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BACKGROUND: In the last decade, technical innovations have resulted in the development of several minimally invasive diagnostic cancer tools. Within women at high risk of developing ovarian or endometrial cancer (EC) due to hereditary cancer syndrome, there is an urgent need for minimally invasive and patient-friendly methods to detect ovarian cancer and EC at an early stage. MATERIALS AND METHODS: We performed a systematic search of studies using DNA methylation or mutation analysis, microbiome, or proteomics performed on cervicovaginal specimens (smear, swab, or tampon) intended to detect ovarian and EC published until January 2024. RESULTS: Included studies (n = 36) showed high heterogeneity in terms of biomarkers used and outcomes, and only a few studies reported on the detection of biomarkers in high-risk subgroups. CONCLUSION: Based on the findings in this review, DNA methylation techniques seem to be the most promising for detecting ovarian and EC at early stages in the general population. Future validation of cervicovaginal DNA methylation techniques is needed to determine whether this technique might be beneficial in hereditary high-risk subgroups.
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Biomarcadores Tumorais , Metilação de DNA , Detecção Precoce de Câncer , Neoplasias do Endométrio , Neoplasias Ovarianas , Humanos , Feminino , Neoplasias do Endométrio/diagnóstico , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/metabolismo , Detecção Precoce de Câncer/métodos , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/genética , Biomarcadores Tumorais/genética , Vagina/metabolismo , Vagina/microbiologia , Colo do Útero/metabolismo , Colo do Útero/patologia , Proteômica/métodosRESUMO
BACKGROUND: Response to hormonal therapy in advanced and recurrent endometrial cancer (EC) can be predicted by oestrogen and progesterone receptor immunohistochemical (ER/PR-IHC) expression, with response rates of 60% in PR-IHC > 50% cases. ER/PR-IHC can vary by tumour location and is frequently lost with tumour progression. Therefore, we explored the relationship between ER/PR-IHC expression and tumour location in EC. METHODS: Pre-treatment tumour biopsies from 6 different sites of 80 cases treated with hormonal therapy were analysed for ER/PR-IHC expression and classified into categories 0-10%, 10-50%, and >50%. The ER pathway activity score (ERPAS) was determined based on mRNA levels of ER-related target genes, reflecting the actual activity of the ER receptor. RESULTS: There was a trend towards lower PR-IHC (33% had PR > 50%) and ERPAS (27% had ERPAS > 15) in lymphogenic metastases compared to other locations (p = 0.074). Hematogenous and intra-abdominal metastases appeared to have high ER/PR-IHC and ERPAS (85% and 89% ER-IHC > 50%; 64% and 78% PR-IHC > 50%; 60% and 71% ERPAS > 15, not significant). Tumour grade and previous radiotherapy did not affect ER/PR-IHC or ERPAS. CONCLUSIONS: A trend towards lower PR-IHC and ERPAS was observed in lymphogenic sites. Verification in larger cohorts is needed to confirm these findings, which may have implications for the use of hormonal therapy in the future.
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Prehabilitation is an upcoming strategy to optimize patient's functional capacity, nutritional status, and psychosocial well-being in order to reduce surgical complications and enhance recovery. This study aims to assess the feasibility of implementing a multimodal prehabilitation program into the standard care of gynecological oncology patients at an academic hospital in terms of recruitment, adherence, and safety, which were assessed by the number of patients eligible, recruitment rate, participation rate, and adherence to individual modalities. Data were derived from the F4S PREHAB trial, a single-center stepped-wedge trial implementing a multimodal prehabilitation program among various surgical specialties. All patients undergoing elective surgery as part of treatment for ovarian, uterine, and vulvar cancer at the Radboudumc, an academic hospital in The Netherlands, between May 2022 and September 2023 were considered eligible for the F4S PREHAB trial and, consequently, were included in this cohort study. The multimodal prehabilitation program comprised a physical exercise intervention, nutritional intervention, psychological intervention, and an intoxication cessation program. A total of 152 patients were eligible and approached for participation of which 111 consented to participate, resulting in a recruitment rate of 73%. Participants attended an average of six exercise sessions and adhered to 85% of possible training sessions. Respectively, 93% and 98% of participants adhered to the prescribed daily protein and vitamin suppletion. Ten participants were referred to a psychologist and completed consultations. Out of nine active smokers, two managed to quit smoking. A total of 59% adhered to alcohol cessation advice. No adverse events were reported. This study demonstrates that introducing a multimodal prehabilitation program into the standard care of gynecological oncology patients is feasible in terms of recruitment and adherence, with no serious adverse events.
