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Background: The COVID pandemic has resulted in significant changes many aspects of daily living. To understand the impact that COVID-19 has had on the myeloproliferative neoplasm (MPN) patient population, we conducted an internet based survey. Methods: Survey: This survey was hosted Mayo Clinic's secured REDCap system for online surveys with a link to the survey alongside a brief description posted via the www.mpnqol.com website, as well as other MPN organizational partners. Survey responses were completely anonymous. Questions included MPN-Total symptom score (TSS), NCCN distress thermometer (NCCN-DT), questions regarding impact on medical care, and questions from CDC COVID-19 community survey question bank regarding the impact of social distancing as well as changes in health behaviors. Distress thermometer, MPN-TSS, and/or questions related to the impact of COVID-19 on MPN treatment were analyzed by: MPN diagnosis, among those with ET, PV, or MF diagnoses; medication status; stay at home order; community spread; and country. Associations were tested using Kruskal-Wallis or Wilcoxon rank sum tests (for continuous variables) or Fisher Exact tests (for categorical variables). Analysis: Results: Patient Demographics (Table 1): 1560 people responded to the survey, 1217 were eligible for analysis. Median age was 62 (range: 21-93), and 298 (24.6%) respondents were male. There were respondents from USA, Australia, Canada, Netherlands, Ireland, and UK. 233 patients (19.2%) have myelofibrosis, 419 (34.6%) polycythemia vera and 543 (44.8%) essential thrombocythemia. At the time of the COVID outbreak, 1026 (84.3%) were on MPN directed medical therapy, including ruxolitinib (15.3%), interferon (14.7%), hydroxyurea (42.7%) and ASA (47.7%). 165 (13.6%) respondents received COVID testing, of which 5 had positive tests. Impact on MPN Care (Table 2): We sought to understand how patient's clinical care changed. Over half respondents who spoke to their MPN doctor had a telemedicine visit after COVID19 (57.1%). 422 (36.5%) patients spaced out visits, of which 99 (22.7%) felt there were consequences. A change in therapy due to COVID-1 occurred in only 5.4% of patients. MPN Symptom Burden and QoL: Data captured on the NCCN-DT had a median of 4 (0-10). MPN-SAF-TSS composite score was collected in 1150 respondents, median score was 26 (0-90). These scores are higher than those previously reported. Pandemic Impact on Lifestyle (Table 1): 595 (49.5%) of patients report living in a community where there is significant COVID-19 spread. 946 (78.9%) reported that COVID-19 has impacted their day to day life. 198 (17.2%) of patients agreed, or strongly agreed that COVID had a significant impact on their finances. 799 (67.8%) had a stay at home order. Of those who quarantined (112), the median duration was 30d (1-120). The majority of people increased hand-washing, and cleaning habits. 954 (81.7%) respondents reported wearing masks in public. 908 (76.8%) reported increased stress from social distancing. The majority of respondents report using healthy coping habits, such as reaching out to friends/loved ones, breathing and relaxation, as well as healthy diet. Less than 15% of patients report unhealthy coping strategies, such as use of opioids, benzodiazepines, alcohol, or cannabis Factors associated with response: There were no differences in responses based on type of MPN. If a patient was on medication, they were more likely to have spoken to their provider (p<0.001). If there was a stay at home order in place, there was a higher MPN-TSS score (p<0.001). If the respondent lived in an area of high community spread, they had a higher NCCN-DT score (p<0.001). Patients in the USA had a higher NCCN-DT score (p=0.001), were more likely to stretch out the duration of time between visits (p<0.001) and less likely to have a telemedicine visit (p<0.001). Although fewer respondents in the USA thought COVID-19 was a serious disease (p=0.02), a higher percentage of respondents wore masks (p <0.001). Conclusions: In our survey of MPN patients, there were many changes noted in clinical care. The use