Citations

Abstract Abstract 596 Background Large population-based studies have demonstrated a significant improvement in survival (OS) for patients (pts) with multiple myeloma (MM) over time since the mid-1990s. The improvement has mostly affected younger patients suggesting a beneficial impact of AHCT. The availability of novel drugs within the last decade and their impact on the utilization and outcomes of AHCT recipients is unknown. Methods We retrospectively reviewed the characteristics and outcomes of 20,278 patients undergoing AHCT within 12 months of diagnosis in USA and Canada and reported to CIBMTR in the periods of 1995–1999 (n=2226), 2000–2004 (n=6408) and 2005–2010 (n=11644) including a subgroup of 4373 individuals with detailed patient, disease and treatment information. We subsequently compared survival and analyzed patient, disease and treatment characteristics across the three periods with the time period serving as a surrogate for pre- and post-transplant exposure to novel agents. Results Across the 3 time periods, there was a marked increase in the number of upfront transplants across all age groups (Figure 1a). Patients receiving upfront HSCT in the more recent period were older, less likely to have stage 3 MM at diagnosis and more likely to have received thalidomide (<1 % vs. 22% vs. 52%), lenalidomide (0% vs. <1% vs. 21%) or bortezomib (0% vs. 2% vs. 35%) and have chemosensitive disease at the time of AHCT. The proportion of African-American patients remained low and stable across the three periods (14 vs. 13 vs. 15%). Over the 3 periods, there was a decrease in chemotherapy based stem cell mobilization and increase of single agent G-CSF based mobilization (24% vs. 24% vs. 41%). The use of single agent Melphalan conditioning increased from 54% in 1995–1999 to nearly 100% in the latest period concomitant with near disappearance of total body irradiation-based and multi-drug conditioning regimens. Compared with 1995–99 cohort, survival was superior in the 2000–04 and 2005–09 cohorts at 24 (72% vs. 79% vs. 84%, P<0.001), 48 (54% vs. 60% vs. 64%, P<0.001) and 60 months (47% vs. 52% vs. 55%, P<0.001) (Figure 1b). In multivariate analysis, we found that transplant in the 2000–04 period (HR=0.77, 95% C.I. 0.67–0.89) or in the 2005–10 period (HR=0.68, 95% C.I. 0.59–0.79) along with Karnofsky performance score of 80–100 (HR=0.59, 95% CI 0.51–0.70) and chemosensitivity (HR= 0.76, 95% C.I. 0.66–0.87) were associated with lower risk of death. Factors associated with higher risk of death were age 50–65 (HR=1.29 95% 1.13–1.47), age 65–80 (HR=1.45, 1.23–1.72), Durie-Salmon or ISS stage III at diagnosis (HR 1.56, 95% C.I. 1.39–1.76) and more than one prior line of therapy (HR=1.15, 95% C.I. 1.03–1.28). In comparison to patients transplanted in 1995–99, post relapse survival was superior for patients transplanted in 2000–04 and 2005–10 at 24 months (58% vs. 65% vs. 72%, P=0.005 and <0.001 respectively) and 48 months (33% vs. 39% vs. 40%, P=0.023 and 0.033 respectively). The use of maintenance therapy has changed with 27% in 1995–99 receiving planned interferon vs. 23% in 2005–09 receiving planned thalidomide, lenalidomide or bortezomib maintenance. Conclusions Utilization of upfront AHCT is increasing in the USA, particularly in older patients. Improvement in survival for MM patients seen in population studies results not only from greater utilization of AHCT but also from the improvement in outcomes after AHCT and a significant recent improvement in post-relapse survival. Pre- and post-transplant exposure to novel agents likely contributes to survival. AHCT and novel agents are complementary and should be combined for the optimal management of newly diagnosed MM. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 143 IL-12 induces IFN-g production and contributes to anti-tumor immunity. However, administration of IL-12 in cancer patients has resulted in a limited clinical benefit. In follicular B-cell lymphoma (FL), a clinical trial of IL-12 in combination with rituximab showed a lower response rate in patients treated with the combination than in patients treated with rituximab alone (Clin Cancer Res 2006), suggesting that, in contrast to the observations in vitro or in vivo in mice, IL-12 actually plays a detrimental role in FL patients. Recently, a type of immune response, termed “ T cell exhaustion” describing a condition in which T cells exhibit reduced differentiation, proliferation, and effector function, has been shown to impair anti-tumor immunity and result in disease progression. TIM-3, a family member of T-cell immunoglobulin and mucin domian-containing proteins, inhibits TH1-mediated immune response and promotes immunological tolerance. A recent study has suggested that TIM-3 may play an important role in mediating T cell exhaustion. However, the biological and clinical relevance of TIM-3 in cancers remains completely unknown. In this study, we determined whether T cell exhaustion exists in the tumor microenvironment, whether IL-12 contributes to T cell exhaustion, and whether TIM-3-mediated T cell exhaustion impacts patient outcome in FL. We found that serum IL-12 levels were elevated in FL patients compared to healthy individuals (median: 0.50 ng/ml, n=30 vs 0.32 ng/ml, n=22; p= 0.03) and that elevated serum IL-12 levels were associated with a poor outcome in these patients when treated with rituximab alone as initial therapy. Using 0.56 ng/ml as a cutoff, patients with serum IL-12 levels of greater than 0.56 ng/ml had a significantly shorter time to progression than patients with IL-12 levels less than 0.56 ng/ml (12 months versus 40 months; p=0.001). Both lymphoma B cells and monocytes were able to produce IL-12 and contributed to elevated serum levels of IL-12 in FL. Importantly, we found that IL-12 strongly induced TIM-3 expression in a dose-dependent manner. Endogenous production of IL-12 by lymphoma B cells and monocytes was capable of regulating TIM-3 expression on T cells from FL. As a consequence, TIM-3 was highly expressed on a subset of T cells from PBMCs or lymph nodes from FL patients while its expression was negligible or moderate on T cells from normal PBMCs or benign lymph nodes, respectively. The number of TIM-3-expressing T cells accounted for approximately 32% and 39% of CD4+ or CD8+ T cells in biopsy specimens and 6.2% and 6.7% in peripheral blood of FL patients. TIM-3+ T cells, co-expressed with PD-1, exhibited a reduced ability to proliferate and decreased cytokine production compared to TIM-3- T cells. Similarly, IL-12-induced TIM-3+ T cells gradually lost the capacity to produce cytokines over a period of time. These results suggest that TIM-3-expressing T cells are functionally exhausted. In addition, TIM-3+ T cells were prone to apoptotic induction by its ligand galectin (Gal) -9. The phosphorylation of p38 was higher in TIM-3+ T cells compared to TIM-3- T cells when exposed to Gal-9, suggesting MAPK pathway was involved in Gal-9-mediated apoptosis of TIM-3+ T cells. Finally, increased numbers of intratumoral TIM-3-expressing cells were associated with a higher histological grade, higher LDH levels and a poor survival in FL patients. Taken together, these results indicate that IL-12, in contrast to its role in augmenting immune response through IFN-g, induces T cell exhaustion by upregulating TIM-3 expression. We further demonstrated that lymphoma B cells produce IL-12 thereby contributing to T cell exhaustion by promoting TIM-3 expression on intratumoral T cells. Impairment of anti-tumor immunity due to T cell exhaustion induced by the IL-12-TIM-3 pathway may account for the observation that high levels of serum IL-12 and increased number of TIM-3+CD4+ T cells correlate with a worse outcome in FL patients. These findings not only reveal a novel IL-12-TIM-3 pathway that plays an important role in impairing tumor immunity and detrimentally affecting prognosis in FL patients, but may have therapeutic potential for cancer patients. Disclosures: No relevant conflicts of interest to declare.

