{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:44:53Z","timestamp":1760060693500,"version":"build-2065373602"},"reference-count":40,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,9,12]],"date-time":"2025-09-12T00:00:00Z","timestamp":1757635200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"\u201cVictor Babes\u201d University of Medicine and Pharmacy Timisoara"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinics and Practice"],"abstract":"<jats:p>Background and Objectives: Vitamin D deficiency and psychological distress have been linked to cancer biology, but their relevance to tumor differentiation in head-and-neck squamous cell carcinoma (HNSCC) is uncertain. Materials and Methods: In this cross-sectional study at the Department of Otolaryngology, County Hospital of Timi\u0219oara, Romania, we enrolled newly diagnosed HNC patients from October 2023 to December 2024, analyzing 199 SCC patients after exclusions. Vitamin D status was assessed using serum 25-OH-vitamin D levels, and distress was measured with the validated Romanian version of the Hospital Anxiety and Depression Scale (HADS). Tumor aggressiveness was defined by histological grade (G3 vs. G1\u2013G2). Univariate, multivariate, and subgroup analyses were conducted, adjusting for confounders like smoking. Results: Vitamin D deficiency (&lt;20 ng\/mL) was prevalent (80.40%), with median 25-OH-vitamin D levels of 15.1 ng\/mL. Univariate analysis revealed a modest association between vitamin D deficiency and poorly differentiated tumors (G3 vs. G1\u2013G2; OR = 1.79, p = 0.055) and between clinically significant anxiety (HADS-A \u2265 8) and G3 tumors (OR = 1.71, p = 0.059). A weak negative correlation was observed between 25-OH-vitamin D levels and HADS-A scores (rho = \u22120.17, p = 0.052). In multivariate analysis adjusted for age, smoking, and tumor location, these associations weakened (vitamin D deficiency: OR = 1.55, p = 0.082; HADS-A \u22658: OR = 1.56, p = 0.113). Subgroup analysis suggested a trend toward higher odds of G3 tumors in patients with both vitamin D deficiency and high anxiety (OR = 1.72, p = 0.075). Conclusions: Univariate analyses indicated potential links between vitamin D deficiency, psychological distress, and tumor aggressiveness in HNSCC, but these did not reach statistical significance after adjustment for confounders. The observed trends, particularly in subgroups with combined deficiency and distress, suggest a possible interplay worth exploring further. To conclude, neither vitamin-D deficiency nor clinically significant distress independently predicted poor histological differentiation after adjustment; observed trends, including a possible distress\u2013vitamin-D interaction, are hypothesis-generating and warrant testing in larger, longitudinal cohorts.<\/jats:p>","DOI":"10.3390\/clinpract15090164","type":"journal-article","created":{"date-parts":[[2025,9,12]],"date-time":"2025-09-12T13:43:02Z","timestamp":1757684582000},"page":"164","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Low Vitamin D and High Psychological Distress: Are They Associated with Poor Differentiation in Head and Neck Cancer?"],"prefix":"10.3390","volume":"15","author":[{"given":"Bogdan","family":"Hirtie","sequence":"first","affiliation":[{"name":"Doctoral School, Department of General Medicine, \u201cVictor Babes\u201d University of Medicine and Pharmacy, Eftimie Murgu Square No. 2, 300041 Timisoara, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ana-Maria","family":"Stanoiu","sequence":"additional","affiliation":[{"name":"Doctoral School, Department of General Medicine, \u201cVictor Babes\u201d University of Medicine and Pharmacy, Eftimie Murgu Square No. 2, 300041 Timisoara, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kristine","family":"Guran","sequence":"additional","affiliation":[{"name":"Doctoral School, Department of General Medicine, \u201cVictor Babes\u201d University of Medicine and Pharmacy, Eftimie Murgu Square No. 2, 300041 Timisoara, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-0320-6904","authenticated-orcid":false,"given":"Norberth-Istvan","family":"Varga","sequence":"additional","affiliation":[{"name":"Doctoral School, Department of General Medicine, \u201cVictor Babes\u201d University of Medicine and Pharmacy, Eftimie Murgu Square No. 2, 300041 Timisoara, Romania"},{"name":"Department of Nursing, \u201cVictor Babes\u201d