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SMAD4, a tumor suppressor gene, is lost in up to 60%–90% of pancreatic adenocarcinomas (PDAs). Loss of SMAD4 allows tumor progression by upregulating autophagy, a cell survival mechanism that counteracts apoptosis and allows intracellular recycling of macromolecules. Hydroxychloroquine (HCQ) is an autophagy inhibitor. We studied whether HCQ treatment in SMAD4 deficient PDA may prevent therapeutic resistance induced by autophagy upregulation. We retrospectively analyzed the SMAD4 status of patients with PDA enrolled in two prospective clinical trials evaluating pre‐operative HCQ. The first dose escalation trial demonstrated the safety of preoperative gemcitabine with HCQ (NCT01128296). More recently, a randomized trial of gemcitabine/nab‐paclitaxel +/− HCQ evaluated Evans Grade histopathologic response (NCT01978184). The effect of SMAD4 loss on response to HCQ and chemotherapy was studied for association with clinical outcome. Fisher’s exact test and log‐rank test were used to assess response and survival. Fifty‐two patients receiving HCQ with neoadjuvant chemotherapy were studied. Twenty‐five patients had SMAD4 loss (48%). 76% of HCQ‐treated patients with SMAD4 loss obtained a histopathologic response greater than or equal to 2A, compared with only 37% with SMAD4 intact (p = 0.006). Although loss of SMAD4 has been associated with worse outcomes, in the current study, loss of SMAD4 was not associated with a detriment in median overall survival in HCQ‐treated patients (34.43 months in SMAD4 loss vs. 27.27 months in SMAD4 intact, p = 0.18). The addition of HCQ to neoadjuvant chemotherapy in patients with PDA may improve treatment response in those with SMAD4 loss. Further study of the relationship among SMAD4, autophagy, and treatment outcomes in PDA is warranted.

Clinical trials reporting the robust antitumor activity of immune checkpoint inhibitors (ICIs) in microsatellite instability-high (MSI-H) solid tumors have used tissue-based testing to determine the MSI-H status. This study assessed if MSI-H detected by a plasma-based circulating tumor DNA liquid biopsy test predicts robust response to ICI in patients with pancreatic ductal adenocarcinoma (PDAC). Retrospective analysis of patients with PDAC and MSI-H identified on Guardant360 from October 2018 to April 2021 was performed; clinical outcomes were submitted by treating providers. From 52 patients with PDAC +MSI-H, outcomes were available for 10 (19%) with a median age of 68 years (range: 56–82 years); the majority were male (80%) and had metastatic disease (80%). Nine of 10 patients were treated with ICI. Eight out of nine patients received single-agent pembrolizumab (8/9), while one received ipilimumab plus nivolumab. The overall response rate by Response Evaluation Criteria in Solid Tumors was 77% (7/9). The median progression-free survival and overall survival were not reached in this cohort. The median duration of treatment with ICI was 8 months (range: 1–24), and six out of seven responders continued to show response at the time of data cut-off after a median follow-up of 21 months (range: 11–33). Tissue-based MSI results were concordant with plasma-based G360 results in five of six patients (83%) who had tissue-based test results available, with G360 identifying one more patient with MSI-H than tissue testing. These results suggest that detecting MSI-H by a well-validated liquid biopsy test could predict a robust response to ICI in patients with PDAC. The use of liquid biopsy may expand the identification of PDAC patients with MSI-H tumors and enable treatment with ICI resulting in improved outcomes.

Introduction: Colorectal cancer (CRC) is the second leading cause of cancer death in the United States (US). Primary care physicians (PCP) are critical towards a successful CRC screening program. However, the impact of availability of PCP on CRC-related mortality is not well studied. Materials and Methods: We extracted data on crude incidence and mortality rates of CRC among all 50 states and District of Columbia (D.C.) from the Center for Disease Control (CDC) WONDER database for the year 2019. Data on number of actively practicing PCPs in all 50 states and D.C. for the year 2020 were obtained from Association of American Medical Colleges (AAMC) State Physician Workforce Data Report. The correlation between the ratio of number of PCPs per CRC case with age-adjusted mortality rate (AAMR) for CRC was studied by state and within White and African American (AA) populations from 2017-2019. Pearson’s co-efficient was used to study correlations and T-test was used for comparing independent samples. Statistical analysis was performed using VassarStats. Results: The median AAMR for CRC from 2017-2019 in the US was 13.2 (IQR 11,15.4) per 100,000 population. AAMR for CRC was significantly higher among AA versus White populations (t=5.79, p Conclusion: Results of this study suggest that greater availability of primary care physicians correlates with lower CRC-related mortality. AA have a significantly higher AAMR for CRC with a lower PCP per CRC case ratio. This may indicate a lower access to primary care among AA populations with CRC. Our results underscore the need to expand access to primary care among AA populations with the goal of minimizing disparities in CRC-related mortality. Citation Format: Udhayvir S. Grewal, Shiva J. Gaddam, Manik Aggarwal, Subhash C. Garikipati, Prabhat Kumar, Naomi Fei. Correlation of availability of primary care physicians and colorectal cancer-related mortality in the United States: Do racial disparities exist. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6488.