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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.
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Anemia , Neoplasias do Endométrio , Trombocitose , Feminino , Humanos , Anemia/etiologia , Biomarcadores , Estudos de Coortes , Neoplasias do Endométrio/complicações , Neoplasias do Endométrio/radioterapia , Neoplasias do Endométrio/cirurgia , Leucocitose , Trombocitose/etiologia , Estudos RetrospectivosRESUMO
Endometrial biopsies are important in the diagnostic workup of women who present with abnormal uterine bleeding or hereditary risk of endometrial cancer. In general, approximately 10% of all endometrial biopsies demonstrate endometrial (pre)malignancy that requires specific treatment. As the diagnostic evaluation of mostly benign cases results in a substantial workload for pathologists, artificial intelligence (AI)-assisted preselection of biopsies could optimize the workflow. This study aimed to assess the feasibility of AI-assisted diagnosis for endometrial biopsies (endometrial Pipelle biopsy computer-aided diagnosis), trained on daily-practice whole-slide images instead of highly selected images. Endometrial biopsies were classified into 6 clinically relevant categories defined as follows: nonrepresentative, normal, nonneoplastic, hyperplasia without atypia, hyperplasia with atypia, and malignant. The agreement among 15 pathologists, within these classifications, was evaluated in 91 endometrial biopsies. Next, an algorithm (trained on a total of 2819 endometrial biopsies) rated the same 91 cases, and we compared its performance using the pathologist's classification as the reference standard. The interrater reliability among pathologists was moderate with a mean Cohen's kappa of 0.51, whereas for a binary classification into benign vs (pre)malignant, the agreement was substantial with a mean Cohen's kappa of 0.66. The AI algorithm performed slightly worse for the 6 categories with a moderate Cohen's kappa of 0.43 but was comparable for the binary classification with a substantial Cohen's kappa of 0.65. AI-assisted diagnosis of endometrial biopsies was demonstrated to be feasible in discriminating between benign and (pre)malignant endometrial tissues, even when trained on unselected cases. Endometrial premalignancies remain challenging for both pathologists and AI algorithms. Future steps to improve reliability of the diagnosis are needed to achieve a more refined AI-assisted diagnostic solution for endometrial biopsies that covers both premalignant and malignant diagnoses.
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Inteligência Artificial , Computadores , Humanos , Feminino , Estudos de Viabilidade , Hiperplasia , Reprodutibilidade dos Testes , BiópsiaRESUMO
Preoperative cardiopulmonary exercise testing (CPET) provides an objective assessment of functional capability. In other intra-abdominal surgical specialties, CPET outcomes are predictive of operative morbidity. However, in ovarian cancer surgery, its predictive value remains unknown. In this study, we evaluated the association between CPET performance and surgical morbidity in ovarian cancer patients. Secondly, we assessed the association between CPET performance and other surgical outcomes (i.e., hospital stay, readmission and residual disease). This was a retrospective cohort study of patients undergoing primary surgery for ovarian cancer between 2020 and 2023. CPET performance included peak oxygen uptake (VO2 max), ventilatory efficiency (VE/VO2) and anaerobic threshold. Outcomes were operative morbidity and included intra- and postoperative complications (Clavien-Dindo), hospital stay, readmission within 30 days and residual disease. A total of 142 patients were included. A lower VO2 peak and a higher VE/VCO2 were both associated with the occurrence of postoperative complications, and a poorer anaerobic threshold was associated with more transfusions. VE/VCO2 remained significantly associated after multivariate analysis (p = 0.035). None of the CPET outcomes were associated with length of stay, readmission or residual disease. In conclusion, VE/VCO2 was significantly associated with an increased risk of all-cause postoperative complications in ovarian cancer patients undergoing primary surgery.
