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.

Confirmation of the utility of the CA-125 elimination rate (KELIM) as an indicator of the chemosensitivity in advanced-stage ovarian cancer in a "real-life setting".

OBJECTIVE: The modeled CA-125 ELIMination rate constant K (KELIM) has been validated as a marker of response to chemotherapy in >12,000 patients with advanced epithelial ovarian carcinoma (EOC) treated in first-line setting enrolled in >12 clinical trials. Patient KELIM is calculable online https://www.biomarker-kinetics.org/presentation. The objective was to investigate the prognostic value of KELIM in a large real-life national cancer registry with non-selected patients. METHODS: We investigated 4,025 EOC patients from the Netherlands Cancer Registry treated with neoadjuvant chemotherapy (NACT) ± followed by interval debulking surgery (IDS). Patient KELIM values were calculated in patients with ≥ 3 CA-125 measurements during NACT. KELIM was standardized with a pre-specified cut-off and scored as unfavorable/favorable (<1.0/≥1.0). KELIM's prognostic value regarding radiological response, completeness of IDS, progression-free survival (PFS), and overall survival (OS) was assessed using univariate/multivariate analyses. RESULTS: The data from 1,582 patients treated with heterogeneous chemotherapy regimens and sequences were assessable. KELIM was prognostic for radiological response and the likelihood of complete IDS after NACT (odds ratio=2.59; 95% confidence interval [CI]=2.04-3.29). Moreover, KELIM was independently associated with PFS (hazard ratio [HR]=0.76; 95% CI=0.66-0.87), and OS (HR=0.79; 95% CI=0.69-0.91). Combining KELIM with the completeness of the IDS resulted in 3 prognostic groups (satisfactory, intermediate, and poor) with significant OS differences, namely a good, intermediate, and poor survival respectively. CONCLUSION: The value of KELIM, as a pragmatic indicator of response to chemotherapy, was maintained in a large real-life population-based cohort, highlighting its applicability in routine conditions.

The prognostic value of tumor-stroma ratio and a newly developed computer-aided quantitative analysis of routine H&E slides in high-grade serous ovarian cancer.

Introduction: Tumor-stroma ratio (TSR) is prognostic in multiple cancers, while its role in high-grade serous ovarian cancer (HGSOC) remains unclear. Despite the prognostic insight gained from genetic profiles and tumor-infiltrating lymphocytes (TILs), the prognostic use of histology slides remains limited, while it enables the identification of tumor characteristics via computational pathology reducing scoring time and costs. To address this, this study aimed to assess TSR's prognostic role in HGSOC and its association with TILs. We additionally developed an algorithm, Ovarian-TSR (OTSR), using deep learning for TSR scoring, comparing it to manual scoring. Methods: 340 patients with advanced-stage who underwent primary debulking surgery (PDS) or neo-adjuvant chemotherapy (NACT) with interval debulking (IDS). TSR was assessed in both the most invasive (MI) and whole tumor (WT) regions through manual scoring by pathologists and quantification using OTSR. Patients were categorized as stroma-rich (≥ 50% stroma) or stroma-poor (< 50%). TILs were evaluated via immunohistochemical staining. Results: In PDS, stroma-rich tumors were significantly associated with a more frequent papillary growth pattern (60% vs 34%), while In NACT stroma-rich tumors had a lower Tumor Regression Grading (TRG 4&5, 21% vs 57%) and increased pleural metastasis (25% vs 16%). Stroma-rich patients had significantly shorter overall and progression-free survival compared to stroma-poor (31 versus 45 months; P < 0.0001, and 15 versus 17 months; P = 0.0008, respectively). Combining stromal percentage and TILs led to three distinct survival groups with good (stroma-poor, high TIL), medium (stroma-rich, high TIL, or; stroma-poor, Low TIL), and poor(stroma-rich, low TIL) survival. These survival groups remained significant in CD8 and CD103 in multivariable analysis (Hazard ratio (HR) = 1.42, 95% Confidence-interval (CI) = 1.02-1.99; HR = 1.49, 95% CI = 1.01-2.18, and HR = 1.48, 95% CI = 1.05-2.08; HR = 2.24, 95% CI = 1.55-3.23, respectively). OTSR was able to recapitulate these results and demonstrated high concordance with expert pathologists (correlation = 0.83). Conclusions: TSR is an independent prognostic factor for survival assessment in HGSOC. Stroma-rich tumors have a worse prognosis and, in the case of NACT, a higher likelihood of pleural metastasis. OTSR provides a cost and time-efficient way of determining TSR with high reproducibility and reduced inter-observer variability.