University of Medicine and Pharmacy, 300041 Timisoara, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-3870-6986","authenticated-orcid":false,"given":"Claudia Raluca Balasa","family":"Virzob","sequence":"additional","affiliation":[{"name":"Department of Nursing, \u201cVictor Babes\u201d University of Medicine and Pharmacy, 300041 Timisoara, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1335-6845","authenticated-orcid":false,"given":"Delia","family":"Hutanu","sequence":"additional","affiliation":[{"name":"Department Biology-Chemistry, Faculty of Chemistry-Biology-Geography, West University of Timisoara, Pestalozzi, 16, 300315 Timisoara, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3734-7991","authenticated-orcid":false,"given":"Adrian","family":"Cote","sequence":"additional","affiliation":[{"name":"Department of Surgical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, 410073 Oradea, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rodica Anamaria","family":"Negrean","sequence":"additional","affiliation":[{"name":"Department of Preclinical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, 410073 Oradea, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7210-1263","authenticated-orcid":false,"given":"Delia Ioana","family":"Horhat","sequence":"additional","affiliation":[{"name":"ENT Department, \u201cVictor Babes\u201d University of Medicine and Pharmacy, Eftimie Murgu Square No. 2, 300041 Timisoara, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cristian Ion","family":"Mot","sequence":"additional","affiliation":[{"name":"ENT Department, \u201cVictor Babes\u201d University of Medicine and Pharmacy, Eftimie Murgu Square No. 2, 300041 Timisoara, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1038\/s41572-020-00224-3","article-title":"Head and neck squamous cell carcinoma. Nature reviews","volume":"6","author":"Johnson","year":"2020","journal-title":"Dis. Primers"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"105184","DOI":"10.1016\/j.oraloncology.2021.105184","article-title":"Trends in disease-specific survival of head and neck squamous cell carcinoma patients treated in a single institution over a 30-year period","volume":"115","author":"Casasayas","year":"2021","journal-title":"Oral Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Guo, K., Xiao, W., Chen, X., Zhao, Z., Lin, Y., and Chen, G. (2021). Epidemiological Trends of Head and Neck Cancer: A Population-Based Study. BioMed Res. Int., 2021.","DOI":"10.1155\/2021\/1738932"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Barsouk, A., Aluru, J.S., Rawla, P., Saginala, K., and Barsouk, A. (2023). Epidemiology, Risk Factors, and Prevention of Head and Neck Squamous Cell Carcinoma. Med. Sci., 11.","DOI":"10.3390\/medsci11020042"},{"key":"ref_5","first-page":"122","article-title":"Head and Neck cancers-major changes in the American Joint Committee on cancer eighth edition cancer staging manual","volume":"67","author":"Lydiatt","year":"2017","journal-title":"CA Cancer J. Clin."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Hu, Q., Lv, S., Wang, X., Pan, P., Gong, W., and Mei, J. (2025). Global burden and future trends of head and neck cancer: A deep learning-based analysis (1980\u20132030). PLoS ONE, 20.","DOI":"10.1371\/journal.pone.0320184"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1","DOI":"10.4103\/JLP.JLP_49_17","article-title":"Vitamin D and gastrointestinal cancer","volume":"10","author":"Mahendra","year":"2018","journal-title":"J. Lab. Physicians"},{"key":"ref_8","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_9","doi-asserted-by":"crossref","first-page":"e188","DOI":"10.4317\/medoral.20368","article-title":"Serum vitamin D levels of patients with oral squamous cell carcinoma (OSCC) and expression of vitamin D receptor in oral precancerous lesions and OSCC","volume":"20","author":"Grimm","year":"2015","journal-title":"Med. Oral Patol. Oral Cir. Bucal"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Starska-Kowarska, K. (2023). Role of Vitamin D in Head and Neck Cancer-Immune Function, Anti-Tumour Effect, and Its Impact on Patient Prognosis. Nutrients, 15.","DOI":"10.3390\/nu15112592"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Mot, C.I., Horhat, D.I., Balica, N.C., Hirtie, B., Varga, N.