80 Background: Incidence of colorectal cancer (CRC) among adolescents and young adults (AYA) is increasing. A significant proportion of adolescents and young adults (AYA) with colorectal cancer (CRC) lack traceable genetic risk factors. We sought to study the impact of lifestyle-related risk factors on the incidence and mortality of CRC in these patients. Methods: We extracted data on crude incidence and mortality rates of CRC (reported per 100,000 population) for ages 15-39 years in all 50 U.S. states and District of Columbia from the Center for Disease Control (CDC) WONDER database (1999-2018). Data on risk factors such as obesity, physical activity, alcohol and tobacco abuse and nutrition were obtained from the Behavioral Risk Factor Surveillance System (BRFSS, 2020). Correlations were analyzed using Pearson’s co-efficient. p < 0.05 was considered statistically significant. Statistical analysis was performed using VassarStats. Results: Median crude incidence and mortality rates of CRC in AYA in the US from 1999-2018 were 3.8 (IQR 3.2, 4.4) and 0.7 (IQR 0.5,0.9) per 100,000 population respectively. States with higher age-adjusted prevalence of obesity per 100,000 had higher incidence (r = 0.36, p = 0.01) and mortality rates (r = 0.49, p = 0.0002) of CRC in AYA population. States with a higher age-adjusted prevalence of adherence to recommended weekly aerobic activity had lower incidence (r = -0.4515, p = 0.001) and mortality (r = -0.569, p < 0.0001) rates. While states with higher age-adjusted prevalence of tobacco abuse had higher incidence rate of CRC (r = 0.33, p = 0.02), there was no correlation with mortality rates (r = 0.24, p = 0.09). Higher prevalence of alcohol consumption was associated with decreased mortality rate (r = -0.44, p = 0.001), with no impact on incidence rate (r = -0.16, p = 0.26). States with lower daily consumption of fruits had higher incidence (r = 0.37, p = 0.01) and mortality rates (r = 0.59, p < 0.0001). No correlation of daily consumption of vegetables with incidence (r = -0.1516, p = 0.29) and mortality (r = 0.18, p = 0.22) rates was noted. Conclusions: In the current analysis, higher prevalence of obesity, lower rates of aerobic activity and lower daily consumption of fruits were strongly associated with increased incidence and mortality rates. The impact of tobacco abuse and alcohol consumption was more variable. Apart from improving access to genetic testing and counseling, efforts aimed at mitigating the rise of CRC incidence among AYA should also focus on traditional lifestyle-related risk factors.

Background SMAD4, a tumor suppressor gene, is inactivated or deleted in 60–90% of pancreatic adenocarcinomas (PDA). Loss of SMAD4 allows tumor progression by limiting cell cycle arrest and apoptosis and increasing metastases. SMAD4 deficient PDA cells are resistant to radiotherapy by upregulating autophagy, a cell survival mechanism that counteracts apoptotic mechanisms and allows intracellular recycling of macromolecules and organelles. Hydroxychloroquine (HCQ) is an orally available autophagy inhibitor with an established toxicity profile. We studied whether HCQ treatment in SMAD4 deficient PDA may prevent therapeutic resistance induced by autophagy upregulation. Methods We retrospectively analyzed the SMAD4 status of PDA patients enrolled in two prospective clinical trials evaluating administration of preoperative HCQ. The first dose escalation trial demonstrated the safety of preoperative gemcitabine with HCQ (NCT01128296). More recently, a randomized trial of gemcitabine/nab-paclitaxel +/- HCQ evaluated Evans Grade histopathologic response (NCT01978184). Immunohistochemistry of resected specimens for SMAD4 was previously performed. Patients not treated at the max HCQ dose (n = 5), not resected (n = 2) or with SMAD4 staining unavailable were excluded (n = 10). The effect of SMAD4 loss on response to HCQ and chemotherapy was studied for association with clinical outcome. Fisher’s exact test and log-rank test were used to assess response and survival. Results 52 patients receiving HCQ with neoadjuvant chemotherapy were studied. 25 of these patients had SMAD4 loss (48%). 76% of HCQ treated patients with SMAD4 loss obtained a histopathologic response ≥ 2A, compared to only 37% with SMAD4 intact (p = 0.006). In contrast with prevailing views, loss of SMAD4 was not associated with a detriment in median overall survival in HCQ treated patients (34.43 months in SMAD4 loss vs. 27.27 months in SMAD4 intact, p = 0.18). Conclusions The addition of HCQ to neoadjuvant chemotherapy in patients with PDA may improve treatment response in those with SMAD4 loss. Further study of the relationship between SMAD4, autophagy and treatment outcomes in PDA is warranted.

