Continuity Unveiled: Evaluating Cytoreduction Outcomes for Advanced Ovarian Cancer Amidst the COVID-19 Era at an ESGO Designated Centre of Excellence.

BACKGROUND/AIM: The COVID-19 pandemic brought unprecedented global changes, necessitating adjustments to address public health challenges. The impact on advanced epithelial ovarian cancer (EOC) surgery, marked by increased perioperative risks, and changes in management plans was explored in this study based on promptly published British Gynaecologic Cancer Society (BGCS) and European Society of Gynaecologic Oncology (ESGO) guidelines. PATIENTS AND METHODS: Retrospective data from 332 patients with advanced EOC who underwent cytoreductive surgery at a UK tertiary center were analyzed, and the outcomes were compared between pre-COVID-19 (2018-2019) (n=189) and COVID-19 era (2020-2021) (n=143) cohorts, covering the same timeframe (March to December). Primary outcomes included residual disease (RD) and progression-free survival (PFS), while secondary outcomes were the ESGO quality indicators (QIs) for advanced EOC surgery. Kaplan-Meier curves were produced to illustrate PFS. RESULTS: Complete cytoreduction rates remained comparable at 74.07% and 72.03% for pre-COVID-19 and COVID-19 groups, respectively. Differences were observed in ECOG performance status (p=0.015), Intensive Care Unit (ICU) admissions (p=0.039) with less interval debulking surgeries (p=0.03), lower surgical complexity scores (p=0.02), and longer operative times in the COVID-19 group (p=0.01) compared to the pre-COVID-19 group. The median PFS rates were 37 months and 34 months in the pre-COVID-19 and COVID-19 groups, respectively (p=0.08). The surgical QIs 1-3 remained uncompromised during the COVID-19 era. CONCLUSION: Management modifications prompted by the COVID-19 pandemic did not adversely impact cytoreduction rates or PFS.

Prerequisites to improve surgical cytoreduction in FIGO stage III/IV epithelial ovarian cancer and subsequent clinical ramifications.

BACKGROUND: No residual disease (CC 0) following cytoreductive surgery is pivotal for the prognosis of women with advanced stage epithelial ovarian cancer (EOC). Improving CC 0 resection rates without increasing morbidity and no delay in subsequent chemotherapy favors a better outcome in these women. Prerequisites to facilitate this surgical paradigm shift and subsequent ramifications need to be addressed. This quality improvement study assessed 559 women with advanced EOC who had cytoreductive surgery between January 2014 and December 2019 in our tertiary referral centre. Following implementation of the Enhanced Recovery After Surgery (ERAS) pathway and prehabilitation protocols, the surgical management paradigm in advanced EOC patients shifted towards maximal surgical effort cytoreduction in 2016. Surgical outcome parameters before, during, and after this paradigm shift were compared. The primary outcome measure was residual disease (RD). The secondary outcome parameters were postoperative morbidity, operative time (OT), length of stay (LOS) and progression-free-survival (PFS). RESULTS: R0 resection rate in patients with advanced EOC increased from 57.3% to 74.4% after the paradigm shift in surgical management whilst peri-operative morbidity and delays in adjuvant chemotherapy were unchanged. The mean OT increased from 133 + 55 min to 197 + 85 min, and postoperative high dependency/intensive care unit (HDU/ICU) admissions increased from 8.1% to 33.1%. The subsequent mean LOS increased from 7.0 + 2.6 to 8.4 + 4.9 days. The median PFS was 33 months. There was no difference for PFS in the three time frames but a trend towards improvement was observed. CONCLUSIONS: Improved CC 0 surgical cytoreduction rates without compromising morbidity in advanced EOC is achievable owing to the right conditions. Maximal effort cytoreductive surgery should solely be carried out in high output tertiary referral centres due to the associated substantial prerequisites and ramifications.

Exploring the Potential Role of Upper Abdominal Peritonectomy in Advanced Ovarian Cancer Cytoreductive Surgery Using Explainable Artificial Intelligence.

