Browsing by Author "Tong, Yan"
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Item A comparative study between single-operator pancreatoscopy with intraductal lithotripsy and extracorporeal shock wave lithotripsy for the management of large main pancreatic duct stones(Springer, 2022) Bick, Benjamin L.; Patel, Feenalie; Easler, Jeffrey J.; Tong, Yan; Watkins, James L.; McHenry, Lee; Lehman, Glen; Fogel, Evan L.; Gromski, Mark A.; Sherman, Stuart; Medicine, School of MedicineBackground and aims: Endoscopic management of large main pancreatic ductal (MPD) stones often require treatment with lithotripsy. Extracorporeal shock wave lithotripsy (ESWL) has been the mainstay therapy, and single-operator pancreatoscopy with intraductal (intracorporeal) lithotripsy (SOPIL) is an emerging technique. However, no comparative studies between these techniques exist. We therefore aimed to compare ESWL to SOPIL for the treatment of large MPD stones. Methods: This is a retrospective cohort study comparing patients who were treated with ESWL or SOPIL from September 2013 to September 2019 at a single tertiary center. Logistic regression was performed to identify factors associated with technical success and efficient stone clearance (≤ 2 procedures to clear stones). Results: There were 240 patients who were treated with ESWL and 18 treated with SOPIL. The overall technical success rate of stone clearance was 224/258 (86.8%), which was similar between the ESWL and SOPIL groups (86.7% vs 88.9%, p = 1.000). A SOPIL approach required fewer total procedures (1.6 ± 0.6 vs 3.1 ± 1.5, p < 0.001) and less aggregate procedure time (101.6 ± 68.2 vs 191.8 ± 111.6 min, p = 0.001). Adverse event rates were similar between the groups (6.3% vs 5.6%, p = 1.000). The use of SOPIL was independently associated with greater efficiency compared to ESWL (OR 5.241 [1.348-20.369], p = 0.017). Stone size > 10 mm was associated with less efficient stone clearance (OR 0.484 [0.256-0.912], p = 0.025). Conclusion: Both ESWL and SOPIL are safe and effective endoscopic adjunct modalities for treating large pancreatic duct stones. SOPIL is an emerging alternative to ESWL that is potentially more efficient for lithotripsy and MPD stone clearance.Item A Multi-Center, Single Arm, Phase Ib study of Pembrolizumab (MK-3475) in Combination with Chemotherapy for Patients with Advanced Colorectal Cancer: HCRN GI14-186(Springer, 2021) Herting, Cameron J.; Farren, Matthew R.; Tong, Yan; Liu, Ziyue; O’Neil, Bert; Bekaii-Saab, Tanios; Noonan, Anne; McQuinn, Christopher; Mace, Thomas A.; Shaib, Walid; Wu, Christina; El-Rayes, Bassel F.; Shahda, Safi; Lesinski, Gregory B.; Biostatistics and Health Data Science, Richard M. Fairbanks School of Public HealthModified FOLFOX6 is an established therapy for patients with metastatic colorectal cancer (mCRC). We conducted a single-arm phase Ib study to address the hypothesis that addition of pembrolizumab to this regimen could safely and effectively improve patient outcomes (NCT02375672). The relationship between immune biomarkers and clinical response were assessed in an exploratory manner. Patients with mCRC received concurrent pembrolizumab and modified FOLFOX6. The study included safety run-in for the first six patients. The primary objective was median progression-free survival (mPFS), with secondary objectives including median overall survival, safety, and exploratory assessment of immune changes. To assess immunological impact, peripheral blood was collected at baseline and during treatment. The levels of soluble factors were measured via bioplex, while a panel of checkpoint molecules and phenotypically defined cell populations were assessed with flow cytometry and correlated with RECIST and mPFS. Due to incidences of grade 3 and grade 4 neutropenia in the safety lead-in, the dose of mFOLFOX6 was reduced in the expansion cohort. Median PFS was 8.8 months and median OS was not reached at data cutoff. Best responses of stable disease, partial response, and complete response were observed in 43.3%, 50.0%, and 6.7% of patients, respectively. Several soluble and cellular immune biomarkers were associated with improved RECIST and mPFS. Immunosuppressive myeloid and T cell subsets that were analyzed were not associated with response. Primary endpoint was not superior to historic control. Biomarkers that were associated with improved response may be informative for future regimens combining chemotherapy with immune checkpoint inhibitors.Item Apurinic/Apyrimidinic Endonuclease/Redox Factor-1 (APE1/Ref-1) redox function negatively regulates NRF2(2015-01) Fishel, Melissa L.; Wu, Xue; Devlin, Cecilia M.; Logsdon, Derek P.; Jiang, Yanlin; Luo, Meihua; He, Ying; Yu, Zhangsheng; Tong, Yan; Lipking, Kelsey P.; Maitra, Anirban; Rajeshkumar, N. V.; Scandura, Glenda; Kelley, Mark R.; Ivan, Mircea; Department of Pediatrics, Indiana University School of MedicineApurinic/apyrimidinic