HE4 is an independent prognostic marker in endometrial cancer patients

Objective

To evaluate the prognostic value of pretherapeutic serum HE4 in endometrial cancer in comparison to CA125.

Methods

HE4 and CA125 serum levels were analyzed by means of chemiluminescent microparticle immunoassays in 183 patients with endometrial cancer treated at the Department of Obstetrics and Gynecology, Innsbruck Medical University, between 1999 and 2009. The Kaplan-Meier method and Cox's proportional hazards analysis were performed to determine the prognostic significance of HE4, CA125 and the combination of both markers.

Results

In univariate analysis both markers, HE4 and CA125, were of prognostic value for overall survival (p < 0.001 and p = 0.028) and disease-free survival (p = 0.015 and p = 0.045). In multivariate analysis HE4 was seen to have independent prognostic value in overall survival (HR 2.407, p = 0.017) in contrast to CA125. The combination of both markers showed a higher hazard ratio (HR 4.04, p = 0.023) for overall survival in comparison to HE4 alone. In the subgroup endometrioid histological type (n = 132) only HE4 was of prognostic value for overall survival in univariate (p = 0.001) and multivariate analysis (p = 0.023).

Conclusions

Pretherapeutic serum HE4 levels alone and in combination with CA125 are an independent prognostic marker in endometrial cancer patients.     

Lymphvascular space involvement: an independent prognostic factor in endometrial cancer

PURPOSE OF INVESTIGATION: To evaluate whether lymphvascular space involvement (LVSI) is a risk factor for relapse of disease and lymph node metastasis in endometrial cancer. METHODS: From 1978 till 2003, 609 patients with epithelial endometrial cancer were treated at the Groningen University Medical Center. The association of LVSI and relapse of disease was evaluated in the total group of 609 patients and in a 'low' and 'high' risk stage I endometrial cancer group. In 239 surgically staged patients, the relation of LVSI and lymph node metastasis was investigated. RESULTS: The median age at diagnosis was 63 years (range 27-92 years) with a median follow-up of 58 months (range 0-236 months). More than half of the patients (56%) received adjuvant radiotherapy. LVSI was present in 123 patients (25,6%), and a prognostic factor for relapse of disease (multivariate analysis, P < 0.0001). In the 'low' and 'high' risk stage I endometrial cancer patients an increase of 2.6 times in relapse of disease was observed in the presence of LVSI. LVSI positive tumors were more likely to have metastasized to the pelvic lymph nodes (multivariate analysis, P = 0.001). In patients with proven negative nodes, LVSI was a prognostic factor for relapse of disease (univariate analysis, P = 0.02). CONCLUSION: LVSI is a predictor of nodal disease and an independent prognostic factor for relapse of disease in all stages of endometrial cancer. Patients with stage I endometrial cancer with positive LVSI are at risk for relapse of disease and might therefore benefit from adjuvant therapy. CONTENT: The presence of lymphvascular space involvement (LVSI) in endometrial cancer is significantly and independently associated with an increased risk of pelvic lymph node metastases and/or relapse of disease.     

Prediction of cervical involvement in endometrial cancer by hysteroscopy

Objective This study evaluated the ability of hysteroscopy to preoperatively predict cervical involvement in endometrial cancer.Methods The records of 110 surgically staged consecutive endometrial cancer patients treated at our institution from 1997 to 2003 were retrospectively analyzed. Data on demographics, preoperative staging procedures, surgical pathology reports, and adjuvant treatments were retrieved.Results Fourteen (12.7%) patients had cervical involvement (stage II) according to the surgical pathology report, of whom nine (8.1%) had stage IIA and five (4.6%) had stage IIB. Clinical evaluation by speculoscopy and palpation had failed to reveal any indication of cervical involvement. Preoperative diagnostic hysteroscopy procedures were included. None of the hysteroscopy procedures revealed any suspicious lesion in the cervical canal. Conclusion Hysteroscopy and clinical examination fail to adequately predict cervical involvement in endometrial carcinoma. Fractional D&C appears to be the best method until a more effective alternative becomes available.Drs. Almog and Gutman contributed equally to this paper.     