The impact of adipose tissue distribution on endometrial cancer: a systematic review.

Introduction: Endometrial cancer (EC) is the most common gynecological cancer with a rising incidence, attributed to advanced life expectancy and obesity. Adipose tissue (AT) is an important endocrine organ, and its metabolic activity is affected by the different anatomical distribution or locations. AT distribution influences a number of diseases. In EC, it remains unclear whether the type of AT distribution affects development or prognosis. This systematic review aimed to determine whether AT distribution is associated with patient characteristics, disease characteristics, and patient prognosis in EC. Materials and methods: A search was conducted in Medline, MEDLINE EMBASE, and Cochrane Library. We included studies that enrolled patients with EC with any histological subtype and that distinguished between the visceral and subcutaneous AT compartment. In eligible studies, correlative analyses were performed for all outcome measures and AT distribution. Results: Eleven retrospective studies were included, with a wide range of measurements for the visceral and subcutaneous AT compartments. AT distribution was found to be significantly correlated to a number of relevant (disease) characteristics including obesity measures, histological subtype, lymph node metastasis, and sex steroid levels. Five studies reported on survival parameters including overall survival, progression-free survival and disease-specific survival, and they found that increased VAT volume was statistically significantly associated with a worse survival. Discussion/conclusion: This review demonstrates that there are significant correlations between AT distribution and prognosis, body mass index, sex steroid levels, and disease characteristics like histology. Well-designed, prospective, and larger-scale studies are needed to pinpoint these differences more specifically and understand how it can add in prediction and even therapy in EC.

Stage, treatment and survival of low-grade serous ovarian carcinoma in the Netherlands: A nationwide study.

INTRODUCTION: Serous ovarian carcinomas constitute the largest group of epithelial ovarian cancer (60%-75%) and are further classified into high- and low-grade serous carcinoma. Low-grade serous carcinoma (LGSC) is a relatively rare subtype (approximately 5% of serous carcinomas) and epidemiologic studies of large cohorts are scarce. With the present study we aimed to report trends in stage, primary treatment and relative survival of LGSC of the ovary in a large cohort of patients in an effort to identify opportunities to improve clinical practice and outcome of this relatively rare disease. MATERIAL AND METHODS: Patients diagnosed with LGSC between 2000 and 2019 were identified from the Netherlands Cancer Registry (n = 855). Trends in FIGO stages and primary treatment were analyzed with the Cochran-Armitage trend test, and differences in and trends of 5-year relative survival were analyzed using multivariable Poisson regression. RESULTS: Over time, LGSC was increasingly diagnosed as stage III (39.9%-59.0%) and IV disease (5.7%-14.4%) and less often as stage I (34.6%-13.5%; p < 0.001). Primary debulking surgery was the most common strategy (76.2%), although interval debulking surgery was preferred more often over the years (10.6%-31.1%; p < 0.001). Following primary surgery, there was >1 cm residual disease in only 15/252 patients (6%), compared with 17/95 patients (17.9%) after interval surgery. Full cohort 5-year survival was 61% and survival after primary debulking surgery was superior to the outcome following interval debulking surgery (60% vs 34%). Survival following primary debulking surgery without macroscopic residual disease (73%) was better compared with ≤1 cm (47%) and >1 cm residual disease (22%). Survival following interval debulking surgery without macroscopic residual disease (51%) was significantly higher than after >1 cm residual disease (24%). Except FIGO stage II (85%-92%), survival did not change significantly over time. CONCLUSIONS: Over the years, LGSC has been diagnosed as FIGO stage III and stage IV disease more often and interval debulking surgery has been increasingly preferred over primary debulking in these patients. Relative survival did not change over time (except for stage II) and worse survival outcomes after interval debulking surgery were observed. The results support the common recommendation to perform primary debulking surgery in patients eligible for primary surgery.

