Autocrine expression of the epidermal growth factor receptor ligand heparin-binding EGF-like growth factor in cervical cancer.

In cervical cancer, the epidermal growth factor receptor (EGFR) is overexpressed in 70-90% of the cases and has been associated with poor prognosis. EGFR-based therapy is currently being explored in cervical cancer. We investigated which EGFR ligand is primarily expressed in cervical cancer and which cell type functions as the major source of this ligand. We hypothesized that macrophages are the main source of EGFR ligands and that a paracrine loop between tumor cells and macrophages is responsible for ligand expression. mRNA expression analysis was performed on 32 cervical cancer cases to determine the expression of the EGFR ligands amphiregulin, ß-cellulin, epidermal growth factor (EGF), epiregulin, heparin-binding EGF-like growth factor (HB­EGF) and transforming growth factor α (TGFα). Subsequently, protein expression was determined immunohistochemically on 36 additional cases. To assess whether macrophages are the major source of EGFR ligands, immunohistochemical double staining was performed on four representative tissue slides. Expression of the chemokines granulocyte-macrophage colony-stimulating factor (GM-CSF) and C-C motif ligand 2 (CCL2) was determined by mRNA in situ hybridization. Of the known EGFR ligands, HB­EGF had the highest mRNA expression and HB­EGF and EGFR protein expression were highly correlated. Tumor specimens with high EGFR expression showed higher numbers of macrophages, and higher expression of GM-CSF and CCL2, but only a small subset (9%) of macrophages was found to be HB­EGF-positive. Strikingly, 78% of cervical cancer specimens were found to express HB­EGF. Standardized assessment of staining intensity, using spectral imaging analysis, showed that HB­EGF expression was higher in the tumor compartment than in the stromal compartment. These results suggest that HB­EGF is an important EGFR ligand in cervical cancer and that cervical cancer cells are the predominant source of HB­EGF. Therefore, we propose an autocrine EGFR stimulation model in cervical carcinomas.

Potential use of lymph node-derived HPV-specific T cells for adoptive cell therapy of cervical cancer.

Adoptive transfer of tumor-specific T cells, expanded from tumor-infiltrating lymphocytes or from peripheral blood, is a promising immunotherapeutic approach for the treatment of cancer. Here, we studied whether the tumor-draining lymph nodes (TDLN) of patients with human papillomavirus (HPV)-induced cervical cancer can be used as a source for ACT. The objectives were to isolate lymph node mononuclear cells (LNMC) from TDLN and optimally expand HPV-specific CD4+ and CD8+ T cells under clinical grade conditions. TDLN were isolated from 11 patients with early-stage cervical cancer during radical surgery. Isolated lymphocytes were expanded in the presence of HPV16 E6 and E7 clinical grade synthetic long peptides and IL-2 for 22 days and then analyzed for HPV16 specificity by proliferation assay, multiparameter flow cytometry and cytokine analysis as well as for CD25 and FoxP3 expression. Stimulation of LNMC resulted in expansion of polyclonal HPV-specific T cells in all patients. On average a 36-fold expansion of a CD4+ and/or CD8+ HPV16-specific T cell population was observed, which maintained its capacity for secondary expansion. The T helper type 1 cytokine IFNγ was produced in all cell cultures and in some cases also the Th2 cytokines IL-10 and IL-5. The procedure was highly reproducible, as evidenced by complete repeats of the stimulation procedures under research and under full good manufacturing practice conditions. In conclusion, TDLN represent a rich source of polyclonal HPV16 E6- and E7-specific T cells, which can be expanded under clinical grade conditions for adoptive immunotherapy in patients with cervical cancer.

A Novel Tumor-Specific Agent for Intraoperative Near-Infrared Fluorescence Imaging: A Translational Study in Healthy Volunteers and Patients with Ovarian Cancer.

