Browsing by Author "Messersmith, Wells"

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    Pathological Complete Response in Patients With Resected Pancreatic Adenocarcinoma After Preoperative Chemotherapy
    (American Medical Association, 2024-06-03) Stoop, Thomas F.; Oba, Atsushi; Wu, Y. H. Andrew; Beaty, Laurel E.; Colborn, Kathryn L.; Janssen, Boris V.; Al-Musawi, Mohammed H.; Rodriguez Franco, Salvador; Sugawara, Toshitaka; Franklin, Oskar; Jain, Ajay; Saiura, Akio; Sauvanet, Alain; Coppola, Alessandro; Javed, Ammar A.; Groot Koerkamp, Bas; Miller, Braden N.; Mack, Claudia E.; Hashimoto, Daisuke; Caputo, Damiano; Kleive, Dyre; Sereni, Elisabetta; Belfiori, Giulio; Ichida, Hirofumi; van Dam, Jacob L.; Dembinski, Jeanne; Akahoshi, Keiichi; Roberts, Keith J.; Tanaka, Kimitaka; Labori, Knut J.; Falconi, Massimo; House, Michael G.; Sugimoto, Motokazu; Tanabe, Minoru; Gotohda, Naoto; Krohn, Paul S.; Burkhart, Richard A.; Thakkar, Rohan G.; Pande, Rupaly; Dokmak, Safi; Hirano, Satoshi; Burgdorf, Stefan K.; Crippa, Stefano; van Roessel, Stijn; Satoi, Sohei; White, Steven A.; Hackert, Thilo; Nguyen, Trang K.; Yamamoto, Tomohisa; Nakamura, Toru; Bachu, Vismaya; Burns, William R.; Inoue, Yosuke; Takahashi, Yu; Ushida, Yuta; Aslami, Zohra V.; Verbeke, Caroline S.; Fariña, Arantza; He, Jin; Wilmink, Johanna W.; Messersmith, Wells; Verheij, Joanne; Kaplan, Jeffrey; Schulick, Richard D.; Besselink, Marc G.; Del Chiaro, Marco; Surgery, School of Medicine
    Importance: Preoperative chemo(radio)therapy is increasingly used in patients with localized pancreatic adenocarcinoma, leading to pathological complete response (pCR) in a small subset of patients. However, multicenter studies with in-depth data about pCR are lacking. Objective: To investigate the incidence, outcome, and risk factors of pCR after preoperative chemo(radio)therapy. Design, setting, and participants: This observational, international, multicenter cohort study assessed all consecutive patients with pathology-proven localized pancreatic adenocarcinoma who underwent resection after 2 or more cycles of chemotherapy (with or without radiotherapy) in 19 centers from 8 countries (January 1, 2010, to December 31, 2018). Data collection was performed from February 1, 2020, to April 30, 2022, and analyses from January 1, 2022, to December 31, 2023. Median follow-up was 19 months. Exposures: Preoperative chemotherapy (with or without radiotherapy) followed by resection. Main outcomes and measures: The incidence of pCR (defined as absence of vital tumor cells in the sampled pancreas specimen after resection), its association with OS from surgery, and factors associated with pCR. Factors associated with overall survival (OS) and pCR were investigated with Cox proportional hazards and logistic regression models, respectively. Results: Overall, 1758 patients (mean [SD] age, 64 [9] years; 879 [50.0%] male) were studied. The rate of pCR was 4.8% (n = 85), and pCR was associated with OS (hazard ratio, 0.46; 95% CI, 0.26-0.83). The 1-, 3-, and 5-year OS rates were 95%, 82%, and 63% in patients with pCR vs 80%, 46%, and 30% in patients without pCR, respectively (P < .001). Factors associated with pCR included preoperative multiagent chemotherapy other than (m)FOLFIRINOX ([modified] leucovorin calcium [folinic acid], fluorouracil, irinotecan hydrochloride, and oxaliplatin) (odds ratio [OR], 0.48; 95% CI, 0.26-0.87), preoperative conventional radiotherapy (OR, 2.03; 95% CI, 1.00-4.10), preoperative stereotactic body radiotherapy (OR, 8.91; 95% CI, 4.17-19.05), radiologic response (OR, 13.00; 95% CI, 7.02-24.08), and normal(ized) serum carbohydrate antigen 19-9 after preoperative therapy (OR, 3.76; 95% CI, 1.79-7.89). Conclusions and relevance: This international, retrospective cohort study found that pCR occurred in 4.8% of patients with resected localized pancreatic adenocarcinoma after preoperative chemo(radio)therapy. Although pCR does not reflect cure, it is associated with improved OS, with a doubled 5-year OS of 63% compared with 30% in patients without pCR. Factors associated with pCR related to preoperative chemo(radio)therapy regimens and anatomical and biological disease response features may have implications for treatment strategies that require validation in prospective studies because they may not universally apply to all patients with pancreatic adenocarcinoma.
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    Targeting Treg-Expressed STAT3 Enhances NK-Mediated Surveillance of Metastasis and Improves Therapeutic Response in Pancreatic Adenocarcinoma
    (American Association for Cancer Research, 2022) Piper, Miles; Van Court, Benjamin; Mueller, Adam; Watanabe, Shuichi; Bickett, Thomas; Bhatia, Shilpa; Darragh, Laurel B.; Mayeda, Max; Nguyen, Diemmy; Gadwa, Jacob; Knitz, Michael; Corbo, Sophia; Morgan, Rustain; Lee, Jung-Jae; Dent, Alexander; Goodman, Karyn; Messersmith, Wells; Schulick, Rich; Del Chiaro, Marco; Zhu, Yuwen; Kedl, Ross M.; Lenz, Laurel; Karam, Sana D.; Microbiology and Immunology, School of Medicine
    Purpose: Metastasis remains a major hurdle in treating aggressive malignancies such as pancreatic ductal adenocarcinoma (PDAC). Improving response to treatment, therefore, requires a more detailed characterization of the cellular populations involved in controlling metastatic burden. Experimental design: PDAC patient tissue samples were subjected to RNA sequencing analysis to identify changes in immune infiltration following radiotherapy. Genetically engineered mouse strains in combination with orthotopic tumor models of PDAC were used to characterize disease progression. Flow cytometry was used to analyze tumor infiltrating, circulating, and nodal immune populations. Results: We demonstrate that although radiotherapy increases the infiltration and activation of dendritic cells (DC), it also increases the infiltration of regulatory T cells (Treg) while failing to recruit natural killer (NK) and CD8 T cells in PDAC patient tissue samples. In murine orthotopic tumor models, we show that genetic and pharmacologic depletion of Tregs and NK cells enhances and attenuates response to radiotherapy, respectively. We further demonstrate that targeted inhibition of STAT3 on Tregs results in improved control of local and distant disease progression and enhanced NK-mediated immunosurveillance of metastasis. Moreover, combination treatment of STAT3 antisense oligonucleotide (ASO) and radiotherapy invigorated systemic immune activation and conferred a survival advantage in orthotopic and metastatic tumor models. Finally, we show the response to STAT3 ASO + radiotherapy treatment is dependent on NK and DC subsets. Conclusions: Our results suggest targeting Treg-mediated immunosuppression is a critical step in mediating a response to treatment, and identifying NK cells as not only a prognostic marker of improved survival, but also as an effector population that functions to combat metastasis.