Case-mix adjustment to compare hospital performances regarding complications after cytoreductive surgery for ovarian cancer: a nationwide population-based study.

OBJECTIVE: Complication rates after cytoreductive surgery are important quality indicators for hospitals that treat patients with advanced-stage ovarian cancer. Case-mix factors are patient and tumor characteristics that may influence hospital outcomes such as the complication rates. Currently, no case-mix adjustment model exists for complications after cytoreductive surgery; therefore, it is unclear whether hospitals are being compared correctly. This study aims to develop the first case-mix adjustment model for complications after surgery for advanced-stage ovarian cancer, enabling an accurate comparison between hospitals. METHODS: This population-based study included all patients undergoing cytoreductive surgery for advanced-stage ovarian cancer registered in the Netherlands in 2017-2019. Case-mix variables were identified and assessed using logistic regressions. The primary outcome was the composite outcome measure 'complicated course'. Patients had a complicated course when at least one of the following criteria were met: (1) any complication combined with a prolonged length of hospital stay; (2) complication requiring reintervention; (3) any complication with a prolonged length of stay in the intensive care unit; or (4) 30-day mortality or in-hospital mortality during admission following surgery. Inter-hospital variation was analyzed using univariable and multivariable logistic regressions and visualized using funnel plots. RESULTS: A total of 1822 patients were included, of which 10.7% (n=195) had a complicated course. Comorbidity and tumor stage had a significant impact on complicated course rates in multivariable logistic regression. Inter-hospital variation was not significant for case-mix factors. Complicated course rates ranged between 2.2% and 29.1%, and case-mix adjusted observed/expected ratios ranged from 0.20 to 2.67 between hospitals. Three hospitals performed outside the confidence intervals for complicated course rates. These hospitals remained outliers after case-mix adjustment. CONCLUSION: There is variation between hospitals regarding complicated course rates after cytoreductive surgery for ovarian cancer in the Netherlands. While comorbidity and tumor stage significantly affected the complicated course rates, adjusting for case-mix factors did not significantly affect hospital outcomes. The limited impact of case-mix adjustment could be a result of the Dutch centralized healthcare model.

The effect of progestin therapy in advanced and recurrent endometrial cancer: A systematic review and meta-analysis.

BACKGROUND: Fifteen percent of patients with endometrial cancer (EC) have advanced stage disease or develop a recurrence. Progestins have been applied as systemic treatment for decades, but there is limited evidence on response prediction with biomarkers and toxicity. OBJECTIVES: To review the response and toxicity of progestin therapy and stratify response to progesterone receptor (PR) expression and tumour grade. SEARCH STRATEGY: We used the search terms 'Endometrial cancer', 'Progestins', 'Disease progression', 'Recurrence' and related terms in Pubmed, Embase and Cochrane databases. SELECTION CRITERIA: Studies on patients with advanced stage or recurrent EC treated with progestin monotherapy were included. Studies on adjuvant therapy, with fewer than ten cases and with sarcoma histology were excluded. DATA COLLECTION AND ANALYSIS: Evaluation for bias was performed with the Revised Cochrane RoB2 tool for randomised studies and the ROBINS-I tool for non-randomised studies. A random effects meta-analysis was performed with the overall response rate (ORR), clinical benefit rate and toxicity as primary outcome measures. MAIN RESULTS: Twenty-six studies (1639 patients) were included. The ORR of progestin therapy was 30% (95% CI 25-36), the clinical benefit rate was 52% (95% CI 42-61). In PR-positive EC, the ORR was 55%, compared with 12% in PR-negative disease (risk difference 43%, 95% CI 15-71). Severe toxicity occurred in 6.5%. CONCLUSIONS: Progestin therapy is a viable treatment option in patients with advanced stage and recurrent EC with low toxicity and high ORR in PR-positive disease. The role of PR expression in relation to progression-free survival and overall survival is unclear.

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.

Homologous Recombination Deficiency and Cyclin E1 Amplification Are Correlated with Immune Cell Infiltration and Survival in High-Grade Serous Ovarian Cancer.