INTRODUCTION: Acute portal vein thrombosis (PVT) is a rare diagnosis frequently associated with cirrhosis. Clinical presentation is typically nonspecific with potentially catastrophic short-term complications including sepsis, bowel infarction, and death. Management strategies differ for acute and chronic PVT. Guidelines for treating acute PVT recommend immediate initiation of systemic anticoagulation. Direct and indirect thrombolytic therapy (mechanical thrombectomy and fibrinolytic therapy) may be used in combination with systemic anticoagulation in the setting of bowel ischemia or as an adjunct in patients with a contraindication to systemic anticoagulation. We aimed to assess the success of thrombolytic therapy for non-malignant acute PVT and to compare the success of direct versus indirect thrombolytic therapy. METHODS: This was a systematic review and meta-analysis in which two independent librarians searched the following databases from the date of inception to March 2019: Ovid Medline, Ovid Embase, Scopus and Web of Science. All included studies provided technical and clinical success data, as well as adverse events, and technique(s) used for the intervention of non-malignant acute PVT. RESULTS: The two independent database searches yielded 143 citations, of which 79 duplicates were removed leaving a total of 64 references and 11 were included in our analyses. The overall success rate of thrombolytic therapy using the random effects model was 83% (95%CI: 0.67, 0.92; P = <0.01; I 2 = 61%). The overall clinical improvement rate of thrombolytic therapy using the fixed effects model was 95% (95%CI: 0.88, 0.98; P = 0.73; I 2 = 0%). The overall mortality of thrombolytic therapy using the fixed effects model was 5% (95%CI: 0.03, 0.11; P = 0.92; I 2 = 0%). In the direct and indirect thrombolytic groups, the rate of technical success was 84% and 52%, respectively, with an odds ratio of 3.37 (95%CI (0.96, 7.67), P -value = 0.127). CONCLUSION: Our analysis demonstrates that thrombolytic therapy successfully eliminates non-malignant acute PVTs with low rates of mortality. Direct thrombolysis may produce increased efficacy compared to indirect thrombolytic therapy. Larger prospective randomized trials comparing these interventions are warranted.

INTRODUCTION: Prometheus IBD sgi Diagnostic (SGI) is an Inflammatory Bowel Disease (IBD) advanced diagnostic test developed by Prometheus Laboratories. It employs a diagnostic algorithm combining serologic, genetic, and inflammatory markers to help with clinical decision making in determining the accuracy of a diagnosis of IBD in patients suspected to have the disease. Moreover, among those it identifies as having IBD, it also seeks to assist in distinguishing those with Crohn's vs. those with ulcerative colitis (UC). In this observational clinical decision making study, we sought to examine the real world application of the SGI at a single tertiary care IBD practice especially in correctly identifying those with Crohn's vs. those with UC. METHODS: We included all adult IBD patients seen at a single tertiary IBD center practice from 2014 to 2017 that had baseline SGI done and during care at the practice, had a diagnosis of IBD (Crohn's or UC) established. We calculated sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), accuracy, and area under the curve based on results of SGI at baseline visit and the eventual established diagnosis of UC or CD. RESULTS: Of a total of 275 patients, there were 96 (34.9%) male patients and 179 (65.1%) female patients. The median age of these patients was 45.8. There were a total of 201 patients with biopsy proven CD. Of these, 104 were identified as having CD based on the baseline SGI and 97 who were identified as not having CD. Based on these data, the sensitivity of the SGI for CD at the practice was 52%, specificity was 88%, PPV was 92%, NPV was 40.1%, diagnostic accuracy was 61.5%, and Area under ROC was 70%. There were 66 patients with biopsy proven UC. Of these, 44 were identified as having UC based on the baseline SGI and 22 were identified as not having UC. Based on these data, the sensitivity of the SGI for UC at the practice was 67%, specificity was 85%, PPV was 58%, NPV was 89%, accuracy was 80%, and Area under ROC was 76%. CONCLUSION: Based on the results of this study, we conclude that the SGI is not a robust initial test in identifying those with Crohn's or those with UC. However, in a cohort of IBD patients seen at a tertiary care IBD practice, it is reasonably specific and accurate when it comes to correctly confirming Crohn's and even more so UC in patients with a caveat that the results should be interpreted in the proper clinical context and with the backing of other clinical indicators.

