Voiding recovery after radical parametrectomy in cervical cancer patients: An international prospective multicentre trial - SENTIX.

OBJECTIVE: Voiding dysfunctions represent a leading morbidity after radical hysterectomy performed in patients with early-stage cervical cancer. The aim of this study was to perform ad hoc analysis of factors influencing voiding recovery in SENTIX (SENTinel lymph node biopsy in cervIX cancer) trial. METHODS: The SENTIX trial (47 sites, 18 countries) is a prospective study on sentinel lymph node biopsy without pelvic lymphadenectomy in patients with early-stage cervical cancer. Overall, the data of 300 patients were analysed. Voiding recovery was defined as the number of days from surgery to bladder catheter/epicystostomy removal or to post-voiding urine residuum ≤50 mL. RESULTS: The median voiding recovery time was three days (5th-95th percentile: 0-21): 235 (78.3%) patients recovered in <7 days and 293 (97.7%) in <30 days. Only seven (2.3%) patients recovered after >30 days. In the multivariate analysis, only previous pregnancy (p = 0.033) and type of parametrectomy (p < 0.001) significantly influenced voiding recovery >7 days post-surgery. Type-B parametrectomy was associated with a higher risk of delayed voiding recovery than type-C1 (OR = 4.69; p = 0.023 vs. OR = 3.62; p = 0.052, respectively), followed by type-C2 (OR = 5.84; p = 0.011). Both previous pregnancy and type C2 parametrectomy independently prolonged time to voiding recovery by two days. CONCLUSIONS: Time to voiding recovery is significantly related to previous pregnancy and type of parametrectomy but it is not influenced by surgical approach (open vs minimally invasive), age, or BMI. Type B parametrectomy, without direct visualisation of nerves, was associated with longer recovery than nerve-sparing type C1. Importantly, voiding dysfunctions after radical surgery are temporary, and the majority of the patients recover in less than 30 days, including patients after C2 parametrectomy.

Tumour-free distance: a novel prognostic marker in patients with early-stage cervical cancer treated by primary surgery.

BACKGROUND: Models predicting recurrence risk (RR) of cervical cancer are used to tailor adjuvant treatment after radical surgery. The goal of our study was to compare available prognostic factors and to develop a prognostic model that would be easy to standardise and use in routine clinical practice. METHODS: All consecutive patients with early-stage cervical cancer treated by primary surgery in a single referral centre (01/2007-12/2016) were eligible if assessed by standardised protocols for pre-operative imaging and pathology. Fifteen prognostic markers were evaluated in 379 patients, out of which 320 lymph node (LN)-negative. RESULTS: The best predictive model for the whole cohort entailed a combination of tumour-free distance (TFD) ≤ 3.5 mm and LN positivity, which separated two subgroups with a substantially distinct RR 36% and 6.5%, respectively. In LN-negative patients, a combination of TFD ≤ 3.5 mm and adenosquamous tumour type separated a group of nine patients with RR 33% from the rest of the group with 6% RR. CONCLUSIONS: A newly identified prognostic marker, TFD, surpassed all traditional tumour-related markers in the RR assessment. Predictive models combining TFD, which can be easily accessed on pre-operative imaging, with LN status or tumour type can be used in daily practice and can help to identify patients with the highest RR.

Micrometastases in Sentinel Lymph Nodes Represent a Significant Negative Prognostic Factor in Early-Stage Cervical Cancer: A Single-Institutional Retrospective Cohort Study.