BACKGROUND: How molecular profiles are associated with tumor microenvironment (TME) in high-grade serous ovarian cancer (HGSOC) is incompletely understood. Therefore, we analyzed the TME and molecular profiles of HGSOC and assessed their associations with overall survival (OS). METHODS: Patients with advanced-stage HGSOC treated in three Dutch hospitals between 2008-2015 were included. Patient data were collected from medical records. BRCA1/2 mutation, BRCA1 promotor methylation analyses, and copy number variations were used to define molecular profiles. Immune cells were assessed with immunohistochemical staining. RESULTS: 348 patients were categorized as BRCA mutation (BRCAm) (BRCAm or promotor methylation) (30%), non-BRCA mutated HRD (19%), Cyclin E1 (CCNE1)-amplification (13%), non-BRCAmut HRD and CCNE1-amplification (double classifier) (20%), and no specific molecular profile (NSMP) (18%). BRCAm showed highest immune cell densities and CCNE1-amplification lowest. BRCAm showed the most favorable OS (52.5 months), compared to non-BRCAmut HRD (41.0 months), CCNE1-amplification (28.0 months), double classifier (27.8 months), and NSMP (35.4 months). Higher immune cell densities showed a favorable OS compared to lower, also within the profiles. CD8+, CD20+, and CD103+ cells remained associated with OS in multivariable analysis. CONCLUSIONS: Molecular profiles and TME are associated with OS. TME differs per profile, with higher immune cell densities showing a favorable OS, even within the profiles. HGSOC does not reflect one entity but comprises different entities based on molecular profiles and TME.

Guideline adherence in ovarian cancer for surgical staging in the Netherlands.

OBJECTIVE: Previous studies have shown low adherence to surgical staging guidelines in patients with clinical early-stage ovarian carcinoma. The aim of this study was to identify guideline adherence for surgical staging and to show the distribution of each surgical item within the study population. In addition, we examined whether regional variation in the Netherlands exists for complete surgical staging. METHODS: Patients with ovarian cancer and surgical staging registered in the Dutch Gynecological Oncology Audit between January 1, 2015 and December 31, 2019 in the Netherlands were included. Complete surgical staging was defined according to the Dutch evidence-based guideline. Surgical items were ranked and illustrated. Variation in complete surgical staging for eight regional cancer networks was shown in funnel plots. Manual validation of registered data was performed in three gynecological oncology centers. RESULTS: 604 patients underwent surgical staging, 365 (60%) underwent an incomplete staging procedure, 295 (81%) were registered with early-stage disease (International Federation of Gynecology and Obstetrics I-IIA) and, of these patients, 115 (39%) received adjuvant chemotherapy. Patients with incomplete surgical staging were operated more often with minimal invasive techniques (laparoscopy or robot) compared with patients in the complete staging group (p<0.001). Sampling of cytology/ascites was the most frequently lacking factor (29%). Manual validation of data in three gynecological oncology centers identified reasons for incomplete staging, the most common being 'perioperative findings' such as dense adhesions between tumor and peritoneum, consistent with advanced stage disease (≥IIA). Regional variation for complete surgical staging showed two regions performing outside the confidence intervals (12.5% and 25.5%, mean 40%). CONCLUSION: Guideline adherence for staging was lower than expected and validation of data gave additional insights into the reasons that were contributing to incomplete surgical staging. Moreover, this analysis showed that regional variation for surgical staging exists, which forms a starting point to improve and harmonize staging procedures for these patients nationwide.

Surgical treatment for clinical early-stage expansile and infiltrative mucinous ovarian cancer: can staging surgeries safely be omitted?