PURPOSE: Completeness of cytoreductive surgery is a key prognostic factor for survival in patients with ovarian cancer. The ability to differentiate clearly between malignant and healthy tissue is essential for achieving complete cytoreduction. Using current approaches, this differentiation is often difficult and can lead to incomplete tumor removal. Near-infrared fluorescence imaging has the potential to improve the detection of malignant tissue during surgery, significantly improving outcome. Here, we report the use of OTL38, a near-infrared (796 nm) fluorescent agent, that binds folate receptor alpha, which is expressed in >90% of epithelial ovarian cancers. EXPERIMENTAL DESIGN: We first performed a randomized, placebo-controlled study in 30 healthy volunteers. Four single increasing doses of OTL38 were delivered intravenously. At fixed times following drug delivery, tolerability and blood/skin pharmacokinetics were assessed. Next, using the results of the first study, three doses were selected and administered to 12 patients who had epithelial ovarian cancer and were scheduled for cytoreductive surgery. We measured tolerability and blood pharmacokinetics, as well as the ability to detect the tumor using intraoperative fluorescence imaging. RESULTS: Intravenous infusion of OTL38 in 30 healthy volunteers yielded an optimal dosage range and time window for intraoperative imaging. In 12 patients with ovarian cancer, OTL38 accumulated in folate receptor alpha-positive tumors and metastases, enabling the surgeon to resect an additional 29% of malignant lesions that were not identified previously using inspection and/or palpation. CONCLUSIONS: This study demonstrates that performing real-time intraoperative near-infrared fluorescence imaging using a tumor-specific agent is feasible and potentially clinically beneficial. Clin Cancer Res; 22(12); 2929-38. ©2016 AACR.

Exploring Morphologic and Molecular Aspects of Endometrial Cancer Under Progesterone Treatment in the Context of Fertility Preservation.

OBJECTIVE: The standard treatment of early-stage (FIGO [International Federation of Gynecology and Obstetrics] I) endometrioid endometrial cancer (EEC) is hysterectomy with bilateral salpingo-oophorectomy. An alternative approach for younger women with low-grade EEC who wish to preserve fertility may be hormonal treatment. Previous studies have suggested that progesterone may elicit its antitumor effect in EEC by interacting with the Wingless (Wnt) and/or phosphatidylinositol 3-kinase (PI3K)/Akt pathways. Therefore, we explored whether common activating genetic alterations in Wnt and PI3K/Akt signaling correlated with nonresponsiveness to progesterone therapy for low-grade EEC. In addition, we investigated whether benign morphology under progesterone treatment is accompanied by the absence of genetic changes. METHODS: We analyzed molecular alterations in the Wnt and PI3K/Akt signaling in 84 serial endometrial samples from 11 premenopausal patients with progesterone receptor-positive low-grade EEC conservatively treated with progesterone and correlated these with histological and clinical follow-up. RESULTS: There were 6 responders and 5 nonresponders to progesterone treatment. The response rate to progesterone treatment was 55%, and the relapse rate was 83%. All responders had alterations in both the Wnt and PI3K/Akt pathway before treatment. In the nonresponder group, tumors inconsistently showed alterations in none, 1, or both pathways. Normalization of the endometrium morphology under progesterone treatment is accompanied by the absence of the genetic changes found in the specimen before treatment. CONCLUSIONS: We found that activating molecular alterations in either Wnt or PI3K/Akt signaling pathways did not predict resistance to progesterone treatment. It seems that morphological response goes along with disappearance of the established mutations. This exploratory study suggests that Wnt or PI3K/Akt status is unable to predict response to progesterone treatment in patients with EEC.

Vaccination against Oncoproteins of HPV16 for Noninvasive Vulvar/Vaginal Lesions: Lesion Clearance Is Related to the Strength of the T-Cell Response.

PURPOSE: Therapeutic vaccination with human papillomavirus type 16 (HPV16) E6 and E7 synthetic long peptides (SLP) is effective against HPV16-induced high-grade vulvar and vaginal intraepithelial neoplasia (VIN/VaIN). However, clinical nonresponders displayed weak CD8(+) T-cell reactivity. Here, we studied if imiquimod applied at the vaccine site could improve CD8(+) T-cell reactivity, clinical efficacy, and safety of HPV16-SLP (ISA101). EXPERIMENTAL DESIGN: A multicenter open-label, randomized controlled trial was conducted in patients with HPV16(+) high-grade VIN/VaIN. Patients received ISA101 vaccination with or without application of 5% imiquimod at the vaccine site. The primary objective was the induction of a directly ex vivo detectable HPV16-specific CD8(+) T-cell response. The secondary objectives were clinical responses (lesion size, histology, and virology) and their relation with the strength of vaccination-induced immune responses. RESULTS: Forty-three patients were assigned to either ISA101 with imiquimod (n = 21) or ISA101 only (n = 22). Imiquimod did not improve the outcomes of vaccination. However, vaccine-induced clinical responses were observed in 18 of 34 (53%; 95% CI, 35.1-70.2) patients at 3 months and in 15 of 29 (52%; 95% CI, 32.5-70.6) patients, 8 of whom displayed a complete histologic response, at 12 months after the last vaccination. All patients displayed vaccine-induced T-cell responses, which were significantly stronger in patients with complete responses. Importantly, viral clearance occurred in all but one of the patients with complete histologic clearance. CONCLUSIONS: This new study confirms that clinical efficacy of ISA101 vaccination is related to the strength of vaccine-induced HPV16-specific T-cell immunity and is an effective therapy for HPV16-induced high-grade VIN/VaIN. Clin Cancer Res; 22(10); 2342-50. ©2016 AACRSee related commentary by Karaki et al., p. 2317.

