Abnormal preoperative haematological parameters in Endometrial cancer; reflecting tumour aggressiveness or reduced response to radiotherapy?

BACKGROUND: In endometrial cancer (EC), preoperative anaemia, thrombocytosis and leucocytosis appear to be associated with worse prognosis. It remains unclear whether these parameters solely reflect tumour aggressiveness, or also impact response to adjuvant treatment. Therefore, our primary aim is to evaluate the prognostic relevance of anaemia, thrombocytosis and leucocytosis on survival in EC. Secondary, to explore their predictive relevance in response to radiotherapy in EC. METHODS: A retrospective multicentre cohort study was performed within 10 hospitals. Preoperative haematological parameters were defined as: Anaemia - haemoglobin <7.45 mmol/L (<12 g/Dl), thrombocytosis - platelets >400 × 109 platelets/L, leucocytosis - leukocytes >10 × 109/L. The relationship of haematological parameters with clinicopathological characteristics, ESGO/ESTRO/ESP risk groups and survival were evaluated. Furthermore, the predictive value of haematological parameters was determined on the overall response to adjuvant radiotherapy and for the ESGO/ESTRO/ESP intermediate-risk group solely receiving radiotherapy. RESULTS: A total of 894 patients were included with a median follow-up of 4.5 years. Anaemia was present in 103 (11.5%), thrombocytosis in 79 (8.8%) and leucocytosis in 114 (12.7%) patients. The presence of anaemia or thrombocytosis was significantly associated with ESGO/ESTRO/ESP high-risk (respectively, P = 0.002 and P = 0.041). In the entire cohort, anaemia remained independently associated with decreased disease-specific survival (HR 2.31, 95% CI (1.19-4.50), P = 0.013) after adjusting for age, the abnormal haematological parameters and ESGO/ESTRO/ESP risk groups. In patients that were treated with adjuvant radiotherapy (n = 239), anaemia was associated with significant reduced 5-year disease-specific and recurrence-free survival (P = 0.005 and P = 0.025, respectively). In ESGO/ESTRO/ESP intermediate risk patients that received solely vaginal brachytherapy (n = 74), anaemia was associated with reduced disease-specific survival (P = 0.041). CONCLUSIONS: Current data demonstrate the importance of preoperative anaemia as independent prognostic factor in patients with EC. Moreover, anaemia seems to be associated with reduced response to radiotherapy. Prospective validation in a larger study cohort is needed to verify anaemia as predictive biomarker for radiotherapy.What is already known on this subject? In endometrial cancer, preoperative abnormal haematological parameters like, anaemia, thrombocytosis and leucocytosis appears to be associated with FIGO advanced-stage and unfavourable outcome.What do the results of this study add? It remains unclear whether anaemia, thrombocytosis or leucocytosis solely reflecting worse prognosis by advanced tumour stage, or also impact response to adjuvant treatment. Current data demonstrate that anaemia is independent associated with decreased disease-specific survival and anaemia seems related with reduced response to radiotherapy and in specific to vaginal brachytherapy in ESGO/ESTRO/ESP intermediate risk patients.What are the implications of these findings for clinical practice and/or further research? Specific applied adjuvant treatment is needed if patients with anaemia have a reduced response to radiotherapy in EC. Prospective validation in a larger study cohort is required to verify anaemia as predictive biomarker for radiotherapy and to further evaluate the prognostic/predictive impact of anaemia in addition to the molecular subgroups.

In this study we focused on three specific blood values before surgery to predict survival outcomes in endometrial cancer patients: low haemoglobin (anaemia), high platelet count (thrombocytosis) and high white blood cell count (leucocytosis). We studied 894 patients with endometrial cancer over about 4.5 years, in which 11.5% had anaemia, 8.8% thrombocytosis and 12.7% leucocytosis. Anaemia was linked to a lower chance of surviving endometrial cancer, even after we considering patients' age, thrombocytosis, leucocytosis and the endometrial cancer risk classification groups. In patients who received radiotherapy after surgery (293 patients), anaemia was linked to a lower change of surviving and cancer coming back within 5 years. In patients within the intermediate endometrial cancer risk classification group who only received specific radiotherapy (74 patients), anaemia was even linked with lower chance of survival. In conclusion, anaemia is an important factor in predicting endometrial cancer outcomes, and it might also make radiotherapy less effective for some patients.