INTRODUCTION: Crohn's Disease (CD) is a chronic inflammatory condition, primarily of the gastrointestinal tract with an increasing incidence and prevalence worldwide. In clinical practice, gastroenterologists are often faced with challenges in evaluating disease activity, severity, and prognosis to guide appropriate management of CD. We studied the association between serum albumin level and the rate of active clinical disease in CD patients seen at a tertiary care Inflammatory Bowel Disease (IBD) referral center. METHODS: We designed a retrospective cohort study using adult patients (>18 years) with CD followed for at least one year at University of Alabama at Birmingham (UAB) IBD center by a single trained IBD specialist between 2014-2018. Serum albumin levels were divided into: low mean serum albumin (≤3.2 mg/dL) vs. appropriate mean serum albumin (>3.2 mg/dL). Clinical disease activity was measured using the Harvey-Bradshaw index (HBI). Active disease was defined as HBI score of 8 or higher. Poisson Regression Models (GPR) for Rate Data were used to estimate partially adjusted and fully adjusted incidence rate ratios (IRR) of active clinical disease among CD patients. We also examined IRRs for serum albumin level as a continuous variable. RESULTS: In this single IBD practice at UAB, 269 patients with CD had albumin drawn at initial visit and serially at each subsequent visit. Poisson regression model adjusted for age, gender, race, duration of disease, steroid use, smoking and Crohns location demonstrated that CD patients with a low mean serum albumin during clinical observation were approximately 1.5 times more likely to have active clinical disease during observation (IRR 1.49, 95% CI 1.04-2.15, P = 0.032) compared to those with a serum albumin level of >3.2 mg/dL. The adjusted model with serum albumin as a continuous variable demonstrated that with every unit (0.1 mg/dL) reduction in mean serum albumin, there was 30% higher likelihood of active Crohns in clinic (IRR 1.30, 95% CI 1.02-1.66, P = 0.037). CONCLUSION: Lower mean serum albumin during clinical observation is associated with a higher likelihood of active clinical disease among CD patients. Whether interventions designed to correct or increase serum albumin stores/levels in these patients would be beneficial remains to be examined.

INTRODUCTION: Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). Tofacitinib safety and efficacy were demonstrated in patients (pts) with moderate to severe UC in 3 Phase 3 studies, 1 and are being evaluated in an ongoing, open-label, long-term extension (OLE) study. 2 METHODS: We present updated safety and efficacy data from the OCTAVE Open OLE study (NCT01470612; Sep 2018; database not locked) 2 in completers/treatment failures in OCTAVE Sustain (NCT01458574) or non-responders in OCTAVE Induction 1/2 (NCT01465763/NCT01458951). Week (Wk) 8 data (OCTAVE Induction 1/2) and Wk 52 (completers) or early-termination data (OCTAVE Sustain) determined eligibility. Pts in remission (total Mayo score ≤2, no individual subscore >1, rectal bleeding subscore 0) at Wk 52 of OCTAVE Sustain (central read) received tofacitinib 5 mg twice daily (BID) in the OLE study; all others received 10 mg BID. At Month 2, all pts had endoscopy, and induction non-responders with no clinical response were withdrawn. Incidence rates (IRs; unique pts with events per 100 pt-years [PY]) for adverse events (AEs) of special interest were calculated. Efficacy endpoints were derived from Mayo score (local read). RESULTS: Of 944 pts receiving ≥1 tofacitinib dose (for up to 5.5 years), 175 (18.5%) and 769 (81.5%) received 5 and 10 mg BID, respectively (454 and 1550 PY, respectively). 337 (35.7%) pts discontinued due to insufficient clinical response and 78 (8.3%) due to AEs excl. worsening UC. The most frequent AE class was infections and infestations (52.1%). The most frequent AEs were nasopharyngitis (20.3%) and worsening UC (19.5%). IRs (95% CI) for “Tofacitinib All” were: serious infections 1.61 (1.10, 2.27); herpes zoster (all) 3.35 (2.58, 4.27); major adverse cardiovascular events 0.15 (0.03, 0.44); malignancies excl. non-melanoma skin cancer (NMSC) 0.85 (0.50, 1.36); and NMSC 0.81 (0.46, 1.32), with no clustering of malignancy type. Table 1 shows AEs and IRs by dose. No new safety risks were identified. Table 2 shows efficacy data at Month 36. CONCLUSION: In pts with UC in the OLE study, no new safety risks emerged at 5.5 years vs earlier OLE analyses 2 or with tofacitinib in rheumatoid arthritis. Efficacy data continue to support long-term efficacy of tofacitinib 5 or 10 mg BID up to 36 months beyond OCTAVE Sustain.