The Value of Intraoperative Near-Infrared Fluorescence Imaging Based on Enhanced Permeability and Retention of Indocyanine Green: Feasibility and False-Positives in Ovarian Cancer.

OBJECTIVE: In ovarian cancer, two of the most important prognostic factors for survival are completeness of staging and completeness of cytoreductive surgery. Therefore, intra-operative visualization of tumor lesions is of great importance. Preclinical data already demonstrated tumor visualization in a mouse-model using near-infrared (NIR) fluorescence imaging and indocyanine green (ICG) as a result of enhanced permeability and retention (EPR). The aim of this study was to determine feasibility of intraoperative ovarian cancer metastases imaging using NIR fluorescence imaging and ICG in a clinical setting. METHODS: Ten patients suspected of ovarian cancer scheduled for staging or cytoreductive surgery were included. Patients received 20 mg ICG intravenously after opening the abdominal cavity. The mini-FLARE NIR fluorescence imaging system was used to detect NIR fluorescent lesions. RESULTS: 6 out of 10 patients had malignant disease of the ovary or fallopian tube, of which 2 had metastatic disease outside the pelvis. Eight metastatic lesions were detected in these 2 patients, which were all NIR fluorescent. However, 13 non-malignant lesions were also NIR fluorescent, resulting in a false-positive rate of 62%. There was no significant difference in tumor-to-background ratio between malignant and benign lesions (2.0 vs 2.0; P=0.99). CONCLUSIONS: This is the first clinical trial demonstrating intraoperative detection of ovarian cancer metastases using NIR fluorescence imaging and ICG. Despite detection of all malignant lesions, a high false-positive rate was observed. Therefore, NIR fluorescence imaging using ICG based on the EPR effect is not satisfactory for the detection of ovarian cancer metastases. The need for tumor-specific intraoperative agents remains. TRIAL REGISTRATION: ISRCTN Registry ISRCTN16945066.

Intraepithelial macrophage infiltration is related to a high number of regulatory T cells and promotes a progressive course of HPV-induced vulvar neoplasia.

Human papilloma virus (HPV)-induced usual-type vulvar intraepithelial neoplasia (uVIN) is infiltrated by myeloid cells but the type and role of these cells is unclear. We used triple immunofluorescent confocal microscopy to locate, identify and quantify myeloid cells based on their staining pattern for CD14, CD33 and CD163 in a cohort of 43 primary and 20 recurrent uVIN lesions, 21 carcinomas and 26 normal vulvar tissues. The progressive course of uVIN is characterized by an increase in both intraepithelial and stromal mature M1 and M2 macrophages. While the M2 macrophages outnumber M1 macrophages in healthy controls and uVIN, they are matched in number by M1 macrophages in cancer. Importantly, uVIN patients with a dense intraepithelial infiltration with mature CD14+ macrophages (irrespective of M1 or M2 type) displayed approximately a six times higher risk to develop a recurrence and a high number of these cells constituted an independent prognostic factor for recurrence. In addition, a dense intraepithelial CD14+ cell infiltration was associated with high numbers of intraepithelial CD4+ Tregs and low numbers of stromal CD8+TIM3+ T cells. Patients with low numbers of intraepithelial CD14+ cells and high numbers of stromal CD8+TIM3+ cells showed the best recurrence-free survival. These data clearly show the importance of the local immune response in HPV-induced vulvar neoplasia and may be of help in predicting the prognosis of patients or their response to immunotherapy.

