Citations

Abstract The uptake or expression of hepatitis B virus (HBV) proteins by dendritic cells (DCs) is considered important for disease outcome. Differential expression of microRNA (miRNA) may have a role in viral persistence and hepatocellular injury. The miRNA expression was investigated by microarray in DCs from different stages of HBV infection and liver disease namely, immune active (IA; n = 20); low replicative (LR; n = 20); HBeAg negative ( n = 20); acute viral hepatitis (AVH, n = 20) and healthy controls ( n = 20). miRNA levels were analyzed by unsupervised hierarchical clustering and principal component analyses and validated by quantitative polymerase Chain Reaction (qPCR). The miRNA‐messenger RNA (mRNA)regulatory networks identified 19 miRNAs and 12 target gene interactions in major histocompatibility complex and other immune pathways. miR‐2278, miR‐615‐3p, and miR‐3681‐3p were downregulated in the IA group compared to healthy control, miR‐152‐3p and miR‐3613‐3p in the LR group compared to IA group and miR‐152‐3p and miR‐503‐3p in HBe negative compared to LR group. However, miR‐7‐1‐1‐3p, miR‐192‐5p, miR‐195‐5p, and miR‐32‐5p in LR, miR‐342‐3p, and miR‐940 in HBe negative, and miR‐34a‐5p, miR‐130b‐3p, miR‐221‐3p, miR‐320a, miR‐324‐5p, and miR‐484 in AVH were upregulated. Further, qPCR confirmed changes in miRNA levels and their target genes associated with antigen processing and presentation. Thus, a deregulated network of miRNAs‐mRNAs in DCs seems responsible for an impaired immune response during HBV pathogenesis.

Introduction: A number of clinical and radiological predictors of either stone impaction or ureteral stone passage (SP) have been proposed. We aimed at identifying the key predictors of successful SP by using readily available CT-based tools/measurements. Methods: Patients presenting to the emergency department from February 2017 to February 2018 with an acute unilateral ureteral stone confirmed on non-contrast CT and managed conservatively were followed for SP. Patients with renal impairment, sepsis or requiring emergent intervention were excluded. Patients were followed at 1 month to confirm SP (stone collection/repeat imaging) or failure of passage. The CT variables analyzed included: Stone factors [location, size, volume, HU density (HUD)], impaction factors [ureteral HUD above and below the stone, maximal ureteral wall thickness (UWT) at the stone site, contralateral UWT, and ureteral diameter above and below the stone]. Binary logistic regression analysis was performed to identify predictors of SP. Results: Forty-nine patients met study inclusion criteria, of whom 32 (65.3%) passed the stone without further intervention. Patients with successful passage were more likely to have smaller, lower volume and less dense stones located in the distal ureter ( p < 0.01). Lower ureteral HUD below the stone, lower maximal UWT, and lower ureteral diameter above the stone were associated with successful passage ( p < 0.01). On multivariable logistic regression analysis, only maximal UWT at the stone site was a significant independent predictor of SP outcome ( p = 0.01). Youden's criterion identified 2.3 mm as the optimal UWT cut-off point, which will accurately predict SP with 82.4% sensitivity and 87.5% specificity. Conclusions: Maximal UWT at the stone site was the most significant predictor of successful passage in acute unilateral ureteral stones, with an optimal cut-off point of 2.3 mm. Further prospective studies are needed to accurately predict spontaneous SP.

Abstract Late recurrence of prostate cancer after remission with prior radical prostatectomy is uncommon. This is a unique case of biochemical recurrence after being in remission for 12 years. The patient presented with swelling of the right lower extremity with pelvic MRI demonstrating an arterially enhancing filling defect in the right common iliac. An 18F-fluciclovine PET/CT showed corresponding increased intravascular radiotracer activity. Targeted biopsy of the intravascular lesion showed poorly differentiated carcinoma, suggestive of prostate origin. Although MRI evaluation is the mainstay for pelvic evaluation, characterization with 18F-fluciclovine PET/CT imaging adds high whole-body specificity and diagnostic accuracy.