Identification of FRAS1 as a human endometrial carcinoma-derived protein in serum of xenograft model

Objective

The value of clinical specimens in identification of tumor biomarker is limited to the great individual variations among patients, the high complexity and dynamic range of protein components, and the possibility that the identified proteins are not produced by cancer cells but are due to secondary body defense mechanisms. Herein we developed a xenograft model system, in which human endometrial carcinoma cells formed a tumor in an immune-deficient nude mouse, to instantly detect proteins derived from cancer cells.

Methods

Using one-dimensional electrophoresis, liquid chromatography, and Q-TOF-MS/MS and FT-ICR-MS/MS analyses, the human-specific proteins in the serum of xenograft mouse could be identified and monitored without the great variations observed in a patient-based approach.

Results

We successfully identified 224 proteins, in which 175 (78.1%) were of mouse origin, and 45 (20.1%) were unable to be assigned as human or mouse origin. FRAS1 was identified as a uniquely human-originated protein. Its expression profile was then confirmed by Western blotting in serum samples from xenograft mice, and patients bearing endometrial carcinoma and healthy controls.

Conclusions

Although the mechanism of FRAS1 derivation by cancer cells remains to be illustrated, our results suggest that the xenograft model presented here should be a promising tool in the discovery of tumor biomarkers.     

Epidural analgesia is associated with an increased incidence of postoperative complications in patients requiring an abdominal hysterectomy for early stage endometrial cancer

Objective

Analgesia and early quality of recovery may be improved by epidural analgesia. We aimed to assess the effect of receiving epidural analgesia on surgical adverse events and quality of life after laparotomy for endometrial cancer.

Methods

Patients were enrolled in an international, multicentre, prospective randomised trial of outcomes for laparoscopic versus open surgical treatment for the management of apparent stage I endometrial cancer (LACE trial).The current analysis focussed on patients who received an open abdominal hysterectomy via vertical midline incision only (n = 257), examining outcomes in patients who did (n = 108) and did not (n = 149) receive epidural analgesia.

Results

Baseline characteristics were comparable between patients with or without epidural analgesia. More patients without epidural (34%) ceased opioid analgesia 3–5 days after surgery compared to patients who had an epidural (7%; p < 0.01). Postoperative complications (any grade) occurred in 86% of patients with and in 66% of patients without an epidural (p < 0.01) but there was no difference in serious adverse events (p = 0.19). Epidural analgesia was associated with increased length of stay (up to 48 days compared to up to 34 days in the non-epidural group). There was no difference in postoperative quality of life up to six months after surgery.

Conclusions

Epidural analgesia was associated with an increase in any, but not serious, postoperative complications and length of stay after abdominal hysterectomy. Randomised controlled trials are needed to examine the effect of epidural analgesia on surgical adverse events, especially as the present data do not support a quality of life benefit with epidural analgesia.     

Wee1 is a novel independent prognostic marker of poor survival in post-chemotherapy ovarian carcinoma effusions

Objective

Wee1-like kinase (Wee1) is a tyrosine kinase which negatively regulates entry into mitosis at the G2 to M-phase transition and has a role in inhibition of unscheduled DNA replication in S-phase. The present study investigated the clinical role of Wee1 in advanced-stage (FIGO III–IV) ovarian serous carcinoma.

Methods

Wee1 protein expression was analyzed in 287 effusions using immunohistochemistry. Expression was analyzed for association with clinicopathologic parameters, including survival. Forty-five effusions were additionally studied using Western blotting. Wee1 was further silenced in SKOV3 and OVCAR8 cells by siRNA knockdown and proliferation was assessed.

Results

Nuclear expression of Wee1 in tumor cells was observed in 265/287 (92%) and 45/45 (100%) effusions by immunohistochemistry and Western blotting, respectively. Wee1 expression by immunohistochemistry was significantly higher in post-chemotherapy disease recurrence compared to pre-chemotherapy effusions obtained at diagnosis (p = 0.002). Wee1 silencing in SKOV3 and OVCAR8 cells reduced proliferation. In univariate survival analysis of the entire cohort, a trend was observed between high (> 25% of cells) Wee1 expression and poor overall survival (p = 0.083). Survival analysis for 109 patients with post-chemotherapy effusions showed significant association between Wee1 expression and poor overall survival (p = 0.004), a finding which retained its independent prognostic role in Cox multivariate analysis (p = 0.003).