Primary Ovarian Tumors With Lymphogenic and Hematogenic Metastasis Express High MMP-14, Which Colocalizes With Highly Sulfated Chondroitin Sulfate in the Stroma.

Lymphogenic and hematogenic metastases are uncommon in ovarian cancer, especially at presentation. We hypothesized that MMP-14 and MMP-2, CD44, and highly sulfated chondroitin sulfate (CS-E) may be overexpressed in tumors with these metastatic patterns. These molecules are all present in the ovarian tumor microenvironment, wherein they may interact. In an ovarian cancer cohort of 44 patients with metastases in lymph nodes, spleen, and/or liver, the presence of MMP-14, MMP-2, CD44, and CS-E in both the primary tumor and the metastases was determined with immunohistochemistry and related to clinical characteristics. Immunohistochemical expression was found for MMP-14 in all primary tumors as well as in all metastases and for MMP-2 expression in most of the samples. Most primary tumors with synchronous metastases were positive for CS-E, as well as most primary tumors with metachronous lymphogenic metastases. The expression of the MMPs and CS-E in the stroma seemed to colocalize. For CD44 immunohistochemical expression, this relationship was not found. Epithelial MMP-14 on the one hand and stromal CS-E on the other hand seem to be essential players in ovarian cancer with lymphogenic and hematogenic metastases. CD44 expression is not correlated with the other markers. More research on the interaction of these molecules and their role in the process of dissimination of disease is warranted.

Paper-Based Survivorship Care Plans May be Less Helpful for Cancer Patients Who Search for Disease-Related Information on the Internet: Results of the Registrationsystem Oncological Gynecology (ROGY) Care Randomized Trial.

BACKGROUND: The Institute of Medicine recommends Survivorship Care Plans (SCPs) for all cancer survivors. However, it is unclear whether certain patient groups may or may not benefit from SCPs. OBJECTIVE: The aim was to assess whether the effects of an automatically generated paper SCP on patients' satisfaction with information provision and care, illness perceptions, and health care utilization were moderated by disease-related Internet use. METHODS: Twelve hospitals were randomized to either SCP care or usual care in the pragmatic cluster randomized Registrationsystem Oncological GYnecology (ROGY) Care trial. Newly diagnosed endometrial cancer patients completed questionnaires after diagnosis (N=221; response: 74.7%, 221/296), 6 months (n=158), and 12 months (n=147), including patients' satisfaction with information provision and care, illness perceptions, health care utilization (how many times patients visited a medical specialist or primary care physician about their cancer in the past 6 months), and disease-related Internet use (whether patients used the Internet to look for information about cancer). RESULTS: In total, 80 of 221 (36.2%) patients used the Internet to obtain disease-related information. Disease-related Internet use moderated the SCP care effect on the amount of information received about the disease (P=.03) and medical tests (P=.01), helpfulness of the information (P=.01), and how well patients understood their illness (P=.04). All stratified analyses were not statistically significant. However, it appeared that patients who did not seek disease-related information on the Internet in the SCP care arm reported receiving more information about their disease (mean 63.9, SD 20.1 vs mean 58.3, SD 23.7) and medical tests (mean 70.6, SD 23.5 vs mean 64.7, SD 24.9), finding the information more helpful (76.7, SD 22.9 vs mean 67.8, SD 27.2; scale 0-100), and understanding their illness better (mean 6.6, SD 3.0 vs mean 6.1, SD 3.2; scale 1-10) than patients in the usual care arm did. In addition, although all stratified analyses were not significant, patients who did seek disease-related information on the Internet in the SCP care arm appeared to receive less information about their disease (mean 65.7, SD 23.4 vs mean 67.1, SD 20.7) and medical tests (mean 72.4, SD 23.5 vs mean 75.3, SD 21.6), did not find the information more helpful (mean 78.6, SD 21.2 vs mean 76.0, SD 22.0), and reported less understanding of their illness (mean 6.3, SD 2.8 vs mean 7.1, SD 2.7) than patients in the usual care arm did. CONCLUSIONS: Paper SCPs appear to improve the amount of information received about the disease and medical tests, the helpfulness of the information, and understanding of the illness for patients who do not search for disease-related information on the Internet. In contrast, paper SCPs do not seem beneficial for patients who do seek disease-related information on the Internet. TRIAL REGISTRATION: ClinicalTrials.gov NCT01185626; https://clinicaltrials.gov/ct2/show/NCT01185626 (Archived by WebCite at http://www.webcitation.org/6fpaMXsDn).