The data on the prognostic significance of low volume metastases in lymph nodes (LN) are inconsistent. The aim of this study was to retrospectively analyze the outcome of a large group of patients treated with sentinel lymph node (SLN) biopsy at a single referral center. Patients with cervical cancer, stage T1a-T2b, common tumor types, negative LN on preoperative staging, treated by primary surgery between 01/2007 and 12/2016, with at least unilateral SLN detection were included. Patients with abandoned radical surgery due to intraoperative SLN positivity detected by frozen section were excluded. All SLNs were postoperatively processed by an intensive protocol for pathological ultrastaging. Altogether, 226 patients were analyzed. Positive LN were detected in 38 (17%) cases; macrometastases (MAC), micrometastases (MIC), isolated tumor cells (ITC) in 14, 16, and 8 patients. With the median follow-up of 65 months, 22 recurrences occurred. Disease-free survival (DFS) reached 90% in the whole group, 93% in LN-negative cases, 89% in cases with MAC, 69% with MIC, and 87% with ITC. The presence of MIC in SLN was associated with significantly decreased DFS and OS. Patients with MIC and MAC should be managed similarly, and SLN ultrastaging should become an integral part of the management of patients with early-stage cervical cancer.

Central Pathology Review in SENTIX, A Prospective Observational International Study on Sentinel Lymph Node Biopsy in Patients with Early-Stage Cervical Cancer (ENGOT-CX2).

The quality of pathological assessment is crucial for the safety of patients with cervical cancer if pelvic lymph node dissection is to be replaced by sentinel lymph node (SLN) biopsy. Central pathology review of SLN pathological ultrastaging was conducted in the prospective SENTIX/European Network of Gynaecological Oncological Trial (ENGOT)-CX2 study. All specimens from at least two patients per site were submitted for the central review. For cases with major or critical deviations, the sites were requested to submit all samples from all additional patients for second-round assessment. From the group of 300 patients, samples from 83 cases from 37 sites were reviewed in the first round. Minor, major, critical, and no deviations were identified in 28%, 19%, 14%, and 39% of cases, respectively. Samples from 26 patients were submitted for the second-round review, with only two major deviations found. In conclusion, a high rate of major or critical deviations was identified in the first round of the central pathology review (28% of samples). This reflects a substantial heterogeneity in current practice, despite trial protocol requirements. The importance of the central review conducted prospectively at the early phase of the trial is demonstrated by a substantial improvement of SLN ultrastaging quality in the second-round review.

Impact of sentinel lymph node frozen section evaluation to avoid combined treatment in early-stage cervical cancer.

BACKGROUND: The need for radical surgery followed by adjuvant chemoradiation may be reduced by abandoning radical surgery in patients in whom lymph node involvement is detected intra-operatively. OBJECTIVES: To analyze, in a retrospective cohort study, the efficacy of the algorithm using intra-operative pathological assessment of sentinel lymph nodes. METHODS: A retrospective single-institution study was carried out, which analyzed data from all consecutive patients with cervical cancer who were referred for primary surgical treatment between May 2005 and December 2015. Inclusion criteria were as follows: (1) TNM stage T1a1 with lymphovascular space invasion, T1a2, T1b, T2a, and selected T2b with incipient parametrial invasion; (2) adenocarcinoma, squamous cell carcinoma, or adenosquamous carcinoma; (3) no evidence of enlarged suspicious nodes or distant metastases on pre-operative imaging; (4) primary surgery with curative intent; (5) successful detection of sentinel lymph node, at least, unilaterally. All patients had at least one sentinel lymph node detected and submitted for frozen section evaluation. When sentinel lymph node involvement was detected intra-operatively, the cervical procedure was abandoned and the patient was referred for definitive chemoradiation. Radical surgery was completed in patients with intra-operative negative sentinel lymph nodes. The reliability of intra-operative sentinel lymph node assessment was evaluated by calculating the sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio, and negative likelihood ratio. RESULTS: The study included a total of 309 patients. Sentinel lymph nodes were detected bilaterally in 86% of the patients. Lymph node positivity was detected intra-operatively in 18 (6%) patients in whom the cervical procedure was abandoned. Adjuvant radiotherapy after completed radical surgery was given to 29 (9%) patients, including 20 patients with macrometastases (8) or micrometastases (12) reported from the final histology, eight patients with positive parametria (all ≤3 mm), and one patient with a positive vaginal resection margin. The sensitivity, specificity, positive predictive value, and negative predictive value for the intra-operative detection of lymph node positivity (macrometastases or micrometastases) was 47% (95% CI 31% to 64%), 100%, 100%, and 93% (95% CI 90% to 96%), respectively. A total of 18 (6%) patients were spared combined treatment owing to the intra-operative sentinel lymph node triage; 29 patients (9%) received combined treatment with both radical surgery and adjuvant radiotherapy CONCLUSIONS: Of 47 patients with high-risk prognostic risk factors (lymph node, parametria, or surgical margin involvement), combined treatment was successfully avoided in 18 (38%). Despite an effort to triage the patients intra-operatively, 9% received a combination of cervical procedure and adjuvant chemoradiation, mostly owing to the low sensitivity of the frozen section in the detection of micrometastases and macrometastases.