The Surgical Complexity Score (SCS) has been widely used to describe the surgical effort during advanced stage epithelial ovarian cancer (EOC) cytoreduction. Referring to a variety of multi-visceral resections, it best combines the numbers with the complexity of the sub-procedures. Nevertheless, not all potential surgical procedures are described by this score. Lately, the European Society for Gynaecological Oncology (ESGO) has established standard outcome quality indicators pertinent to achieving complete cytoreduction (CC0). There is a need to define what weight all these surgical sub-procedures comprising CC0 would be given. Prospectively collected data from 560 surgically cytoreduced advanced stage EOC patients were analysed at a UK tertiary referral centre.We adapted the structured ESGO ovarian cancer report template. We employed the eXtreme Gradient Boosting (XGBoost) algorithm to model a long list of surgical sub-procedures. We applied the Shapley Additive explanations (SHAP) framework to provide global (cohort) explainability. We used Cox regression for survival analysis and constructed Kaplan-Meier curves. The XGBoost model predicted CC0 with an acceptable accuracy (area under curve [AUC] = 0.70; 95% confidence interval [CI] = 0.63-0.76). Visual quantification of the feature importance for the prediction of CC0 identified upper abdominal peritonectomy (UAP) as the most important feature, followed by regional lymphadenectomies. The UAP best correlated with bladder peritonectomy and diaphragmatic stripping (Pearson's correlations > 0.5). Clear inflection points were shown by pelvic and para-aortic lymph node dissection and ileocecal resection/right hemicolectomy, which increased the probability for CC0. When UAP was solely added to a composite model comprising of engineered features, it substantially enhanced its predictive value (AUC = 0.80, CI = 0.75-0.84). The UAP was predictive of poorer progression-free survival (HR = 1.76, CI 1.14-2.70, P: 0.01) but not overall survival (HR = 1.06, CI 0.56-1.99, P: 0.86). The SCS did not have significant survival impact. Machine Learning allows for operational feature selection by weighting the relative importance of those surgical sub-procedures that appear to be more predictive of CC0. Our study identifies UAP as the most important procedural predictor of CC0 in surgically cytoreduced advanced-stage EOC women. The classification model presented here can potentially be trained with a larger number of samples to generate a robust digital surgical reference in high output tertiary centres. The upper abdominal quadrants should be thoroughly inspected to ensure that CC0 is achievable.

RoBERTa-Assisted Outcome Prediction in Ovarian Cancer Cytoreductive Surgery Using Operative Notes.

INTRODUCTION: Contemporary efforts to predict surgical outcomes focus on the associations between traditional discrete surgical risk factors. We aimed to determine whether natural language processing (NLP) of unstructured operative notes improves the prediction of residual disease in women with advanced epithelial ovarian cancer (EOC) following cytoreductive surgery. METHODS: Electronic Health Records were queried to identify women with advanced EOC including their operative notes. The Term Frequency - Inverse Document Frequency (TF-IDF) score was used to quantify the discrimination capacity of sequences of words (n-grams) regarding the existence of residual disease. We employed the state-of-the-art RoBERTa-based classifier to process unstructured surgical notes. Discrimination was measured using standard performance metrics. An XGBoost model was then trained on the same dataset using both discrete and engineered clinical features along with the probabilities outputted by the RoBERTa classifier. RESULTS: The cohort consisted of 555 cases of EOC cytoreduction performed by eight surgeons between January 2014 and December 2019. Discrete word clouds weighted by n-gram TF-IDF score difference between R0 and non-R0 resection were identified. The words 'adherent' and 'miliary disease' best discriminated between the two groups. The RoBERTa model reached high evaluation metrics (AUROC .86; AUPRC .87, precision, recall, and F1 score of .77 and accuracy of .81). Equally, it outperformed models that used discrete clinical and engineered features and outplayed the performance of other state-of-the-art NLP tools. When the probabilities from the RoBERTa classifier were combined with commonly used predictors in the XGBoost model, a marginal improvement in the overall model's performance was observed (AUROC and AUPRC of .91, with all other metrics the same). CONCLUSION/IMPLICATIONS: We applied a sui generis approach to extract information from the abundant textual surgical data and demonstrated how it can be effectively used for classification prediction, outperforming models relying on conventional structured data. State-of-art NLP applications in biomedical texts can improve modern EOC care.

Immune Checkpoint Inhibitors Targeting the PD-1/PD-L1 Pathway in Advanced, Recurrent Endometrial Cancer: A Scoping Review with SWOT Analysis.

