Citations

Background: Brugada syndrome (BrS) is an oligogenic arrhythmic disease with increased risk of sudden cardiac arrest. Several BrS or ECG traits-related single-nucleotide polymorphisms (SNPs) were identified through previous genome-wide association studies in white patients. We aimed to validate these SNPs in BrS patients in the Taiwanese population, assessing the cumulative effect of risk alleles and the BrS-polygenic risk score in predicting cardiac events. Methods: We genotyped 190 unrelated BrS patients using the TWB Array, and Taiwan Biobank was used as controls. SNPs not included in the array were imputed by IMPUTE2. Cox proportional hazards model was used to evaluate the associations between each particular SNP, the collective BrS-polygenic risk score, and clinical outcomes. Results: Of the 88 previously reported SNPs, 22 were validated in Taiwanese BrS patients ( P <0.05). Of the 22 SNPs, 2 (rs10428132 and rs9388451) were linked with susceptibility to BrS, 10 were SNPs previously reaching genome-wide significance, and 10 were SNPs associated with ECG traits. For the 3 most commonly reported SNPs, disease risk increased consistently with the number of risk alleles (odds ratio, 3.54; P trend =1.38×10 −9 for 5 risk alleles versus 1). Similar patterns were observed in both SCN5A mutation+ (odds ratio, 3.66; P trend =0.049) and SCN5A mutation− (odds ratio, 3.75; P trend =8.54×10 −9 ) subgroups. Furthermore, BrS patients without SCN5A mutations had more risk alleles than BrS patients with SCN5A mutations regardless of the range of polygenic risk scores. Three SNPs (rs4687718, rs7784776, and rs2968863) showed significant associations with the composite outcome (sudden cardiac arrest plus syncope, hazard ratio, 2.13, 1.48, and 0.41; P =0.02, 0.006, and 0.008, respectively). Conclusions: Our findings suggested that some SNPs associated with BrS or ECG traits exist across multiple populations. The cumulative risk of the BrS-related SNPs is similar to that in white BrS patients, but it appears to correlate with the absence of SCN5A mutations.

5583 Background: FDA has approved three novel AAs [Apalutamide(A), Darolutamide(D) and Enzalutamide(E)] in combination with Androgen deprivation therapy ( ADT) for treatment of (nmCRPC) patients (pts). We report the cost-effectiveness of these drugs from the US perspective to help facilitate the choice of these agents for clinical practice. Methods: A life time Markov state-transition model was constructed with three health states (Metastasis-Free Survival[MFS], Metastatic disease, and Death) to compare cost-effectiveness of AA therapies for treatment of nmCRPC based on US healthcare payer perspective. A network meta-analysis of MFS and OS was conducted due to the lack of head to head trials. An approximation of the original individual-level patient time-to-event data were derived from digitized Kaplan-Meier curves for OS and MFS. Weibull distributions was selected as the best fitted model fitted and extrapolated as per the NICE decision support unit recommendations. Medication costs were based on wholesale acquisition cost. Adverse event (AE) grades 3/4 management costs were incorporated in the model. Discount rate of 3% per year was applied to costs and effects. Life years (LYs) and quality adjusted life years (QALYs) for each treatment as well as the incremental cost effectiveness (ICER) and cost utility (ICUR) ratios were estimated. Base case analyses (BCA) and probabilistic sensitivity analyses (PSA) were estimated. Results: The table summarizes the results form BCA analyses. A+ADT offers best gain in LYs (8.37yrs) and QALYs (5.30 yrs) but at higher cost. Conclusions: Apalutamide was associated with gains in LYs and QALYs traded off with higher lifetime cost relative to other AA alternatives. ADT was associated with lower gains in LYs and QALYs traded off with lower lifetime cost relative to other alternatives. Based on a $150,000/QALY threshold pay off, A+ADT is likely more cost effective compared to E+ADT or ADT alone; while E+ ADT may be more cost effective compared to D+ ADT. [Table: see text]

