Citations

Abstract Background: Familial adenomatous polyposis (FAP) is the most common hereditary polyposis syndrome. It is an autosomal dominant inherited disorder characterized by the early onset of hundreds to thousands of adenomatous polyps throughout the colon. If left untreated, nearly all individuals with this syndrome develop colorectal cancer (CRC) by the third decade of life. Prophylactic colectomy is the standard of care, but individuals remain at risk for malignant transformation of duodenal polyps, rectal polyps for those who have undergone rectal-sparing surgeries, and ileal pouch polyps for those with ileal pouch-anal anastomoses. Multiple studies with both nonselective and selective cyclooxygenase inhibitors (such as sulindac or celecoxib) have shown that anti-inflammatory agents may prevent the formation and inhibit the growth of colorectal adenomatous polyps. However, toxicities associated with these agents and their limited efficacy have prevented their further development. Therefore, there is a high unmet need for novel treatment options to reduce polyp burden, delay or eliminate the need for colectomy and recurrent rectal surgery, and intercept the development of adenocarcinomas in individuals with FAP. Polyps from individuals with FAP display inflammatory features associated with the activation of the IL-23/IL-17/JAK/STAT3 pathway. This inflammation is thought to contribute to further carcinogenesis, culminating in tumor development. Specifically, IL-23 is linked to tumor growth and progression in CRC, and adenomas with high-grade dysplasia showed elevated levels of IL-17A and pSTAT3. Guselkumab, a human monoclonal antibody directed against the p19 subunit of IL-23, specifically targets IL-23 and inhibits its interaction with the IL-23 receptor. Pre-clinical models suggest that inhibition of IL-23 signaling will result in less inflammation and reduce tumor development. Methods: This randomized, blind, placebo-controlled study will evaluate the safety and efficacy of guselkumab in adults with FAP (genetic or clinical diagnosis) who have already undergone colectomy. Polyps with a sum of diameters ≥10 mm in the rectum or pouch are required. Subjects will be randomized equally to one of three study arms: 100 mg, 300 mg, or placebo given subcutaneously every 4 weeks for 6 doses. The primary efficacy endpoint is percentage change from baseline in rectal/pouch polyp burden after 24 weeks. Secondary efficacy endpoints include duodenal polyp burden change and changes in InSiGHT and Spigelman staging. Exploratory translational research objectives will explore changes in RNA expression profiles, epigenomic profiles, cytokine levels, and the microbiome. Exclusion criteria include prior IL-23 targeted therapies and any polyps >1 cm that cannot be removed. While participating, subjects are required to stop any other FAP-directed drug therapy except for aspirin. As of January 2019, 18% of the planned 72 subjects have been enrolled. ClinicalTrials.gov Identifier: NCT03649971. Citation Format: Eduardo Vilar-Sanchez, Carol Burke, Marcia R. Cruz Correa, Evelien Dekker, William M. Grady, Philippe Grandval, Bryson W. Katona, Xavier Llor, Douglas L. Riegert-Johnson, Jean-Christophe Saurin, Peter Stanich, Daniel A. Sussman, David Weinberg, Edward F. Attiyeh, Devanand Joseph, Kelly Raybold, Gary V. Borzillo, Thomas J. Prior, Michael Smith, Hong Xie, Kurtis E. Bachman, Jeffrey R. Infante, Niloy Jewel Samadder. A phase 1b, multicenter, randomized, blinded, placebo-controlled study to evaluate the efficacy of guselkumab in subjects with familial adenomatous polyposis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT236.

