{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T05:39:36Z","timestamp":1787031576578,"version":"build-2736575974"},"reference-count":17,"publisher":"Termedia Sp. z.o.o.","issue":"4","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pol J Pathol"],"abstract":"<jats:p>Cervical carcinogenesis unfolds within a\u00a0complex tissue ecosystem. While epithelial biomarkers and HPV status inform risk, the\u00a0contribution of\u00a0local neural circuits and their relationship to angiogenesis and cytotoxic immunity remains insufficiently defined in cervical intraepithelial neoplasia (CIN).&lt;br \/&gt;\nIn a\u00a0balanced, archival cohort (n = 135; 27 per group: normal, CIN1, CIN2, CIN3, squamous cell carcinoma \u2013 SCC), whole-slide images were analyzed using a\u00a0pre-specified QuPath pipeline with fixed thresholds and area normalization.  We created composite indices: a\u00a0neuro-epithelial coupling index (NECI) integrating nerve density, caliber, PGP9.5 signal, and inverse nerve-basement membrane (BM) distance; a\u00a0vascular remodeling index (VRI) integrating CD31\/CD34 microvessel density, vascular endothelial growth factor, vessel caliber, and peribasement vessels.&lt;br \/&gt;\nCytotoxic access was captured by CD8 density within 0\u201350 \u00b5m of\u00a0nerves (NACD50) NECI and VRI increased monotonically with grade (group medians, normal  \uf0ae SCC: NECI \u20131.29, \u20130.64, 0.00, 1.33, 3.54; VRI \u20131.35, \u20130.58, 0.00, 1.14, 2.06). Neurovascular progression index values differ between grades (\u20131.32, \u20130.64, 0.00, 1.24, 2.66). The\u00a0minimum nerve-BM distance shortened stepwise. In contrast, nerve-adjacent CD8 access declined with grade: NACD50 fell (\u2248 5, 8, 4,  2, 1 cells\/mm\u00b2) and nerve-avoidance ratio decreased (\u2248 0.9, 0.8, 0.6, 0.4, 0.3),  indicating progressive perineural CD8 exclusion. &lt;br \/&gt;\nAcross the\u00a0full histologic spectrum, neuro-epithelial proximity and vascular remodeling intensify, whereas cytotoxic access to the\u00a0perineural niche declines. These nerve-anchored, spatially explicit metrics add a\u00a0neural dimension to cervical carcinogenesis and nominate the\u00a00\u201350 \u00b5m perineural zone as a\u00a0quantifiable compartment for risk stratification and interventional trials. External validation and calibrated modeling are warranted.<\/jats:p>","DOI":"10.5114\/pjp.2025.158907","type":"journal-article","created":{"date-parts":[[2026,1,29]],"date-time":"2026-01-29T13:58:25Z","timestamp":1769695105000},"page":"318-328","source":"Crossref","is-referenced-by-count":2,"title":["Neural proximity, vascular remodeling, and perineural immune exclusion across the\u00a0cervical neoplasia spectrum \u2013 a\u00a0whole-slide, nerve-anchored spatial analysis  of\u00a0135 cases"],"prefix":"10.5114","volume":"76","author":[{"given":"Giorgi-Jemal","family":"Gogitidze","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shota","family":"Kepuladze","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George","family":"Burkadze","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"3061","published-online":{"date-parts":[[2026,1,28]]},"reference":[{"key":"ref-1687555","doi-asserted-by":"crossref","unstructured":"Hughes RT, L\u00e4ck CM, Sachs JR, Hiatt KD, Smith S, Ste- ber CR, et al. 