Expression of coinhibitory receptors on T cells in the microenvironment of usual vulvar intraepithelial neoplasia is related to proinflammatory effector T cells and an increased recurrence-free survival.

Human papillomavirus-induced usual-type vulvar intraepithelial neoplasia (uVIN) are infiltrated by immune cells but apparently not cleared. A potential explanation for this is an impaired T cell effector function by an immunesuppressive milieu, coinfiltrating regulatory T cells or the expression of coinhibitory molecules. Here, the role of these potential inhibitory mechanisms was evaluated by a detailed immunohistochemical analysis of T cell infiltration in the context of FoxP3, Tbet, indoleamine 2,3-dioxygenase, programmed cell death 1, T cell immunoglobulin mucin 3 (TIM3), natural killer cell lectin-like receptor A (NKG2A) and galectins-1, -3 and -9. Paraffin-embedded tissues of primary uVIN lesions (n=43), recurrent uVIN lesions (n=20), vulvar carcinoma (n=21) and healthy vulvar tissue (n=26) were studied. We show that the vulva constitutes an area intensely surveyed by CD8+, CD4+, Tbet+ and regulatory T cell populations, parts of which express the examined coinhibitory molecules. In uVIN especially, the number of regulatory T cells and TIM3+ T cells increased. The expression of the coinhibitory markers TIM3 and NKG2A probably reflected a higher degree of T cell activation as a dense infiltration with stromal CD8+TIM3+ T cells and CD3+NKG2A+ T cells was related to the absence of recurrences and/or a prolonged recurrence-free survival. A dense coinfiltrate with regulatory T cells was negatively associated with the time to recurrence, most dominantly when the stromal CD8+TIM3+ infiltration was limited. This notion was sustained in vulvar carcinoma's where the numbers of regulatory T cells progressively increased to outnumber coinfiltrating CD8+TIM3+ T cells and CD3+NKG2A+ T cells.

Self-reported sexual, bowel and bladder function in cervical cancer patients following different treatment modalities: longitudinal prospective cohort study.

OBJECTIVE: Conventional radical hysterectomy with pelvic lymphadenectomy (RHL) for early-stage cervical cancer is associated with significant bladder, anorectal, and sexual dysfunction. Nerve-sparing modification of RHL (NS-RHL) has been developed with the aim to reduce surgical treatment-related morbidity. Postoperative radiation therapy (RT) is offered to patients with unfavorable prognostic features to improve local control. The aim of the study was to assess self-reported morbidity of various types of treatment in cervical cancer patients. METHODS: Self-reported symptoms were prospectively assessed before and 1 and 2 years after treatment by the Dutch Gynaecologic Leiden Questionnaire. RESULTS: Included were 229 women (123 NS-RHL and 106 conventional RHL). Ninety-four (41%) received RT. Up to 2 years (response rate, 81%), women reported significantly more bowel, bladder, and sexual symptoms compared with the pretreatment situation. No significant difference was found between the conventional RHL and NS-RHL with the exception of the unexpected finding that a smaller percentage in the NS-RHL group (34% vs 68%) complained about numbness of the labia and/ or thigh. Radiation therapy had a negative impact on diarrhea, urine incontinence, lymphedema, and sexual symptoms (especially a narrow/short vagina). CONCLUSIONS: In the current longitudinal cohort study, treatment for early-stage cervical cancer was associated with worse subjective bladder, anorectal, and sexual functioning, irrespective of the surgical procedure used. Postoperative RT resulted in a significant deterioration of these functions. The results have to be interpreted with caution in view of the study design and method used.

Loss of heterozygosity and copy number alterations in flow-sorted bulky cervical cancer.