Conclusions

Wee1 is frequently expressed in ovarian serous carcinoma effusions, and its expression is significantly higher following exposure to chemotherapy. The present study is the first to report that Wee1 is an independent prognostic marker in serous ovarian carcinoma.     

Efficacy and prognostic implications of administering adjuvant chemotherapy to patients with endometrial cancer that is confined to the uterus

OBJECTIVE: The purpose of this study was to determine the value of prognostic factors and to assess the efficacy of adjuvant chemotherapy in patients with endometrial cancer confined to the uterus. STUDY DESIGN: Patients surgically stage IB, IC and II endometrial cancer according to the International Federation of Gynecology and Obstetrics were enrolled in this study. Stage IIIA tumors with positive peritoneal cytology, in the absence of other evidence of extra uterine disease, were also included. RESULTS: One hundred and sixty-seven patients fulfilled the eligibility criteria and 58 patients (34.7%) underwent combination chemotherapy. Disease recurrence occurred in 10 patients within a median time of 17 months. Histologic grade 3 was an independent prognostic factor for both disease-free and overall survival rates. Fourteen of 23 patients with histologic grade 3 tumors received adjuvant chemotherapy consisting of cyclophosphamide (or etoposide), epirubicin and cisplatin (in 1989-1999) or paclitaxel, pirarubicin and carboplatin (in 2000-2002). The 5-year disease-free and overall survival rates for these individuals was 92.3%, a value significantly higher than those in patients who had not undergone chemotherapy (50.0%). CONCLUSIONS: Histologic grade of 3 is an independent prognostic marker in patients with endometrial cancer confined to the uterus and adjuvant chemotherapy might improve the survival rates in these patients.     

CD105 expression is an independent predictor of survival in patients with endometrial cancer

OBJECTIVE: The purpose of this study was to detect the prognostic value of CD105 (endoglin) and also to compare with CD34 and vascular endothelial growth factor (VEGF) in patients with endometrial adenocancer. METHODS: Ninety patients with endometrial carcinoma, who were treated at Gazi University Hospital, were included. Staging was performed according to the FIGO recommendations. Angiogenesis was estimated by using CD105 and CD34 and tested for possible significant relation with age, stage, histologic type, grade, depth of myometrial invasion, lymphovascular space invasion, lymph node metastasis, and overall survival (OS). In addition, VEGF staining intensity and distribution were analyzed with respect to all these variables. RESULTS: The mean age at the time of diagnosis was 57.7 years (range, 28-81 years). The mean microvessel density (MVD) for CD105 was 32.87+/-19.99, and it was 55.46+/-31.25 for CD34 (P<0.001). A significant correlation was noted between these two markers (r=0.257, P=0.02). The mean VEGF score was 4.13+/-1.73, and it was significantly correlated with MV counts determined by CD105 (r=0.291, P=0.006). It was not significantly related with CD34 (r=0.031, P=0.78). With respect to clinicopathological variables, none of the comparisons was found to be significant. The mean follow-up period was 60.5 months. To analyze the prognostic value of MVD, the patients were divided into three groups with respect to quartiles (or=75%). With CD105 staining, the 5-year OS rates for patients with the highest MVD count (>or=75%) were significantly poorer than the remaining two groups (P=0.01 for both). None of the comparisons for CD34 was significant. Survival analysis for VEGF was performed by grouping patients using staining characteristics. No significant difference was noted for OS. Multivariate analysis showed that MVD determined by CD105 correlated significantly and independently with OS (P=0.02). None of the remaining variables was significant in multivariate analysis. CONCLUSION: The current study showed that CD105 is an independent predictor of survival in patients with endometrial cancer. We recommend the use of this highly specific and prognosis-related antigen in further investigations.     