SummaryReduced‐intensity conditioning (RIC) allogeneic haematopoietic cell transplantation (allo‐HCT) is a curative option for select relapsed/refractory Hodgkin lymphoma (HL) patients; however, there are sparse data to support superiority of any particular conditioning regimen. We analyzed 492 adult patients undergoing human leucocyte antigen (HLA)‐matched sibling or unrelated donor allo‐HCT for HL between 2008 and 2016, utilizing RIC with either fludarabine/busulfan (Flu/Bu), fludarabine/melphalan (Flu/Mel140) or fludarabine/cyclophosphamide (Flu/Cy). Multivariable regression analysis was performed using a significance level of <0·01. There were no significant differences between regimens in risk for non‐relapse mortality (NRM) (P = 0·54), relapse/progression (P = 0·02) or progression‐free survival (PFS) (P = 0·14). Flu/Cy conditioning was associated with decreased risk of mortality in the first 11 months after allo‐HCT (HR = 0·28; 95% CI = 0·10–0·73; P = 0·009), but beyond 11 months post allo‐HCT it was associated with a significantly higher risk of mortality, (HR = 2·46; 95% CI = 0·1.32–4·61; P = 0·005). Four‐year adjusted overall survival (OS) was similar across regimens at 62% for Flu/Bu, 59% for Flu/Mel140 and 55% for Flu/Cy (P = 0·64), respectively. These data confirm the choice of RIC for allo‐HCT in HL does not influence risk of relapse, NRM or PFS. Although no OS benefit was seen between Flu/Bu and Flu/Mel 140; Flu/Cy was associated with a significantly higher risk of mortality beyond 11 months from allo‐HCT (possibly due to late NRM events).

Background: Accurate diagnosis of brain tumor is crucial for adequate surgical strategy. Our institution follows a comprehensive preoperative evaluation based on clinical and imaging information. Methods: To assess the precision of preoperative diagnosis, we compared the “top three list” of differential diagnosis (the first, second, and third diagnoses according to the WHO 2007 classification including grading) of 1061 brain tumors, prospectively and consecutively registered in preoperative case conferences from 2010 to the end of 2017, with postoperative pathology reports. Results: The correct diagnosis rate (sensitivity) of the first diagnosis was 75.8% in total. The sensitivity of the first diagnosis was high (84–94%) in hypothalamic-pituitary and extra-axial tumors, 67–75% in intra-axial tumors, and relatively low (29–42%) in intraventricular and pineal region tumors. Among major three intra-axial tumors, the sensitivity was highest in brain metastasis: 83.8% followed by malignant lymphoma: 81.4% and glioblastoma multiforme: 73.1%. Sensitivity was generally low (≦60%) in other gliomas. These sensitivities generally improved when the second and third diagnoses were included; 86.3% in total. Positive predictive value (PPV) was 76.9% in total. All the three preoperative diagnoses were incorrect in 3.4% (36/1061) of cases even when broader brain tumor classification was applied. Conclusion: Our institutional experience on precision of preoperative diagnosis appeared around 75% of sensitivity and PPV for brain tumor. Sensitivity improved by 10% when the second and third diagnoses were included. Neurosurgeons should be aware of these features of precision in preoperative differential diagnosis of a brain tumor for better surgical strategy and to adequately inform the patients.

TPS7569 Background: Progress in genome technology allows analysis of previously completed trials to identify patients subgroups potentially benefiting from therapy. Enzastaurin is a potent inhibitor of protein kinase C beta (PKC- b) and suppresses the phosphoinositide 3-kinase (PI3K)/AKT pathway. The safety and efficacy of Enzastaurin has been tested in more than 60 clinical trials including 2 major studies in DLBCL: (1) PRELUDE (A phase III maintenance trial of Enzastaurin vs Placebo, N=758) ( Crump, 2016), and (2) S028 (A randomized phase II study of Enzastaurin/R-CHOP vs R-CHOP in frontline intermediate/high-risk DLBCL, N=101) ( Hainsworth, 2016). DNA samples extracted from blood of patients from PRELUDE were retrospectively genotyped using whole genome SNP arrays. From the genome wide screening a novel genetic biomarker, DGM1, was identified showing high correlation with response to Enzastaurin treatment ( Luo, ASH 2018). Importantly, these findings were replicated in the phase II S028 study. In the S028 study the hazard ratio (HR) for OS in high-risk (IPI ≥ 3) DGM1 positive (+) patients who received Enzastaurin/R-CHOP was 0.28 (0.1-0.81) when compared to subjects who received R-CHOP, a benefit favoring Enzastaurin (p=0.018). These data suggest that addition of Enzastaurin to R-CHOP may significantly improve outcome in frontline high-risk DGM1 (+) DLBCL. The ENGINE study was initiated to validate this finding in a prospective study. Methods: Adult patients must have untreated CD20+ DLBCL, IPI ≥ 3. Patients are randomized 1:1 to Enzastaurin/R-CHOP or Placebo/R-CHOP for 6 cycles during combination phase. Each subject’s treatment assignment will be unblinded after response assessment at the end of the combination phase. Subjects randomized to the investigational arm who have a complete or partial response will have the option to continue in the single agent phase to receive Enzastaurin for up to 2 additional years. The study intends to enroll approximately 235 patients with primary endpoint of OS in DGM1 (+) patients. The study is ongoing with 51 sites open in the US and China. As of 22 Jan 2019, 70 patients have been randomized. Clinical trial information: NCT03263026.

