Taparra, Kekoa

Abstract Extra copies of centrosomes are frequently observed in cancer cells. To survive and proliferate, cancer cells have developed strategies to cluster extra-centrosomes to form bipolar mitotic spindles. The aim of this study was to investigate whether centrosome clustering (CC) inhibition (CCi) would preferentially radiosensitize non–small cell lung cancer (NSCLC). Griseofulvin (GF; FDA-approved treatment) inhibits CC, and combined with radiation treatment (RT), resulted in a significant increase in the number of NSCLC cells with multipolar spindles, and decreased cell viability and colony formation ability in vitro. In vivo, GF treatment was well tolerated by mice, and the combined therapy of GF and radiation treatment resulted in a significant tumor growth delay. Both GF and radiation treatment also induced the generation of micronuclei (MN) in vitro and in vivo and activated cyclic GMP-AMP synthase (cGAS) in NSCLC cells. A significant increase in downstream cGAS-STING pathway activation was seen after combination treatment in A549 radioresistant cells that was dependent on cGAS. In conclusion, GF increased radiation treatment efficacy in lung cancer preclinical models in vitro and in vivo. This effect may be associated with the generation of MN and the activation of cGAS. These data suggest that the combination therapy of CCi, radiation treatment, and immunotherapy could be a promising strategy to treat NSCLC.

80 Background: The Asian American, Native Hawaiian, and Other Pacific Islander (AA/NHPI) population is the fastest growing and most socioeconomically heterogeneous racial/ethnic group in the US. AA/NHPI breast cancer outcomes are often reported as superior to Non-Hispanic Whites (NHW) however evidence suggests aggregating AA/NHPI masks disparities among subpopulations. As NHPI is often ignored as one of five official US races, this study aims to disaggregate AA and NHPI to unmask breast cancer disparities. Methods: An IRB exempt, retrospective cohort study using the National Cancer Database was conducted for women diagnosed with breast cancer in 2004-2016. AA and NHPI patients were compared with the majority NHW group. AA was separated into pertinent geographical origins: East Asian (EA; Chinese, Japanese, Korean), South Asian (SA; Indian, Pakistani), and Southeast Asian (SEA; Filipino, Vietnamese, Laotian, Hmong, Cambodian). Descriptive statistics were used. Logistic and Cox proportional hazard regressions assessed adjusted Odds Ratios (aORs) and adjusted Hazards Ratios (aHR), respectively, with 95% confidence intervals (95%CI). Analyses were adjusted for patient factors (age, insurance, income, rural/urban, education, hospital region, hospital distance, Deyo comorbidity score) and cancer characteristics (grade, stage, metastases, diagnosis year, hormone status). Results: Of 2,073,822 women there were 28,311 EA, 13,259 SA, 21,645 SEA, 5,375 NHPI, and 2,005,232 NHW. The median age was 62 years with median 66 month follow-up. Compared to NHW (9.6%), presentation with late-stage disease (Stage III/IV) was higher in NHPI (12%), SA (12%), and SEA (11%), but not EA (7.5%). On adjusted analysis (Table), EA was the only group with a statistical difference from NHW with aOR=0.85 (95%CI=0.76-0.94). Kaplan-Meier test for overall survival (OS) showed differences between ethnic/racial groups with NHPI having worse OS than AA subpopulations (p<0.0001). On adjusted analysis (Table), all AA subpopulations had lower risk of death compared to NHW: EA (aHR=0.69; 95%CI=0.64-0.74), SA (aHR=0.65; 95CI=0.59-0.71), and SEA (aHR=0.78; 95%CI=0.73-0.84) however the NHPI group had a greater risk of death (aHR=1.14; 95%CI=1.02-1.28). Conclusions: NHPI women with breast cancer have worse outcomes compared to NHW. This is masked by superior AA outcomes when aggregated. The continual improper aggregation of AA with NHPI downplays NHPI cancer disparities. Proper disaggregation of NHPI from AA warrants greater attention.[Table: see text]

e18523 Background: Noninvasive breast cancers ( e.g. ductal and lobular carcinoma in situ) are highly treatable nonobligate precursors to invasive breast cancers. However, even after treatment, some women develop second breast cancers (SBCs), increasing their mortality risk. Prognosticators may inform treatment recommendations for women at higher risk of SBC. In this study, risk factors for SBC were evaluated using deidentified data from the Hawaiʻi Tumor Registry (HTR), an NCI SEER registry. The HTR covers a uniquely multiethnic, statewide population allowing for elucidation of disparities in understudied U.S. populations. Methods: Women initially diagnosed between 1973-2017 with noninvasive (ductal and lobular) breast cancer were identified. Patient demographics, cancer characteristics, and treatment information were