Results of recent clinical trials using the immune check point inhibitors (ICI) pembrolizumab or dostarlimab with/without lenvatinib has led to their approval for specific molecular subgroups of advanced recurrent endometrial cancer (EC). Herein, we summarise the clinical data leading to this first tissue-agnostic approval. As this novel therapy is not yet available in the United Kingdom standard care setting, we explore the strengths, weaknesses, opportunities, and threats (SWOT) of ICI treatment in EC. Major databases were searched focusing on clinical trials using programmed cell death protein 1 (PD-1) and its ligand (PD-L1) ICI which ultimately contributed to anti-PD-1 approval in EC. We performed a data quality assessment, reviewing survival and safety analysis. We included 15 studies involving 1609 EC patients: 458 with mismatch repair deficiency (MMRd)/microsatellite instability-high (MSI-H) status and 1084 with mismatch repair proficiency/microsatellite stable (MMRp/MSS) status. Pembrolizumab/dostarlimab have been approved for MMRd ECs, with the addition of lenvatinib for MMRp cases in the recurrent setting. Future efforts will focus on the pathological assessment of biomarkers to determine molecular phenotypes that correlate with response or resistance to ICI in order to identify patients most likely to benefit from this treatment.

The Future of AI in Ovarian Cancer Research: The Large Language Models Perspective.

Conversational large language model (LLM)-based chatbots utilize neural networks to process natural language. By generating highly sophisticated outputs from contextual input text, they revolutionize the access to further learning, leading to the development of new skills and personalized interactions. Although they are not developed to provide healthcare, their potential to address biomedical issues is rather unexplored. Healthcare digitalization and documentation of electronic health records is now developing into a standard practice. Developing tools to facilitate clinical review of unstructured data such as LLMs can derive clinical meaningful insights for ovarian cancer, a heterogeneous but devastating disease. Compared to standard approaches, they can host capacity to condense results and optimize analysis time. To help accelerate research in biomedical language processing and improve the validity of scientific writing, task-specific and domain-specific language models may be required. In turn, we propose a bespoke, proprietary ovarian cancer-specific natural language using solely in-domain text, whereas transfer learning drifts away from the pretrained language models to fine-tune task-specific models for all possible downstream applications. This venture will be fueled by the abundance of unstructured text information in the electronic health records resulting in ovarian cancer research ultimately reaching its linguistic home.

A Systematic Review of Systematic Reviews on the Use of Aromatase Inhibitors for the Treatment of Endometriosis: The Evidence to Date.

Endometriosis is a chronic gynecologic condition that affects around 6-10% of reproductive age women. This clinical entity is characterized with pelvic pain, dysmenorrhea, dyspareunia, and infertility which are the most often presenting symptoms. Aromatase P450 is the key enzyme for ovarian estrogen biosynthesis and there is evidence that endometriotic lesions express aromatase and are able to synthesize their own estrogens. Aromatase inhibitors (AIs) are potent drugs that suppress the estrogen synthesis via suppression of aromatase. We performed a systematic review of systematic reviews and narrative reviews on the use of aromatase inhibitors in the medical management of endometriosis. We searched: PubMed (1950-2022), Google Scholar (2004-2022), Cochrane Library (2010-2022) and Researchgate (2010-2022). The search included the following medical subject headings (MeSH) or keywords: "Aromatase Inhibitors" AND "Endometriosis" AND "Systematic reviews" OR "Systematic review" AND "Reviews" OR "Reviews" AND "Endometriosis". The electronic database search yielded initially 12,106 studies from the different databases. Further assessment of the studies resulted in exclusion of (n = 12,015) studies due to duplicates and irrelevance; Finally, 24 studies were selected for inclusion, 5 were Systematic reviews and 19 were Narrative reviews. The 5 systematic reviews were assessed by AMSTAR-2 criteria and were found to have low quality. Narrative reviews were assessed with SANRA criteria and were found to have high-quality aromatase inhibitors are potent drugs that can manage the endometriosis-related symptoms in cases where initial medical management has failed to show positive results. However, their use is limited by the adverse effects that are linked with menopausal symptoms. aromatase inhibitors can be administered as an alternative treatment in patients. Future studies with randomized design are required to reach safer conclusions and further investigation. These studies should define the therapeutic dose, new add-back therapy modalities. Future directions should examine the most-appropriate way of administration and the duration of therapy.

Development of a Novel Intra-Operative Score to Record Diseases' Anatomic Fingerprints (ANAFI Score) for the Prediction of Complete Cytoreduction in Advanced-Stage Ovarian Cancer by Using Machine Learning and Explainable Artificial Intelligence.