Introduction: Reduced-intensity and non-myeloablative (RIC/NMA) conditioning regimens are frequently used in alloHCT for NHL, because they are associated with decreased non-relapse mortality (NRM) risk in comparison with myeloablative conditioning regimens and allow older patients and patients with comorbidities to receive alloHCT. However, the optimal RIC/NMA regimen in allo-HCT for NHL is not known. Using the CIBMTR database we compared the transplant outcomes between the commonly used RIC/NMA regimens in NHL. Methods: 1823 adult (≥18 years) NHL patients in CIBMTR registry undergoing alloHCT using matched related or unrelated donors, between 2008-2016 were included. Analysis was limited to patients receiving four commonly used RIC/NMA regimens: fludarabine/ i.v. busulfan (6.4mg/kg) (Flu/Bu), fludarabine/melphalan (140mg/m^2) (Flu/Mel 140), fludarabine/cyclophosphamide (Fly/Cy) and Flu/Cy with 2Gy Total Body Irradiation (Flu/Cy/TBI). Graft-versus-host disease (GVHD) prophylaxis was limited to calcineurin inhibitor-based regimens. Patients who received post transplantation cyclophosphamide for GVHD prophylaxis were excluded. The primary outcome was overall survival (OS). Secondary outcomes included cumulative incidence of NRM, relapse, progression-free survival (PFS) and cumulative incidence of acute and chronic GVHD. Probabilities of OS and PFS were calculated using the Kaplan-Meier estimator. Multivariable regression analysis was performed for GVHD, relapse/progression, NRM, PFS, and OS. Covariates with a p&lt;0.01 were considered significant. Results: The study cohort was divided into 4 groups; Flu/Bu (n=458), Flu/Cy/TBI (n=89), Flu/Mel 140 (n=885) and Flu/Cy (n=391). The baseline characteristics are shown in Table 1. The 4 cohorts were comparable with respect to median patient age, gender, donor type, remission status at alloHCT, and use of prior auto HCT. There was no interaction between NHL histological subtype and type of conditioning regimen. Results of multivariate analysis are shown in Table 2. The Flu/Mel 140 regimen was associated with a higher NRM (HR 1.78, 95% CI 1.37-2.31; p&lt;0.001) when compared to Flu/Bu. Although the risk of relapse with Flu/Mel 140 was lower when compared to Flu/Bu (HR 0.79, 95% CI 0.66-0.94); p=0.007), this did not result in an improvement in PFS. Moreover, the Flu/Mel 140 cohort had an inferior OS (HR 1.34, 95% CI 1.13-1.59; p&lt;0.001) when compared to Flu/Bu. There was no significant difference in terms of OS, PFS, relapse and NRM between Flu/Bu, Flu/Cy and Flu/Cy/TBI. There was no difference in risk of grade 3-4 acute GVHD across the four cohorts and compared to Flu/Cy/TBI, Flu/Mel 140 had a higher risk of chronic GVHD (HR 1.38, 95% CI 1.15-1.65; p&lt;0.001). Four year adjusted PFS was 38% for Flu/Bu, 51% for Flu/Cy/TBI, 39% for Flu/Mel 140 and 35% for Flu/Cy (p=0.07). Four year adjusted OS was 58% for Flu/Bu, 67% for Flu/Cy/TBI, 49% for Flu/Mel 140 and 63% for Flu/Cy (p&lt;0.001). Disease relapse was the most common cause of death across all 4 cohorts. Conclusion: This is the largest analysis comparing the impact of various RIC/NMA conditioning regimens on the outcomes of NHL patients undergoing alloHCT. We report that the choice of RIC/NMA conditioning regimen significantly impacted OS. The most commonly used conditioning regimen, Flu/Mel 140 was associated with a higher NRM and an inferior OS. The Flu/Bu, Flu/Cy, and Flu/CY/TBI conditioning regimens appear to provide comparable OS. Disclosures Ghosh: Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau; SGN: Consultancy, Honoraria, Research Funding, Speakers Bureau; TG Therapeutics: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Research Funding; Genentech: Research Funding; Forty Seven Inc: Research Funding; AstraZeneca: Honoraria, Speakers Bureau. Kharfan-Dabaja:Pharmacyclics: Consultancy; Daiichi Sankyo: Consultancy. Sureda:Amgen: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Sanofi: Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support; Novartis: Honoraria; Roche: Honoraria. Hamadani:Merck: Research Funding; ADC Therapeutics: Consultancy, Research Funding; Celgene: Consultancy; Otsuka: Research Funding; Medimmune: Consultancy, Research Funding; Takeda: Research Funding; Pharmacyclics: Consultancy; Janssen: Consultancy; Sanofi Genzyme: Research Funding, Speakers Bureau.