e21674 Background: The purpose of this study was to assess patterns of disease progression for patients with metastatic non-small cell lung cancer (NSCLC) on checkpoint inhibitor immunotherapy in order to help guide effective use of targeted radiation therapy to sites of gross disease most likely to progress. Methods: This single center, retrospective study included all patients diagnosed with Stage IV NSCLC between June 2015 and February 2019 who received at least 2 cycles of nivolumab, pembrolizumab, or atezolizumab, with or without concurrent chemotherapy. Immune RECIST criteria were used to assess patterns of disease progression, and progression-free survival (PFS), excluding irradiated tumors. Descriptive statistics were used to report baseline patient and tumor characteristics. The Chi square and log-rank tests were used to determine whether any baseline clinical characteristics were associated with progressive disease in initial sites only (vs. new or combined sites), and PFS, respectively. Factors assessed included initial metastatic sites, tumor histology, performance status, PD-L1 expression, untreated primary tumor, history of brain metastasis, number of metastatic sites involved, and use of concurrent chemo-immunotherapy. Results: Among 143 eligible patients with a median follow-up of 11 months, 97 (68%) developed disease progression. Of these, 67 patients (69.1%) progressed only at initial disease site(s), 10 patients (10.3%) progressed only at new disease site(s), and 20 patients (20.6%) progressed in both initial and new sites. Rates of disease progression based on tumor location were higher for liver (64%) and lung metastases (61%) than for other metastatic sites (33-36%) or the primary tumor (24%). Only higher PD-L1 expression ( p= 0.002) and absence of lung metastasis ( p= 0.048) at baseline were associated with improved PFS. No baseline characteristics significantly impacted the probability of initial disease site-only progression, though a trend was observed for untreated primary tumor (72% vs. 56%, p= 0.169). Conclusions: The dominant pattern of disease progression for patients with metastatic NSCLC on checkpoint inhibitor immunotherapy is in the initial sites of disease alone, whereas only 10% of patients progressed in new disease site(s) alone, suggesting a potential role for local radiation therapy as a complementary treatment modality. Pre-treatment patient and tumor characteristics did not predict patients most likely to benefit.

Background Minimal research has explored community dwelling adults’ knowledge of the human papillomavirus (HPV) in relation to head and neck cancer (HNC). The purpose of this study was to report on community dwelling adults’ knowledge of HPV in relation to infection, symptoms, and the development of HNC. Methods Cross-sectional assessment of community-dwelling adults on history of behavioral risk factors for HNC, health literacy, and knowledge regarding HPV in relation to HNC. Results Of those who completed the measure of health literacy, 17.1% read at or below an 8th grade level. Participants reported a range of history of behaviors putting them at increased risk for HPV and HNC. Respondents answered an average of 67.2% of HPV questions correctly, only one person answered all 15 questions correctly. There were no differences in knowledge of HPV in relation to HNC based upon demographics, suburban versus urban location, health literacy, or cancer history. Conclusions Adults reported a range of behaviors associated with an increased risk of HPV transmission but also displayed large gaps in knowledge regarding HPV in relation to HNC.

