Krpata, Tami

OBJECTIVE Severe (level 3) hypoglycemia is a life-threatening complication of diabetes associated with substantial risk of recurrence and long-term morbidity. This study examined how adults with diabetes interpreted severe hypoglycemic events and why they declined participation in a community paramedicine program (Diabetes Rescue, Engagement, and Management [Diabetes-REM]) designed to prevent recurrence. RESEARCH DESIGN AND METHODS We conducted semistructured qualitative interviews with adults with type 1 or type 2 diabetes who experienced severe hypoglycemia requiring emergency medical services and declined enrollment in Diabetes-REM. Interviews explored hypoglycemia management experiences and reasons for nonparticipation and were explored using thematic analysis. RESULTS Sixteen adults (44% female; mean age 60 years, range 25–83) participated. Four interrelated themes emerged. First, participants normalized glucose variability as a baseline condition of diabetes and interpreted severe events as situational and correctable when a cause was identifiable, or as inevitable when it was not, rather than as evidence of increased risk. Second, participants relied on prevention systems encompassing habitual routines, caregiver involvement, and glucose-monitoring technologies. Third, severe episodes were frightening and disruptive but typically prompted adjustments to personal management over pursuit of additional clinical support. Finally, reasons for declining Diabetes-REM included time constraints (56%), perceived lack of benefit (25%), and privacy concerns or discomfort with home visits (25%). CONCLUSIONS Among adults who declined a community paramedicine hypoglycemia prevention intervention, severe events were absorbed into existing self-management frameworks rather than viewed as signals of increased risk. Programs targeting hypoglycemia recurrence should account for patients’ risk perceptions and existing management systems, positioning support as complementary rather than corrective.

Abstract Introduction: Pragmatic trials aim to speed translation to practice by integrating study procedures in routine care settings. This study evaluated implementation outcomes related to clinician and patient recruitment and participation in a trial of community paramedicine (CP) and presents successes and challenges of maintaining pragmatic study features. Methods: Adults in the pre-hospital setting, emergency department (ED), or hospital being considered for referral to the ED/hospital or continued hospitalization for intermediate-level care were randomized 1:1 to CP care or usual care. Referral and enrollment data were tracked administratively, and patient characteristics were abstracted from the electronic health record (EHR). Enrolled patients completed baseline surveys, and a subset of intervention patients were interviewed. All CPs and a sample of clinicians and administrators were invited to complete a survey and interview. Results: Between January 2022 and February 2023, 240 enrolled patients (42% rural) completed surveys, and 22 completed an interview; 63 staff completed surveys and 20 completed an interview. Ninety-three clinicians in 27 departments made at least one referral. Factors related to referrals included program awareness and understanding the CP practice scope. Most patients were enrolled in the hospital, but characteristics were similar to the primary care population and included older and medically complex patients. Challenges to achieving representativeness included limited EHR infrastructure, constraints related to patient consenting, and clinician concerns about patient randomization disrupting preferred care. Conclusion: Future pragmatic trials in busy clinical settings may benefit from regulatory policies and EHR capabilities that allow for real-world study conduct and representative participation. Trial registration: NCT05232799.

Abstract Background: Smoking is the most common etiology for lung cancer and smoking cessation does not eliminate the risk. An emerging area of interest for risk reduction is immunoprevention. MUC1 glycoprotein is aberrantly expressed in adenocarcinomas, including lung cancer and their premalignant lesions. MUC1 vaccine in the premalignant or high-risk setting may be effective in halting neoplastic development and progression. Trial design: Through the NCI-funded Cancer Prevention Network (CPN), we conducted a two-center pilot trial to evaluate immunogenicity of the MUC1 vaccine (assessed at 12 weeks), and safety (assessed at up to 24 weeks) in current and former heavy smokers. 87 participants were screened in order to have at least 40 evaluable for baseline and 12-week immunogenicity assessments. Smoking history of ≥30 pack-years and either current (still smoking or quit < 1 year prior to pre-registration) or former smoker (quit 1-15 years prior to pre-registration); ages 55-80 years; ECOG performance status ≤1; CT scan of the chest done ≤ 6 months prior to pre-registration showing either negative findings (no nodules) or solid or part-solid nodules < 6 mm in size (consistent with < 1% probability of malignancy, Lung-RADs Version 1.0). Exclusion criteria were standard for lung cancer screening. Methods: MUC1 peptide plus polyICLC adjuvant (Hiltonol) vaccine was given at week 0, 2 and 10. Blood was collected for safety tests and immune assays pre and 2 weeks post each vaccine, and at week 24. Anti-MUC1 IgG titer was evaluated by ELISA. Based on previous studies of this vaccine, 40 evaluable participants would provide 96% power to detect immune response rate of 15% versus 40%, using a 2-sided test of proportions with type I error rate of 0.05. PBMC were assayed for the presence of regulatory T cells (Treg) and myeloid derived suppressor cells (MDSC) (secondary endpoint). Circulating levels of inflammatory cytokines and hsCRP were evaluated using commercially available tests (exploratory endpoint). AEs and toxicities were monitored for up to 24 weeks from the first vaccine. Results: 87 individuals were screened and 50 registered. 45 completed the study, 26 current and 19 former smokers (time since last smoked: average 7.8 years; 11 months -13 years). The vaccine was well-tolerated with injection site reactions being the most common AE. Immune response to the vaccine was lower than expected, with 2 current and 2 former smokers developing anti-MUC1 IgG titers ≥2 fold higher at week 12 over baseline (10%). We found high circulating levels of MDSCs in PBMC of both current and former smokers and very low or no serum cytokines. Conclusions: A preventative vaccine trial was feasible in individuals at high risk for lung cancer. However, we discovered a high level of immune suppression, previously documented only in advanced lung cancer. Mitigating the development of lung cancer in heavy smokers through vaccine administration may be limited by related immunosuppression. Citation Format: Olivera J. Finn, Julie Ward, Tami Krpata, Samantha Fatis, John McKolanis, Jia Xue, Pamela Beatty, Camille Jacqueline, Sharon Kaufman, Colleen Akerley, April Felt, Karrie Fursa, Anne Holland, Liz S. Ambulay, Nathan Foster, Ryan McMurray, Carrie Strand, Andres M. Salazar, Lisa Bengtson, Eva Szabo, Paul Limburg, Malgorzata Wojtowicz, David E. Midthun, Arjun Pennathur. A pilot study of a MUC1 vaccine in current and former smokers at high risk for lung cancer. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr PR002.