Clinicopathologic significance of DNA mismatch repair protein status in endometrial cancer

ObjectiveThe prognostic implications of DNA mismatch repair protein (MMRP) have not been determined in endometrial cancer. Therefore, in this study, we aimed to evaluate the clinicopathologic characteristics of DNA MMRP deficiency in endometrial cancer.Materials and methodsWe examined the MMRP status of 206 patients with endometrial carcinomas, using immunohistochemistry, and analyzed their clinicopathologic factors and survival outcomes stratified by MMRP status using the Kaplan–Meier method and Cox regression analysis.ResultsForty-three cases were deficient for at least one MMRP (20.9%). Loss of MLH1 was the most common (13.1%), followed by MSH6 (7.8%). MMRP deficiency was significantly associated with lympho-vascular space invasion, deep myometrial invasion, and adjuvant treatment (P = 0.032, 0.041, and 0.047, respectively). MMRP-deficient patients had a better overall survival (OS), particularly at advanced cancer stages (III/IV) (100% vs. 73.7%, P = 0.170) or if they had received adjuvant treatment (100% vs. 86.7%, P = 0.087).ConclusionAlthough MMRP deficiency was associated with unfavorable prognostic risk factors in endometrial cancer, we found a trend in favor of OS in MMRP-deficient patients. More studies are needed to confirm its prognostic implication.     

Lymphovascular space invasion is an independent risk factor for nodal disease and poor outcomes in endometrioid endometrial cancer

Objective

Adjuvant radiotherapy improves local control but not survival in women with endometrial cancer. This benefit was shown in staged patients with “high intermediate risk” (HIR) disease. Other studies have challenged the need for systematic staging including lymphadenectomy. We sought to determine whether LVSI alone or in combination with other histologic factors predicts lymph node (LN) metastasis in patients with endometrioid endometrial cancer.

Methods

A retrospective review was conducted of patients with endometrioid endometrial carcinoma who had confirmed presence/absence of LVSI and clinicopathologic data necessary to identify HIR criteria. Kaplan-Meier curves were generated and univariate and multivariate analyses performed as appropriate.

Results

We identified 757 eligible patients and 628 underwent systematic lymphadenectomy for staging purposes. In the surgically staged group, 242 (38%) patients met uterine HIR criteria and 196 (31%) had LVSI. Both HIR and LVSI were significantly associated with LN metastasis. Among the HIR positive group, 59 had LN metastasis (OR 4.46, 95% CI 2.72-7.32, P < 0.0001). Sixty-six LVSI positive patients had nodal metastasis (OR 11.04, 95% CI 6.39-19.07, P < 0.0001). The NPV of LVSI and HIR negative specimens was 95.6% and 93.4% respectively. In multivariate analysis, PFS and OS were significantly reduced in both LVSI positive (P < 0.0001) and HIR patients (P < 0.0001) when compared to patients who were LVSI and HIR negative.

Conclusions

HIR status and LVSI are highly associated with LN metastasis. These features are useful in assessing risk of metastatic disease and may serve as a surrogate for prediction of extrauterine disease.     

基于TCGA数据库分析KIF20 A在子宫内膜癌中的表达和意义

目的:检测驱动蛋白家族成员20A(KIF20A)在子宫内膜癌中的表达及其预后价值.方法:下载癌症基因组图谱(TCGA)中子宫内膜癌组织和癌旁组织样本的基因表达谱数据和临床数据,比较KIF20 A在子宫内膜癌组织和癌旁组织中的表达,并检测KIF20 A表达水平与患者生存预后的关系.结果:子宫内膜癌组织中KIF20 A表达...     

The value of serum albumin as a novel independent marker for prognosis in patients with endometrial cancer

Objective

Hypoalbuminemia, a known marker for malnutrition and increased morbidity and mortality, has been associated with impaired prognosis in different cancer entities. The present study investigates the prognostic value of pre-treatment serum albumin levels for survival in patients with endometrial cancer.

Study design

Within the present cohort study, we evaluated 337 consecutive patients with endometrial cancer and investigated the association of pre-treatment serum albumin levels and clinical-pathological parameters. We performed univariate log-rank tests and multivariable Cox regression models to assess the association between pre-treatment serum albumin levels and survival.