5077 Background: Several ICIs are used in first and subsequent lines of therapy for mRCC, either alone or in combination with another ICI or targeted therapy (TT). There are no data on the efficacy and safety of using an ICI in patients who have already received an ICI in a prior line of therapy. Methods: We reviewed patients with mRCC at 8 institutions who received 2 separate lines of ICI therapy (ICI-1, ICI-2), including as a single-agent and/or combination with other agents. The primary outcomes were overall response rate (ORR) and time to progression (TTP) with ICI-1 and ICI-2. Immune-related adverse events (irAEs) were graded using CTCAEv5.0. Results: 65 patients were included. Median age at diagnosis of mRCC was 60 years (range 30-86) and the majority had clear cell RCC (n=56, 86%). Median follow-up was 3.5 years (95% CI 2.9-4.4). Median lines at which ICI-1 and ICI-2 were received were 1 (1-6) and 3 (2-8) respectively. Reasons for discontinuing ICI-1 were disease progression (n=47, 72%), toxicity (n=15, 23%) or other (n=3, 5%). Therapies received at ICI-2 were single-agent ICI (n=26, 40%), or combinations of ICI with another ICI (n=20, 31%), TT (n=11, 17%) or other agent (n=8, 12%). Responses to ICI-1 and ICI-2 are shown in the Table; ORR to ICI-2 was significantly lower than to ICI-1 (23% vs. 36%, p=0.044). Amongst those who responded to ICI-2 (n=14), 7 (50%) received single-agent ICI, and the remainder received ICI in combination with another ICI (n=4, 29%) or TT (n=3, 21%); 7 patients (50%) had previously responded to ICI-1. The ORR to ICI-2 was higher in responders to ICI-1 (32%) compared to those with SD (17%) or PD (15%) to ICI-1. Median TTP (mTTP) at ICI-2 was shorter compared to ICI-1 (5.3 months vs. 8.5 months, Wilcoxon p=0.024). 29 patients (45%) experienced an irAE with ICI-2; 8 (12%) and 3 (5%) had a grade 3 or 4 irAE respectively, with 3 (30%) of these patients having previously had ≥grade 3 irAE to ICI-1. There were no treatment-related deaths. Conclusions: The ORR to ICI-2 was 23%, which is comparable to that seen with ICI after prior TT. Responses were seen even amongst those receiving single-agent ICI at ICI-2 and the likelihood of response to ICI-2 was higher if a patient had previously responded to ICI-1. No increase in toxicity with ICI-2 was apparent. Additional data from prospective studies are needed to determine whether sequential ICI has a role in treatment of mRCC. [Table: see text]

e16771 Background: AbGn-107 is an ADC directed against AG-7 antigen, a Lewis A-like glycol-epitope expressed in 24-61% of gastric (G), colorectal (CRC), pancreatic (PDA), and biliary (BIL) cancers. Based on promising antitumor activity of AbGn-107 in both in vitro and in vivo preclinical studies, we performed a Phase Ia trial in patients with the aforementioned GI malignancies. Methods: Standard 3+3 dose escalation was used. Key eligibility included locally advanced or metastatic G, CRC, PDA, or BIL cancer, previously treated, ECOG PS 0-1; positive AG-7 expression was not required. Two dosing intervals were tested: AbGn-107 administered i.v. Q4 weeks (at doses ranging from 0.1-1.2 mg/kg) and Q2 weeks (at doses from 0.8-1.0 mg/kg). Dose limiting toxicities (DLT) were based on grade 3/4 hematologic and non-heme AEs occurring during the initial 4-week rx window. Patients were treated until disease progression or unacceptable toxicity, with tumor assessments Q8 weeks. 1o objectives: safety and MTD; 2o objectives: PK, immunogenicity, and efficacy defined by ORR (RECIST 1.1). Results: 35 patients were enrolled across 6 dose levels (median age 61.5 yo (range 40 – 81); G (0)/CRC (12)/PDA (20)/BIL (3); median # lines of prior rx = 3 (range 1-7). Safety: 5 patients experienced Grade 3 or 4 neutropenia, all at higher dose levels, inc. 1 episode of febrile neutropenia. Other frequent drug-related AEs, mostly grade 1/2, inc. fatigue (29%), nausea (20%), and diarrhea (14%). DLTs included grade 4 CK elevation (n = 1) at 0.8 mg/kg Q4W and grade 3 arthralgias (n = 1) at 1.2 mg/kg Q4W. Based on safety profile and PK data, 1.0 mg/kg Q2W was selected as the dose schedule for cohort expansion phase. Efficacy: Median duration of treatment = 56 days (range, 8 – 225 days). Six pts have demonstrated a minor response by RECIST (range, -1.3 to -21.1%); 4 pts (all PDA) have had durable dz control > 180 days. Conclusions: Overall, AbGn-107 appears well-tolerated with encouraging prelim signs of efficacy in unselected pts with heavily pre-treated advanced GI cancers. Updated safety and efficacy data will be provided at the time of the meeting for the cohort expansion phase of this study (currently open across multiple sites in U.S. and Taiwan), in which subjects with G, CRC, PDA, and BIL cancers are pre-screened for high levels of AG-7 tumor expression. Clinical trial information: NCT02908451 .