PURPOSE OF REVIEW: Mucinous ovarian cancers (MOCs) are categorized into infiltrative and expansile subtypes. These subtypes have different characteristics and prognoses. Patients with clinical early-stage disease of both subtypes currently undergo surgical staging (peritoneal washing, biopsies, omentectomy). Peritoneal and lymph node metastases of expansile MOC are rare, but whereas lymph node sampling (LNS) is omitted in these patients, peritoneal staging is not. Therefore, we collected all available MOC data to determine whether staging surgeries could safely be omitted in clinical early-stage expansile and infiltrative MOC. RECENT FINDINGS: Current literature confirms that peritoneal metastases are rare in expansile MOC: more than 90% of patients have early-stage disease. Only 3.4% of the patients with clinical early-stage expansile MOC had positive peritoneal washings at surgical staging. Patients with infiltrative MOC were diagnosed more frequently with advanced-stage disease (21-54%). Moreover, upstaging clinical early-stage infiltrative MOC based on positive cytology, peritoneum and omentum metastases occurred in 10.3% of the patients. Therefore, we recommend that patients with early-stage infiltrative MOC undergo peritoneal staging and LNS. However, in addition to omitting LNS, we can also safely recommend omitting peritoneal staging in patients with clinical early stage expansile MOC. SUMMARY: Peritoneal metastases are rare in clinical early-stage expansile MOC and peritoneal staging can therefore safely be omitted.

The added value of SLN mapping with indocyanine green in low- and intermediate-risk endometrial cancer management: a systematic review and meta-analysis.

OBJECTIVE: The aim of this study was to assess the SLN detection rate in presumed early stage, low- and intermediate-risk endometrial cancers, the incidence of SLN metastases, and the negative predictive value of SLN mapping performed with indocyanine green (ICG). METHODS: A systematic review with meta-analyses was conducted. Study inclusion criteria were A) low- and intermediate-risk endometrial cancer, B) the use of ICG per cervical injection; C) a minimum of twenty included patients per study. To assess the negative predictive value of SLN mapping, D) a subsequent lymphadenectomy was an additional inclusion criterion. RESULTS: Fourteen studies were selected, involving 2,117 patients. The overall and bilateral SLN detection rates were 95.6% (95% confidence interval [CI]=92.4%-97.9%) and 76.5% (95% CI=68.1%-84.0%), respectively. The incidence of SLN metastases was 9.6% (95% CI=5.1%-15.2%) in patients with grade 1-2 endometrial cancer and 11.8% (95% CI=8.1%-16.1%) in patients with grade 1-3 endometrial cancer. The negative predictive value of SLN mapping was 100% (95% CI=98.8%-100%) in studies that included grade 1-2 endometrial cancer and 99.2% (95% CI=97.9%-99.9%) in studies that also included grade 3. CONCLUSION: SLN mapping with ICG is feasible with a high detection rate and negative predictive value in low- and intermediate-risk endometrial cancers. Given the incidence of SLN metastases is approximately 10% in those patients, SLN mapping may lead to stage shifting with potential therapeutic consequences. Given the high negative predictive value with SLN mapping, routine lymphadenectomy should be omitted in low- and intermediate-risk endometrial cancer.

Topical Imiquimod Treatment of High-grade Cervical Intraepithelial Neoplasia (TOPIC-3): A Nonrandomized Multicenter Study.

Topical imiquimod could be an alternative, noninvasive, treatment modality for high-grade cervical intraepithelial neoplasia (CIN). However, evidence is limited, and there are no studies that compared treatment effectiveness and side effects of topical imiquimod cream to standard large loop excision of the transformation zone (LLETZ) treatment. A multi-center, nonrandomized controlled trial was performed among women with a histologic diagnosis of CIN 2/3. Women were treated with either vaginal imiquimod (6.25 mg 3 times weekly for 8 to 16 wk) or LLETZ according to their own preference. Successful treatment was defined as the absence of high-grade dysplasia at the first follow-up interval after treatment (at 20 wk for the imiquimod group and at 26 wk for the LLETZ group). Secondary outcome measures were high-risk human papillomavirus (hrHPV) clearance, side effects, and predictive factors for successful imiquimod treatment. Imiquimod treatment was successful in 60% of women who completed imiquimod treatment and 95% of women treated with LLETZ. hrHPV clearance occurred in 69% and 67% in the imiquimod group and LLETZ group, respectively. This study provides further evidence on topical imiquimod cream as a feasible and safe treatment modality for high-grade CIN. Although the effectiveness is considerably lower than LLETZ treatment, imiquimod treatment could prevent initial surgical treatment in over 40% of women and should be offered to a selected population of women who wish to avoid (repeated) surgical treatment of high-grade CIN.

