{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,27]],"date-time":"2026-06-27T04:48:04Z","timestamp":1782535684613,"version":"3.54.5"},"reference-count":31,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T00:00:00Z","timestamp":1782086400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Sports, Science, and Technology","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"crossref"}]},{"name":"JSPS KAKENHI","award":["20H03537"],"award-info":[{"award-number":["20H03537"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background\/Objectives: Parathyroid hormone (PTH), which rises compensatory with vitamin D insufficiency and has been shown to down-regulate vitamin D receptor expression, represents a biologically plausible effect modifier. We investigated whether pretreatment serum PTH modifies the effect of postoperative vitamin D supplementation on relapse-free survival, and whether adding tumor p53 status further refines subgroup identification in an exploratory analysis. Methods: This post hoc analysis utilized data from the AMATERASU trial (UMIN000001977), a single-center, randomized, double-blind, placebo-controlled trial evaluating vitamin D3 (2000 IU\/day) versus placebo in patients with curatively resected stage I\u2013III digestive tract cancers (maximum follow-up, 7.5 years). Patients were dichotomized at the cohort median PTH (41 pg\/mL). The primary outcome was relapse-free survival (RFS), analyzed using multivariable Cox proportional hazards models. Results: Of 417 randomized patients, 410 had baseline PTH data. In the lower PTH subgroup (\u226441 pg\/mL), vitamin D significantly improved RFS compared with placebo (fully adjusted hazard ratio [HR], 0.45; 95% confidence interval [CI], 0.24\u20130.81; p = 0.008). Conversely, no benefit was observed in the higher PTH subgroup (&gt;41 pg\/mL; fully adjusted HR, 1.25; 95% CI, 0.64\u20132.44; p for interaction = 0.016). Exploratory stratification of 365 patients with p53 data showed that the supplementation benefit appeared greatest in patients with both low PTH (\u226441 pg\/mL) and p53-positive tumors (fully adjusted HR, 0.38; 95% CI, 0.18\u20130.78; p = 0.009). Conclusions: Pretreatment serum PTH is a candidate effect modifier of postoperative vitamin D supplementation in digestive tract cancers.<\/jats:p>","DOI":"10.3390\/cancers18122015","type":"journal-article","created":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T06:13:37Z","timestamp":1782195217000},"page":"2015","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Parathyroid Hormone Modifies the Effect of Vitamin D Supplementation on Risk of Relapse or Death in Patients with Digestive Tract Cancer: A Post Hoc Subgroup Analysis of the AMATERASU Randomized Clinical Trial"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-0050-5649","authenticated-orcid":false,"given":"Akitaka","family":"Sasaki","sequence":"first","affiliation":[{"name":"Division of Molecular Epidemiology, The Jikei University School of Medicine, 3-25-8, Nishi-Shimbashi, Minato-Ku, Tokyo 105-8461, Japan"},{"name":"Department of Surgery, The Jikei University School of Medicine, 3-25-8, Nishi-Shimbashi, Minato-Ku, Tokyo 105-8461, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3649-4519","authenticated-orcid":false,"given":"Taisuke","family":"Akutsu","sequence":"additional","affiliation":[{"name":"Division of Molecular Epidemiology, The Jikei University School of Medicine, 3-25-8, Nishi-Shimbashi, Minato-Ku, Tokyo 105-8461, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hironori","family":"Ohdaira","sequence":"additional","affiliation":[{"name":"Department of Surgery, International University of Health and Welfare Hospital, 537-3 Iguchi, Nasushiobara, Tochigi 329-2763, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yutaka","family":"Suzuki","sequence":"additional","affiliation":[{"name":"Department of Surgery, International University of Health and Welfare Hospital, 537-3 Iguchi, Nasushiobara, Tochigi 329-2763, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ken","family":"Eto","sequence":"additional","affiliation":[{"name":"Department of Surgery, The Jikei University School of Medicine, 3-25-8, Nishi-Shimbashi, Minato-Ku, Tokyo 105-8461, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7395-5831","authenticated-orcid":false,"given":"Mitsuyoshi","family":"Urashima","sequence":"additional","affiliation":[{"name":"Division of Molecular Epidemiology, The Jikei University School of Medicine, 3-25-8, Nishi-Shimbashi, Minato-Ku, Tokyo 