collected. Univariate (UVA) and multivariate (MVA) logistic regression analyses were used to identify factors associated with SBC, defined as a breast cancer diagnosis > 6 months after their prior cancer. Results: Of 7,057 women diagnosed with a first noninvasive breast cancer, 696 (10%) developed SBC. Invasive ipsilateral (iiSBC) and invasive contralateral (icSBC) disease represented 9% and 20% of patients who developed SBC, respectively. The five most prevalent ethnic groups were Chinese, Filipino, Japanese, Native Hawaiian, and White. When adjusting for confounders, women who developed iiSBC were more likely to be Native Hawaiian (odds ratio [OR] = 3.20, 95% CI = 2.07-4.94) or Filipino (OR = 1.72, 95%CI = 1.02-2.91) when compared to Whites; diagnosed between 1990-1999 (OR = 2.06, 95%CI = 1.27-3.34); and not have undergone surgical treatment (OR = 2.93, 95%CI = 1.42-6.04). Women who developed iiSBC were less likely to be > 50 years old (OR = 0.67, 95%CI = 0.49-0.90); diagnosed between 2010-2017 (OR = 0.18, 95%CI = 0.09-0.35); received lumpectomy with radiation therapy (OR = 0.54, 95%CI = 0.35-0.72); and undergone mastectomy (OR = 0.48, 95%CI = 0.32-0.72). Women who developed an icSBC were more likely to be Native Hawaiian (OR = 1.58, 95%CI = 1.06-2.35) or Filipino (OR = 1.60, 95%CI = 1.06-2.42). These women were also less likely to have been diagnosed between 2010-2017 (OR = 0.30, 95%CI = 0.17-0.53). On a subset analysis separating all patients with SBC by first course treatment type, there were no statistically significant differences for treatment type based on race/ethnicity. Conclusions: Overall, in this observational study, Native Hawaiian women, Filipino women, and younger women had increased odds of developing invasive SBC. This study highlights racial disparities in SBC development risk that was not previously appreciated among disaggregated groups of Pacific Islanders and Asian women when compared to White women. This may help oncologists understand the risk of developing SBC in these understudied populations.

BACKGROUND: Historically, one in five Hodgkin Lymphoma (HL) patients treated with bleomycin develop bleomycin pulmonary toxicity (BPT), a life-threatening interstitial pneumonitis. The current treatment paradigm consists of prompt discontinuation of bleomycin, administration of corticosteroids, antibiotics, hospital admission, respiratory therapy, or intensive care. BPT represents a challenge for patients with HL as it not only impairs respiratory function, but also has negative impacts on clinical outcomes. A collection of a dozen studies suggest BPT has a mortality rate just short of 10% of patients who develop BPT. Given recent data on bleomycin omission with negative interim PET scan, we assessed changes in BPT rates and severity over the past 15 years. Overall, treatment protocol characterization and patient characteristics most responsive to BPT treatment are poorly understood. OBJECTIVES: In this study, we investigated the clinical impact and treatment strategies in patients with BPT. Our goals were to: 1) Identify HL patients in the last decades who developed BPT and identify risk factors for BPT, 2) evaluate the impact of BPT on long-term clinical outcomes, and 3) characterize patterns of treatment strategies among patients with HL who develop BPT. METHODS: A single-center, retrospective analysis was preformed using patient data from the Mayo Clinic Lymphoma Database (Rochester, MN) consisting of 1,299 patients diagnosed with HL. All patients were diagnosed between 2003-2018. Inclusion criteria included 1) newly diagnosed, biopsy proven HL, 2) upfront treatment with ABVD, 3) treatment was received at our institution. All patients were assessed for clinically relevant HL characteristics including stage of disease, presence of bulky disease, presence of B symptoms, Eastern Cooperative Oncology Group (ECOG) performance status, BPT risk factors, and bleomycin treatment regimen. BPT was clinically defined as 1) Presence of pulmonary symptoms, 2) bilateral interstitial infiltrates on imaging, and 3) no evidence of infectious etiology. Patients treated in the "Early Era" (2000s) were compared to patients in the "Recent Era" (2010s). Comparison of continuous variables between BPT groups was assessed with Wilcox rank-sum test. OS and PFS were estimated via the Kaplan-Meier method. Approval of the protocol by the Mayo Clinic Institutional Review Board (IRB) was obtained and all patients were consented accordingly. RESULTS: One-hundred twenty six patients met the inclusion criteria for this study. Median follow-up for PFS and OS was 5.5 years (95%CI = 4.8-6.4) and 5.8 years (95%CI = 5.0-7.0), respectively. The 10-year OS and PFS among all patients were 85.1% (95%CI = 77.8-93.1) and 86.3% (95%CI = 80.1-93.0), respectively. Forty-seven patients (37% of