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Bioengineering (Basel) 2025; 12: 377.","DOI":"10.3390\/bioengineering12040377"},{"key":"ref-1687558","doi-asserted-by":"crossref","unstructured":"Zhang Z, Liu M, An Y, Gao C, Wang T, Zhang Z, et al. Targeting immune microenvironment in cervical cancer: current research and advances. J Translat Med 2025; 23: 888.","DOI":"10.1186\/s12967-025-06896-3"},{"key":"ref-1687559","doi-asserted-by":"crossref","unstructured":"Huang S, Zhu J, Yu L, Huang Y, Hu Y. Cancer-nervous system crosstalk: from biological mechanism to therapeutic opportunities. Mol Cancer 2025; 24: 133.","DOI":"10.1186\/s12943-025-02336-4"},{"key":"ref-1687560","doi-asserted-by":"crossref","unstructured":"Zhang X, Liu L, Chai Y, Zhang J, Deng Q, Chen X. Reimagi- ning the\u00a0meninges from a\u00a0neuroimmune perspective: a\u00a0boundary, but not peripheral. J Neuroinflammation; 2024; 21: 299.","DOI":"10.1186\/s12974-024-03286-2"},{"key":"ref-1687561","doi-asserted-by":"crossref","unstructured":"Dudley AC, Griffioen AW. Pathological angiogenesis: mechanisms and therapeutic strategies. Angiogenesis 2023; 26: 313.","DOI":"10.1007\/s10456-023-09876-7"},{"key":"ref-1687562","doi-asserted-by":"crossref","unstructured":"Shalabi S, Belayachi A, Larriv\u00e9e B. Involvement of\u00a0neuronal factors in tumor angiogenesis and the\u00a0shaping of\u00a0the\u00a0cancer microenvironment. Front Immunol 2024; 15: 1284629.","DOI":"10.3389\/fimmu.2024.1284629"},{"key":"ref-1687563","doi-asserted-by":"crossref","unstructured":"Wang H, Huo R, He K, Li C, Zhang S, Yu M, et al. Perineural invasion in colorectal cancer: mechanisms of\u00a0action and clinical relevance. Cell Oncol 2023; 47: 1.","DOI":"10.1007\/s13402-023-00857-y"},{"key":"ref-1687564","doi-asserted-by":"crossref","unstructured":"Loopik D, Bentley HA, Eijgenraam MN, IntHout J, Bek- kers RLM, Bentley J. The\u00a0natural history of\u00a0cervical intraepithelialneoplasia grades 1, 2, and 3: a\u00a0systematic review and meta-analysis. J Lower Genital Tract Dis 2021; 25: 221.","DOI":"10.1097\/LGT.0000000000000604"},{"key":"ref-1687565","doi-asserted-by":"crossref","unstructured":"Gao X, Wang Q, Huang T, Xu C, Yang X, Zhang L, et al. Cervical cancer-produced neuromedin-B reprograms Schwann cells to initiate perineural invasion. Cell Death Dis 2024; 15: 636.","DOI":"10.1038\/s41419-024-07030-9"},{"key":"ref-1687566","doi-asserted-by":"crossref","unstructured":"Pu T, Sun J, Ren G, Li H. Neuro-immune crosstalk in cancer: mechanisms and therapeutic implications. Signal Transduct Target Ther 2025; 10: 176.","DOI":"10.1038\/s41392-025-02241-8"},{"key":"ref-1687567","doi-asserted-by":"crossref","unstructured":"Yang Y, Cui J, Kong Y, Hou Y, Ma C. Organoids: new frontiers in tumor immune microenvironment research. Front Immunol 2024; 15: 1422031.","DOI":"10.3389\/fimmu.2024.1422031"},{"key":"ref-1687568","doi-asserted-by":"crossref","unstructured":"Ahmed I, Zhang W, Cheung P, Basnet V, Ali Z, Tse M, et al. AI-based virtual immunocytochemistry for rapid and robust fine needle aspiration biopsy diagnosis. Diagn Pathol 2025; 20: 86.","DOI":"10.1186\/s13000-025-01687-2"},{"key":"ref-1687569","doi-asserted-by":"crossref","unstructured":"Weber S, Menees KB, Park J, Agin-Liebes J, Lin CC, Alca-lay RN, et al. Distinctive CD56dim NK subset profiles and increased NKG2D expression in blood NK cells of\u00a0Parkinson\u2019s disease patients. NPJ Parkinsons Dis 2024; 10: 36.","DOI":"10.1038\/s41531-024-00652-y"},{"key":"ref-1687570","doi-asserted-by":"crossref","unstructured":"Kusch N, Storm JJ, Macioszek A, Kisselmann E, Knabbe C, Kaltschmidt B, et al. A\u00a0Critical role of\u00a0culture medium selection in maximizing the\u00a0purity and expansion of\u00a0natural killer cells. Cells 2024; 13: 1148.","DOI":"10.3390\/cells13131148"},{"key":"ref-1687571","doi-asserted-by":"crossref","unstructured":"Kuehl M, Okabayashi Y, Wong MN, Gernhold L, Gut G, Kaiser N, et al. 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