Results

Pre-treatment serum albumin levels were inversely proportionally associated with FIGO tumor stage, histological grade, and patients’ age. In a multivariable analysis pre-treatment serum albumin levels (p = 0.02 and p = 0.001), FIGO tumor stage (p < 0.001 and p < 0.001), and histological grade (p = 0.002 and p < 0.001) were independently associated with disease-free and progression-free survival, respectively.

Conclusion

Pre-treatment serum albumin is a novel and independent prognostic parameter for disease-free and progression-free survival in patients with endometrial cancer.     

细胞周期素D1在子宫内膜癌中的表达及其临床意义

目的　探讨细胞周期素D1(CyclinD1)蛋白在子宫内膜癌中的表达及其临床意义。方法　采用免疫组化方法 (SP法 )检测CyclinD1蛋白在 5 2例子宫内膜癌和 2 6例正常子宫内膜组织中的表达。结果　CyclinD1蛋白阳性表达位于胞核内 ,染色为棕褐色颗粒状 ,在子宫内膜癌组织阳性表达率为 5 5 8% (2 9/ 5 2 ) ,而正常内膜组阳性表达率为 11 5 % (3/ 2 6 )。内膜癌CyclinD1蛋白阳性表达者分化程度低且多有肌层浸润 ,二者阳性率有显著性差别 (P <0 0 5 )。结论　对内膜癌CyclinD1蛋白表达的检测有助于分析其细胞分化程度及其有无肌层浸润。     

p21CIP1/WAF1蛋白和增殖细胞核抗原在子宫内膜癌中的表达

目的：研究细胞周期调控与子宫内膜癌的关系。方法：应用免疫组化技术对45份子宫内膜癌组织中P21CIP1／WAF1蛋白和增殖细胞核抗原（PCNA）进行检测。结果：45份子宫内膜癌组织中30份（66．7％）P21CIP1／WAF1蛋白阳性，对照组均为阳性（P＜0．01）、PCNA（＋）18份，（＋＋）21份。P21CIP1／WAF1阳性率与PCNA指数呈负相关（P＜0．05）。结论：子宫内膜癌的发生与细胞周期调控有关。     

芳香化酶蛋白及性激素受体等在子宫内膜病变组织中的表达变化及意义

目的探讨芳香化酶蛋白、雌激素受体（ER）、孕激素受体（PR）及细胞增殖相关核抗原Ki67在子宫内膜病变组织中的阳性表达率及其在子宫内膜病变的诊断和治疗中的价值。方法采用免疫组化链霉菌抗生物素蛋白-过氧化物酶链接（SP）法,检测148例子宫内膜病变患者（观察组,其中子宫内膜增殖症30例,轻、中、重度子宫内膜非典型增生各10例,子宫内膜腺癌88例）及30例因患宫颈原位癌行子宫全切除术患者的正常子宫内膜组织（对照组,其中增殖期及分泌期子宫内膜各15例）中芳香化酶蛋白、ER、PR及Ki67的阳性表达率。结果（1）观察组子宫内膜增殖症、子宫内膜非典型增生组织芳香化酶蛋白、ER、PR、Ki67的阳性表达率与对照组增殖期内膜比较,差异无统计学意义（P〉0．05）;（2）观察组子宫内膜腺癌组织芳香化酶蛋白阳性表达率为64％（56／88）,与子宫内膜非典型增生（23％,7／30）、子宫内膜增殖症（13％,4／30）及对照组（0／15）比较,差异均有统计学意义（P〈0．01）;（3）芳香化酶蛋白的阳性表达率与子宫内膜腺癌的临床分期（Ⅰ期61％、Ⅱ期77％、Ⅲ期70％、Ⅳ期67％）、肿瘤细胞分化级别（高分化64％,中分化74％,低分化58％）、有无淋巴转移（转移59％,无转移67％）无明显相关性（P〉0．05）。（4）子宫内膜腺癌组织中ER、PR、Ki67的阳性表达率分别为22％（19／88）、19％（17／88）、41％（36／88）,与对照组分别比较,差异均有统计学意义（P〈0．01）。结论子宫内膜良性病变组织与正常内膜组织中,芳香化酶蛋白表达无明显差异;子宫内膜腺癌组织中芳香化酶蛋白的过度表达,可作为诊断子宫内膜腺癌的指标之一。     