Treatment choices for cervical cancer are primarily based on clinical FIGO stage and the post-operative evaluation of prognostic parameters including tumor diameter, parametrial and lymph node involvement, vaso-invasion, infiltration depth, and histological type. The aim of this study was to evaluate genomic changes in bulky cervical tumors and their relation to clinical parameters, using single nucleotide polymorphism (SNP)-analysis. Flow-sorted tumor cells and patient-matched normal cells were extracted from 81 bulky cervical tumors. DNA-index (DI) measurement and whole genome SNP-analysis were performed. Data were analyzed to detect copy number alterations (CNA) and allelic balance state: balanced, imbalanced or pure LOH, and their relation to clinical parameters. The DI varied from 0.92-2.56. Pure LOH was found in ≥40% of samples on chromosome-arms 3p, 4p, 6p, 6q, and 11q, CN gains in >20% on 1q, 3q, 5p, 8q, and 20q, and losses on 2q, 3p, 4p, 11q, and 13q. Over 40% showed gain on 3q. The only significant differences were found between histological types (squamous, adeno and adenosquamous) in the lesser allele intensity ratio (LAIR) (p = 0.035) and in the CNA analysis (p = 0.011). More losses were found on chromosome-arm 2q (FDR = 0.004) in squamous tumors and more gains on 7p, 7q, and 9p in adenosquamous tumors (FDR = 0.006, FDR = 0.004, and FDR = 0.029). Whole genome analysis of bulky cervical cancer shows widespread changes in allelic balance and CN. The overall genetic changes and CNA on specific chromosome-arms differed between histological types. No relation was found with the clinical parameters that currently dictate treatment choice.

Treatment failure in patients with HPV 16-induced vulvar intraepithelial neoplasia: understanding different clinical responses to immunotherapy.

Failure of the immune system to launch a strong and effective immune response to high-risk HPV is related to viral persistence and the development of anogenital (pre)malignant lesions such as vulvar intraepithelial neoplasia (VIN). Different forms of immunotherapy, aimed at overcoming the inertia of the immune system, have been developed and met with clinical success. Unfortunately these, in principal successful, therapeutic approaches also fail to induce clinical responses in a substantial number of cases. In this review, the authors summarize the traits of the immune response to HPV in healthy individuals and in patients with HPV-induced neoplasia. The potential mechanisms involved in the escape of HPV-induced lesions from the immune system indicate gaps in our knowledge. Finally, the interaction between the immune system and VIN is discussed with a special focus on the different forms of immunotherapy applied to treat VIN and the potential causes of therapy failure. The authors conclude that there are a number of pre-existing conditions that determine the patients' responsiveness to immunotherapy. An immunotherapeutic strategy in which different aspects of immune failure are attacked by complementary approaches, will improve the clinical response rate.

Randomized comparison of near-infrared fluorescence lymphatic tracers for sentinel lymph node mapping of cervical cancer.

OBJECTIVE: Near-infrared fluorescence imaging using indocyanine green (ICG) has recently been introduced as a novel technique for sentinel lymph node (SLN) mapping in early-stage cervical cancer. Although preclinical research has shown that ICG adsorbed to human serum albumin (ICG:HSA) improves its performance, the need for HSA has not yet been confirmed in cervical cancer patients. The current randomized study aims to determine whether ICG:HSA offers advantages over using ICG alone. METHODS: Eighteen consecutive early-stage cervical cancer patients scheduled to undergo pelvic lymphadenectomy were included. Prior to surgery, 1.6 mL of 500 µM ICG:HSA or 500 µM ICG alone was injected transvaginally in 4 quadrants around the tumor. The Mini-FLARE imaging system was used for intraoperative NIR fluorescence detection and quantitation. RESULTS: SLNs were identified intraoperatively in 78% of the patients. Patient and tumor characteristics were equally distributed over both treatment groups. No significant difference in signal-to-background ratio (9.3 vs. 10.1, P=.72) or average number of detected SLNs (2.9 vs 2.7, P=.84) was found between the ICG:HSA group and the ICG alone group, respectively. CONCLUSIONS: In conclusion, this double-blind, randomized trial showed no advantage of ICG:HSA over ICG alone for the SLN procedure in early-stage cervical cancer. Further optimization is required to improve the intraoperative detection rate.

Patterns of parametrial involvement in radical hysterectomy specimens of cervical cancer patients.

A tumor in the parametria, either continuous with or separate from the primary malignancy, is an unfavorable prognostic factor in cervical cancer. The incidence of a parametrial tumor localized in blood or lymph vessels, or in tissue, and the relationship of these involvement patterns with pathologic characteristics and prognosis were investigated. Seventy-nine of 763 surgically treated cervical cancer patients (10%) had a tumor in the parametria in hysterectomy specimens. The available patient material was reviewed to discriminate between continuous and discontinuous parametrial tumor growth. The involvement pattern for discontinuous growth was specified on the basis of immunohistochemical staining with different specific markers. Fifty percent of the parametrial tumor involvement found postoperatively was caused by continuous extension of the primary process into the parametria. In the other 50%, the parametrial tumor was separate from the primary process. In this discontinuous group, we found a frequent presence of tumor in the lymph nodes and/or lymph vessels (together 79%) and even a rare appearance of tumor in the blood vessels (14%). A tumor was further found in unspecified vessels in 2 patients (5%), and as isolated foci in 6 patients (14%). Fourteen patients (33%) had more than 1 involvement pattern. Positive pelvic lymph nodes were more frequent in the discontinuous group. The involvement pattern was no independent predictor of overall survival. Parametrial blood vessel involvement was related to the development of distant metastases. The majority (79%) of parametrial involvement in the discontinuous group is caused by lymphatic metastases. Parametrial blood vessel involvement might be an independent predictor for the development of distant metastasis.