Oncological outcome of surgical management in patients with recurrent uterine cancer-a multicenter retrospective cohort study-CEEGOG EX01 Trial.

OBJECTIVES: To assess the survival of patients who have received an operation for recurrent cervical and endometrial cancer and to determine prognostic variables for improved oncologic outcome. METHODS: A retrospective multicenter analysis of the medical records of 518 patients with cervical (N = 288) or endometrial cancer (N = 230) who underwent surgery for disease recurrence and who had completed at least 1 year of follow-up. RESULTS: The median survival reached 57 months for patients with cervical cancer and 113 months for patients with endometrial cancer after surgical treatment of recurrence (p = 0.036). Histological sub-type had a significant impact on overall survival, with the best outcome in endometrial endometrioid cancer (121 months), followed by cervical squamous cell carcinoma, cervical adenocarcinoma, or other types of endometrial cancer (81 vs 35 vs 35 months; p <0.001). The site of recurrence did not significantly influence survival in cervical or in endometrial cancer. Cancer stage at first diagnosis, tumor grade, lymph node status at recurrence, progression-free interval after first diagnosis, and free resection margins were associated with improved overall survival on univariate analysis. On multivariate analysis, the stage at first diagnosis and resection margins were significant independent predictive parameters of an improved oncologic outcome. CONCLUSION: Long-term survival can be achieved via secondary cytoreductive surgery in selected patients with recurrent cervical and endometrial cancer. An excellent outcome is possible even if the recurrence site is located in the lymph nodes. The possibility of achieving complete resection should be the main criterion for patient selection.

Surgical treatment of "intermediate risk" lymph node negative cervical cancer patients without adjuvant radiotherapy-A retrospective cohort study and review of the literature.

OBJECTIVES: The role of adjuvant radiotherapy for lymph node-negative stage IB patients with tumor-related negative prognostic factors is not uniformly accepted. It is advocated based on the GOG 92 trial, which was initiated in 1989. The aim of the current study is to report the oncological outcome of "intermediate risk" patients treated by tailored surgery without adjuvant radiotherapy. Data from two institutions that refer these patients for adjuvant radiotherapy served as a control group. METHODS: Included were patients with stage IB cervical cancer treated with radical hysterectomy and pelvic lymphadenectomy, who had negative pelvic lymph nodes but a combination of negative prognostic factors adopted from the GOG 92 trial. Data were obtained from prospectively collected databases of three institutions. Radical surgery was a single-treatment modality in one of them and in the remaining two institutes it was followed by adjuvant chemoradiation. RESULTS: In 127 patients who received only radical surgery, with a median follow-up of 6.1 years, the local recurrence rate was 1.6% (2 cases), and total recurrence was 6.3% (8 cases). Disease-specific survival at 5 years was 95.7% (91.9%; 99.4%) and 91% (83.7%; 98.3%) at 10 years. The only significant factor for disease-specific survival was tumor size ≥4 cm (P = 0.032). The recurrence rate, local control or overall survival did not differ from the control group. Adjuvant radiotherapy was not a significant prognostic factor within the whole cohort. CONCLUSIONS: An excellent oncological outcome, especially local control, can be achieved by both radical surgery or combined treatment in stage IB lymph node-negative cervical cancer patients with negative prognostic factors. The substantially better outcome than in the GOG 92 trial can be attributed to more accurate pre-operative and pathological staging and an improvement in surgical techniques.