105-8461, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,22]]},"reference":[{"key":"ref_1","first-page":"229","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1038\/nrc3691","article-title":"The role of vitamin D in reducing cancer risk and progression","volume":"14","author":"Feldman","year":"2014","journal-title":"Nat. Rev. Cancer"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1210\/jc.2008-1454","article-title":"Nonclassic actions of vitamin D","volume":"94","author":"Bikle","year":"2009","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Mu\u00f1oz, A., and Grant, W.B. (2022). Vitamin D and cancer: An historical overview of the epidemiology and mechanisms. Nutrients, 14.","DOI":"10.3390\/nu14071448"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2984","DOI":"10.1200\/JCO.2007.15.1027","article-title":"Circulating 25-hydroxyvitamin D levels and survival in patients with colorectal cancer","volume":"26","author":"Ng","year":"2008","journal-title":"J. Clin. Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Mezawa, H., Sugiura, T., Watanabe, M., Norizoe, C., Takahashi, D., Shimojima, A., Tamez, S., Tsutsumi, Y., Yanaga, K., and Urashima, M. (2010). Serum vitamin D levels and survival of patients with colorectal cancer. BMC Cancer, 10.","DOI":"10.1186\/1471-2407-10-347"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"7497","DOI":"10.1158\/1078-0432.CCR-19-0877","article-title":"Plasma 25-hydroxyvitamin D levels and survival in patients with advanced or metastatic colorectal cancer","volume":"25","author":"Yuan","year":"2019","journal-title":"Clin. Cancer Res."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Maalmi, H., Walter, V., Jansen, L., Boakye, D., Sch\u00f6ttker, B., Hoffmeister, M., and Brenner, H. (2018). Association between blood 25-hydroxyvitamin D levels and survival in colorectal cancer patients. Nutrients, 10.","DOI":"10.3390\/nu10070896"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"BSR20201008","DOI":"10.1042\/BSR20201008","article-title":"Low circulating 25-hydroxyvitamin D level is associated with increased colorectal cancer mortality","volume":"40","author":"Wu","year":"2020","journal-title":"Biosci. Rep."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1136\/gutjnl-2018-317922","article-title":"Low plasma vitamin D is associated with adverse colorectal cancer survival after surgical resection","volume":"69","author":"Zgaga","year":"2020","journal-title":"Gut"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1585","DOI":"10.1038\/s41416-024-02643-5","article-title":"Circulating 25-hydroxyvitamin D and survival outcomes of colorectal cancer","volume":"130","author":"Zhang","year":"2024","journal-title":"Br. J. Cancer"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1056\/NEJMoa1809944","article-title":"Vitamin D supplements and prevention of cancer and cardiovascular disease","volume":"380","author":"Manson","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e2025850","DOI":"10.1001\/jamanetworkopen.2020.25850","article-title":"Effect of vitamin D3 supplements on development of advanced cancer","volume":"3","author":"Chandler","year":"2020","journal-title":"JAMA Netw. Open"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1093\/annonc\/mdz059","article-title":"Vitamin D supplementation and total cancer incidence and mortality","volume":"30","author":"Keum","year":"2019","journal-title":"Ann. Oncol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1370","DOI":"10.1001\/jama.2019.2402","article-title":"Effect of high-dose vs standard-dose vitamin D3 supplementation on progression-free survival among patients with advanced or metastatic colorectal cancer: The SUNSHINE randomized clinical trial","volume":"321","author":"Ng","year":"2019","journal-title":"JAMA"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1361","DOI":"10.1001\/jama.2019.2210","article-title":"Effect of vitamin D3 supplementation on relapse-free survival among patients with digestive tract cancers: The AMATERASU randomized clinical trial","volume":"321","author":"Urashima","year":"2019","journal-title":"JAMA"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1158\/1055-9965.EPI-19-0986","article-title":"Effect of vitamin D on relapse-free survival in a subgroup of patients with p53 protein-positive digestive tract cancer: A post hoc analysis of the AMATERASU trial","volume":"29","author":"Akutsu","year":"2020","journal-title":"Cancer Epidemiol. Biomark. Prev."