Ovarian cancer ascites induces skeletal muscle wasting in vitro and reflects sarcopenia in patients.

BACKGROUND: Cachexia-associated skeletal muscle wasting or 'sarcopenia' is highly prevalent in ovarian cancer and contributes to poor outcome. Drivers of cachexia-associated sarcopenia in ovarian cancer remain elusive, underscoring the need for novel and better models to identify tumour factors inducing sarcopenia. We aimed to assess whether factors present in ascites of sarcopenic vs. non-sarcopenic ovarian cancer patients differentially affect protein metabolism in skeletal muscle cells and to determine if these effects are correlated to cachexia-related patient characteristics. METHODS: Fifteen patients with an ovarian mass and ascites underwent extensive physical screening focusing on cachexia-related parameters. Based on computed tomography-based body composition imaging, six cancer patients were classified as sarcopenic and six were not; three patients with a benign condition served as an additional non-sarcopenic control group. Ascites was collected, and concentrations of cachexia-associated factors were assessed by enzyme-linked immunosorbent assay. Subsequently, ascites was used for in vitro exposure of C2C12 myotubes followed by measurements of protein synthesis and breakdown by radioactive isotope tracing, qPCR-based analysis of atrophy-related gene expression, and NF-κB activity reporter assays. RESULTS: C2C12 protein synthesis was lower after exposure to ascites from sarcopenic patients (sarcopenia 3.1 ± 0.1 nmol/h/mg protein vs. non-sarcopenia 5.5 ± 0.2 nmol/h/mg protein, P < 0.01), and protein breakdown rates tended to be higher (sarcopenia 31.2 ± 5.2% vs. non-sarcopenia 20.9 ± 1.9%, P = 0.08). Ascites did not affect MuRF1, Atrogin-1, or REDD1 expression of C2C12 myotubes, but NF-κB activity was specifically increased in cells exposed to ascites from sarcopenic patients (sarcopenia 2.2 ± 0.4-fold compared with control vs. non-sarcopenia 1.2 ± 0.2-fold compared with control, P = 0.01). Protein synthesis and breakdown correlated with NF-κB activity (rs  = -0.60, P = 0.03 and rs  = 0.67, P = 0.01, respectively). The skeletal muscle index of the ascites donors was also correlated to both in vitro protein synthesis (rs  = 0.70, P = 0.005) and protein breakdown rates (rs  = -0.57, P = 0.04). CONCLUSIONS: Ascites of sarcopenic ovarian cancer patients induces pronounced skeletal muscle protein metabolism changes in C2C12 cells that correlate with clinical muscle measures of the patient and that are characteristic of cachexia. The use of ascites offers a new experimental tool to study the impact of both tumour-derived and systemic factors in various cachexia model systems, enabling identification of novel drivers of tissue wasting in ovarian cancer.

Sentinel Lymph Node Mapping in Presumed Low- and Intermediate-Risk Endometrial Cancer Management (SLIM): A Multicenter, Prospective Cohort Study in The Netherlands.

The aim was to investigate the incidence of sentinel lymph node (SLN) metastases and the contribution of SLN mapping in presumed low- and intermediate-risk endometrial cancer (EC). A multicenter, prospective cohort study in presumed low- and intermediate-risk EC patients was performed. Patients underwent SLN mapping using cervical injections of indocyanine green and a minimally invasive hysterectomy with bilateral salpingo-oophorectomy. The primary outcome was the incidence of SLN metastases, leading to adjusted adjuvant treatment. Secondary outcomes were the SLN detection rate and the occurrence of complications. Descriptive statistics and univariate general linear model analyses were used. A total of 152 patients were enrolled, with overall and bilateral SLN detection rates of 91% and 61%, respectively. At final histology, 78.9% of patients (n = 120) had truly low- and intermediate-risk EC. Macro- and micro-metastases were present in 11.2% (n = 17/152), and three patients had isolated tumor cells (2.0%). Nine patients (5.9%) had addition of adjuvant radiotherapy based on SLN metastases only. In 2.0% of patients with high-risk disease, adjuvant therapy was more limited due to negative SLNs. This study emphasizes the importance of SLN mapping in presumed early-stage, grade 1 and 2 EC, leading to individualized adjuvant management, resulting in less undertreatment and overtreatment.