-I., Prodan-Barbulescu, C., Alexandru, A., Ciurariu, E., and Galis, R. (2025). Vitamin D and Clinical Outcomes in Head and Neck Cancer: A Systematic Review. Nutrients, 17.","DOI":"10.3390\/nu17071100"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3343","DOI":"10.1002\/cam4.5200","article-title":"The link between psychological distress and survival in solid tumor patients: A systematic review","volume":"12","author":"Roche","year":"2023","journal-title":"Cancer Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1111\/j.1600-0447.1983.tb09716.x","article-title":"The hospital anxiety and depression scale","volume":"67","author":"Zigmond","year":"1983","journal-title":"Acta Psychiatr. Scand."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1177\/0003489414525020","article-title":"Communicative participation and quality of life in head and neck cancer","volume":"123","author":"Eadie","year":"2014","journal-title":"Ann. Otol. Rhinol. Laryngol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Hirtie, B., Varga, N.I., Oprisoni, A., Tanasescu, S., Boeriu, E., Sorop, V.B., Harich, O., Bota, A.V., and Horhat, D.I. (2025). Beyond the Scalpel: Addressing Communication and Distress in ENT Cancer. Medicina, 61.","DOI":"10.3390\/medicina61010069"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1920","DOI":"10.1073\/pnas.0438019100","article-title":"A mechanism converting psychosocial stress into mononuclear cell activation","volume":"100","author":"Bierhaus","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Liu, Y., Tian, S., Ning, B., Huang, T., Li, Y., and Wei, Y. (2022). Stress and cancer: The mechanisms of immune dysregulation and management. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.1032294"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e10420","DOI":"10.1002\/jbm4.10420","article-title":"Vitamin D and Clinical Cancer Outcomes: A Review of Meta-Analyses","volume":"5","author":"Sluyter","year":"2020","journal-title":"JBMR Plus"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e1476817","DOI":"10.1080\/2162402X.2018.1476817","article-title":"Vitamin D deficiency in head and neck cancer patients\u2014Prevalence, prognostic value and impact on immune function","volume":"7","author":"Bochen","year":"2018","journal-title":"Oncoimmunology"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Pu, Y., Zhu, G., Xu, Y., Zheng, S., Tang, B., Huang, H., Wu, I.X.Y., Huang, D., Liu, Y., and Zhang, X. (2021). Association Between Vitamin D Exposure and Head and Neck Cancer: A Systematic Review with Meta-Analysis. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.627226"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"106605","DOI":"10.1016\/j.phrs.2022.106605","article-title":"Vitamin D protects against depression: Evidence from an umbrella meta-analysis on interventional and observational meta-analyses","volume":"187","author":"Musazadeh","year":"2023","journal-title":"Pharmacol. Res."},{"key":"ref_22","first-page":"5","article-title":"Vitamin D in Head and Neck Cancer: A Systematic Review","volume":"23","author":"Tuokkola","year":"2020","journal-title":"Curr. Oncol. Rep."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"515","DOI":"10.6004\/jadpro.2022.13.5.5","article-title":"Barriers to Adherence to Cancer Treatments Among Head and Neck Cancer Patients","volume":"13","author":"Miller","year":"2022","journal-title":"J. Adv. Pract. Oncol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Huang, R.W., Chang, K.P., Marchi, F., Loh, C.Y.Y., Lin, Y.J., Chang, C.J., and Kao, H.K. (2022). The impact of depression on survival of head and neck cancer patients: A population-based cohort study. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.871915"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1487","DOI":"10.1038\/s41380-019-0595-x","article-title":"Depression and anxiety in relation to cancer incidence and mortality: A systematic review and meta-analysis of cohort studies","volume":"25","author":"Wang","year":"2020","journal-title":"Mol. Psychiatry"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1201","DOI":"10.1158\/1078-0432.CCR-11-0641","article-title":"Molecular pathways: Beta-adrenergic signaling in cancer","volume":"18","author":"Cole","year":"2012","journal-title":"Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1146\/annurev-pharmtox-010510-100611","article-title":"Mechanisms of the anti-cancer and anti-inflammatory actions of vitamin D","volume":"51","author":"Krishnan","year":"2011","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"403","DOI":"10.4103\/ijc.IJC_358_20","article-title":"Serum 