Molecular mechanisms of epidermal growth factor receptor overexpression in patients with cervical cancer.

The epidermal growth factor receptor is overexpressed in 70-90% of cervical cancers. Previously, we have shown that epidermal growth factor receptor overexpression independently predicts poor prognosis in cervical cancer patients, which makes it a potential therapeutic target. The aim of this study was to systematically analyze the molecular mechanism leading to epidermal growth factor receptor overexpression in cervical cancer. All experiments were performed on archival paraffin-embedded material. In 166 cervical cancer patients, cytoplasmic, membrane and phosphorylated epidermal growth factor receptor protein expression were studied in association with patient survival. Membrane epidermal growth factor receptor overexpression was associated with poor disease-specific survival (P=0.027). This association was particularly present in human papillomavirus 16-positive patients (P=0.029). We analyzed whether epidermal growth factor receptor overexpression was caused by gene amplification using fluorescence in situ hybridization. Epidermal growth factor receptor gene copy number was linked to chromosome 7 ploidy, as no gene amplification could be detected when corrected for chromosome 7 centromeric signals. Chromosome 7 aneuploidy was associated with membrane epidermal growth factor receptor overexpression (P=0.013). Additional mutation analysis was performed by sequencing pure, flow-sorted tumor cells, but no mutations were detected. Furthermore, human papillomavirus 16 E5 and E6 oncogene mRNA expression was measured, using quantitative real-time polymerase chain reaction, to determine the association between the human papillomavirus and epidermal growth factor receptor overexpression. High human papillomavirus 16 E5 and E6 mRNA expression were associated with decreased survival (P=0.045 and 0.047, respectively). High human papillomavirus 16 E6 mRNA expression was associated with membrane epidermal growth factor receptor overexpression (P=0.013). This is the first study performed on cancer patient material showing that chromosome 7 aneuploidy and high human papillomavirus 16 E6 mRNA expression lead to membrane epidermal growth factor receptor overexpression in cervical cancer.

Nerve-sparing radical hysterectomy: local recurrence rate, feasibility, and safety in cervical cancer patients stage IA to IIA.

UNLABELLED: To clarify the debate about the possible threat of sparing the pelvic autonomic nerves in radical hysterectomy for cervical cancer to radicality, comparative studies of nerve-sparing and conventional surgery are necessary. The aim of his study was to analyze and compare local recurrence rate, feasibility, and safety of nerve-sparing and non-nerve-sparing radical hysterectomy. METHODS: In a cohort study with 2 years of follow-up, 246 patients with cervical cancer of stages IA to IIA were analyzed: 124 in the non-nerve-sparing group (1994-1999) and 122 in the group where nerve-sparing was the intention-to-treat (2001-2005). Local recurrence rate, local recurrence-free survival, feasibility, and safety were analyzed and compared. RESULTS: The clinical characteristics of the treatment groups were comparable. Sparing the nerves unilaterally or bilaterally was possible in 80% of cases of the nerve-sparing group. Local recurrence rates in the non-nerve-sparing (4.9%) and nerve-sparing (8.3%) group were not significantly different. Mean local recurrence-free survival within 2 years were 22.7 and 22.0 months, respectively. Univariate and multivariate regression analyses showed that nerve-sparing treatment was not a significant prognostic factor for local recurrence. With respect to perioperative and postoperative parameters, operating time and blood loss were less in the nerve-sparing group and mortality was equal (1 patient); the postoperative course of the nerve-sparing group was similar to the state-of-the-art of conventional radical hysterectomy. CONCLUSIONS: On the basis of the results of our study, we consider the nerve-sparing technique for cervical cancer stages IA to IIA feasible and safe.