Gut microbiota and short-chain fatty acid alterations in cachectic cancer patients.

BACKGROUND: Cancer cachexia is characterized by a negative energy balance, muscle and adipose tissue wasting, insulin resistance, and systemic inflammation. Because of its strong negative impact on prognosis and its multifactorial nature that is still not fully understood, cachexia remains an important challenge in the field of cancer treatment. Recent animal studies indicate that the gut microbiota is involved in the pathogenesis and manifestation of cancer cachexia, but human data are lacking. The present study investigates gut microbiota composition, short-chain fatty acids (SCFA), and inflammatory parameters in human cancer cachexia. METHODS: Faecal samples were prospectively collected in patients (N = 107) with pancreatic cancer, lung cancer, breast cancer, or ovarian cancer. Household partners (N = 76) of the patients were included as healthy controls with similar diet and environmental conditions. Patients were classified as cachectic if they lost >5% body weight in the last 6 months. Gut microbiota composition was analysed by sequencing of the 16S rRNA V4 gene region. Faecal SCFA levels were quantified by gas chromatography. Faecal calprotectin was assessed with enzyme-linked immunosorbent assay. Serum C-reactive protein and leucocyte counts were retrieved from medical records. RESULTS: Cachexia prevalence was highest in pancreatic cancer (66.7%), followed by ovarian cancer (25%), lung cancer (20.8%), and breast cancer (17.3%). Microbial α-diversity was not significantly different between cachectic cancer patients (N = 33), non-cachectic cancer patients (N = 74), or healthy controls (N = 76) (species richness P = 0.31; Shannon effective index P = 0.46). Community structure (ß-diversity) tended to differ between these groups (P = 0.053), although overall differences were subtle and no clear clustering of samples was observed. Proteobacteria (P < 0.001), an unknown genus from the Enterobacteriaceae family (P < 0.01), and Veillonella (P < 0.001) were more abundant among cachectic cancer patients. Megamonas (P < 0.05) and Peptococcus (P < 0.001) also showed differential abundance. Faecal levels of all SCFA tended to be lower in cachectic cancer patients, but only acetate concentrations were significantly reduced (P < 0.05). Faecal calprotectin levels were positively correlated with the abundance of Peptococcus, unknown Enterobacteriaceae, and Veillonella. We also identified several correlations and interactions between clinical and microbial parameters. CONCLUSIONS: This clinical study provided the first insights into the alterations of gut microbiota composition and SCFA levels that occur in cachectic cancer patients and how they are related to inflammatory parameters. These results pave the way for further research examining the role of the gut microbiota in cancer cachexia and its potential use as therapeutic target.

Sentinel lymph node identification in early stage ovarian cancer: is it still possible after prior tumor resection?

OBJECTIVE: Sentinel lymph node (SLN) detection in ovarian cancer is feasible when tracers are injected before the pathological ovary is resected. This study aims to investigate whether the SLN identification is also feasible in patients whose ovarian tumor has already been resected with injection of the tracer into the ovarian ligaments stumps, i.e. in the event that a frozen section confirms malignancy. METHODS: Patients who underwent laparotomy with frozen section confirming an ovarian malignancy, and those who underwent a second staging laparotomy after prior resection of a malignant ovarian mass, were included. Blue dye and a radioactive isotope were injected in the stumps of the ligamentum ovarium proprium and the ligamentum infundibulo-pelvicum. After an interval of at least 15-min, the sentinel node(s) were identified using either the gamma-probe and / or blue dye. RESULTS: A total of 11 patients were included in the study, the sentinel node (SLN) procedure was completed in all 11 patients. At least one SLN was identified in 3 patients, resulting in a rather low detection rate of 27,3%. CONCLUSION: In this study we showed that SLN procedure after (previous) resection of the tumor seems inferior to detect sentinel nodes when compared to injection of the tracer in the ovarian ligaments before tumor resection. TRIAL REGISTRATION: NCT02540551.