Patterns of Lymph Node Metastases in Apparent Stage I Low-Grade Epithelial Ovarian Cancer: A Multicenter Study.

OBJECTIVE: The aim of this study was to determine oncological outcomes and incidence of lymph node (LN) metastases in women who underwent systematic pelvic and paraaortic lymphadenectomy for surgical staging of apparent stage I low-grade epithelial ovarian cancer (LGEOC). MATERIALS AND METHODS: A retrospective study was performed at nine institutions across Europe and the US, and patients who underwent surgical staging for presumed stage I LGEOC between 2000 and 2016 were included. To ensure surgical quality, a minimum number of ≥10 pelvic and ≥10 paraaortic LNs was required. Patients with preoperative radiologic or clinical evidence of extraovarian or LN disease, and those with nonepithelial histology, were excluded. RESULTS: The overall incidence of LN metastases was 4.3% in the 163 evaluated patients, and the incidence of LN involvement in serous, endometrioid, and mucinous subtypes was 10.7, 1.5, and 0%, respectively. However, Upstaging due to LN involvement alone occurred in only 2.4% of the patients. Eighty-nine (54.6%) patients received adjuvant chemotherapy due to International Federation of Gynecology and Obstetrics stage IC or higher disease. The 5-year progression-free survival (PFS) and overall survival (OS) were 93.2% (95% confidence interval [CI] 89.4-97.1%) and 94.5% (95% CI 90.9-98.0%), respectively. There was no significant difference in PFS or OS between LN-negative and LN-positive patients. However, fewer patients received adjuvant chemotherapy in the LN-negative group. Multivariate analysis did not identify any independent prognostic factor of survival. CONCLUSION: The risk of LN involvement in nonserous apparent stage I LGEOC appears low, with a rate of <1% in this retrospective analysis, raising questions about the value of lymphadenectomy in those patients. Larger-scale prospective studies are warranted to evaluate the oncologic safety of omitting systematic LN staging in apparent stage I nonserous LGEOC.

Sensitivity of Follow-Up Methods in Patients After Fertility-Sparing Surgery for Cervical Cancers.

OBJECTIVE: The aim of our study was to compare the sensitivity of various methods and their combinations in the follow-up of patients with cervical cancer after fertility-sparing surgery (FSS). METHODS: Included were women with cervical cancer in stages IA2 to IB2 who underwent FSS, which includes pelvic lymphadenectomy, sentinel lymph node biopsy, abdominal radical trachelectomy, vaginal trachelectomy, or needle conization. Follow-up visits were scheduled at 3-month intervals and included symptom-oriented discussion, gynecological and physical examination, colposcopy, Papanicolaou test, human papillomavirus (HPV) DNA test, and ultrasound examination. All cases with a recurrent disease were thoroughly analyzed, and the results of individual examinations were compared. RESULTS: In total, 43 women (IA2, 8; IB1, 33; IB2, 2) were enrolled. The mean patient age was 31 years; most patients were nulliparous (68.4%, 26/38) with squamous cell cancers (26/38). Abdominal radical trachelectomy was performed in 10 women, simple vaginal trachelectomy was performed in 11 women, and conization was performed in 22 women, according to the tumor characteristics and topography. The median duration of the follow-up reached 37 months. Invasive cancer and high- and low-grade squamous intraepithelial lesions were detected in 8, 1, and 1 patients, respectively. All except 1 event were central, detected within the first year after FSS. Only 2 cases were symptomatic. Colposcopy detected 7 of 10 recurrences; 5 of them were HPV positive, and, in 2 cases, a Papanicolaou test revealed abnormalities. Papanicolaou tests were false positive in 27.7%, especially after trachelectomies. CONCLUSIONS: Most patients in whom cancer recurred after FSS reveal central or pelvic lesions, which can be successfully treated with salvage surgery or radiotherapy. The early detection of recurrence is an essential condition for a favorable oncological outcome. Colposcopy alone and in combination with HPV positivity showed the highest sensitivity for the detection of recurrent diseases, whereas other methods had limited reliability.

Results of less radical fertility-sparing procedures with omitted parametrectomy for cervical cancer: 5years of experience.