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The prevalence of an unhealthy lifestyle among patients with gynecological cancer is high and associated with increased risk of all-cause mortality. Although lifestyle changes have the potential to improve outcomes, lifestyle counseling is not routinely integrated into standard care. This review explores research on the barriers to and facilitators of both the promotion of healthy lifestyles by healthcare providers (HCPs) and healthy lifestyle changes by patients with gynecological cancer. The Theoretical Domains Framework (TDF) was used to deductively code the identified factors for a comprehensive understanding of the barriers and facilitators. A search across five databases yielded a total of 12,687 unique studies, of which 43 were included in the review. Of these 43, 39 included gynecological cancer patients and only 6 included HCPs. Among the barriers identified for HCPs, most studies evaluated barriers regarding weight loss counseling. Limited knowledge, reluctance to address weight loss, skepticism about the benefits, and workload concerns were commonly reported barriers for HCPs. HCPs will benefit from education and training in lifestyle counseling, including effective communication skills like motivational interviewing. Gynecological cancer patients lacked tools, support, knowledge, and faced mental health issues, environmental constraints, and physical limitations. The review emphasizes the importance of addressing these barriers and utilizing identified facilitators, such as social support, to promote and support healthy lifestyle behaviors on the part of patients and their promotion by HCPs. Future research should focus not only on patients but also on supporting HCPs and implementing necessary changes in current practices.
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Pessoal de Saúde , Neoplasias , Humanos , Estilo de Vida Saudável , Estilo de Vida , Redução de Peso , Pesquisa QualitativaRESUMO
BACKGROUND: Up to 40% of vulvar cancer patients present with local recurrence within 10 years of follow-up. An inguinofemoral lymphadenectomy (IFL) is indicated if not performed at primary treatment. The incidence and risk factors for lymph node metastases (LNM) at first local recurrence, however, are unclear. Our aim was to determine the incidence of LNM at first local recurrence, in relation to previous groin treatment and clinicopathological factors. METHODS: A multicenter cohort study including vulvar cancer patients with a first macroinvasive local recurrence after primary surgical treatment between 2000 and 2015 was conducted in the Netherlands. Groin status at local recurrence was defined as positive (N+), negative (N-) or unknown (N?) and based on histology, imaging and follow-up. Patient-, tumour- and treatment characteristics of primary and recurrent disease were analysed. RESULTS: Overall, 16.3% (66/404) had a N+ groin status at first local recurrence, 66.4% (268/404) N- and 17.3% (70/404) N? groin status. The incidence of a N+ groin status was comparable after previous SLN and IFL, 11.5% and 13.8%, respectively. A N+ groin status was related to tumour size (25 vs.12 mm; P < 0.001), depth of invasion (5 vs. 3 mm; P < 0.001) and poorly differentiated tumours (22.9 vs. 11.9%; P = 0.050) at local recurrence. CONCLUSIONS: The incidence of LNM at first local recurrence in vulvar cancer patients was 16.3%, and independent of previous type of groin surgery. In accordance with primary diagnosis, tumour size, depth of invasion, and tumour grade were significantly associated with a positive groin status.
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Neoplasias Vulvares , Feminino , Humanos , Metástase Linfática/patologia , Neoplasias Vulvares/epidemiologia , Neoplasias Vulvares/cirurgia , Neoplasias Vulvares/patologia , Estudos de Coortes , Incidência , Recidiva Local de Neoplasia/patologia , Excisão de Linfonodo/efeitos adversos , Linfonodos/cirurgia , Linfonodos/patologia , Biópsia de Linfonodo Sentinela , Estadiamento de NeoplasiasRESUMO
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.
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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.
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BACKGROUND: Uterine clear cell carcinoma (CCC) consists of either pure clear cell histology but can also display other histological components (mixed uterine CCCs). In this study, the molecular and immunohistochemical background of pure and mixed uterine CCC was compared. Secondly, it was evaluated whether histological classification and molecular background affected clinical outcome. METHODS: A retrospective multicenter study was performed comparing pure uterine CCCs (n = 22) and mixed uterine CCCs (n = 21). Targeted next-generation sequencing using a 12-gene targeted panel classified cases as polymerase-ε (POLE) mutated, microsatellite instable (MSI), TP53 wildtype or TP53 mutated. Immunohistochemistry was performed for estrogen receptor, progesterone receptor, L1 cell adhesion molecule, MSH6, and PMS2. RESULTS: The following molecular subgroups were identified for pure and mixed uterine CCCs, respectively: POLE mutated 0% (0/18) and 6% (1/18); MSI in 6% (1/18) and 50% (9/18); TP53 wildtype in 56% (10/18) and 22% (4/18); TP53 mutated in 39% (7/18) and 22% (4/18) (p = 0.013). Patients with mixed CCCs had improved outcome compared to patients with pure CCCs. Frequent TP53 mutations were found in pure CCCs and frequent MSI in mixed CCCs, associated with clinical outcome. CONCLUSION: Pure and mixed uterine CCCs are two entities with different clinical outcomes, which could be explained by different molecular backgrounds. These results underline the relevance of both morphological and molecular evaluation, and may assist in tailoring treatment.