Immunohistochemical expression of MMP-14 and MMP-2, and MMP-2 activity during human ovarian follicular development.

BACKGROUND: The aim of this study was to investigate the presence of MMP-14 and MMP-2 during human ovarian follicular development using immunohistochemistry, and the activity of MMP-2 in follicular fluid using zymography. METHODS: Ovarian tissue collected from the archives of the Department of Pathology was examined and medical records and histopathology were reviewed. Follicular fluids were collected at the IVF-department and analyzed using zymography. RESULTS: MMP-14 and MMP-2 were increasingly found in the growing follicles and MMP-2 was highly expressed in the corpus luteum. Pro-MMP-2 was present in follicular fluid of IVF-patients. CONCLUSIONS: The presence of MMP-14 and MMP-2 during human ovarian follicular development from the primordial follicle to the tertiary follicle and corpus luteum is confirmed, as was indicated by earlier animal studies following stimulation with gonadotrophins.

Preoperative CA125 Significantly Improves Risk Stratification in High-Grade Endometrial Cancer.

Patients with high-grade endometrial carcinoma (EC) have an increased risk of tumor spread and lymph node metastasis (LNM). Preoperative imaging and CA125 can be used in work-up. As data on cancer antigen 125 (CA125) in high-grade EC are limited, we aimed to study primarily the predictive value of CA125, and secondarily the contributive value of computed tomography (CT) for advanced stage and LNM. Patients with high-grade EC (n = 333) and available preoperative CA125 were included retrospectively. The association of CA125 and CT findings with LNM was analyzed by logistic regression. Elevated CA125 ((>35 U/mL), (35.2% (68/193)) was significantly associated with stage III-IV disease (60.3% (41/68)) compared with normal CA125 (20.8% (26/125), [p < 0.001]), and with reduced disease-specific-(DSS) (p < 0.001) and overall survival (OS) (p < 0.001). The overall accuracy of predicting LNM by CT resulted in an area under the curve (AUC) of 0.623 (p < 0.001) independent of CA125. Stratification by CA125 resulted in an AUC of 0.484 (normal), and 0.660 (elevated). In multivariate analysis elevated CA125, non-endometrioid histology, pathological deep myometrial invasion ≥50%, and cervical involvement were significant predictors of LNM, whereas suspected LNM on CT was not. This shows that elevated CA125 is a relevant independent predictor of advanced stage and outcome specifically in high-grade EC.

Relevance of Molecular Profiling in Patients With Low-Grade Endometrial Cancer.