OBJECTIVE: The aim of our study was to describe oncological and obstetrical outcomes in patients who underwent less radical fertility-sparing surgical (FSS) procedures with omitted parametrectomy for cervical cancer. METHODS: Included were women with cervical cancer stages IA2-IB2 who were under the age of 40 and desired future pregnancy. Patients underwent pelvic lymphadenectomy and sentinel lymph node biopsy. Node-negative cases underwent subsequent cervical surgery and were further analyzed. Neoadjuvant chemotherapy (NAC) was administered in patients with tumors >2cm and/or involving >2/3 of cervical stroma. Simple vaginal trachelectomy or needle conization were performed according to tumor extent and topography. The follow-up period started once free surgical margins were reached. RESULTS: Out of 44 women enrolled, 32 women (IA2=7, IB1=23, IB2=2) successfully completed FSS. NAC was administered in 9 (28.1%) cases. A simple trachelectomy was performed in 11 patients and needle conization in 21 patients. During the follow-up, 6 out of 32 women became pregnant. Of these, 1 miscarried and 5 successfully delivered. Disease recurred in 6 patients; 5 recurrences were central and 1 recurrence presented as an ovarian mass. Invasive cervical carcinoma, high-grade squamous intraepithelial (HSIL), and low-grade squamous intraepithelial (LSIL) lesions were detected in 4, 1 and 1 patients, respectively. Three of them received NAC. All events were detected within 16months after surgery. CONCLUSIONS: Nearly 27% of patients cannot complete FSS due to node positivity, progression during NAC, or involved margins. The total recurrence rate reached 18.8%, with the majority of invasive recurrences detected in patients after NAC followed by FSS. These patients represent cases at a higher risk of recurrence even if adequate free margins are reached by surgery. Nearly half of the cohort did not consider pregnancy in the near future because of personal reasons.

Diagnostic and prognostic value of presepsin in preterm deliveries.

PROBLEM: To evaluate the association between serum presepsin (soluble CD14 antigen subtype, sCD14-ST) levels soon after the appearance of signs of preterm delivery and preterm delivery within 48 h, before the 34th and 37th gestational weeks and the possible additional value of concurrently evaluated ultrasound vaginal cervicometry with serum presepsin measurement. METHODOLOGY: A total of 60 females were included. Serum presepsin was measured by a chemiluminescent immunoassay. Sonographic evaluation of cervical length in all females was conducted by transvaginal ultrasound. RESULTS: Patients who delivered within 48 h after analysis showed significantly higher presepsin concentrations compared to females with later deliveries. Higher presepsin was proven also for deliveries before/after weeks 34 and 37. A combined finding of cervical length shortening below 18 mm and presepsin level increasing above 623.5 pg/mL could point to the significantly high risk of preterm delivery. CONCLUSION: Elevated maternal serum concentration of sCD14-ST could be an independent and relevant risk factor for preterm delivery.

Low levels of circulating T-regulatory lymphocytes and short cervical length are associated with preterm labor.

Recent discoveries suggest that T-regulatory lymphocytes (Treg) might play an important role in the pathophysiology of preterm labor. The aim of this study was to assess the relationship among the levels of maternal circulating Treg cells, uterine cervical length, and the risk of preterm labor. Sixty women with regular contractions and/or cervical incompetence at 24-32 weeks' gestation were recruited into a prospective study. Each patient underwent transvaginal ultrasound examination of the cervical length, and regulatory T cells were quantified in peripheral blood samples by flow cytometry. Patients with cervical incompetence were prescribed vaginal progesterone until birth. Measurements of Treg levels and cervical length correlated with the timing of labor. The risk of preterm labor happening within 48 h of testing was demonstrated to be almost 35 times higher (OR=35.21, CI 13.3; 214, p<0.001) in the group with simultaneously low Treg values (<0.031 × 10(9)/L) and a shortened uterine cervix (<17.5mm), compared with the situation where both of these values were normal. Similar results were found in predicting preterm delivery before 34 weeks, or between 34 and 37 weeks. A statistically nonsignificant trend toward increased cervical length and increased Treg count was noted in the women on progesterone treatment. We show for the first time that the combined assessment of Treg cell count and cervical length is a much better predictor of preterm delivery than either parameter used on its own. This combined approach may offer clinical application in patients who present with risk factors for preterm labor.