Borderline ovarian tumor frozen section diagnoses with features suspicious of invasive cancer: a retrospective study.

BACKGROUND: A frozen section diagnosis of a borderline ovarian tumor with suspicious features of invasive carcinoma ("at least borderline" or synonymous descriptions) presents us with the dilemma of whether or not to perform a full ovarian cancer staging procedure. Quantification of this dilemma may help us with the issue of this clinical decision. The present study assessed and compared both the prevalence of straightforward borderline and "at least borderline" frozen section diagnoses and the proportion of these women with a final histopathological diagnosis of invasive carcinoma, with a special interest in histologic subtypes. METHODS: A retrospective cohort study was performed in three hospitals in The Netherlands. All women that underwent ovarian surgery with perioperative frozen section evaluation in one of these hospitals between January 2007 and July 2018 were identified and included in case of a borderline or "at least borderline" frozen section diagnosis and a borderline ovarian tumor or invasive carcinoma as a final diagnosis. RESULTS: A total of 223 women were included, of which 41 women (18.4%) were diagnosed with "at least borderline" at frozen section. Thirteen of forty-one women (31.7%) following "at least borderline" frozen section diagnosis and 14 of 182 women (7.7%) following a straightforward borderline frozen section diagnosis were diagnosed with invasive carcinoma at paraffin section evaluation (p < 0.001). When compared to straightforward borderline frozen section diagnoses, the proportion of women diagnosed with invasive carcinoma increased from 3.1 to 35.7% for serous tumors (p = 0.001), 10.0 to 21.7% for mucinous tumors (p = 0.129) and 50.0 to 75.0% (p = 0.452) in case of other histologic subtypes following an "at least borderline" frozen section diagnosis. CONCLUSIONS: Overall, when compared to women with a decisive borderline frozen section diagnosis, women diagnosed with "at least borderline" frozen section diagnoses were found to have a higher chance of carcinoma upon final diagnosis (7.7% vs 31.7%). Especially in the serous subtype, full staging during initial surgery might be considered after preoperative consent to prevent a second surgical procedure or chemotherapy in unstaged women. Further studies are needed to evaluate whether additional sampling in case of an "at least borderline" diagnosis may decrease the risk of surgical over-treatment.

Clinicopathologic predictors of early relapse in advanced epithelial ovarian cancer: development of prediction models using nationwide data.

OBJECTIVE: To identify clinicopathologic factors predictive of early relapse (platinum-free interval (PFI) of ≤6 months) in advanced epithelial ovarian cancer (EOC) in first-line treatment, and to develop and internally validate risk prediction models for early relapse. METHODS: All consecutive patients diagnosed with advanced stage EOC between 01-01-2008 and 31-12-2015 were identified from the Netherlands Cancer Registry. Patients who underwent cytoreductive surgery and platinum-based chemotherapy as initial EOC treatment were selected. Two prediction models, i.e. pretreatment and postoperative, were developed. Candidate predictors of early relapse were fitted into multivariable logistic regression models. Model performance was assessed on calibration and discrimination. Internal validation was performed through bootstrapping to correct for model optimism. RESULTS: A total of 4,557 advanced EOC patients were identified, including 1,302 early relapsers and 3,171 late or non-relapsers. Early relapsers were more likely to have FIGO stage IV, mucinous or clear cell type EOC, ascites, >1 cm residual disease, and to have undergone NACT-ICS. The final pretreatment model demonstrated subpar model performance (AUC = 0.64 [95 %-CI 0.62-0.66]). The final postoperative model based on age, FIGO stage, pretreatment CA-125 level, histologic subtype, presence of ascites, treatment approach, and residual disease after debulking, demonstrated adequate model performance (AUC = 0.72 [95 %-CI 0.71-0.74]). Bootstrap validation revealed minimal optimism of the final postoperative model. CONCLUSION: A (postoperative) discriminative model has been developed and presented online that predicts the risk of early relapse in advanced EOC patients. Although external validation is still required, this prediction model can support patient counselling in daily clinical practice.