of telemedicine was common, and at least a third had significant changes in their care. Most experienced increased stress, however, employed healthy coping strategies. Only a minority of patients had a COVID test, and only 5 were positive, further data will be needed to understand the impact of COVID infection. Figure 1 Disclosures Harrison: Roche: Honoraria; Incyte Corporation: Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau; Sierra Oncology: Honoraria; Promedior: Honoraria; Shire: Honoraria, Speakers Bureau; AOP Orphan Pharmaceuticals: Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau; Janssen: Speakers Bureau; Gilead Sciences: Honoraria, Speakers Bureau; CTI Biopharma Corp: Honoraria, Speakers Bureau. Pemmaraju:Affymetrix: Other: Grant Support, Research Funding; Plexxikon: Research Funding; Incyte Corporation: Honoraria; Roche Diagnostics: Honoraria; Blueprint Medicines: Honoraria; Novartis: Honoraria, Research Funding; SagerStrong Foundation: Other: Grant Support; DAVA Oncology: Honoraria; Samus Therapeutics: Research Funding; Cellectis: Research Funding; Daiichi Sankyo: Research Funding; Celgene: Honoraria; AbbVie: Honoraria, Research Funding; Stemline Therapeutics: Honoraria, Research Funding; MustangBio: Honoraria; LFB Biotechnologies: Honoraria; Pacylex Pharmaceuticals: Consultancy. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees; Blueprint: Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Gupta:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol MyersSquibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Research Funding; Pfizer: Consultancy. Mascarenhas:Celgene, Prelude, Galecto, Promedior, Geron, Constellation, and Incyte: Consultancy; Incyte, Kartos, Roche, Promedior, Merck, Merus, Arog, CTI Biopharma, Janssen, and PharmaEssentia: Other: Research funding (institution). Shimoda:Kyowa Hakko Kirin Co., Ltd.: Research Funding; Pfizer Inc.: Research Funding; Otsuka Pharmaceutical: Research Funding; Celgene: Honoraria; Perseus Proteomics: Research Funding; PharmaEssentia Japan: Research Funding; AbbVie Inc.: Research Funding; Astellas Pharma: Research Funding; Merck & Co.: Research Funding; CHUGAI PHARMACEUTICAL CO., LTD.: Research Funding; Bristol-Myers Squibb: Honoraria; Takeda Pharmaceutical Company: Honoraria; Novartis: Honoraria, Research Funding; Shire plc: Honoraria; Asahi Kasei Medical: Research Funding; Japanese Society of Hematology: Research Funding; The Shinnihon Foundation of Advanced Medical Treatment Research: Research Funding. Kiladjian:AOP Orphan: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Komatsu:AbbVie: Other: member of safety assessment committee in M13-834 clinical trial.; Otsuka Pharmaceutical Co., Ltd., Shire Japan KK, Novartis Pharma KK, PharmaEssentia Japan KK, Fuso Pharmaceutical Industries, Ltd., Fujifilm Wako Pure Chemical Corporation, Chugai Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Takeda Pharmaceutica: Research Funding; Meiji Seika Pharma Co., Ltd.: Patents & Royalties: PCT/JP2020/008434, Research Funding; PPMX: Consultancy, Research Funding; Otsuka Pharmaceutical Co., Ltd., PharmaEssentia Japan KK, AbbVie GK, Celgene KK, Novartis Pharma KK, Shire Japan KK, Japan Tobacco Inc: Consultancy; Takeda Pharmaceutical Co., Ltd, Novartis Pharma KK, Shire Japan KK: Speakers Bureau. Abello:Takeda: Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Amgen: Consultancy, Research Funding; Dr. Reddy's: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding. Gomez-Almaguer:Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Scherber:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Mauro:Novartis: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding; Sun Pharma/SPARC: Research Funding; Takeda: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding; Pfizer: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding. Mesa:Samus Therapeutics: Research Funding; Novartis: Consultancy; Genentech: Research Funding; Incyte: Research Funding; Bristol Myers Squibb: Research Funding; AbbVie: Research Funding; CTI BioPharma: Research Funding; Sierra Oncology: Consultancy; LaJolla Pharmaceutical Company: Consultancy; Promedior: Research Funding.