Importance: Patients with low-grade (ie, grade 1-2) endometrial cancer (EC) are characterized by their favorable prognosis compared with patients with high-grade (ie, grade 3) EC. With the implementation of molecular profiling, the prognostic relevance of tumor grading might lose attention. As most patients present with low-grade EC and have an excellent outcome, the value of molecular profiling for these patients is unclear. Objective: To determine the association of molecular profiling with outcomes among patients with low-grade EC. Design, Setting, and Participants: This retrospective cohort study included a multicenter international European cohort of patients diagnosed with EC between 1994 and 2018, with a median follow-up of 5.9 years. Molecular subgroups were determined by next-generation sequencing using single-molecule molecular inversion probes and by immunohistochemistry. Subsequently, tumors were classified as polymerase epsilon (POLE)-altered, microsatellite instable (MSI), tumor protein p53 (TP53)-altered, or no specific molecular profile (NSMP). Patients diagnosed with any histological subtypes and FIGO (International Federation of Gynecology and Obstetrics) stages of EC were included, but patients with early-stage EC (FIGO I-II) were only included if they had known lymph node status. Data were analyzed February 20 to June 16, 2022. Exposures: Molecular testing of the 4 molecular subgroups. Main Outcomes and Measures: The main outcome was disease-specific survival (DSS) within the molecular subgroups. Results: A total of 393 patients with EC were included, with a median (range) age of 64.0 (31.0-86.0) years and median (range) body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) of 29.1 (18.0-58.3). Most patients presented with early-stage (290 patients [73.8%]) and low-grade (209 patients [53.2%]) disease. Of all patients, 33 (8.4%) had POLE-altered EC, 78 (19.8%) had MSI EC, 72 (18.3%) had TP53-altered EC, and 210 (53.4%) had NSMP EC. Across all molecular subgroups, patients with low-grade EC had superior 5-year DSS compared with those with high-grade EC, varying between 90% to 100% vs 41% to 90% (P < .001). Multivariable analysis in the entire cohort including age, tumor grade, FIGO stage, lymphovascular space invasion, and the molecular subgroups as covariates found that only high-grade (hazard ratio [HR], 4.29; 95% CI, 2.15-8.53; P < .001), TP53-altered (HR, 1.76; 95% CI, 1.04-2.95; P = .03), and FIGO stage III or IV (HR, 4.26; 95% CI, 2.50-7.26; P < .001) disease were independently associated with reduced DSS. Conclusions and Relevance: This cohort study found that patients with low-grade EC had an excellent prognosis independent of molecular subgroup. These findings do not support routine molecular profiling in patients with low-grade EC, and they demonstrate the importance of primary diagnostic tumor grading and selective profiling in low-grade EC to increase cost-effectiveness.

Clinical value of morphometric and DNA flow cytometric variables as independent predictors of survival in epithelial ovarian carcinoma: a 5-year follow-up study.

The aim of this follow-up study is to validate the clinical significance of quantitative morphometric and DNA flow cytometric variables as independent prognostic factors of overall survival and progression-free survival in epithelial ovarian carcinoma. Tumor samples were collected from 135 patients with epithelial ovarian carcinoma at 3 hospitals in the Netherlands. Evaluated clinico-pathologic variables were age, histologic subtype, differentiation grade, clinical stage [International Federation of Gynecology and Obstetrics (FIGO)], presence of ascites, serum CA-125, and the completeness of debulking surgery. Morphometry and DNA flow cytometric techniques were assessed on each tumor sample to determine the mitotic activity index (MAI), volume percentage epithelium, mean nuclear area (MNA), standard deviation of MNA (SD MNA), nuclear perimeter (NP), and DNA ploidy. Univariate analysis showed that differentiation grade, FIGO stage, presence of ascites, preoperative CA-125 levels, DNA ploidy, and MAI, NP, and MNA were of significant prognostic value. After multivariate analysis (using forward Cox proportional hazard analysis), only differentiation grade and FIGO stage remained significant. From this study, we can conclude that morphometry and DNA flow cytometry are not independent prognosticators and therefore have no clinical value in predicting prognosis in ovarian carcinoma.

Improved preoperative risk stratification with CA-125 in low-grade endometrial cancer: a multicenter prospective cohort study.