Importance Black individuals are more likely than white individuals to develop dementia. Whether higher blood pressure (BP) levels in black individuals explain differences between black and white individuals in dementia risk is uncertain. Objective To determine whether cumulative BP levels explain racial differences in cognitive decline. Design, Setting, and Participants Individual participant data from 5 cohorts (January 1971 to December 2017) were pooled from the Atherosclerosis Risk in Communities Study, Coronary Artery Risk Development in Young Adults Study, Cardiovascular Health Study, Framingham Offspring Study, and Northern Manhattan Study. Outcomes were standardized as t scores (mean [SD], 50 [10]); a 1-point difference represented a 0.1-SD difference in cognition. The median (interquartile range) follow-up was 12.4 (5.9-21.0) years. Analysis began September 2018. Main Outcomes and Measures The primary outcome was change in global cognition, and secondary outcomes were change in memory and executive function. Exposures Race (black vs white). Results Among 34 349 participants, 19 378 individuals who were free of stroke and dementia and had longitudinal BP, cognitive, and covariate data were included in the analysis. The mean (SD) age at first cognitive assessment was 59.8 (10.4) years and ranged from 5 to 95 years. Of 19 378 individuals, 10 724 (55.3%) were female and 15 526 (80.1%) were white. Compared with white individuals, black individuals had significantly faster declines in global cognition (−0.03 points per year faster [95% CI, −0.05 to −0.01]; P = .004) and memory (−0.08 points per year faster [95% CI, −0.11 to −0.06]; P < .001) but significantly slower declines in executive function (0.09 points per year slower [95% CI, 0.08-0.10]; P < .001). Time-dependent cumulative mean systolic BP level was associated with significantly faster declines in global cognition (−0.018 points per year faster per each 10–mm Hg increase [95% CI, −0.023 to −0.014]; P < .001), memory (−0.028 points per year faster per each 10–mm Hg increase [95% CI, −0.035 to −0.021]; P < .001), and executive function (−0.01 points per year faster per each 10–mm Hg increase [95% CI, −0.014 to −0.007]; P < .001). After adjusting for cumulative mean systolic BP, differences between black and white individuals in cognitive slopes were attenuated for global cognition (−0.01 points per year [95% CI, −0.03 to 0.01]; P = .56) and memory (−0.06 points per year [95% CI, −0.08 to −0.03]; P < .001) but not executive function (0.10 points per year [95% CI, 0.09-0.11]; P < .001). Conclusions and Relevance These results suggest that black individuals’ higher cumulative BP levels may contribute to racial differences in later-life cognitive decline.

Over recent decades, crystallographic software for data processing and structure refinement has improved dramatically, resulting in more accurate and detailed crystal structures. It is, therefore, sometimes valuable to have a second look at “old” diffraction data, especially when earlier interpretation of the electron density maps was rather difficult. Here, we present updated crystal structures of Drosophila melanogaster acetylcholinesterase (DmAChE) originally published in [Harel et al., Prot Sci (2000) 9:1063-1072], which reveal features previously unnoticed. Thus, previously unmodeled density in the native active site can be interpreted as stable acetylation of the catalytic serine. Similarly, a strong density in the DmAChE/ZA complex originally attributed to a sulfate ion is better interpreted as a small molecule that is covalently bound. This small molecule can be modeled as either a propionate or a glycinate. The complex is reminiscent of the carboxylate butyrylcholinesterase complexes observed in crystal structures of human butyrylcholinesterases from various sources, and demonstrates the remarkable ability of cholinesterases to stabilize covalent complexes with carboxylates. A very strong peak of density (10 σ) at covalent distance from the Cβ of the catalytic serine is present in the DmAChE/ZAI complex. This can be undoubtedly attributed to an iodine atom, suggesting an unanticipated iodo/hydroxyl exchange between Ser238 and the inhibitor, possibly driven by the intense X-ray irradiation. Finally, the binding of tacrine-derived inhibitors, such as ZA (1DX4) or the iodinated analog, ZAI (1QON) results in the appearance of an open channel that connects the base of the active-site gorge to the solvent. This channel, which arises due to the absence of the conserved tyrosine present in vertebrate cholinesterases, could be exploited to design inhibitors specific to insect cholinesterases. The present study demonstrates that updated processing of older diffraction images, and the re-refinement of older diffraction data, can produce valuable information that could not be detected in the original analysis, and strongly supports the preservation of the diffraction images in public data banks.

63 Background: A novel vaccine strategy may prevent recurrence in high-risk melanoma patients (pts). The TLPLDC vaccine uses yeast cell wall particles (YCWP) to load tumor lysate into autologous dendritic cells (DC). In this phase IIb trial of TLPLDC vs. placebo in resected stage III/IV pts, TLPLDC increased 24 month (mo) disease free survival (DFS) in the per treatment (PT) population. Here, we present a 24mo DFS subgroup analysis and estimated overall 36mo DFS. Methods: Disease-free pts were randomized 2:1 to the TLPLDC vaccine vs. unloaded YCWP+DC at 0, 1, 2, 6, 12, and 18mo. The protocol was amended to allow concurrent adjuvant checkpoint inhibitor (CPI) therapy once approved. The pre-specified PT population included only pts completing the primary vaccine/placebo series (PVS) at 6 mo. Kaplan-Meier estimates of DFS were used to compare treatment arms by stage (III or IV) and CPI therapy (yes/no) in the ITT and PT populations. Results: 144 pts were randomized (103 TLPLDC, 41 placebo); 98 pts (66 TLPLDC, 32 placebo) completed the PVS. There were no clinicopathologic differences between treatment groups. There was no difference in 24mo DFS in stage III pts (n = 112), but in stage IV pts (n = 32), the 24mo DFS was 44% vs 0% (TLPLDC vs placebo) (p = 0.41) in ITT and 73.3% vs. 0% (HR 0.14, p = 0.002) in PT. Stage IV pts were more likely to receive CPI than stage III pts (50% vs. 30%, p = 0.003). There was no difference in 24mo DFS for pts who did not receive CPI (n = 102), but in pts who received CPI (n = 42), the 24mo DFS was 49.3% vs. 31.3% (p = 0.71) in ITT and 68.8% vs. 41.7% (HR 0.46, p = 0.28) in PT, showing a trend toward improved DFS in pts who completed the PVS and received CPI (n = 31). Overall, the 36mo estimated DFS was 34.2% vs. 21.6% (p = 0.89) for ITT and 56.9% vs. 27.9% (p = 0.021) for PT. Conclusions: The TLPLDC vaccine improved DFS in patients completing the PVS at 24 and 36 mos, particularly in the resected stage IV subset. The apparent synergistic effect with TLPLDC + CPI will be confirmed in a phase III study evaluating adjuvant TLPLDC + CPI vs. CPI alone in resected stage IV melanoma pts. Clinical trial information: NCT02301611.