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Carcinoma , Neoplasias do Endométrio , Feminino , Humanos , Neoplasias do Endométrio/patologia , Endométrio/patologia , Mutação , Carcinoma/patologia , Estudos Retrospectivos , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/análiseRESUMO
PURPOSE: Preoperative risk stratification of newly diagnosed endometrial carcinoma (EC) patients has been hindered by only moderate prediction performance for many years. Recently ENDORISK, a Bayesian network model, showed high predictive performance. It was the aim of this study to validate ENDORISK by applying the model to a population-based case series of EC patients. METHODS: ENDORISK was applied to a retrospective cohort of women surgically treated for EC from 2003 to 2013. Prediction accuracy for LNM as well as 5-year DSS was investigated. The model's overall performance was quantified by the Brier score, discriminative performance by area under the curve (AUC). RESULTS: A complete dataset was evaluable from 247 patients. 78.1% cases were endometrioid histotype. The majority of patients (n = 156;63.2%) had stage IA disease. Overall, positive lymph nodes were found in 20 (8.1%) patients. Using ENDORISK predicted probabilities, most (n = 156;63.2%) patients have been assigned to low or very low risk group with a false-negative rate of 0.6%. AUC for LNM prediction was 0.851 [95% confidence interval (CI) 0.761-0.941] with a Brier score of 0.06. For 5-year DSS the AUC was 0.698 (95% CI 0.595-0.800) as Brier score has been calculated 0.09. CONCLUSIONS: We were able to successfully validate ENDORISK for prediction of LNM and 5-year DSS. Next steps will now have to focus on ENDORISK performance in daily clinical practice. In addition, incorporating TCGA-derived molecular subtypes will be of key importance for future extended use. This study may support further promoting of data-based decision-making tools for personalized treatment of EC.
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Neoplasias do Endométrio , Humanos , Feminino , Prognóstico , Estudos Retrospectivos , Teorema de Bayes , Neoplasias do Endométrio/patologia , Medição de Risco , Linfonodos/patologiaRESUMO
OBJECTIVE: This study presents the diagnostic performance of four different preoperative imaging workups (IWs) for prediction of lymph node metastases (LNMs) in endometrial cancer (EC): pelvic MRI alone (IW1), MRI and [18F]FDG-PET/CT in all patients (IW2), MRI with selective [18F]FDG-PET/CT if high-risk preoperative histology (IW3), and MRI with selective [18F]FDG-PET/CT if MRI indicates FIGO stage ≥ 1B (IW4). METHODS: In 361 EC patients, preoperative staging parameters from both pelvic MRI and [18F]FDG-PET/CT were recorded. Area under receiver operating characteristic curves (ROC AUC) compared the diagnostic performance for the different imaging parameters and workups for predicting surgicopathological FIGO stage. Survival data were assessed using Kaplan-Meier estimator with log-rank test. RESULTS: MRI and [18F]FDG-PET/CT staging parameters yielded similar AUCs for predicting corresponding FIGO staging parameters in low-risk versus high-risk histology groups (p ≥ 0.16). The sensitivities, specificities, and AUCs for LNM prediction were as follows: IW1-33% [9/27], 95% [185/193], and 0.64; IW2-56% [15/27], 90% [174/193], and 0.73 (p = 0.04 vs. IW1); IW3-44% [12/27], 94% [181/193], and 0.69 (p = 0.13 vs. IW1); and IW4-52% [14/27], 91% [176/193], and 0.72 (p = 0.06 vs. IW1). IW3 and IW4 selected 34% [121/361] and 54% [194/361] to [18F]FDG-PET/CT, respectively. Employing IW4 identified three distinct patient risk groups that exhibited increasing FIGO stage (p < 0.001) and stepwise reductions in survival (p ≤ 0.002). CONCLUSION: Selective [18F]FDG-PET/CT in patients with high-risk MRI findings yields better detection of LNM than MRI alone, and similar diagnostic performance to that of MRI and [18F]FDG-PET/CT in all. KEY POINTS: ⢠Imaging by MRI and [18F]FDG PET/CT yields similar diagnostic performance in low- and high-risk histology groups for predicting central FIGO staging parameters. ⢠Utilizing a stepwise imaging workup with MRI in all patients and [18F]FDG-PET/CT in selected patients based on MRI findings identifies preoperative risk groups exhibiting significantly different survival. ⢠The proposed imaging workup selecting ~54% of the patients to [18F]FDG-PET/CT yield better detection of LNMs than MRI alone, and similar LNM detection to that of MRI and [18F]FDG-PET/CT in all.