endonuclease/redox factor-1 (APE1/Ref-1) (henceforth referred to as Ref-1) is a multifunctional protein that in addition to its base excision DNA repair activity exerts redox control of multiple transcription factors, including nuclear factor κ-light chain enhancer of activated B cells (NF-κB), STAT3, activator protein-1 (AP-1), hypoxia-inducible factor-1 (HIF-1), and tumor protein 53 (p53). In recent years, Ref-1 has emerged as a promising therapeutic target in cancer, particularly in pancreatic ductal carcinoma. Although a significant amount of research has centered on Ref-1, no wide-ranging approach had been performed on the effects of Ref-1 inhibition and transcription factor activity perturbation. Starting with a broader approach, we identified a previously unsuspected effect on the nuclear factor erythroid-related factor 2 (NRF2), a critical regulator of cellular defenses against oxidative stress. Based on genetic and small molecule inhibitor-based methodologies, we demonstrated that repression of Ref-1 potently activates NRF2 and its downstream targets in a dose-dependent fashion, and that the redox, rather than the DNA repair function of Ref-1 is critical for this effect. Intriguingly, our results also indicate that this pathway does not involve reactive oxygen species. The link between Ref-1 and NRF2 appears to be present in all cells tested in vitro, noncancerous and cancerous, including patient-derived tumor samples. In particular, we focused on understanding the implications of the novel interaction between these two pathways in primary pancreatic ductal adenocarcinoma tumor cells and provide the first evidence that this mechanism has implications for overcoming the resistance against experimental drugs targeting Ref-1 activity, with clear translational implications.Item Association of Chlamydia trachomatis infection with redetection of human papillomavirus after apparent clearance(Oxford, 2013-11) Shew, Marcia L.; Ermel, Aaron C.; Weaver, Bree A.; Tong, Yan; Tu, Wanzhu; Kester, Laura M.; Denski, Cheryl; Fortenberry, J. Dennis; Brown, Darron R.; Pediatrics, School of MedicineBACKGROUND: Persistent infection with oncogenic human papillomavirus (HPV) is associated with an increased risk of cervical malignancy. Redetection of type-specific HPV after a period of nondetection may be caused by reactivation of a low-level persistent infection. Little is known about factors associated with type-specific HPV redetection. METHODS: For a longitudinal cohort of adolescent women with frequent behavioral and sexually transmitted infection (STI) information (every 3 months), Cox proportional hazard models were used to assess the influence of sexual behaviors and STIs on the redetection of oncogenic or high-risk HPV infections. RESULTS: A total of 210 type-specific high-risk HPV detection episode periods were identified in this longitudinal cohort; 71 (33.8%) were characterized by a period of nondetection followed by redetection. Chlamydia trachomatis (hazard ratio [HR], 3.14; 95% confidence interval [CI], 1.44-6.86) was associated with redetection; redetection was >2 times more likely with each additional self-reported sex partner in the past 3 months (HR, 2.26; 95% CI, 1.35-3.78). CONCLUSIONS: This study demonstrates the role of C. trachomatis and number of recent sexual partners in type-specific HPV redetection. Given that persistent oncogenic HPV infections are associated with cancer-related outcomes, understanding the potential role of such factors in the pathogenesis of HPV-related outcomes is important.Item Association of HPV types 6, 11, 16, and 18 DNA detection and serological response in unvaccinated adolescent women(Wiley, 2013-10) Tong, Yan; Ermel, Aaron; Tu, Wanzhu; Shew, Marcia; Brown, Darron R.; Department of Biostatistics, Richard M. Fairbanks School of Public HealthAntibodies directed against the human papillomavirus (HPV) L1 protein are detected in approximately 70% of individuals with HPV infections. The factors associated with a serological response are not characterized. It is hypothesized that the HPV viral load, duration of detection, or both would be associated with seropositivity in adolescent women. Adolescent women (n = 117), ages 15-17 at enrolment were followed for a mean of 6.2 years. Quarterly vaginal swabs (mean 22 per participant) were used to identify HPV 6, 11, 16, or 18 DNA (Roche PCR/Linear Array). Type-specific HPV infection was defined as ≥2 positive assays. To approximate viral load, Roche PCR/Linear Array test strips were scored visually based on the strength of signal relative to beta-globin controls. Sera collected near the end of study were tested by cLIA. Regression models were fit to assess associations between strength of signal (as represented by mean and cumulative strength of signal), duration of HPV detection, seropositivity, and serotiter. Detection of HPV DNA was associated with seropositivity for