377 Background: Neoadjuvant therapy has been associated with a median overall survival (OS) of 18 – 23 months (mo) in patients (pts) with BR pancreatic ductal adenocarcinoma (PDAC). To establish reference regimens to which novel treatments can be compared in future studies, we evaluated neoadjuvant mFOLFIRINOX with or without RT in BR PDAC in a phase II National Clinical Trials Network (NCTN) trial. Methods: Pts with ECOG PS 0-1 and BR PDAC confirmed by central real-time radiographic review after pre-registration were randomized to either arm A: 8 cycles of neoadjuvant mFOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, leucovorin 400 mg/m2 and infusional 5-fluorouracil 2400 mg/m2 over 46 hours), or arm B: 7 cycles of mFOLFIRINOX followed by stereotactic body RT (SBRT, 33-40 Gy in 5 fractions [fx]) or hypofractionated image guided RT (HIGRT, 25 Gy in 5 fx). Pts in either arm without disease progression underwent pancreatectomy, then 4 cycles of adjuvant mFOLFOX6 (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2 and infusional 5-fluorouracil 2400 mg/m2 over 46 hours). The primary endpoint, 18-mo OS rate, of each arm was compared to a historical control of 50%. Planned interim analysis mandated closure of either arm in which <11 of first 30 accrued pts underwent R0 resection. Results: 155 pts pre-registered and 126 pts were enrolled to arm A (N=70; 54 randomized, 16 following closure of arm B) or arm B (N=56; closed at interim analysis, all pts randomized prior to closure). Median age (A: 63y, B: 67y), median CA 19-9 level (A: 171 U/ml, B: 248 U/ml) and ECOG PS (A: 51% PS 0, B: 57% PS 0) of registered pts were similar between arms (p > 0.05). Treatment detailed in Table. The 18-mo OS rate based on Kaplan Meier estimates was 67.9% (95%CI: 54.6 – 78.0) in arm A and 47.3% (95%CI: 33.7 – 59.7) in arm B. Among pts who underwent pancreatectomy, 18-mo OS rate was 93.1% (95%CI: 84.3 – 100) and 78.9% (95%CI: 62.6 – 99.6) in arm A and B, respectively. With median follow-up of 27 and 31 mo, median OS was 31.0 (95%CI: 22.2 – NE) mo and 17.1 (95%CI: 12.8 – 24.4) mo in arm A and B, respectively. Conclusions: Neoadjuvant mFOLFIRINOX was associated with favorable OS relative to historical data in pts with BL PDAC in this phase II NCTN trial. mFOLFIRINOX with hypofractionated RT did not improve OS compared to historical data. mFOLFIRINOX represents a reference regimen in this setting and a backbone on which to add novel agents. Support: U10CA180821, U10CA180882, U24CA196171; https://acknowledgments.alliancefound.org Clinical trial information: NCT02839343. [Table: see text]

343 Background: Alliance/CALGB 80802, a randomized phase III trial, evaluated sorafenib plus doxorubicin vs. doxorubicin in pts with HCC and showed no improvement in median overall survival (OS) (HR[95CI] 1.05[0.83-1.31]) or PFS (HR[95CI] 0.93[0.75-1.16]). In HCC surrogacy of tumor response with OS remains controversial, in part due to varying criteria used for response evaluation (e.g., RECIST1.1 and mRECIST). We evaluated the performance of several models to predict OS using pretreatment clinical and radiomic variables. Methods: In CALBG 80802, we segmented all measurable tumor lesions on sequential CT scans. A lesion’s imaging phenotype was deciphered with 23 uncorrelated quantitative imaging features measured at baseline and week (wk) 10 (first follow-up). An OS landmark survival analysis was conducted at wk 10. Patients were randomly assigned (3:1) to training (n = 92) and validation (n = 37) sets. In a training set, 6 random forest predictive models (6 signatures) used features that best predicted OS using 3 sets of variables: radiomics only (n = 23), clinical only (n = 9), radiomics and clinical (n = 32). Two time points (baseline only or baseline + wk 10) were assessed. Each signature's output was an individualized prediction and a continuous value ranging from 0 to 1 (from most to least favorable predicted OS). The primary endpoint was to compare these models' performance to predict OS using error rate (Harrell's concordance-index) in the validation set. Results: Of the 6 training signatures evaluated, the one achieving the highest performance in the validation set was an 8-feature signature combining radiomics and clinical variables measured at two time points (baseline + wk 10) with an error rate of 35.6%. The variables [rank of importance] (table) selected by the signature included baseline clinical features (albumin[1], AFP[2], Child-Pugh[4]), baseline radiomics features (component 17[3], component 1[5], component 9[7], tumor volume[8]) and wk 10 radiomics features (delta tumor volume[6]). Variable delta tumor volume [6] used a more enhanced estimation of tumor burden at baseline and a delta tumor volumetric measurement; compared to RECIST1.1 measurement of percentage change in unidimensional measurement of a subset of target lesions. The four quartiles of the signature were significantly associated with OS (Log-Rank, P < 0.0001). Conclusions: The selected combined radiomic and clinical composite signature provided the best prediction for OS in the 80802 study patients’ population. It is a suggested way forward to go beyond single anatomic measurement techniques such as RECIST or mRECIST. [Table: see text]