Receptor for advanced glycation end products (RAGE) and glyoxalase I gene polymorphisms in pathological pregnancy.

OBJECTIVES: The aim of the study was to analyze polymorphisms of receptor for advanced glycation end products (RAGE) gene, and glyoxalase I gene and soluble RAGE, sRAGE, in physiological and pathological pregnancy. DESIGN AND METHODS: Polymorphisms of RAGE gene (-429 T/C, -374 T/A, 557 G/A, 2184 A/G) and glyoxalase I gene (A419C) and sRAGE serum levels were determined in 284 women with pathological and physiological pregnancy. RESULTS: No differences in distribution of genotype and allelic frequencies of studied polymorphisms were found. GA genotype of RAGE 557 G/A polymorphism (known as Gly82Ser) is associated with lower sRAGE serum levels in healthy pregnant women compared to GG genotype (483 ± 104 vs. 692 ± 262 pg/mL, p=0.008). sRAGE correlates negatively with ALT in patients with pregnancy intrahepatic cholestasis (r=-0.536, p=0.05). CONCLUSIONS: We did not show any association of RAGE and glyoxalase I gene polymorphisms with pathological pregnancy, however further studies are needed to confirm the results.

Should hysteroscopy be provided for patients who have undergone instrumental intrauterine intervention after delivery?

We investigated the frequency of pathology, especially intrauterine adhesions, after instrumental evacuation within 24 h of delivery in a prospective observational intervention study on 100 women where a 'see and treat' hysteroscopy was performed after three to four months. There were two possible etiology groups: intrauterine adhesions [classified according by European Society for Gynaecological Endoscopy (ESGE) grades I-IV] and residual tissue (classified as minimal and considerable). Adhesions were found in 18% of patients, as follows: ESGE I-II in 13% and ESGE III-IV in 5%. Residual tissue was present in 33%, as follows: minimal in 23% and considerable in 10%. There were 6% who had both mild adhesions and minimal residual tissue, while 43% of the women had normal intrauterine findings. Of the women, 32% were symptomatic (spotting, bleeding). Only residual tissue correlated with symptoms (r=0.376; p<0.001). There is a high prevalence of acquired intrauterine pathology (57%) in women who require early instrumental evacuation.

Association of pregnancy-associated plasma protein A polymorphism with preeclampsia - a pilot study.

OBJECTIVES: The aim of the study was to investigate genetic and biochemical background of PAPP-A (pregnancy-associated plasma protein A) in patients with risk pregnancies. DESIGN AND METHODS: Five PAPP-A gene polymorphisms and PAPP-A maternal serum levels were studied together in 165 women in third trimester pregnancies complicated with threatening preterm labor (n=98), preeclampsia (n=35), intrauterine growth restriction (n=34) and ICP (intrahepatic cholestasis of pregnancy) (n=15). 114 healthy pregnant women served as controls. RESULTS: Preeclamptic patients had significantly higher frequency of TT genotype of Cys327Cys polymorphism compared to controls (p<0.01). Patients with ICP had increased serum levels of PAPP-A compared to controls and correlation analysis showed significant relationship between PAPP-A and CRP (C-reactive protein) in the patients with intrauterine growth restriction (r=0.49, p=0.007). CONCLUSION: Our study indicates the association of TT genotype of Cys327Cys polymorphism of the PAPP-A gene with preeclampsia. However, further study with larger groups of preeclamptic patients is needed to confirm our results.

Low maternal serum matrix metalloproteinase (MMP)-2 concentrations are associated with preterm labor and fetal inflammatory response.