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Neoplasias do Endométrio , Fluordesoxiglucose F18 , Feminino , Humanos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Tomografia por Emissão de Pósitrons/métodos , Linfonodos/diagnóstico por imagem , Linfonodos/patologia , Imageamento por Ressonância Magnética/métodos , Neoplasias do Endométrio/diagnóstico por imagem , Neoplasias do Endométrio/cirurgia , Metástase Linfática/diagnóstico por imagem , Metástase Linfática/patologia , Estadiamento de Neoplasias , Compostos Radiofarmacêuticos/farmacologiaRESUMO
The development and validation of Clinical Decision Support Models (CDSM) based on Bayesian networks (BN) is commonly done in a collaborative work between medical researchers providing the domain expertise and computer scientists developing the decision support model. Although modern tools provide facilities for data-driven model generation, domain experts are required to validate the accuracy of the learned model and to provide expert knowledge for fine-tuning it while computer scientists are needed to integrate this knowledge in the learned model (hybrid modeling approach). This generally time-expensive procedure hampers CDSM generation and updating. To address this problem, we developed a novel interactive visual approach allowing medical researchers with less knowledge in CDSM to develop and validate BNs based on domain specific data mainly independently and thus, diminishing the need for an additional computer scientist. In this context, we abstracted and simplified the common workflow in BN development as well as adjusted the workflow to medical experts' needs. We demonstrate our visual approach with data of endometrial cancer patients and evaluated it with six medical researchers who are domain experts in the gynecological field.
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Sistemas de Apoio a Decisões Clínicas , Humanos , Teorema de Bayes , Gráficos por ComputadorRESUMO
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.
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Neoplasias do Endométrio , Progestinas , Feminino , Humanos , Progestinas/efeitos adversos , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/patologiaRESUMO
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.
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Carcinoma Endometrioide , Neoplasias do Endométrio , Feminino , Humanos , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Carcinoma Endometrioide/patologia , Estudos Retrospectivos , Estudos de Coortes , PrognósticoRESUMO
Histopathologic assessment of high-risk endometrial cancer (EC) suffers from intersubject variability and poor reproducibility. The pragmatic classification in four molecular subgroups helps to overcome these limits, showing a significant prognostic value. The "no specific molecular profile" (NSMP) is the most heterogeneous EC subgroup, requiring further characterization to better guide its clinical management. DNA sequencing of POLE exonuclease domain and immunohistochemistry for PMS2, MSH6, and p53 were performed in order to stratify a cohort of 94 high-risk EC patients in the four molecular subgroups. Moreover, a panel of seven additional biomarkers was tested. Patients were found to be 16% POLE-mutated, 36% mismatch repair-deficient, 27% p53-abnormal, and 21% NSMP. In the multivariable model, molecular groups confirmed their significant association with disease-specific survival and progression-free survival, with p53-abnormal and NSMP endometrial cancer characterized by poor outcomes. Among the additional evaluated biomarkers, L1CAM was the only one with a significant prognostic value within the NSMP subgroup. NSMP/L1CAM-positive patients experienced the worst outcome and were "early-relapsing" after platinum-based chemotherapy, with a significantly shorter platinum-free interval compared to L1CAM-negative patients. L1CAM appears to be a promising candidate as a prognostic and predictive biomarker in the high-risk NSMP subgroup, which is actually known to lack specific molecular markers.