325 Background: Alliance/CALGB 80802 randomized phase III trial evaluated DO+S vs. S in pts with aHCC, and showed no improvement in median OS. Multi-drug resistant pathway mitigation by the Ras/Raf/MEK/ERK pathway and bFGF-mediated activation of Raf-1 promotes the formation of antiapoptotic Raf-1 and ASK1 complex, induced by anthracyclines. S efficiently blocks NS5A-recruited c-Raf mediated HCV replication and viral gene expression. Once inhibited by S, VEGF expression of HepG2 may limit HCV cellular entry. Release of Raf-1-Ask-1 dimer and inhibition of Raf-1 via S putatively differ in the presence or absence of DO. We hypothesize treatment with S reduces HCV titer levels (TL) and influence pts’ outcome. Methods: In 80802 HCV pts, TL were evaluated in both arms at baseline and post-baseline at Day 1 of Cycles 2, 3, and every 2 cycles and at progression or discontinuation of therapy. HCV undetectable (HCV-UN) levels were defined as < 50 copies/mL. TL were evaluated in relation to OS and PFS. HCV RNA levels were measured by TaqMan PCR and by genotype. Results: Of 356 pts, 83 were HCV+ with more Black/African American (25/50 = 50%) vs. White (54/239 = 23%) or other race groups (4/67 = 6%) (p < 0.0001). HCV titer data were available on 54 pts (S: 28, DO+S: 26). At baseline, 12 pts (S: 7, DO+S: 5) were HCV-UN, and post-baseline HCV TL did not significantly differ between treatment arms; one patient in each arm went from detectable (HCV-D) to HCV-UN. Post-baseline, 40 pts were HCV-D vs. 14 who were HCV-UN (S+DO: 8, S: 6 pts). Except for the two pts who became HCV-UN, baseline HCV-D vs. HCV-UN titers was similar to that status post-baseline. PFS and OS between HCV-D and HCV-UN both at baseline and post-baseline are delineated in the table. Conclusions: We observed that S did not influence HCV TL. Pts treated with DO+S vs. S had worse PFS if they had HCV-UN, and further that higher levels of HCV titers at baseline were associated with significantly improved PFS. Given the small sample size, these findings warrant further prospective evaluation. Support: U10CA180821, U10CA180882, U24CA196171; Bayer, Bristol-Myers-Squibb, and Sanofi. https://acknowledgments.alliancefound.org . Clinical trial information: NCT01015833. [Table: see text]

108 Background: Primary tumor sidedness has emerged as a prognostic and predictive biomarker for patients (pts) with metastatic colorectal cancer (mCRC). Tumor bulk has also been postulated to predict response to anti-EGFR therapy. We sought to evaluate the role of tumor bulk as a predictive biomarker to anti-EGFR therapy in pts with left- (LS) and right-sided (RS) mCRC. Methods: Data from 476 pts with mCRC enrolled across 2 first-line trials of anti-EGFR plus chemotherapy versus chemotherapy were pooled. Pts were included if there was available information on tumor sidedness and tumor bulk. All were KRAS wild-type and BRAF wild-type or unknown BRAF status. The right colon was defined as the cecum through the transverse colon, and the left colon as the splenic flexure through the rectum. Tumor bulk was the mean tumor size of target lesions at baseline, bulky defined as > 3.5 cm. Overall survival (OS) and progression-free survival (PFS) were assessed using Kaplan-Meier and Cox models adjusting for performance status (PS), platelet count, primary tumor (PT) resection, number of metastatic sites, and stratified by study. Results: Pts with bulky tumors (211, 44%) had higher PS, white blood cell and platelet counts, higher CEA, fewer sites of metastatic disease, more liver than lung metastases, and fewer had PT resection. OS and PFS medians in months (mos) are presented in the table with 95% confidence intervals (95%CIs). Bulky tumors had inferior median OS compared with non-bulky (mOS, 17.9 vs. 21.3 mos, HRadj 1.33, 95% CI 1.05-1.69, P = 0.016) although median PFS was similar (mPFS, 8.6 vs. 8.7 mos, HRadj 1.15, 95% CI 0.92-1.42, P = 0.21). Conclusions: Tumor bulk is an independent prognostic factor for OS in KRAS wild-type and BRAF wild-type or unknown BRAF status pts. Pts with non-bulky RS tumors have survival outcomes similar to pts with bulky LS tumors. Although the mPFS for pts with RS tumors treated with anti-EGFR therapy was the lowest across subgroups, this finding was not statistically significant. Further research is warranted into whether pts with bulky RS tumors benefit from anti-EGFR therapy. Clinical trial information: NCT00182715, NCT00640081. [Table: see text]