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e2328886","DOI":"10.1001\/jamanetworkopen.2023.28886","article-title":"Effect of vitamin D supplements on relapse or death in a p53-immunoreactive subgroup with digestive tract cancer: Post hoc analysis of the AMATERASU randomized clinical trial","volume":"6","author":"Kanno","year":"2023","journal-title":"JAMA Netw. Open"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Akutsu, T., Kanno, K., Okada, S., Ohdaira, H., Suzuki, Y., and Urashima, M. (2021). Effect of vitamin D supplements on relapse of digestive tract cancer with tumor stromal immune response. Cancers, 13.","DOI":"10.3390\/cancers13184708"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1210\/edrv.22.4.0437","article-title":"Vitamin D deficiency and secondary hyperparathyroidism in the elderly: Consequences for bone loss and fractures and therapeutic implications","volume":"22","author":"Lips","year":"2001","journal-title":"Endocr. Rev."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1414","DOI":"10.1158\/1055-9965.EPI-24-0477","article-title":"High parathyroid hormone rather than low vitamin D is associated with reduced event-free survival in childhood cancer","volume":"33","author":"Grasemann","year":"2024","journal-title":"Cancer Epidemiol. Biomark. Prev."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"4693","DOI":"10.1158\/1078-0432.CCR-17-0257","article-title":"Analytic, preanalytic, and clinical validation of p53 IHC for detection of TP53 missense mutation in prostate cancer","volume":"23","author":"Guedes","year":"2017","journal-title":"Clin. Cancer Res."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Liu, J., Li, W., Deng, M., Liu, D., Ma, Q., and Feng, X. (2016). Immunohistochemical determination of p53 protein overexpression for predicting p53 gene mutations in hepatocellular carcinoma. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0159636"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Lotito, A., Teramoto, M., Cheung, M., Becker, K., and Sukumar, D. (2017). Serum parathyroid hormone responses to vitamin D supplementation in overweight\/obese adults. Nutrients, 9.","DOI":"10.3390\/nu9030241"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1056\/NEJMra070553","article-title":"Vitamin D deficiency","volume":"357","author":"Holick","year":"2007","journal-title":"N. Engl. J. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"942","DOI":"10.1210\/endo-127-2-942","article-title":"Parathyroid hormone down-regulates 1,25-dihydroxyvitamin D receptors (VDR) and VDR messenger ribonucleic acid in vitro and blocks homologous up-regulation of VDR in vivo","volume":"127","author":"Reinhardt","year":"1990","journal-title":"Endocrinology"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1016\/j.semcancer.2020.05.018","article-title":"An update on vitamin D signaling and cancer","volume":"79","author":"Carlberg","year":"2022","journal-title":"Semin. Cancer Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/j.eprac.2021.09.005","article-title":"Association of serum parathyroid hormone levels with all-cause and cause-specific mortality among U.S. adults","volume":"28","author":"Kato","year":"2022","journal-title":"Endocr. Pract."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1016\/j.ccr.2009.11.025","article-title":"Modulation of the vitamin D3 response by cancer-associated mutant p53","volume":"17","author":"Stambolsky","year":"2010","journal-title":"Cancer Cell"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"4574","DOI":"10.1158\/0008-5472.CAN-05-2562","article-title":"Comparative genome analysis identifies the vitamin D receptor gene as a direct target of p53-mediated transcriptional activation","volume":"66","author":"Maruyama","year":"2006","journal-title":"Cancer Res."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Reichrath, J., Reichrath, S., Heyne, K., Vogt, T., and Roemer, K. (2014). Tumor suppression in skin and other tissues via cross-talk between vitamin D- and p53-signaling. Front. Physiol., 5.","DOI":"10.3389\/fphys.2014.00166"}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/12\/2015\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,27]],"date-time":"2026-06-27T04:34:54Z","timestamp":1782534894000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/12\/2015"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,22]]},"references-count":31,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["cancers18122015"],"URL":"https:\/\/doi.org\/10.3390\/cancers18122015","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,22]]}}}