OBJECTIVES: to assess the relationship between maternal and umbilical serum concentrations of matrix metalloproteinases (MMP)-2,8,9, the soluble receptor for advanced glycation end products (sRAGE) and IL-10 and premature delivery and fetal inflammation. METHODS: maternal serum levels of MMPs, sRAGE, IL-10 and C-reactive protein (CRP) were determined in 67 women with preterm labor and in 38 healthy pregnant women of similar gestational age (GA). In the group with preterm labor we also determined umbilical concentrations of MMPs, IL-6 and sRAGE. The group with preterm labor was additionally divided based on the presence of funisitis and elevations of fetal umbilical IL-6 concentrations. RESULTS: maternal serum levels of MMP-2 and sRAGE were significantly lower in women with preterm labor compared to women with normal pregnancy. Additionally, within the group of women with preterm labor, maternal serum MMP-2 concentrations were significantly lower in the subgroup with funisitis and in the subgroup with elevated umbilical concentration of IL-6. CONCLUSION: our results demonstrate significantly different serum concentrations of MMP-2 and sRAGE in women with preterm labor compared to healthy pregnant patients of the same GA.

Soluble receptor for advanced glycation end products in physiological and pathological pregnancy.

OBJECTIVE: The receptor for advanced glycation end products, RAGE, has been implicated in pathogenesis of many diseases. Soluble RAGE, sRAGE, extracellular domain of RAGE, is new biomarker. The aim of the study was to determine sRAGE levels in physiological pregnancy and their changes in pregnancies complicated by preterm labor or preeclampsia. DESIGN AND METHODS: Serum levels of sRAGE were determined in 79 healthy pregnant women, 42 pregnant women in preterm labor or with preeclampsia and 24 non-pregnant controls. RESULTS: sRAGE serum levels are decreased in physiological pregnancy compared to healthy non-pregnant controls (p<0.001). Serum sRAGE concentrations are higher in the 2nd trimester of physiological pregnancy, compared to the 1st and 3rd trimesters of pregnancy (p<0.001). sRAGE levels in women with preterm labor are decreased (p<0.05) and correlate negatively with the leukocyte count (r=-0.47, p<0.05). In women with preeclampsia, sRAGE is elevated (p<0.05) and correlates with serum creatinine concentration (r=0.54, p<0.05) and with uric acid concentration (r=0.51, p<0.05). CONCLUSION: Our results clearly demonstrate significant differences in serum sRAGE levels in physiological pregnancy and in pathological states in pregnancy, however, further studies are required demonstrate the usefulness and significance of sRAGE.

Glyoxalase I Glu111Ala polymorphism in patients with breast cancer.

Effect of advanced glycation end products (AGEs) in the pathogenesis of cancer could be diminished by interaction with soluble RAGE or by reducing AGE-precursors via glyoxalase I. Glu111Ala polymorphism of glyoxalase I gene, AGEs, and sRAGE serum levels were studied in 113 breast cancer patients and in 58 controls. Higher frequency of the mutated C allele was found in patients with negative estrogen receptors and in patients in clinical stage III compared to controls (P< 0.05). The presence of the C allele could represent a negative prognostic factor; however, further studies are needed to confirm this hypothesis.

RAGE polymorphisms, renal function and histological finding at 12 months after renal transplantation.

OBJECTIVES: Rage (receptor for advanced glycation end products) is involved in pathogenesis of many diseases. The aim of the study was to test whether polymorphisms of RAGE gene are associated with the outcome of kidney transplantation. DESIGN AND METHODS: Four polymorphisms of the RAGE gene (-429T/C, -374T/A, Gly82Ser and 2184A/G) were assessed in 145 renal transplant recipients and their relationship to histological changes in 12 months protocol kidney graft biopsy and renal function was examined. RESULTS: Genotype frequencies of each polymorphism corresponded to expected frequencies according to Hardy-Weinberg equilibrium. No differences between allelic and genotype frequencies among patients with normal histological findings, chronic allograft nephropathy and subclinical rejection were observed. CONCLUSION: This is the first study on polymorphisms of the RAGE gene in patients with the transplanted kidney. No association of RAGE selected gene polymorphisms with 12-months outcome of renal transplants was shown in study.