four types combined and for types 6, 16, and 18. Overall, 70.1% of DNA positive episodes were associated with type-specific seropositivity. The cumulative HPV DNA signal strength during periods of HPV detection for types 6, 11, 16, and 18 combined was associated with seropositivity (OR = 1.21, 95% CI 1.02-1.44 P = 0.026). No other HPV DNA predictors were found to be associated with seropositivity or serotiter.Item Association of Plasma Aflatoxin With Persistent Detection of Oncogenic Human Papillomaviruses in Cervical Samples From Kenyan Women Enrolled in a Longitudinal Study(BMC, 2023-06-06) Tong, Yan; Tonui, Philip; Orang’o, Omenge; Zhang, Jianjun; Maina, Titus; Muthoka, Kapten; Groopman, John; Smith, Joshua; Madeen, Erin; Ermel, Aaron; Loehrer, Patrick; Brown, Darron R.; Biostatistics, School of Public HealthBackground: Cervical cancer is caused by oncogenic human papillomaviruses (HR-HPV) and is common among Kenyan women. Identification of factors that increase HR-HPV persistence is critically important. Kenyan women exposed to aflatoxin have an increased risk of HR-HPV detection in cervical specimens. This analysis was performed to examine associations between aflatoxin and HR-HPV persistence. Methods: Kenyan women were enrolled in a prospective study. The analytical cohort for this analysis included 67 HIV-uninfected women (mean age 34 years) who completed at least two of three annual study visits and had an available blood sample. Plasma aflatoxin was detected using ultra-high pressure liquid chromatography (UHPLC)-isotope dilution mass spectrometry. Annual cervical swabs were tested for HPV (Roche Linear Array). Ordinal logistic regression models were fitted to examine associations of aflatoxin and HPV persistence. Results: Aflatoxin was detected in 59.7% of women and was associated with higher risk of persistent detection of any HPV type (OR = 3.03, 95%CI = 1.08-8.55, P = 0.036), HR-HPV types (OR = 3.63, 95%CI = 1.30-10.13, P = 0.014), and HR-HPV types not included in the 9-valent HPV vaccine (OR = 4.46, 95%CI = 1.13-17.58, P = 0.032). Conclusions: Aflatoxin detection was associated with increased risk of HR-HPV persistence in Kenyan women. Further studies, including mechanistic studies are needed to determine if aflatoxin synergistically interacts with HR-HPV to increase cervical cancer risk.Item Cisplatin +/− rucaparib after preoperative chemotherapy in patients with triple-negative or BRCA mutated breast cancer(Springer Nature, 2021-03-22) Kalra, Maitri; Tong, Yan; Jones, David R.; Walsh, Tom; Danso, Michael A.; Ma, Cynthia X.; Silverman, Paula; King, Mary-Claire; Badve, Sunil S.; Perkins, Susan M.; Miller, Kathy D.; Biostatistics, School of Public HealthPatients with triple-negative breast cancer (TNBC) who have residual disease after neoadjuvant therapy have a high risk of recurrence. We tested the impact of DNA-damaging chemotherapy alone or with PARP inhibition in this high-risk population. Patients with TNBC or deleterious BRCA mutation (TNBC/BRCAmut) who had >2 cm of invasive disease in the breast or persistent lymph node (LN) involvement after neoadjuvant therapy were assigned 1:1 to cisplatin alone or with rucaparib. Germline mutations were identified with BROCA analysis. The primary endpoint was 2-year disease-free survival (DFS) with 80% power to detect an HR 0.5. From Feb 2010 to May 2013, 128 patients were enrolled. Median tumor size at surgery was 1.9 cm (0-11.5 cm) with 1 (0-38) involved LN; median Residual Cancer Burden (RCB) score was 2.6. Six patients had known deleterious BRCA1 or BRCA2 mutations at study entry, but BROCA identified deleterious mutations in 22% of patients with available samples. Toxicity was similar in both arms. Despite frequent dose reductions (21% of patients) and delays (43.8% of patients), 73% of patients completed planned cisplatin. Rucaparib exposure was limited with median concentration 275 (82-4694) ng/mL post-infusion on day 3. The addition of rucaparib to cisplatin did not increase 2-year DFS (54.2% cisplatin vs. 64.1% cisplatin + rucaparib; P = 0.29). In the high-risk post preoperative TNBC/BRCAmut setting, the addition of low-dose rucaparib did not improve 2-year DFS or increase the toxicity of cisplatin. Genetic testing was underutilized in this high-risk population.Item Combined inhibition of Ref‐1 and STAT3 leads to synergistic tumour inhibition in multiple cancers using 3D and in vivo tumour co‐culture models(Wiley, 2021-01) Caston, Rachel A.; Shah, Fenil; Starcher, Colton L.; Wireman, Randall; Babb, Olivia; Grimard, Michelle; McGeown, Jack; Armstrong, Lee; Tong, Yan; Pili, Roberto; Rupert, Joseph; Zimmers, Teresa A.; Elmi, Adily N.; Pollok, Karen E.; Motea, Edward A.; Kelley, Mark R.; Fishel, Melissa L.; Pediatrics, School of MedicineWith a plethora of molecularly targeted agents under investigation in cancer, a clear need exists to understand which pathways can be targeted simultaneously