25-hydroxy vitamin-D levels in head and neck cancer chemoradiation therapy: Potential in cancer therapeutics","volume":"61","author":"Bhanu","year":"2024","journal-title":"Indian J. Cancer"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1092","DOI":"10.1038\/bjc.2017.44","article-title":"The impact of vitamin D pathway genetic variation and circulating 25-hydroxyvitamin D on cancer outcome: Systematic review and meta-analysis","volume":"116","author":"Farrington","year":"2017","journal-title":"Br. J. Cancer"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"582","DOI":"10.4103\/jcrt.JCRT_641_16","article-title":"Impact of smoking on pathological features in oral cavity squamous cell carcinoma","volume":"15","author":"Ghanem","year":"2019","journal-title":"J. Cancer Res. Ther."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"5820","DOI":"10.1002\/fsn3.2488","article-title":"Smoking behavior and circulating vitamin D levels in adults: A meta-analysis","volume":"9","author":"Yang","year":"2021","journal-title":"Food Sci. Nutr."},{"key":"ref_32","first-page":"1568","article-title":"Impact of Vitamin D Supplementation on Head and Neck Cancer Patients Receiving Radiotherapy","volume":"95","author":"Abdelaziz","year":"2022","journal-title":"Egypt. J. Hosp. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"145","DOI":"10.5114\/wo.2017.68623","article-title":"Expression of vitamin D receptor and vitamin D status in patients with oral neoplasms and effect of vitamin D supplementation on quality of life in advanced cancer treatment","volume":"21","author":"Anand","year":"2017","journal-title":"Contemp. Oncol.\/Wsp\u00f3\u0142czesna Onkol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e006128","DOI":"10.1136\/bmjopen-2014-006128","article-title":"The effect on quality of life of vitamin D administration for advanced cancer treatment (VIDAFACT study): Protocol of a randomised controlled trial","volume":"4","author":"Dusso","year":"2014","journal-title":"BMJ Open"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"866","DOI":"10.1200\/JCO.19.00128","article-title":"Patient-Clinician Communication Issues in Palliative Care for Patients with Advanced Cancer","volume":"38","author":"Back","year":"2020","journal-title":"J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1016\/j.pec.2005.05.005","article-title":"Recipients\u2019 perspective on breaking bad news: How you put it really makes a difference","volume":"58","author":"Kindlimann","year":"2005","journal-title":"Patient Educ. Couns."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1146\/annurev.publhealth.25.101802.123134","article-title":"Physician gender and patient-centered communication: A critical review of empirical research","volume":"25","author":"Roter","year":"2004","journal-title":"Annu. Rev. Public Health"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1002\/pon.949","article-title":"The communication goals and needs of cancer patients: A review","volume":"14","author":"Hack","year":"2005","journal-title":"Psych-Ooncology"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"344","DOI":"10.4103\/ijcm.ijcm_534_23","article-title":"Missed Opportunities in Early Diagnosis of Head and Neck Cancer in Patients in Tamil Nadu\u2014A Mixed Method Study","volume":"50","author":"Jayabharathi","year":"2025","journal-title":"Indian J. Community Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.oraloncology.2018.12.029","article-title":"Travel time to provider is associated with advanced stage at diagnosis among low income head and neck squamous cell carcinoma patients in North Carolina","volume":"89","author":"Farquhar","year":"2019","journal-title":"Oral Oncol."}],"container-title":["Clinics and Practice"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2039-7283\/15\/9\/164\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:44:44Z","timestamp":1760035484000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2039-7283\/15\/9\/164"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,12]]},"references-count":40,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2025,9]]}},"alternative-id":["clinpract15090164"],"URL":"https:\/\/doi.org\/10.3390\/clinpract15090164","relation":{},"ISSN":["2039-7283"],"issn-type":[{"type":"electronic","value":"2039-7283"}],"subject":[],"published":{"date-parts":[[2025,9,12]]}}}