Cryoglobulins are proteins that form ‘cloudy’ precipitates at temperatures

761 Background: SMAD4, a tumor suppressor gene, is inactivated or deleted in 60-90% of pancreatic adenocarcinomas (PDA). Loss of SMAD4 allows tumor progression by limiting cell cycle arrest and apoptosis and increasing metastases. SMAD4 deficient PDA cells are resistant to radiotherapy by upregulation of autophagy, a cell survival mechanism that allows intracellular recycling of macromolecules and organelles. Hydroxychloroquine (HCQ) is a known autophagy inhibitor, suggesting that HCQ treatment in SMAD4 deficient PDA may prevent therapeutic resistance induced by autophagy upregulation. Methods: We retrospectively analyzed the SMAD4 status of PDA patients enrolled in two prospective clinical trials evaluating preoperative HCQ. The first dose escalation trial demonstrated the safety of preoperative gemcitabine with HCQ ( NCT01128296 ). More recently, a randomized trial of gemcitabine/nab-paclitaxel +/- HCQ evaluated Evans Grade histopathologic response ( NCT01978184 ). Immunohistochemistry of resected specimens for SMAD4 was previously performed. Patients not treated at the max HCQ dose (n = 5), not resected (n = 2) or with SMAD4 staining unavailable were excluded (n = 10). The effect of SMAD4 loss on response to HCQ and chemotherapy was studied for association with clinical outcome. Fisher’s exact test and log-rank test were used to assess response and survival. Results: 52 patients receiving HCQ with neoadjuvant chemotherapy and 24 patients receiving neoadjuvant chemotherapy alone were studied. Of the HCQ group, 25 patients had SMAD4 loss (48%), compared with 15 control patients (63%, p = 0.32). 76% of HCQ treated patients with SMAD4 loss obtained a histopathologic response ≥2A, compared to only 37% with SMAD4 intact (p = 0.006). In the control group, loss of SMAD4 was associated with a nonsignificant detriment in 3 year OS (25% vs. 78%, p = 0.3) that was less apparent in patients treated with HCQ (46% vs. 47%, p = 0.18). Conclusions: The addition of HCQ to neoadjuvant chemotherapy in PDA may improve treatment response in patients with SMAD4 loss. Further study of the relationship between SMAD4, autophagy and treatment outcomes in PDA is warranted.

Sporadic Burkitt’s Lymphoma (BL) is a highly aggressive form of non-Hodgkin’s lymphoma which requires prompt diagnosis and treatment. Though usual presentation involves abdominal lymphadenopathy with possible solid organ involvement, sporadic BL can rarely present with peritoneal lymphomatosis. We present a unique case with rapid evolution of BL presenting as peritoneal and omental lymphomatosis with hepatic lesions and pelvic and pericardial adenopathy.

Dermatomyositis (DM) is a unique inflammatory myopathy with clinical findings of proximal muscle weakness, characteristic rash, and elevated muscle enzymes. The association of DM and malignancy, most commonly adenocarcinoma, is well known. There have been few case reports of primary myelofibrosis associated with DM. We present the case of a 69-year-old male with a history of polycythemia vera (PV) who developed proximal muscle weakness, dysphagia, and rash. He was found to have elevated creatinine kinase and skin biopsy was consistent with DM. Due to persistent pancytopenia a bone marrow biopsy was performed and showed postpolycythemic myelofibrosis. To our knowledge, this is the first case reported of this unique association.

Cardiolipin (CL) is the signature phospholipid of mitochondrial membranes. CL deficiency leads to defects in mitochondrial function. Using a targeted synthetic lethality screen to identify defects that exacerbate CL deficiency, we determined that deletion of mitochondrial morphology genes in cells lacking CL leads to severe growth defects. We show that ER membrane proteins Get1p and Get2p are required for maintaining normal levels of CL. We propose that these proteins regulate the level of CL by maintaining wild type-like tubular mitochondrial morphology. The genetic interactions observed in this study identify novel physiological modifiers that are required for maintenance of CL levels and mitochondrial morphology.

Objectives:1) Assess swallowing function longitudinally using standardized questionnaires in a cohort of oropharyngeal cancer patients treated with transoral robotic surgery (TORS). 2) Compare the effect of tumor T-stage on swallowing outcomes.Methods:A prospective, institutional review board (IRB)-approved database of all patients undergoing TORS for oropharyngeal cancer at a tertiary-care academic institution was queried from November 2010-October 2012. Demographic data as well as longitudinal assessment of swallowing outcomes were collected. Standardized questionnaires included: University of Washington Quality of Life question 5 (UW-QOLq5), MD Anderson Dysphagia Inventory (MDADI), and Functional Oral Intake Scale (FOIS). Two-sided Wilcoxon signed-rank tests were used to compare baseline values with corresponding 1, 3, 6, and 12 months post-surgery. Two-sided Wilcoxon rank-sum tests were used to test for differences between T-stages.Results:Thirty-nine patients were studied with a mean age of 60.7 (42-...

