Serum HE4 is correlated to prognostic factors and survival in patients with endometrial cancer.

The extent of surgery and the decision for adjuvant treatment in patients with endometrial cancer (EC) depend on the presence of risk factors for lymph node metastases and disease recurrence. Postoperative markers such as myometrial infiltration and specific mutations can select patients for adjuvant treatment but will not influence surgical planning. A biomarker stratifying patients into low-risk and high-risk groups before surgery could identify patients who benefit from more extensive surgery. Therefore, we evaluated the correlation of serum biomarker HE4 with clinical and recently identified prognostic pathological variables and survival. Patients treated for endometrial cancer between 1994 and 2014 were included. Serum HE4 concentration was measured in preoperatively obtained samples. A total of 88 patients were eligible for analysis. The majority (64%) was diagnosed with endometrioid-type adenocarcinoma. Serum HE4 concentration is significantly associated with stage of disease (p = 0.001), deep myometrial invasion (p < 0.001), exact depth of myometrial invasion (≥4 mm) (p = 0.01), tumour-free distance to serosa (≤7 mm) (p < 0.001), extensive lymph vascular space invasion (p = 0.04) and cervical involvement (p = 0.001). HE4 concentration and nodal involvement were correlated, although not significant (p = 0.17). Serum HE4 is an independent prognostic factor for recurrence-free survival (HR 5.12 per 10-fold increase in HE4, 95% CI 1.54-17.1) and overall survival (HR 7.48 per 10-fold increase in HE4, 95% CI 1.76-31.7). HE4 is a prognostic marker in endometrial cancer and is helpful in addition to other variables for the preoperative risk stratification of patients with endometrial cancer.

New biomarkers in epithelial ovarian cancer: needed or redundant?

OBJECTIVE: For many years, intensive research has been dedicated to the development of sensitive biomarkers to detect various malignant diseases, including for the differentiation between a benign or malignant ovarian mass. One of these biomarkers is human epididymal protein 4 (HE4), which has been shown to have a higher specificity than, and comparable sensitivity to CA 125. HE4 is included in some predictive models. These new models have not yet been widely implemented in standard clinical care. The authors investigated the perceived need for new biomarkers and prediction models among Dutch gynecologists. MATERIALS AND METHODS: A web-based survey containing 38 questions was sent to all gynecologists (in training) registered by the Dutch Society of Obstetrics and Gynecology. RESULTS: 313 respondents completed the survey (23% response rate), of which 29% were specialized in or devoted at least part of their practice to oncology. Approximately two-thirds of the respondents indicated that there is a need for a new biomarker. Respondents indicated that they would use HE4 primarily as a diagnostic tool in the case of a pelvic mass (57%), followed by screening in case of risk factors (30%), detection of recurrent disease (23%), monitoring therapy response (22%), and as a prognostic factor (10%). Only 11% would not use HE4 at all. CONCLUSION: Evaluating the need for new technologies and diagnostics, including biomarkers, is important to avoid expensive research with min- imal clinical implications. In general, there is a perceived need for a new biomarker, if it can be used to improve the accuracy of diagnosis in patients with a pelvic mass.

Serum human epididymal protein 4 (HE4) as biomarker for the differentiation between epithelial ovarian cancer and ovarian metastases of gastrointestinal origin.

OBJECTIVE: About 5-15% of all malignant ovarian tumors are metastases from other malignancies such as gastrointestinal tumors, breast cancer or melanoma. Also other gynecological tumors can metastasize to the ovaries. It is crucial to differentiate between primary epithelial ovarian cancer (EOC) and ovarian metastases because different treatment is required. The clinical value of human epididymal secretory protein 4 (HE4) as a serum biomarker in primary ovarian cancer has been established. The use of HE4 in the differentiation between primary ovarian cancer and ovarian metastases from other malignancies has never been investigated. METHODS: HE4, CA125 and CEA were measured in 192 patients with EOC (n=147) or ovarian metastases (n=40). Univariate and multivariate logistic regression analyses were done. Sensitivity, specificity and area under the curve (AUC) were calculated for all markers and ratios hereof using receiver operating characteristics methodology. RESULTS: Median serum HE4 concentration was significantly higher in patients with EOC compared to patients with ovarian metastases (431 pmol/L vs 68 pmol/L, p<0.001). HE4 and CEA were independent factors in differentiating between EOC and ovarian metastases (both p<0.001) while CA125 was not (p=0.33). The HE4(2.5)/CEA ratio demonstrated the highest discriminative value (ROC-AUC 0.94) compared to HE4, CEA, CA125 or CA125/CEA ratio (0.88, 0.78, 0.80 and 0.89 respectively) and showed a specificity of 82.5% at set sensitivity of 90% in discriminating EOC from ovarian metastases. CONCLUSION: HE4 can be used in combination with CEA to make the distinction between EOC and ovarian metastases from gastrointestinal origin.

A predictive model combining human epididymal protein 4 and radiologic features for the diagnosis of ovarian cancer.