all patients) met criteria for BPT. The estimated 10-year OS for BPT and non-BPT patients were 74.7% (95%CI = 61.8-90.5) and 91.7% (95%CI = 83.9-100.0), respectively. The estimated 10-year PFS for BPT and non-BPT patients were 84.7% (95%CI = 74.8-95.8) and 87.0% (95%CI = 79.1-95.8), respectively. In univariable analysis, BPT negatively impacted OS (HR=3.6, 95%CI: 1.2-10.6). However, bleomycin omission did not impact OS (HR=1.3, 95%CI=0.5-3.7). BPT-mortality was 17%. In multivariable analysis, BPT was not significantly associated with OS after adjusting for baseline characteristics (HR=3.0, 95%CI=0.9-9.9). Patients were older (median: 46 vs 33 years) and received less bleomycin (median: 107 vs 215 units) compared to non-BPT patients. BPT was most often managed with bleomycin omission with 59% of patients (74 of 126 patients) having omitted bleomycin at some point during treatment. Patients treated in the "Recent Era" (2010s) had lower BPT rates (28% vs 48%), mortality (10% vs 21%), bleomycin dose (143 vs 204 units), and bleomycin cycles (7 vs 12 cycles), yet higher prophylactic bleomycin omission (59% vs 8%) compared to "Early Era" (2000s). Patients treated in the Recent Era compared to Early Era had a reduction of BPT treatment with steroids, hospital admission, respiratory therapy, and ICU admission by 12%, 22%, 14%, 13%, respectively. CONCLUSION: Overall, our data suggests BPT continues to impact OS in HL patients treated with ABVD, however BPT treatment is decreasing as management changed in recent years. Disclosures Ansell: Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; LAM Therapeutics: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Seattle Genetics: Research Funding; Affimed: Research Funding; Mayo Clinic Rochester: Employment; Regeneron: Research Funding; Trillium: Research Funding; Seattle Genetics: Research Funding; LAM Therapeutics: Research Funding; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding.

BACKGROUND: The evidence regarding the association of preoperative biologic exposure and postoperative outcomes remains controversial for both antitumor necrosis factor agents and vedolizumab and largely unknown for ustekinumab. OBJECTIVE: The purpose of this study was to determine differences in the rates of 30-day postoperative overall infectious complications and intra-abdominal septic complications among the 3 classes of biologic therapies as compared with no biologic therapy. DESIGN: This was a retrospective review. SETTINGS: The study was conducted at an IBD referral center. PATIENTS: Adult patients with Crohn’s disease who received an antitumor necrosis factor, vedolizumab, ustekinumab, or no biologic therapy within 12 weeks of a major abdominal operation between May 20, 2014, and December 31, 2017, were included. MAIN OUTCOMES MEASURES: Thirty-day overall postoperative infectious complications and intra-abdominal septic complications were measured. RESULTS: A total of 712 patients with Crohn’s disease were included; 272 patients were exposed to an antitumor necrosis factor agents, 127 to vedolizumab, 38 to ustekinumab, and 275 to no biologic therapy within the 12 weeks before an abdominal operation. Patients exposed to a biologic were more likely to be taking a concurrent immunomodulator, but there was no difference in concurrent corticosteroid usage. The particular class of biologic was not independently associated with total overall infectious complications. Vedolizumab was associated with an increased rate of intra-abdominal sepsis on univariate analysis but not on multivariable analysis. Combination immunosuppression was associated with both an increased rate of overall postoperative infectious complications and intra-abdominal sepsis. LIMITATIONS: The study was limited by its retrospective design and single-center data. CONCLUSIONS: The overall rate of total infectious complications or intra-abdominal septic complications was not increased based on preoperative exposure to a particular class of biologic. Rates increased with combination immunosuppression of biologic therapy with corticosteroids and previous abdominal resection. See Video Abstract at http://links.lww.com/DCR/B24. BIOLÓGICOS Y COMPLICACIONES POSTOPERATORIAS DE 30 DÍAS DESPUÉS DE LAS OPERACIONES ABDOMINALES PARA LA ENFERMEDAD DE CROHN: ¿EXISTEN DIFERENCIAS EN LOS PERFILES DE SEGURIDAD?: ANTECEDENTES: La evidencia sobre la asociación de la exposición biológica preoperatoria y los resultados postoperatorios sigue siendo controvertida controversial tanto para los agentes del factor de necrosis tumoral (anti-TNF) como para el vedolizumab, y en gran parte desconocida para el ustekinumab. OBJETIVO: Determinar las diferencias en las tasas de complicaciones infecciosas generales postoperatorias de 30 días y complicaciones sépticas intraabdominales entre las tres