AbstractConduits that promote nerve regeneration are currently of great medical concern, particularly when gaps exist between nerve endings. To address this issue, our laboratory previously developed a nerve conduit from biodegradable poly(caprolactone fumarate) (PCLF) that supports peripheral nerve regeneration. The present study improves upon this work by further developing an electrically conductive, positively charged PCLF scaffold through the incorporation of graphene, carbon nanotubes (CNTs), and [2‐(methacryloyloxy)ethyl]trimethylammonium chloride (MTAC) (PCLF–Graphene–CNT–MTAC) using ultraviolet (UV) induced photocrosslinking. Scanning electron microscopy, transmission electron microscopy, and atomic force microscopy were used to assess the incorporation of CNTs and graphene into PCLF–Graphene–CNT–MTAC scaffolds, which displayed enhanced surface roughness and reduced electrochemical impedance when compared to neat PCLF. Scaffolds with these surface modifications also showed improved growth and differentiation of rat pheochromocytoma 12 cells in vitro, with enhanced cell growth, neurite extension, and cellular migration. Furthermore, an increased number of neurite protrusions were observed when the conduit was electrically stimulated. These results show that the electrically conductive PCLF–Graphene–CNT–MTAC nerve scaffolds presented here support the cellular behaviors that are critical for nerve regeneration, ultimately making this material an attractive candidate for regenerative medicine applications.

Abstract Background: Vitamin D deficiency is common in patients presenting with low energy hip fractures. The relationship between Vitamin D levels at the time of a fracture with long term functional outcomes has not been studied. Identifying a benefit to recovery with adequate vitamin D would support supplementation in elderly patients at risk for hip fracture. Methods: A retrospective cohort of patients &gt;/= 50 years, who were treated surgically for low energy hip fracture between July 1 2016 and June 30 2018 were identified. The correlation between Vitamin D levels and functional recovery, assessed using the time up and go (TUG) test, survival at 3 months and 1 year, and readmission within 3 months was examined. The Charlson comorbidity index (CCI) at baseline was also assessed. Results: A total of 216 patients were treated for a hip fracture of which 174 were included with measured baseline Vitamin D levels. A majority were female (112, 64.4%), mean age 79.6 years (+/-11.9), mean Vitamin D level 28.2 ng/ml (+/- 12.4) and mean CCI 5.9 (+/- 2.5). Vitamin D &lt;20 ng/ml was seen in 39 (22.4%) patients and all received appropriate supplementation. 39 (22.4%) individuals died within a year of surgery, among whom 17 (43.6% of 39) passed away within 3 months. 36 (20.7%) were readmitted within 3 months of surgery and 14 (8%) sustained a second fracture within a year. The correlation of Vitamin D levels, taken as a continuous variable, to outcomes, was analyzed using logistic regression. Although not significant, higher Vitamin D was found to be protective against death within 3 months (OR=0.995, p=0.8), but actually increased the odds of death within 1 year (OR=1.008, p=0.62), readmission within 3 months (OR=1.001, p=0.96), second fracture within 1 year (OR=1.017, p=0.33) and failure to recover (OR=1.002, 0.86). After adjusting for age, gender and CCI, Vitamin D levels were non-significantly inversely associated with both TUG 1 and TUG2, with every 1 unit higher Vitamin D associated with a TUG lowered by 0.15 seconds, p=0.42 and 0.44. Vitamin D was poorly correlated to CCI with correlation coefficient of 0.02, p = 0.71. Conclusions: Our results indicate that Vitamin D levels at the time of a hip fracture do not correlate with patients’ functional outcomes. It is possible that replacing vitamin D eliminated the possible negative impact on functional recovery.

