = 3 each, 25.0%). No AEs led to permanent discontinuation of treatment. IDH differentiation syndrome was observed in 1 of 12 (8.3%) patients (grade 2). Electrocardiogram QT prolonged was reported in 2 of 12 patients (17%; grade 1 in 1 patient and grade 2 in 1 patient). Five of 12 patients achieved CR (41.7%; 95% CI 15.2%, 72.3%), 1 achieved PR (8.3%), and 5 achieved mCR (41.7%), resulting in an ORR of 91.7% (95% CI 61.5%, 99.8%). The median duration of CR was not estimable (NE) at the time of datacutoff and the median duration of response was 21.4 months (95% CI 2.3, NE). At 12 months, 60.0% of patients remained in CR. Among 5 patients who were transfusion dependent at baseline, 4 became transfusion independent for ≥56 consecutive days on treatment. Baseline co‐occurring mutations and changes in mIDH1 VAF levels will be presented.Summary/Conclusion:In patients with mIDH1 R/R MDS, IVO monotherapy was well tolerated and induced durable remissions and transfusion independence. These findings support the role of IVO as an effective, oral, targeted treatment for patients with mIDH1 R/R MDS.

Abstract Although neurogastroenterology and motility ( NGM ) disorders are some of the most frequent disorders encountered by practicing gastroenterologists, a structured competency‐based training curriculum developed by NGM experts is lacking. The American Neurogastroenterology and Motility Society ( ANMS ) and the European Society of Neurogastroenterology and Motility ( ESNM ) jointly evaluated the components of NGM training in North America and Europe. Eleven training domains were identified within NGM , consisting of functional gastrointestinal disorders, visceral hypersensitivity and pain pathways, motor disorders within anatomic areas (esophagus, stomach, small bowel and colon, anorectum), mucosal disorders (gastro‐esophageal reflux disease, other mucosal disorders), consequences of systemic disease, consequences of therapy (surgery, endoscopic intervention, medications, other therapy), and transition of pediatric patients into adult practice. A 3‐tiered training curriculum covering these domains is proposed here and endorsed by all NGM societies. Tier 1 NGM knowledge and training is expected of all gastroenterology trainees and practicing gastroenterologists. Tier 2 knowledge and training is appropriate for trainees who anticipate NGM disorder management and NGM function test interpretation being an important part of their careers, which may require competency assessment and credentialing of test interpretation skills. Tier 3 knowledge and training is undertaken by trainees interested in a dedicated NGM career and may be restricted to specific domains within the broad NGM field. The joint ANMS and ESNM task force anticipates that the NGM curriculum will streamline NGM training in North America and Europe and will lead to better identification of centers of excellence where Tier 2 and Tier 3 training can be accomplished.

AbstractBackgroundAn international group of experts evaluated and revised recommendations for ambulatory reflux monitoring for the diagnosis of gastro‐esophageal reflux disease (GERD).MethodsLiterature search was focused on indications and technical recommendations for GERD testing and phenotypes definitions. Statements were proposed and discussed during several structured meetings.Key ResultsReflux testing should be performed after cessation of acid suppressive medication in patients with a low likelihood of GERD. In this setting, testing can be either catheter‐based or wireless pH‐monitoring or pH‐impedance monitoring. In patients with a high probability of GERD (esophagitis grade C and D, histology proven Barrett's mucosa >1 cm, peptic stricture, previous positive pH monitoring) and persistent symptoms, pH‐impedance monitoring should be performed on treatment. Recommendations are provided for data acquisition and analysis. Esophageal acid exposure is considered as pathological if acid exposure time (AET) is greater than 6% on pH testing. Number of reflux episodes and baseline impedance are exploratory metrics that may complement AET. Positive symptom reflux association is defined as symptom index (SI) >50% or symptom association probability (SAP) >95%. A positive symptom‐reflux association in the absence of pathological AET defines hypersensitivity to reflux.Conclusions and InferencesThe consensus group determined that grade C or D esophagitis, peptic stricture, histology proven Barrett's mucosa >1 cm, and esophageal acid exposure greater >6% are sufficient to define pathological GERD. Further testing should be considered when none of these criteria are fulfilled.