Comparison of outcomes and cost for endometrial cancer staging via traditional laparotomy, standard laparoscopy and robotic techniques

ObjectivesThe study purpose was to compare hysterectomy and lymphadenectomy completed via robotic assistance, laparotomy, and laparoscopy for endometrial cancer staging with respect to operative and peri-operative outcomes, complications, adequacy of staging, and cost.MethodsOne hundred and ten patients underwent hysterectomy with bilateral salpingo-oophorectomy, pelvic and para-aortic lymphadenectomy for endometrial cancer staging. All cases were performed by a single surgeon, at a single institution (40 robotic, 40 laparotomy, and 30 laparoscopic) and were retrospectively reviewed to compare demographics and peri-operative variables including, operative time, estimated blood loss, lymph node count, hospital stay, complications, and return to normal activity. Additionally, a cost comparison between all three modalities was performed.ResultsPatients undergoing robotic assisted hysterectomy and staging experienced longer operative time than the laparotomy cohort with no difference in comparison to the laparoscopic cohort (184 min, 108.6 min, 171 min, p < 0.0001, p = 0.14). Estimated blood loss was significantly reduced for the robotic cohort in comparison to the laparotomy cohort and comparable to laparoscopic cohort (166 cc, 316 cc, 253 cc, p = 0.01, p = 0.25). The complication rate was lowest in the robotic cohort (7.5%) relative to the laparotomy (27.5%) and laparoscopic cohorts (20%) (p = 0.015, p = 0.03). Average return to normal activity for the robotic patients was significantly shorter than those undergoing laparotomy (24.1 days versus 52 days, p < 0.0001) and those undergoing laparoscopy (31.6 days, p = 0.005). Lymph node retrieval did not differ between the 3 groups (robotic 17 nodes, laparotomy 14 nodes, laparoscopic 17 nodes). The total average cost for hysterectomy with staging completed via laparotomy was $12,943.60, for standard laparoscopy $7569.80, and for robotic assistance $8212.00. The difference in cost between laparotomy and robotic cohorts was significant p = 0.0001 while there was no statistically significant difference in cost between laparoscopy and robotic cohorts p = 0.06.ConclusionsRobotic hysterectomy provides comparable node retrieval to laparotomy and laparoscopic procedures in the case of the experienced laparoscopic surgeon. While robotic hysterectomy takes longer to perform than hysterectomy completed via laparotomy, it is equivalent to laparoscopic hysterectomy and provides the patient with a more expeditious return to normal activity with reduced post-operative morbidity. Additionally, the average cost for hysterectomy and staging was highest for laparotomy, followed by robotic, and least for standard laparoscopy.     

MiR-31 is an independent prognostic factor and functions as an oncomir in cervical cancer via targeting ARID1A

Objectives

MicroRNAs(miRNAs) play important roles in tumor development and progression. The purposes of this study were to investigate the role of miR-31 in cervical cancer and clarified the regulation of ARID1A by miR-31.

Methods

Quantitative RT-PCR was used to examine miR-31 expression in cervical cancer cell lines and patient specimens. The clinicopathological significance of miR-31 upregulation was further analyzed. The MTT, colony formation, apoptosis, cell cycle, wound healing and Transwell invasion assays, and a xenograft model were performed. A luciferase reporter assay was conducted to confirm the target gene of miR-31, and the results were validated in cell lines and patient specimens.

Results

MiR-31 was significantly up-regulated in cervical cancer cell lines and clinical tissues. The high miR-31 level was significantly correlated with higher FIGO stage, node metastasis, vascular involvement and deep stromal invasion. Patients with high expression of miR-31 had poorer overall survival than patients with low expression. MiR-31 was an independent prognostic factor in cervical cancer in multivariate Cox regression analysis. Down-regulation of miR-31 impaired cell proliferation, colony formation, and cell migration and invasion in vitro, and inhibited xenograft tumor growth in vivo. ARID1A was verified as a direct target of miR-31, which was further confirmed by the inverse expression of miR-31and ARID1A in patient specimens.

Conclusions

The newly identified miR-31/ARID1A pathway provides insight into cervical cancer progression, and may represent a novel therapeutic target.