Abstract Activation of NFkB has been noted in late B-cell malignancies, but no genetic basis for this activation has been shown except for rare mutations of the NFkB pathway in lymphoma and none have been described in MM. Bortezomib, highly tumoricidal in a subset of MM patients, inhibits NFkB suggesting it’s role as a therapeutic target. Here we show for the first time the critical importance of mutations that dysregulate this potential survival pathway in human myeloma cell lines (HMCL) and new diagnosis MM patients. We performed high-density oligonucleotide array CGH (Agilent 44k) on CD138+ selected MM cells from 68 patients and 42 unique HMCL. Initially we focused on small loci, bi-allelically deleted, as markers for inactivation of potential tumor suppressor genes. We next developed FISH probes for the identified loci to confirm the bi-allelic deletions seen by aCGH. We next sequenced all samples with monoallelic deletions, and additional unselected patients, and identified additional inactivating mutations. Multiple novel tumor suppressor genes (TSG) were identified and validated, whose loss of function (both in patients and HMCL) leads to activation of the non-canonical NFkB pathway including: TRAF2 (9q34), TRAF3 (14q32), BIRC2/BIRC3 (11q22) and CYLD (16q12). Functional studies showed that HMCL with deletion or mutations in these genes have markedly increased NFkB2 p52/p100 ratios relative to other HMCL (and for BIRC2/BIRC3 relative to an isogenic line that retains one copy of BIRC2/BIRC3), indicating genetic activation of the non-canonical NFkB pathway. Reintroduction of deleted TSG into HMCL inhibited cell growth and resulted in cell death (see data on abstract by J. Keats et al). We next focused our analysis (of combined aCGH and GEP data) on positive regulators of this pathway. Rare IgH translocations of NIK have recently been identified in MM. By aCGH we identified amplification and rearrangements of NIK. We identified dysregulated expression of TNF family receptors that activate the non-canonical pathway: CD40 (translocation), TACI (amplification) and LTBR. All of the HMCL with these mutations also showed increased NFkB2 p52/p100 ratios, consistent with activation of the non-canonical NFkB. These mutations correlate with a gene expression profile of NFkB activation that is detected in one half of patients. In summary, we have determined for the first time the genetic basis for constitutive NFkB activation - present in 19/42 HMCL, and we estimate in at least one quarter of newly diagnosed patients (approximately one half of those with evidence of NFkB activation by GEP). We propose a mechanism in which positive (TACI, CD40, LTBR) and negative regulators (TRAF2, TRAF3, BIRC2/BIRC3, CYLD) of the pathway converge on NIK to mediate the processing of NFKB2 p100 to p52. The preponderance of genetic evidence suggests that drugs that target the non-canonical NFkB pathway, will be most effective in treating the 50% of MM patients with NFkB activation.

Abstract From a high throughput RNAi screen of the human druggable genome targeting the KMS11 cell line, we identified the suppression of the vacuolar H+- ATPase (V-ATPase) family as cytotoxic to myeloma cells. In the screen, two oligos against each gene for the V-ATPase subunits ATP6V1A and ATP6V1B1 resulted in suppression of cell growth (50% and 60% inhibition of cell viability respectively). We further confirmed this result using both lentiviral shRNA knockdown and two small molecule inhibitors specific for V-ATPase. Silencing of ATP6V1A by lentiviral shRNA knock-down in KMS11 and in OPM1 myeloma cell lines caused 75–80% reduction of cell viability at 5 days post infection (measured by MTT assay). Consistent with this result, the V-ATPase specific inhibitors, bafilomycin A1 and REATA 203, both inhibited the growth of a genetically heterogeneous and standardized panel of 14 human myeloma cell lines in vitro with an IC50 ranging from 2.2 – 8.9 nM (mean 5.25 nM) for bafilomycin A1 and 46–1594 nM (mean 542.5 nM)) for REATA 203. We further demonstrated that patient samples (n=10) were sensitive to 20nM bafilomycin A1 which induced a mean of 58% of MM cells to undergo apoptosis (range 10% to 93%) after 24 hours of treatment. Similar to bafilomycin A1, treatment of primary patient-derived MM cells with 500 nM REATA 203 for 72 hours resulted in a mean 69% apoptosis (range 24% to 97%). In contrast, non-myeloma cells (the CD138- fractions of the bone marrow samples) were less sensitive - mean 9% apoptosis (range from 0% to 34%) under the same treatment conditions. Of high interest, however, unlike most drugs we have studied in pre-clinical myeloma models, the cytotoxicity induced by bafilomycin A1 in MM cell lines is abrogated by co-culture with patient bone marrow stromal cells but is not affected by IL-6 or IGF-1 treatment. Dexamethasone- or melphalan-resistant MM cell lines were also highly sensitive to both bafilomycin A1 and REATA 203. In a xenographic JJN3 mouse model, bafilomycin A1 suppresses and delays growth of tumor in a dose-dependent fashion. Gene expression analysis of normal-donor bone marrow plasma cells (n=19), primary tumor samples from MM patients (n=107) and normal somatic tissues demonstrates ubiquitous expression of most subunits of V-ATPase, however, some subunits are preferentially expressed in myeloma cells compared with normal plasma cells, including ATP6V1F (84% vs. 11%), ATP6V1E1 (29% vs. 5%), ATP6V1G2 (17% vs. 0%) and ATP6V0E 2 (36% vs. 16%). In conclusion, our data indicate that vacuolar H+-ATPase inhibitors are of interest as potential therapeutics for MM.