HPVs need to avoid immune responses of the host in order to establish persistent infection. HPVs achieve this by dampening innate immunity of keratinocytes, the major cell type targeted by HPV. As... Show moreHPVs need to avoid immune responses of the host in order to establish persistent infection. HPVs achieve this by dampening innate immunity of keratinocytes, the major cell type targeted by HPV. As there is reduced production of danger signals including antimicrobial molecules, proinflammatory cytokines and chemokines by keratinocytes, HPV infection remains undetected by the immune system. However, our further data showed that PRR signaling is not completely blocked by hrHPV. Thus, the activation of innate and adaptive immunity at the site of HPV infection is slowed down but not prevented. In order for cancers to grow out they need to suppress the local effector cells. We focused on the role of the PD-1 receptor and its ligands PD-L1 and PD-L2, our data showed that the majority (81%) of the tumors from cervical cancer patients do not express PD-L1. Furthermore, PD-L1 expression was not associated with patient survival. Finally, we presented evidence that the chemokine receptor CXCR7 expression predicts poor disease-free and disease-specific survival in cervical cancer patients. Show less
Objective. The aim of this study is to investigate the impact of treatment policy changes in cervical cancer patients treated with adjuvant (chemo) radiotherapy.Methods. Between 1970 and 2007, 292... Show moreObjective. The aim of this study is to investigate the impact of treatment policy changes in cervical cancer patients treated with adjuvant (chemo) radiotherapy.Methods. Between 1970 and 2007, 292 patients received adjuvant radiotherapy after a radical hysterectomy with pelvic lymphadenectomy for early stage cervical carcinoma. All patients received pelvic radiotherapy (40 Gy-46 Gy in 1.8 Gy-2 Gy/fraction). Vaginal vault brachytherapy boost (10-14 Gy) was increasingly used for patients with high-risk factors, and since 1993 systematically applied in patients with at least 2 of the 3 risk factors: adenocarcinoma, nodal involvement and parametrial invasion. Cisplatin-based chemotherapy was introduced in this group of patients from 2000.Results. The 5-year cumulative risk of local recurrence (CRLR) was 13% (95%CI 9%-17%), resulting in an overall 5-year survival (OS) of 78% (95%CI 83%-73%). Since 1970, the OR for the 5-year locoregional recurrence risk (LRR) decreased from 2.5 to 1.15 (linear-OR = -0.02/year). The OR for the 5-year mortality risk reduced from 2.2 in 1970 to 1.0 in 2007 (linear-OR = -0.03/year). The largest risk reductions were observed before 1990 with a minor rise after 2002. The risk of severe late toxicity reduced from 1.8% to 1.5% (linear-OR = -0.03/year). The addition of concomitant adjuvant chemotherapy since 2000 may have benefited a subgroup of patients with squamous cell carcinoma, but not the patients with adenocarcinoma, and after introduction of chemotherapy the risk of severe late toxicity tripled from 2% to 7%.Conclusion. Since 1970, tumour recurrence risk and mortality have decreased, as radiation dose increased. The potential benefit of concomitant adjuvant chemotherapy could not be demonstrated in this nonrandomized study. (C) 2014 Elsevier Inc. All rights reserved. Show less
Arnold, M.; Liu, L.F.; Kenter, G.G.; Creutzberg, C.L.; Coebergh, J.W.; Soerjomataram, I. 2014
Growth and progression of cervical carcinoma is dependent on a complex interaction between cervical carcinoma cells and composition of the extracellular matrix. For local progression as well as... Show moreGrowth and progression of cervical carcinoma is dependent on a complex interaction between cervical carcinoma cells and composition of the extracellular matrix. For local progression as well as metastasizing, the extracellular matrix needs to be rearranged creating space for tumor cells to expand and angiogenesis to secure supply of nutrients and oxygen and removal of waste products. The net result of all contributing factors will lead to either progression or degradation of cervical cancer. In this thesis the role of contributing factors is investigated, e.g. cytokines, chemokines, inflammatory cells, the role of extracellular matrix and angiogenesis Show less
Kraima, A.C.; Derks, M.; Smit, N.N.; Munsteren, J.C. van; Velden, J. van der; Kenter, G.G.; DeRuiter, M.C. 2014
The thesis describes studies on practical aspects of cervical cancer, concering surgical considerations, and aspects of tumour behaviour and tumour spread. The thesis comprises studies on: the... Show moreThe thesis describes studies on practical aspects of cervical cancer, concering surgical considerations, and aspects of tumour behaviour and tumour spread. The thesis comprises studies on: the comparison of nerve-sparing and non-nerve-sparing radical hysterectomy for cervical cancer; a new surgical technique called the __Swift__ operation, a modification of the Leiden nerve-sparing radical hysterectomy; the use of distilled water to achieve adequate haemostasis during oncologic surgery; patterns of parametrial involvement in cervical cancer; scar recurrences after surgery for cervical cancer; the morphologic characteristics __Barrel Index__ and intra uterine fluid as possible predictors for survival after cervical cancer surgery; the relation between genetic changes (loss of heterozygosity and copy number alterations) and clinical parameters in a whole genome SNP-analysis of bulky cervical tumours. Furthermore, the visualisation of the __Morphogenetic Unit__ on MRI and per-operative is described. Show less
High-risk Human Papilloma Virus (HPV) induced malignancies are an interesting target for immunotherapy as they invariably express the viral proteins E6 and E7 that allow specific recognition of... Show moreHigh-risk Human Papilloma Virus (HPV) induced malignancies are an interesting target for immunotherapy as they invariably express the viral proteins E6 and E7 that allow specific recognition of tumor cells without the risk of inducing autoimmunity. This thesis describes the preclinical development of pDNA vaccine candidates for the treatment of HPV16 induced malignancies. For this purpose gene-shuffled (SH) versions of HPV16 E6 and E7 were used to avoid the risk of transformation at the vaccination site. To improve the immunogenicity of E6SH and E7SH several optimizations strategies were evaluated. First it is shown that genetic fusion with Tetanus Toxin Fragment C (TTFC), results in a dramatic increase in immunogenicity. The resulting vaccine candidates TTFC-E6SH and TTFC-E7SH were also demonstrated to have lost their transforming potential. Secondly it is demonstrated that the mere addition of an endoplasmatic reticulum targeting sequence and a set of promiscuous CD4 helper epitopes results in an enormous increase of the immunogenicity of E6SH and E7SH. This design decreases the risk of raising competing carrier specific immune responses. Finally several nanoparticle based formulations of a model pDNA vaccine were evaluated and it is demonstrated that for in vivo applications it is essential to shield the cationic charge of such nanoparticles. Show less
Viswanathan, A.N.; Creutzberg, C.L.; Craighead, P.; McCormack, M.; Toita, T.; Narayan, K.; ... ; Trimble, E. 2012