Background: Progress in genome technology allows analysis of previously completed trials to identify subgroups potentially benefiting from therapy. Enzastaurin is a potent inhibitor of protein kinase C beta (PKC-β) and suppresses the phosphoinositide 3-kinase (PI3K)/AKT pathway. The safety and efficacy of Enzastaurin has been tested in more than 60 clinical trials including 2 major studies in DLBCL: (1) PRELUDE (A phase III maintenance trial of Enzastaurin vs Placebo, N=758) (Crump, 2016), and (2) S028 (A randomized phase II study of Enzastaurin/R-CHOP vs R-CHOP in frontline intermediate/high-risk DLBCL, N=101) (Hainsworth, 2016). DNA samples extracted from blood of patients from PRELUDE were retrospectively genotyped using whole genome SNP arrays. From the genome wide screening a novel genetic biomarker, DGM1, was identified showing high correlation with response to Enzastaurin treatment (Luo, ASH 2018). Importantly, these findings were replicated in the phase II S028 study. In the S028 study the hazard ratio (HR) for OS in high-risk (IPI ≥ 3) DGM1 positive (+) patients who received Enzastaurin/R-CHOP was 0.28 (0.1-0.81) when compared to subjects who received R-CHOP, a benefit favoring Enzastaurin (p=0.018). These data suggest that addition of Enzastaurin to R-CHOP may significantly improve outcome in frontline high-risk DGM1 (+) DLBCL. The ENGINE study was initiated to validate this finding in a prospective study. Study Design and Methods: Adult patients must have untreated CD20+ DLBCL, IPI ≥ 3. Patients are randomized 1:1 to Enzastaurin/R-CHOP or Placebo/R-CHOP for 6 cycles during combination phase. Each subject's treatment assignment will be unblinded after response assessment at the end of the combination phase. Subjects randomized to the investigational arm who have a complete or partial response will have the option to continue in the single agent phase to receive Enzastaurin for up to 2 additional years. The study intends to enroll approximately 235 patients with primary endpoint of OS in DGM1 (+) patients. The study is ongoing with 57 sites open in the US and China. As of 20 July 2019, 128 patients have been randomized. Clinical trial information: NCT03263026. Disclosures Nowakowski: Genentech, Inc.: Research Funding; Curis: Research Funding; Bayer: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Selvita: Membership on an entity's Board of Directors or advisory committees; NanoString: Research Funding; MorphoSys: Consultancy, Research Funding. Brody:Acerta Pharma: Research Funding; Merck: Research Funding; Celldex Therapeutics: Research Funding; Genentech: Research Funding; Oncovir, Inc.: Research Funding; BMS: Research Funding; Kite Pharma: Research Funding. Lue:Kymera Therapeutics: Honoraria; Astex Pharmaceuticals: Honoraria. Luo:Denovo Biopharma LLC: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Zhang:Denovo Biopharma LLC: Employment. Han:Denovo Biopharma LLC: Employment. Jivani:TRACON Pharmaceuticals, Inc.: Other: Stock; Denovo Biopharma LLC: Employment. Liu:Denovo Biopharma LLC: Employment. Li:Denovo Biopharma LLC: Employment. Sun:Novartis: Other: Stock; Denovo Biopharma LLC: Employment.