OBJECTIVE: Ovarian cancer is the leading cause of death in women with gynecologic cancer. CA125 is the commonly used biomarker in the diagnosis of ovarian cancer, but has limitations in both sensitivity and specificity. Human Epididymal secretory protein (HE4) is a promising biomarker and is included in the Risk of Ovarian Malignancy Algorithm (ROMA) score, which is suggested to further increase the diagnostic accuracy than either marker alone. However, information from ultrasound and CT-scan is not included in this algorithm. This study evaluated the diagnostic accuracy of HE4 in the pre-operative diagnosis of ovarian cancer and the predictive values of biomarkers, ultrasound and CT-scan and combinations hereof. METHODS: HE4 and CA125 were measured in 361 subjects (34 benign, 147 ovarian cancer and 180 controls). Sensitivity, specificity and area under the curve (AUC) for CA125, HE4, ROMA and RMI scores were calculated using the receiver operating characteristic (ROC) methodology. The additional predictive value of ultrasound or CT-scan to the individual markers was analyzed using logistic regression. RESULTS: The sensitivity in predicting ovarian cancer of CA125 was 91% and of HE4 90%. The specificity was 65% and 97% respectively. HE4 demonstrated the highest discrimination (ROC-AUC=0.96), compared to ROMA, RMI and CA125 (AUC=0.95, 0.89 and 0.90 respectively). ROMA did not improve when it was combined with different ultrasound factors. The presence of intra-abdominal metastasis on CT-scan improved the discriminative potential of HE4 (p=0.0004). CONCLUSION: HE4 in combination with CT-scan may be incorporated in the diagnostic work-up in women with a pelvic mass.

Systematic lymphadenectomy in patients with clinical stage II endometrial carcinoma: a case report and review of the literature.

OBJECTIVE: The aim of this case report and review of the literature was to evaluate the effect of adding pelvic and/or para-aortic lymphadenectomy to hysterectomy and bilateral salpingo-oophorectomy (BSO) on the five year recurrence-free survival in patients with clinical Stage II endometrial carcinoma. MATERIALS AND METHODS: A Pubmed, Embase, and Cochrane library search was performed to identify relevant articles. After screening, using predetermined exclusion and inclusion criteria, and critical appraisal, a final of four articles remained. RESULTS: This search only revealed studies with a retrospective design. Two articles showed a significant disease-specific survival benefit in patients undergoing systematic lymphadenectomy for Stage II endometrial carcinoma. In multivariate analyses, conducted in both studies, this improvement in survival was also evident (HR 0.75, 95% CI 0.69 - 0.81, p < 0.001 and HR 0.74, 95% CI 0.58 - 0.93, p = 0.0096). The remaining studies revealed a non-significant ten-year recurrence-free survival (77% vs 65%) and five-year overall survival (72% vs 70%) in favour of patients undergoing systematic lymphadenectomy. CONCLUSION: The practise of performing a systematic lymphadenectomy in patients with clinical Stage II endometrial carcinoma as advocated in guidelines, is not based on evidence from randomised clinical trials. However, lymph node dissection seems to improve the five-year disease-specific survival in retrospective studies.

Combined vertebral fracture assessment and bone mineral density measurement: a new standard in the diagnosis of osteoporosis in academic populations.

UNLABELLED: Vertebral Fracture Analysis enables the detection of vertebral fractures in the same session as bone mineral density testing. Using this method in 2,424 patients, we found unknown vertebral fractures in approximately one out of each six patients with significant impact on management. INTRODUCTION: The presence of osteoporotic vertebral fractures (VF) is an important risk factor for all future fractures independent of BMD. Yet, determination of the VF status has not become standard practice. Vertebral Fracture Assessment (VFA) is a new feature available on modern densitometers. In this study we aimed to determine the prevalence of VF using VFA in all patients referred for BMD testing in a university medical center and to evaluate its added clinical value. METHODS: Prospective diagnostic evaluation study in 2,500 consecutive patients referred for BMD. Patients underwent VFA in supine position after BMD testing. Questionnaires were used to assess perceived added value of VFA. RESULTS: In 2,424 patients (1,573 women), results were evaluable. In 541 patients (22%), VFA detected a prevalent VF that was unknown in 69%. In women, the prevalence was 20% versus 27% found in men (p < 0.0001). The prevalence of VF was 14% in patients with normal BMD (97/678), increased to 21% (229/1,100) in osteopenia and to 26% in those with osteoporosis (215/646) by WHO criteria. After excluding mild fractures VF prevalence was 13% (322/2,424). In 468 of 942 questionnaires (50% response rate), 27% of the referring physicians reported VFA results to impact on patient management. CONCLUSIONS: VFA is a patient friendly new tool with a high diagnostic yield, as it detected unknown VF in one out of each six patients, with significant impact on management. We believe these findings justify considering VFA in all new patients referred for osteoporosis assessment in similar populations.