OBJECTIVES: The global obesity epidemic has great impact on the prevalence of low-grade endometrial carcinoma. The preoperative tumor serum marker cancer antigen 125 (CA-125) might contribute to improved identification of high-risk patients within this group. The study aimed to investigate the prognostic value of CA-125 in relation to established preoperative prognosticators, with a focus on identifying patients with poor outcome in low-grade endometrial carcinoma (EC) patients. METHODS: Prospective multicenter cohort study including all consecutive patients surgically treated for endometrial carcinoma in nine collaborating hospitals from September 2011 until December 2013. All preoperative histopathological diagnoses were reviewed in a blinded manner. Associations between CA-125 and clinicopathological features were determined. Univariable and multivariable analysis by Cox regression were used. Separate analyses were performed for preoperatively designated low-grade and high-grade endometrial carcinoma patients. RESULTS: A total of 333 patients were analyzed. CA-125 was associated with poor prognostic features including advanced International Federation of Gynecology and Obstetrics (FIGO) stage. In multivariable analysis, age, preoperative tumor and CA-125 were significantly associated with disease-free survival (DFS); preoperative grade, tumor type, FIGO and CA-125 were significantly associated with disease-specific survival (DSS). Low-grade EC patients with elevated CA-125 revealed a DFS of 80.6% and DSS of 87.1%, compared to 92.1% and 97.2% in low-grade EC patients with normal CA-125. CONCLUSION: Preoperative elevated CA-125 was associated with poor prognostic features and independently associated with DFS and DSS. Particularly patients with low-grade EC and elevated CA-125 represent a group with poor outcome and should be considered as high-risk endometrial carcinoma.

MMP-14 and CD44 in Epithelial-to-Mesenchymal Transition (EMT) in ovarian cancer.

BACKGROUND: To investigate the expression of MMP-14 and CD44 as well as epithelial-to-mesenchymal transition(EMT)-like changes in ovarian cancer and to determine correlations with clinical outcome. METHODS: In 97 patients with ovarian cancer, MMP-14 and CD44 expression as determined by immunohistochemistry was investigated in relation to EMT-like changes. To determine this, immunohistochemical staining of E-cadherin and vimentin was performed. RESULTS: Patients with expression of both MMP-14 and CD44 in their tumors had a poor prognosis despite complete debulking. Serous histology in advanced-stage tumors (FIGO IIB-IV) correlated with CD44 (rho .286, p < 0.01). Also, CD44 correlated with percentage vimentin expression (rho .217, p < 0.05). In logistic regression analysis with complete debulking as the outcome parameter, CD44 expression was found to be significant (OR 3,571 (95 % Confidence Interval 1,112-11,468) p = 0.032), though this was not the case for MMP-14 and EMT parameters. CONCLUSION: The subgroup of patients with double expression of MMP-14 and CD44 had a poor prognosis despite complete debulking. Serous subtype in advanced-stage patients and CD44 expression were found to be correlated with vimentin expression, and CD44 expression was found to be significantly correlated with complete debulking. However, a significant correlation between EMT and clinical parameters was not found.

Endometrial cancer survivors are unsatisfied with received information about diagnosis, treatment and follow-up: a study from the population-based PROFILES registry.

OBJECTIVE: To evaluate perceived level of and satisfaction with information received by endometrial cancer survivors, and to identify associations with socio-demographic and clinical characteristics. METHODS: All patients diagnosed with endometrial cancer between 1998 and 2007, registered in the Eindhoven Cancer Registry, received a questionnaire including EORTC-QLQ-INFO25. RESULTS: Seventy-seven percent responded (n=742). Most patients indicated receiving quite a bit information about their disease and medical tests. However, most patients were not (54%) or a little (24%) informed about the cause of their disease, and possible side effects (36%; 27%). Especially information about additional help, rehabilitation, psychological assistance, and expected results on social and sexual life was lacking. Five percent was not or a little (36%) satisfied. Four percent found the information not or a little (35%) helpful. Fifteen percent preferred more information. Younger age, more recent diagnosis, radiotherapy, absence of comorbidities, having a partner, having received written information, and higher educational level were associated with higher perceived information receipt. CONCLUSION: Many endometrial cancer survivors are unsatisfied with received information. Several areas of information provision are experienced as insufficient. PRACTICE IMPLICATIONS: More patient-tailored information is probably needed to provide optimal information. Implementation of Survivorship Care Plans might be a way to achieve this.