OBJECTIVEAlthough intracranial arterial aneurysms (IAAs) of childhood are usually idiopathic, it is possible that underlying arteriopathy escapes detection when using conventional diagnostic tools. Quantitative arterial tortuosity (QAT) has been studied as a biomarker of arteriopathy. The authors analyzed cervicocerebral QAT in children with idiopathic IAAs to assess the possibility of arteriopathy.METHODSCases were identified by text-string searches of imaging reports spanning the period January 1993 through June 2017. QAT of cervicocerebral arterial segments was measured from cross-sectional studies using image-processing software. Other imaging and clinical data were confirmed by retrospective electronic record review. Children with idiopathic IAAs and positive case controls, with congenital arteriopathy differentiated according to aneurysm status (with and without an aneurysm), were compared to each other and to healthy controls without vascular risk factors.RESULTSCervicocerebral QAT was measured in 314 children: 24 with idiopathic IAAs, 163 with congenital arteriopathy (including 14 arteriopathic IAAs), and 127 healthy controls. QAT of all vertebrobasilar segments was larger in children with IAAs (idiopathic and arteriopathic forms) (p < 0.05). In children with congenital arteriopathy without an aneurysm, QAT was decreased for the distal cervical vertebral arteries and increased for the supraspinal vertebral artery relative to healthy children. QAT of specific cervicocerebral segments correlated with IAA size and rupture status.CONCLUSIONSCervicocerebral QAT is a biomarker of arteriopathy in children with IAA, even in the absence of other disease markers. Additional findings suggest a correlation of cervicocerebral QAT with IAA size and rupture status and with the presence of IAA in children with congenital arteriopathy.

AbstractDefense systems are vital weapons for prokaryotes to resist heterologous DNA and survive from the constant invasion of viruses, and they are widely used in biochemistry investigation and antimicrobial drug research. So far, numerous types of defense systems have been discovered, but there is no comprehensive defense systems database to organize prokaryotic defense gene datasets. To fill this gap, we unveil the prokaryotic antiviral defense system (PADS) Arsenal (https://bigd.big.ac.cn/padsarsenal), a public database dedicated to gathering, storing, analyzing and visualizing prokaryotic defense gene datasets. The initial version of PADS Arsenal integrates 18 distinctive categories of defense system with the annotation of 6 600 264 genes retrieved from 63,701 genomes across 33 390 species of archaea and bacteria. PADS Arsenal provides various ways to retrieve defense systems related genes information and visualize them with multifarious function modes. Moreover, an online analysis pipeline is integrated into PADS Arsenal to facilitate annotation and evolutionary analysis of defense genes. PADS Arsenal can also visualize the dynamic variation information of defense genes from pan-genome analysis. Overall, PADS Arsenal is a state-of-the-art open comprehensive resource to accelerate the research of prokaryotic defense systems.

Abstract Establishment and subsequent maintenance of distinct chromatin domains during embryonic stem cell (ESC) differentiation are crucial for lineage specification and cell fate determination. Here we show that the histone chaperone Chromatin Assembly Factor 1 (CAF-1), which is recruited to DNA replication forks through its interaction with proliferating cell nuclear antigen (PCNA) for nucleosome assembly, participates in the establishment of H3K27me3-mediated silencing during differentiation. Deletion of CAF-1 p150 subunit impairs the silencing of many genes including Oct4, Sox2 and Nanog as well as the establishment of H3K27me3 at these gene promoters during ESC differentiation. Mutations of PCNA residues involved in recruiting CAF-1 to the chromatin also result in defects in differentiation in vitro and impair early embryonic development as p150 deletion. Together, these results reveal that the CAF-1-PCNA nucleosome assembly pathway plays an important role in the establishment of H3K27me3-mediated silencing during cell fate determination.