clases de terapias biológicas en comparación con ninguna terapia biológica. DISEÑO: Revisión retrospectiva. AMBIENTE: centro de referencia de la enfermedad inflamatoria intestinal. PACIENTES: Pacientes adultos con enfermedad de Crohn que recibieron un factor de necrosis antitumoral, vedolizumab, ustekinumab o ningún tratamiento biológico dentro de las 12 semanas de una operación abdominal mayor entre el 5/20/2014 y el 12/31/2017. PRINCIPALES MEDIDAS DE RESULTADOS: Complicaciones infecciosas postoperatorias generales de 30 días, complicaciones sépticas intraabdominales. RESULTADOS: Se incluyeron setecientos doce pacientes con enfermedad de Crohn; 272 pacientes fueron expuestos a un anti-TNF, 127 a vedolizumab, 38 a ustekinumab y 275 a ninguna terapia biológica dentro de las 12 semanas previas a una operación abdominal. Los pacientes expuestos a un producto biológico tenían más probabilidades de tomar un inmunomodulador concurrente, pero no hubo diferencias en el uso simultáneo de corticosteroides. La clase particular de productos biológicos no se asoció de forma independiente con las complicaciones infecciosas totales. Vedolizumab se asoció con una mayor tasa de sepsis intraabdominal en el análisis univariable, pero no en el análisis multivariable. La inmunosupresión combinada se asoció tanto con una mayor tasa de complicaciones infecciosas postoperatorias generales como con sepsis intraabdominal. LIMITACIONES: Diseño retrospectivo, datos de centro único. CONCLUSIONES: La tasa general de complicaciones infecciosas totales o complicaciones sépticas intraabdominales no aumentó en función de la exposición preoperatoria a una clase particular de productos biológicos. Las tasas aumentaron con la combinación de inmunosupresión de la terapia biológica con corticosteroides y resección abdominal previa. Vea el Resumen del Video en http://links.lww.com/DCR/B24.

Abstract Introduction: Many forms of cancer screening involve imaging technologies utilizing radiation. Broad media coverage of radiation-related health risks may shape the public's perceptions of imaging-based cancer screening, such as mammography. In turn, this may impact patient outcomes by affecting cancer screening decisions. Our primary aim was to evaluate population differences in beliefs about medical radiation exposure in the United States and associations with mammography screening rates in women. Methods: We analyzed data from the National Cancer Institute's Health Information National Trends Survey (HINTS) 2012 administration. Bivariate and multivariate regression analyses were used to evaluate associations of sex, ethnicity, age, annual income, and education with perceptions of harm from medical test radiation exposure. Additional analyses evaluated the role of radiation perception on compliance with current mammography screening recommendations from the United States Preventive Services Task Force. Results: Approximately one-third of respondents indicated that they worried about medical imaging-related radiation exposure. Respondents who perceived medical imaging radiation as harmful to health were more likely to be female, be diagnosed with cancer, have less formal education, report lower socioeconomic status, and identify as an ethnic minority. Most female participants were not in compliance with current breast cancer screening recommendations (weighted percentage = 83.8%). Annual income (p = 0.042) and ethnicity (p = 0.0478) were two variables that were significantly associated with adherence to the recommended mammography screening paradigm. Women without health insurance were more likely to worry about medical imaging-related radiation (p=0.073). Neither health insurance (95%CI = 0.29, 4.99) nor excess worry about radiation exposure from medical imaging devices (95%CI=0.42, 1.89) predicted compliance to mammography screening, after adjusting for relevant sociodemographic variables. Conclusions: These results indicate that some populations may be more concerned about harm from medical device-related radiation than others. Identifying these populations may help improve future cancer patient outcomes by promoting targeted health interventions and communication strategies for these individuals. Women may be more likely to perceive medical imaging radiation exposure as harmful to health, however this alone could not account for why the majority of female respondents were not adhering to recommended mammograms screening guidelines. Future studies are needed to identify the major contributor to low breast cancer screening rates in the United States. Citation Format: Kekoa Taparra, Kay M. Pepin, Alexandra J. Greenberg-Worisek. Associations between perceived medical device-related radiation harm and adherence to mammography screening guidelines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4241.