ORIGINAL ARTICLE – PANCREATIC TUMORS Vitamin D Supplementation is a Promising Therapy for Pancreatic Ductal Adenocarcinoma in Conjunction with Current Chemoradiation Therapy Yosuke Mukai, MD 1 , Daisaku Yamada, MD, PhD 1 , Hidetoshi Eguchi, MD, PhD 1 , Yoshifumi Iwagami, MD, PhD 1 , Tadafumi Asaoka, MD, PhD 1 , Takehiro Noda, MD, PhD 1 , Koichi Kawamoto, MD, PhD 1 , Kunihito Gotoh, MD, PhD 1 , Shogo Kobayashi, MD, PhD 1 , Yutaka Takeda, MD, PhD 1,2 , Masahiro Tanemura, MD, PhD 1,3 , Masaki Mori, MD, PhD 1 , and Yuichiro Doki, MD, PhD 1 1 Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Japan; 2 Department of Surgery, Kansai Rosai Hospital, Amagasaki, Japan; 3 Department of Surgery, Osaka Police Hospital, Tennoji, Japan ABSTRACT Background. The cancer-associated fibroblasts (CAFs) in pancreatic ductal adenocarcinoma (PDAC) are well known to play a dominant role in distant metastasis. Nevertheless, the effect on CAFs with current chemoradiation therapies remains uncertain. Objective. This study aimed to reveal the role of CAFs under current chemoradiation therapy (CRT) and investi- gate the factors regulating CAFs. Methods. a-SMA-positive cells in 86 resected PDAC specimens with/without preoperative CRT were evaluated by immunohistochemistry. Various factors, including the plasma levels of vitamin D, were investigated for associ- ation with the number of CAFs or distant metastasis-free survival (DMFS). Human pancreatic satellite cells (hPSCs) extracted from clinical specimens were used to validate the factors. Results. All PDAC samples contained CAFs but the number varied widely. Multivariate analysis for DMFS indicated a larger number of CAFs was a significant risk factor. Univariate analysis for the number of CAFs iden- tified two clinical factors: preoperative CRT and lower plasma levels of vitamin D. In subgroup analysis, the higher plasma level of vitamin D was a dominant factor for longer DMFS in PDAC patients after preoperative CRT. These results were validated by using extracted hPSCs. Irradiation activated stromal cells into CAFs facilitating malignant characteristics of PDAC and the change was inhibited by vitamin D supplementation in vitro. Conclusion. In conjunction with established current ther- apies, vitamin D supplementation may be an effective treatment for PDAC patients by inactivating CAFs. In the last two centuries, there has been remarkable progress in the field of gastroenterological surgery 1 ; how- ever, pancreatic ductal adenocarcinoma (PDAC) is still one of the leading causes of cancer mortality in developed countries and one of the most lethal malignant neoplasms across the world. 2,3 At present, the only chance for cure and prolonged survival is surgical resection with macro- scopic tumor clearance. 4 Nevertheless, the majority of patients develop recurrence after curative surgery because PDAC commonly spreads more than expected and accompanies the occult tumor beyond the range of surgery, even at resectable stages. 5 PDAC in particular is defined by a dense stromal com- partment, 6 featuring cancer-associated fibroblasts (CAFs) that express a-smooth muscle actin (SMA). 7 CAFs are the main effector cells in the desmoplastic reaction, and pan- creatic stellate cells (PSCs) are the most important source of CAFs. 8 CAFs have a profound influence on tumor pro- gression 9–11 and play an important role in metastasis in PDAC. 12 The most effective chemotherapy regimens that target metastases showed a median survival time of Electronic supplementary material The online version of this article (https://doi.org/10.1245/s10434-018-6431-8) contains supple- mentary material, which is available to authorized users. Ó Society of Surgical Oncology 2018 First Received: 20 September 2017 H. Eguchi, MD, PhD e-mail: heguchi@gesurg.ed.osaka-u.ac.jp Ann Surg Oncol https://doi.org/10.1245/s10434-018-6431-8