Abstract Abstract 39 Three randomized trials have previously reported a progression-free survival (PFS) advantage for patients receiving thalidomide (T) maintenance post ASCT in MM. Two trials reported an overall survival (OS) advantage but the largest trial reported shows no OS advantage and in very high risk MM the use of T was deleterious. Recent trial reports demonstrate a PFS but not yet an OS advantage for patients receiving maintenance lenalidomide. We report results of NCIC CTG MY.10 which compared treatment with T (200 mg daily) and prednisone (50 mg alternate days) (T/P) until progression versus observation alone when used as maintenance therapy following ASCT. Importantly, OS was the 1ry endpoint of this study, 2ry endpoints were PFS, quality of life (QoL), toxicity, and the incidence of venous thromboembolism events (VTE). Eligibility: Patients with MM who had ASCT within 1 year of beginning initial treatment for their disease. Patients were randomized 60–100 days post ASCT and had no other medical condition precluding long term use of T/P. Results: 332 patients were enrolled. Median age was 58 years and the arms were balanced. Patients were stratified by age (<60 or >60), and CR status post transplant. Median follow up is 4 years. Only 14% of patients were in CR post transplant. 111 patients died (50 versus 61 in T/P vs. observation). The median OS was 5 years for observation, and has not yet been reached for T/P, however T/P maintenance therapy did not significantly prolong OS: p = 0.18, HR of maintenance vs. observation 0.77 (95% CI 0.53–1.13). The 4 year survival rate was 68% for T/P and 60% for observation. Age and response to transplant had no significant association with OS (p=0.21), while higher disease stage was associated with shorter OS (p=0.03). The median PFS was 28 months for T/P versus 17 months for observation: p<0.0001, HR of T/P vs. observation 0.56 (95% CI 0.43 – 0.73). The 4 year PFS rate was 32% for T/P treated patients versus 14% for patients on observation. At relapse, treatment by arm (T/P vs observation) included lenalidomide (39 vs 34%), T (13 vs 22%) or bortezomib (50 versus 46%). Non hematologic toxicities were seen in more patients with treatment (Grade 3: 92% T/P vs 49% observation, grade 4: 16% vs 7%). Common toxicities of all grades that were significantly higher in T/P treated patients included hyperglycemia, edema, hypertension, fatigue, Cushingoid appearance, constipation, mouth dryness, dyspepsia, anxiety, memory loss, sensory neuropathy, tremor, blurred vision, depressed consciousness, cataracts, dyspnea and bruising. 7% of patients on maintenance T/P developed a VTE in the absence of prophylaxis versus 0% on observation. NCIC CTG standardized response analysis was use to compare QoL data between the 2 treatment arms. Overall, patients on T/P had worse QoL specifically in physical (p=0.07), role (p=0.08), cognitive (p = 0.01) and global (p=0.06) domains, and worse symptoms with dyspnea (p = 0.0007), constipation (p<0.0001), thirst (p=0.003), swelling in leg (p=0.03), numbness (p=0.02), dry mouth (p<0.0001), and balance problems (p<0.0001). However, patients on T/P reported improvement in appetite (p 0.02), and sleep (p=0.04). Conclusions: T/P maintenance did not improve overall survival, the primary objective of this trial, although a trend in favor of T/P was seen. In contrast, PFS was significantly improved in the T/P arm while toxicity was demonstrably increased and quality of life diminished. Disclosures: Stewart: Millennium: Consultancy; Celgene: Honoraria. Trudel:Celgene: Honoraria. Bahlis:Celgene: Honoraria, Research Funding, Speakers Bureau. White:Celgene: Honoraria, Research Funding. Meyer:Celgene: Honoraria.