Introduction Immunological competence influences the progression of cervical intraepithelial neoplasia (CIN) to invasive cancer. Information on the local immunological changes during the natural course of CIN is central for the development of new therapies.Objective This study defines the populations of tissue-infiltrating immune cells in a cross-sectional cohort of different grades of CIN and also in a longitudinal cohort of regressing, persistent and progressing low-grade (LG)-CIN.Design A cohort of 125 women with LG cytological atypia was recruited, of which 64/125 (51%) women with LG-CIN were followed prospectively for 1 year. Paraffin-embedded entry and exit cervical biopsies were used for immunohistochemistry analysis (CD4, CD8, CD56, FOXP3, CD1a and granzyme B).Results At recruitment, 74/125 (59%), 39/125 (31%) and 12/125 (10%) women referred with LG smears had histologically proven LG-CIN, high-grade (HG) and normal biopsies, respectively.Seventeen of 64 (24.6%) women with LG-CIN progressed to HG-CIN within 1 year. In both LG-CIN and HG-CIN, the predominant intraepithelial cell population were cytotoxic T cells, while CD4+ and FOXP3+ T cells predominated the stromal compartment. Women with LG-CIN who later on regressed displayed a significantly higher number of cytotoxic (granzyme B+) cells in their entry samples. In addition, the ratio between CD8+ cells and granzyme B+ cells was close to 1, suggesting that all infiltrating CD8+ T cells were highly active. In contrast, this ratio was three-fold lower in women, in whom the lesions persisted or progressed.Conclusions This study suggests that the early infiltration of lesions by highly cytotoxic effector cells protects against progression.Keywords Human papillomavirus, immunohistochemistry, local immune cell response.Please cite this paper as: Woo Y, Sterling J, Damay I, Coleman N, Crawford R, van der Burg S, Stanley M. Characterising the local immune responses in cervical intraepithelial neoplasia: a cross-sectional and longitudinal analysis.

SynopsisSeries of mono-and bismaleimides were evaluated as curing agents to determine the effect of structure on crosslinking ability. The activity of N-phenylmaleimide derivatives (monomaleimides) as crosslinking agents is highly dependent upon the substituent on the phenyl group. The activity of bismaleimides is likewise affected by the nature of the moiety connecting the maleimide rings. Isomaleimides and itaconimides are less effective curatives. Initiators for the maleimide cures include peroxides and sulfur accelerators of the thiazole type. Saturated and unsaturated hydrocarbon rubbers, except those containing a high percentage of isobutylene units, are vulcanized by a maleimide-initiator system. One of the attractive features of a maleimide curing system is that the physical properties of the cured rubbers are independent of curing temperature. Further, these vulcanizates have the good aging characteristics typical of nonsulfur-cured vulcanizates. In contrast to sulfur vulcanization, the maleimide curing systems do not markedly affect the ability of elastomers to crystallize when stretched.Therefore, the Ta test cannot be used to assess the state of cure of maleimide-natural rubber vulcanizates. Maleimides containing an appropriate second functional group can be used as self-accelerating curing agents or as adhesives.

Ovarian cancer represents the fifth leading cause of death from all cancers for women. During the last decades overall survival has improved due to the use of new chemotherapy schedules. Still, the majority of patients die of this disease. Research reveals that ovarian cancer patients exhibit significant immune responses against their tumor. In this review the knowledge obtained thus far on the interaction of ovarian cancer tumor cells and the immune system is discussed. Furthermore the role of p53 as tumor antigen and its potential role as target antigen in ovarian cancer is summarized. Based on the increased knowledge on the role of the immune system in ovarian cancer major improvements are to be expected of immunotherapy based treatment of this disease.

Introduction/Background* Atypical hyperplasia (AH) or endometrioid intraepithelial hyperplasia (EIN) refer to a pre-cancerous proliferation of the endometrial glands resulting in an increased ratio of glands to stroma (>3:1). We aimed to identify Immunohistochemistry (IHC) biomarkers to distinguish AH/EIN lesions associated with synchronous endometroid cancer (EC) or imminent progression to EC. Methodology We performed a structured review of the published evidence on MEDLINE from inception to March 6, 2021 and selected the 5 most common "themes" (IHC biomarkers) as defined by the number of available studies and/or specimens included. We synthesised the evidence to provide a consensus on their prognostic value (synchronous cancer or imminent progression). Result(s)* We identified 52 studies from 18 countries. The 5 most discussed biomarkers ("themes") were: Phosphatase and TENsin homolog (PTEN), stromal expression of p16 protein, nuclear localisation of b-catenin, Paired box gene 2 (PAX2), B-cell Lymphoma 2 expression (bcl-2). PTEN loss in AH was associated with increased risk of Endometrial Cancer (EC). Increased stromal p16 was observed in most EC specimens as well as AH compared to benign; EC had the highest expression. Nuclear b-catenin expression seems to increase from benign to pre-malignant AH but not from pre-malignant to EC. A progressive decrease of PAX2 expression was noted in transition from AH to EC. Conclusion* Identification of the most common IHC biomarkers whose expression alter during the transition from benign to AH and subsequently EC can flag those cases that immediate definitive management with hysterectomy is needed. This is important when fertility plan is an argument against hysterectomy. Introduction of artificial intelligence algorithms provides the advantage of integrating multiple diagnostic markers in a single prognostic model.

Purpose Highly malignant uveal melanoma contain increased numbers of lymphocytes and macrophages. We wondered whether hypoxia plays a role in the development of this inflammation. We analysed whether hypoxia induces uveal melanoma cells to release pro‐inflammatory cytokines, and whether tumor supernatant (TSN) affects monocyte migration and differentiation. Methods The expression of pro‐inflammatory genes in freshly cultured uveal melanoma was studied in an in vitro 24 hour hypoxic culture system using qPCR. Cell lines were cultured under normoxic and hypoxic conditions. Chemotaxis was tested using a transwell system with purified monocytes and TSN. Differentiation was tested by adding TSN to a monocyte‐DC culture. CCL2, IL‐6 and PGE2 levels in TSN were determined by ELISA. Results Exposure of freshly‐cultured uveal melanoma cells to hypoxia led to an increased expression of the pro‐inflammatory cytokines PLGF, TGFß, END1, ICAM1 and a lower expression of AIMP1 (EMAP2), CCL2 (MCP‐1), and IL1b. TSN from melanoma cells lines, cultured in normoxic as well as hypoxic conditions, was able to attract monocytes. Migration was independent of tumor‐produced CCL2. Uveal melanoma supernatant inhibits monocyte differentiation. Conclusion Under hypoxic conditions, immune response genes are differentially expressed in cultured primary uveal melanoma cells. TSN from uveal melanoma cell lines is capable of affecting the chemotactic response of monocytes in vitro, irrespectively of the hypoxic or normoxic conditions. Our data suggest that the induction of immune cells is not dependent on intratumoral oxygen level, and the uveal melanoma TSN does not skew macrophage polarization phenotype.