with multiple agents to elicit a maximal killing effect on the tumour. Combination therapy provides the most promise in difficult to treat cancers such as pancreatic. Ref‐1 is a multifunctional protein with a role in redox signalling that activates transcription factors such as NF‐κB, AP‐1, HIF‐1α and STAT3. Formerly, we have demonstrated that dual targeting of Ref‐1 (redox factor‐1) and STAT3 is synergistic and decreases cell viability in pancreatic cancer cells. Data presented here extensively expands upon this work and provides further insights into the relationship of STAT3 and Ref‐1 in multiple cancer types. Using targeted small molecule inhibitors, Ref‐1 redox signalling was blocked along with STAT3 activation, and tumour growth evaluated in the presence and absence of the relevant tumour microenvironment. Our study utilized qPCR, cytotoxicity and in vivo analysis of tumour and cancer‐associated fibroblasts (CAF) response to determine the synergy of Ref‐1 and STAT3 inhibitors. Overall, pancreatic tumours grown in the presence of CAFs were sensitized to the combination of STAT3 and Ref‐1 inhibition in vivo. In vitro bladder and pancreatic cancer demonstrated the most synergistic responses. By disabling both of these important pathways, this combination therapy has the capacity to hinder crosstalk between the tumour and its microenvironment, leading to improved tumour response.Item Combined interprofessional education and system intervention to improve screening older adults for dementia and falls(Taylor & Francis, 2021) Litzelman, Debra K.; Butler, Dawn E.; Iloabuchi, Tochukwu; Frank, Kathryn I.; Bo, Na; Tong, Yan; Garrison, Emilie; Roth, Sarah; Vannerson, Julie; Medicine, School of MedicineThe objective of this study was to increase screening for falls and dementia by improving interprofessional (IP) providers’ and staffs’ knowledge and attitudes toward the care of older patients and team-based care. An intervention, including education about screening and an electronic health record (EHR) flowsheet, was rolled-out across eight Federally Qualified Health Centers (FQHC). Participants were 262 IP health providers who served 6670 patients ≥ age 65 > age 65 . An EHR flowsheet with two-item screeners for falls and dementia triggered automatically for patients ≥ age 65. Documentation of screening for falls and dementia was abstracted from the EHR for the year prior to and the year after the interventions began. Baseline screening rates for falls and dementia were flat; from the start of education intervention until EHR live date, screening rates increased significantly; after EHR live date, the screening rates continued increasing significantly. A combined education-system intervention can improve screening for falls and dementia in FQHC.Item A community-based approach to cervical cancer prevention in western Kenya: An AMPATH feasibility project(Sage, 2022-05-23) Orang’o, Omenge; Tonui, Philip; Muthoka, Kapten; Kiptoo, Stephen; Maina, Titus; Agosa, Mercy; Ermel, Aaron; Tong, Yan; Brown, Darron; Medicine, School of MedicineObjectives: Centralized programs have been ineffective in reducing the burden of cervical cancer among Kenyan women. A community-based pilot study was initiated to screen Kenyan women for cervical cancer and to vaccinate their children against human papillomavirus (HPV). Methods: Women were educated about cervical cancer prevention at community meetings. Women then provided self-collected vaginal swabs for oncogenic HPV testing using the Roche Cobas Assay. All women were then referred to the local clinic for Visual Inspection with Acetic Acid (VIA). Women were offered the quadrivalent HPV vaccine for their children if and when it became available for the study. Results: Women in western Kenya were invited to participate in community meetings. A total of 200 women were enrolled: 151 (75.5%) were HIV-uninfected and 49 (24.5%) were HIV-infected; the median age for all women was 42 years. High-risk (HR)-HPV types were detected in 49 of swabs from all 200 participants (24.5%) including 20.5% of HIV-uninfected women and 36.7% of HIV-infected women (P = .022). VIA was performed on 198 women: 192 had normal examinations and six had abnormal examinations. Five cervical biopsies revealed two cases of CIN 2 and one CIN 3. Although all mothers were willing to have their children (N = 432) vaccinated, the HPV vaccine could not be delivered to Kenya during the study period. Conclusions: Kenyan women were willing to attend community meetings to learn about prevention of cervical cancer, to provide self-collected vaginal swabs for HPV testing, to travel to the Webuye Clinic for VIA following the collection of swabs, and to have their children vaccinated against HPV. HR-HPV was prevalent, especially in HIV-infected women. As a result of this pilot study, this community-based strategy to prevent cervical cancer will be continued in western Kenya.