10 Background: In colon cancer, tumor deposits (TD) have been associated with worse prognosis, but they are included in the TNM staging system only in the absence of lymph node metastasis (i.e., stage III pN1c tumors). Here we aimed at evaluating the prognostic value of TD and the impact of the addition of TD in the count of lymph node metastases in patients with stage III colon cancer from the CALGB/SWOG 80702 phase III trial (NCT01150045). Methods: Pathological reports of all patients were reviewed for the presence and the count of TD, primary tumor sidedness, lymphovascular invasion and perineural invasion. Cases without available pathological report or without specific information of TD were excluded. Prognostic associations were evaluated by multi-variable Cox models adjusting for treatment arm, T-stage, N-stage, lymphovascular invasion, perineural invasion and lymph node ratio. Results: Overall, 2028 patients were included, with 524 (26%) TD-positive and 1504 (74%) TD-negative stage III tumors. Of the TD-positive patients, 80 (15.4%) were node negative (i.e., pN1c), 239 (46.1%) were pN1a/b and 200 (38.55%) were pN2. 17.2% and 37.0% of all pN1a/b and pN2 tumors had TD. Overall median follow-up was 69.3 months. The presence of TD was associated with poorer DFS (adjusted hazard ratio (aHR) = 1.59, 95%CI 1.28-1.91) and OS (aHR = 1.52, 95%CI 1.18-1.95) in the overall population. The negative effect of TD on DFS and OS was observed for both pN1a/b and pN2 groups and confirmed in multivariate Cox model. Among TD-positive patients, the number of TD had a linear negative effect on DFS and OS. Adding TD to the count of lymph node metastases, 104 of 1570 (6.6%) patients initially considered as pN1 were re-staged as pN2. Re-staged pN2 patients experienced worse DFS (3-year DFS rate: 65.5% versus 80.3%, P = .0003) and OS (5-year OS rate: 69.1 versus 87.8%, P = .0005) than patients confirmed as pN1. Re-staged pN2 patients had similar DFS than patients initially staged as pN2 (3-year DFS rate: 65.5% versus 63.1%, P = .1992). OS curves of these 2 groups crossed, with better outcomes during the first 3 years of follow-up but poorer 5-year estimates for re-staged pN2 patients (5-year OS rate: 69.1% versus 74.8%, P = .0436). Conclusions: TD are found in more than one fourth of stage III colon cancer specimens. The number of TD has a linear deleterious effect on patients’ prognosis. Adding the number of TD to the count of lymph node metastases improves the prognostication accuracy of the TNM staging. Support: U10CA180821, U10CA180882; https://acknowledgments.alliancefound.org . Clinical trial information: NCT01150045.

Abstract Background: Dysregulation of ceramide and sphingomyelin levels have been suggested to contribute to the pathogenesis of Alzheimer’s disease (AD). Ceramide transfer proteins (CERTs) are ceramide carriers which are crucial for ceramide and sphingomyelin balance in cells. Extracellular forms of CERTs co-localize with amyloid-β (Aβ) plaques in AD brains. To date, the significance of these observations for the pathophysiology of AD remains uncertain.Methods: A plasmid expressing CERTL, the long isoform of CERTs, was used to study the interaction of CERTL with amyloid precursor protein (APP) by co-immunoprecipitation and immunofluorescence in HEK cells. The recombinant CERTL protein was employed to study interaction of CERTL with amyloid-β (Aβ), Aβ aggregation process in presence of CERTL, and the resulting changes in Aβ toxicity in neuroblastoma cells. CERTL was overexpressed in neurons by adeno associated virus (AAV) in a mouse model of familial AD (5xFAD). Ten weeks after transduction, animals were challenged with behavior tests for memory, anxiety and locomotion. At week twelve, brains were investigated for sphingolipid levels by mass spectrometry, plaques and neuroinflammation by immunohistochemistry, gene expression and/or immunoassay.Results: Here, we report that CERTL, binds to APP, modifies Aβ aggregation and reduces Aβ neurotoxicity in vitro. Furthermore, we show that intracortical injection of AAV, mediating the expression of CERTL, decreases levels of ceramide d18:1/16:0 and increases sphingomyelin levels in the brain of male 5xFAD mice. CERTL in vivo over-expression has a mild effect on animal locomotion, decreases Aβ formation and modulates microglia by decreasing their pro-inflammatory phenotype.Conclusion: Our results demonstrate a crucial role of CERTL in regulating ceramide levels in the brain, in amyloid plaque formation and neuroinflammation, thereby opening research avenues for therapeutic targets of AD and other neurodegenerative diseases.