Objectives:1) Assess self-reported risk factors and knowledge gaps regarding head and neck cancer (HNC) risk factors in a multi-ethnic urban versus suburban population. 2) Improve education regarding behavioral risk factors for HNC, including regarding the transmission of human papillomavirus (HPV).Methods:The current sample includes a total of 118 individuals who presented for free HNC screenings across urban and suburban sites. Ninety-eight consented to complete behavioral risk questionnaires assessing for knowledge regarding HNC, ancestry, smoking/tobacco use, alcohol use, and sexual history.Results:Mean age was 56.63 years old (SD = 14.22, range 23 to 85), 60.2% female, predominantly African American (53.1%), Caucasian (42.7%), and other (4.1%). Those residing in an urban environment were more likely to be African American χ2(1, N = 98)=23.334, P < 0.001, have a history of treatment for some other cancer χ2(1, N=98)=6.063, P = 0.01, be a current smoker χ2(2, N=98)=5.885, P = 0.05, report more cumulati...

Introduction Blood products are a valuable resource associated with infectious and immunological adverse effects, hence the ongoing efforts for blood conservation. Evidence supports the use of restrictive Hemoglobin (Hb) triggers as safe and effective. Nevertheless, transfusion practice remains based largely on physician preference. The use of single-unit (SU) rather than double-unit (DU) transfusions per transfusion episode may be another strategy. Scant retrospective data from the 1960's discarded this idea as being ineffective in treating anemia.A recent European study demonstrated that using a SU transfusion protocol led to a 25% reduction in red blood cell usage amongst patients with hematologic malignancies(Berger et al; Haematologica, 2012). There have been no comparative studies done in the US population outside the orthopedic population which yielded similar benefit (Ma et al; Transfusion Medicine, 2005). Clinical Decision Support Systems (CDSS) are protocols shown to be effective in standardizing practice. At our academic institution, a CDSS was initiated for admissions to the Malignant Hematology and Transplantation Service. From September 2014, a protocol amendment prompted providers to order SU red blood cells (RBCs) for transfusion for Hb Methods Retrospective chart review was performed on all adult patients admitted to the Malignant Hematology and Transplantation Service who received routine RBC transfusions from 9/1/2013- 8/31/2014 (DU-gp) and 9/1/2014 to 8/31/2015 (SU-gp). Patients with active bleeding were excluded. The primary endpoint for this study was median RBC units transfused per admission. Analysis was limited to RBC products only. Chi-square test and t-test were used in the data analysis for categorical variables and continuous variables, respectively. A mixed model was used for repeated measurements. Results 147 patients in 201 admissions in DU-gp and 126 patients in 170 admissions in SU-gp were analyzed. Baseline characteristics are presented in Table 1 with no significant differences noted between groups. Excellent adherence to the CDSS protocol was noted in both the DU (97%) and SU (92%) groups. Baseline admission Hb was similar, but Hb at discharge was significantly higher in DU-gp 9.4 g/dL vs 8.8 g/dL in SU-gp (P=0.005). The median number of transfusion episodes (each time RBC orders were placed) per admission in the DU-gp and SU-gp was 2 (range, 1-16) and 3 (range, 1-27), respectively (P Conclusions Our data show that implementing a CDSS, transfusing single-unit RBCs instead of double-units for Hb < 8g/dL had an excellent adherence, highlighting the feasibility of such a strategy. It is noteworthy that although patients required more transfusion encounters, the overall RBC utilization fell by 29%. Single-unit RBC transfusion was safe, efficacious and significantly reduced the RBC utilization per admission. Prospective data is required to confirm our results as well as assess the potential cost-benefit advantage with single-unit RBC transfusions. Disclosures No relevant conflicts of interest to declare.

The two non-bilayer forming mitochondrial phospholipids cardiolipin (CL) and phosphatidylethanolamine (PE) play crucial roles in maintaining mitochondrial morphology. We have shown previously that CL and PE have overlapping functions, and the loss of both is synthetically lethal. Because the lack of CL does not lead to defects in the mitochondrial network in Saccharomyces cerevisiae, we hypothesized that PE may compensate for CL in the maintenance of mitochondrial tubular morphology and fusion. To test this hypothesis, we constructed a conditional mutant crd1Δpsd1Δ containing null alleles of CRD1 (CL synthase) and PSD1 (mitochondrial phosphatidylserine decarboxylase), in which the wild type CRD1 gene is expressed on a plasmid under control of the TET(OFF) promoter. In the presence of tetracycline, the mutant exhibited highly fragmented mitochondria, loss of mitochondrial DNA, and reduced membrane potential, characteristic of fusion mutants. Deletion of DNM1, required for mitochondrial fission, restored the tubular mitochondrial morphology. Loss of CL and mitochondrial PE led to reduced levels of small and large isoforms of the fusion protein Mgm1p, possibly accounting for the fusion defect. Taken together, these data demonstrate for the first time in vivo that CL and mitochondrial PE are required to maintain tubular mitochondrial morphology and have overlapping functions in mitochondrial fusion.