Abstract Background: Smoking is the most common etiology for lung cancer. Smoking cessation, even when successful, does not eliminate risk of lung cancer. With inconsistent results of lung chemoprevention trials, an emerging area of interest is immunoprevention, in particular vaccines. MUC1 is a transmembrane glycoprotein aberrantly overexpressed in adenocarcinomas, including lung cancer. Abnormal MUC1 expression is also characteristic of premalignant lesions, including bronchial dysplasia and atypical adenomatous hyperplasia. This suggests that immunization with a MUC1 vaccine in the premalignant or high-risk setting, before the tumor and cytotoxic therapy could suppress the immune system, might be effective in inducing strong immunity and reducing cancer risk. Trial design: Leveraging the infrastructure of the NCI-funded Cancer Prevention Network (CPN) consortium, we are conducting a two-center pilot trial to evaluate co-primary endpoints: immunogenicity of the MUC1 peptide plus polyICLC adjuvant vaccine (assessed at 12 weeks) and safety (assessed at up to 24 weeks) in current and former smokers who are at high risk for lung cancer. 50 participants will be screened in order to have 40 evaluable participants for baseline and 12-week immunogenicity assessments. Eligibility: Smoking history of ≥30 pack-years and either current smoker (still smoking or quit < 1 year prior to pre-registration) or former smoker (quit 1-15 years prior to pre-registration); ages 55-80 years; ECOG performance status ≤1; CT scan of the chest done ≤ 6 months prior to pre-registration showing either negative findings (no nodules) or solid or part-solid nodules < 6 mm in size (consistent with < 1% probability of malignancy, Lung-RADs Version 1.0). Exclusion criteria are standard. Immunogenicity and safety: MUC1 peptide plus polyICLC adjuvant vaccine will be administered at week 0, 2 and 10. The primary endpoint is anti-MUC1 IgG titer that is ≥2 fold higher at week 12 compared to baseline. Based on previous studies of this vaccine, we expect that 40 evaluable participants will provide 96% power to detect immunogenicity response rate of 15% versus 40% using a 2-sided test of proportions with type I error rate of 0.05. AEs and toxicities will be monitored for up to 24 weeks from the first vaccine. Secondary Objectives: We will explore differences, if any, in vaccine immunogenicity in current vs. former smokers. Smoking induces chronic inflammation (hallmark of cancer) associated with immunosuppression. We will evaluate pre-vaccination levels of circulating myeloid derived suppressor cells (MDSC) and correlate with the response to the vaccine. We will explore the impact, if any, of this vaccine on the markers of inflammation (hsCRP, IL-6) and the effect of baseline levels of these markers on the ability to successfully vaccinate. We will also assess the relationship between COPD status and immune response in current versus former smokers. The trial is open to accrual. Citation Format: Olivera J. Finn, Julie Ward, Tami Krpata, Lisa Bengtson, John McKolanis, Sharon Kaufman, Colleen Akerley, April Felt, Karrie Fursa, Anne Holland, Nathan Foster, Andres Salazar, Malgorzata Wojtowicz, Eva Szabo, Paul Limburg, David Midthun, Arjun Pennathur. A pilot study of a MUC1 vaccine in current and former smokers at high risk for lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT222.