BACKGROUND: The Peritoneal Carcinomatosis Index (PCI) and the Intra-operative Mapping for Ovarian Cancer (IMO), to a lesser extent, have been universally validated in advanced-stage epithelial ovarian cancer (EOC) to describe the extent of peritoneal dissemination and are proven to be powerful predictors of the surgical outcome with an added sensitivity of assessment at laparotomy of around 70%. This leaves room for improvement because the two-dimensional anatomic scoring model fails to reflect the patient's real anatomy, as seen by a surgeon. We hypothesized that tumor dissemination in specific anatomic locations can be more predictive of complete cytoreduction (CC0) and survival than PCI and IMO tools in EOC patients. (2) Methods: We analyzed prospectively data collected from 508 patients with FIGO-stage IIIB-IVB EOC who underwent cytoreductive surgery between January 2014 and December 2019 at a UK tertiary center. We adapted the structured ESGO ovarian cancer report to provide detailed information on the patterns of tumor dissemination (cancer anatomic fingerprints). We employed the extreme gradient boost (XGBoost) to model only the variables referring to the EOC disseminated patterns, to create an intra-operative score and judge the predictive power of the score alone for complete cytoreduction (CC0). Receiver operating characteristic (ROC) curves were then used for performance comparison between the new score and the existing PCI and IMO tools. We applied the Shapley additive explanations (SHAP) framework to support the feature selection of the narrated cancer fingerprints and provide global and local explainability. Survival analysis was performed using Kaplan-Meier curves and Cox regression. (3) Results: An intra-operative disease score was developed based on specific weights assigned to the cancer anatomic fingerprints. The scores range from 0 to 24. The XGBoost predicted CC0 resection (area under curve (AUC) = 0.88 CI = 0.854-0.913) with high accuracy. Organ-specific dissemination on the small bowel mesentery, large bowel serosa, and diaphragmatic peritoneum were the most crucial features globally. When added to the composite model, the novel score slightly enhanced its predictive value (AUC = 0.91, CI = 0.849-0.963). We identified a "turning point", ≤5, that increased the probability of CC0. Using conventional logistic regression, the new score was superior to the PCI and IMO scores for the prediction of CC0 (AUC = 0.81 vs. 0.73 and 0.67, respectively). In multivariate Cox analysis, a 1-point increase in the new intra-operative score was associated with poorer progression-free (HR: 1.06; 95% CI: 1.03-1.09, p < 0.005) and overall survival (HR: 1.04; 95% CI: 1.01-1.07), by 4% and 6%, respectively. (4) Conclusions: The presence of cancer disseminated in specific anatomical sites, including small bowel mesentery, large bowel serosa, and diaphragmatic peritoneum, can be more predictive of CC0 and survival than the entire PCI and IMO scores. Early intra-operative assessment of these areas only may reveal whether CC0 is achievable. In contrast to the PCI and IMO scores, the novel score remains predictive of adverse survival outcomes.

Explaining the Elusive Nature of a Well-Defined Threshold for Blood Transfusion in Advanced Epithelial Ovarian Cancer Cytoreductive Surgery.

There is no well-defined threshold for intra-operative blood transfusion (BT) in advanced epithelial ovarian cancer (EOC) surgery. To address this, we devised a Machine Learning (ML)-driven prediction algorithm aimed at prompting and elucidating a communication alert for BT based on anticipated peri-operative events independent of existing BT policies. We analyzed data from 403 EOC patients who underwent cytoreductive surgery between 2014 and 2019. The estimated blood volume (EBV), calculated using the formula EBV = weight × 80, served for setting a 10% EBV threshold for individual intervention. Based on known estimated blood loss (EBL), we identified two distinct groups. The Receiver operating characteristic (ROC) curves revealed satisfactory results for predicting events above the established threshold (AUC 0.823, 95% CI 0.76-0.88). Operative time (OT) was the most significant factor influencing predictions. Intra-operative blood loss exceeding 10% EBV was associated with OT > 250 min, primary surgery, serous histology, performance status 0, R2 resection and surgical complexity score > 4. Certain sub-procedures including large bowel resection, stoma formation, ileocecal resection/right hemicolectomy, mesenteric resection, bladder and upper abdominal peritonectomy demonstrated clear associations with an elevated interventional risk. Our findings emphasize the importance of obtaining a rough estimate of OT in advance for precise prediction of blood requirements.

Stratification of Length of Stay Prediction following Surgical Cytoreduction in Advanced High-Grade Serous Ovarian Cancer Patients Using Artificial Intelligence; the Leeds L-AI-OS Score.

(1) Background: Length of stay (LOS) has been suggested as a marker of the effectiveness of short-term care. Artificial Intelligence (AI) technologies could help monitor hospital stays. We developed an AI-based novel predictive LOS score for advanced-stage high-grade serous ovarian cancer (HGSOC) patients following cytoreductive surgery and refined factors significantly affecting LOS. (2) Methods: Machine learning and deep learning methods using artificial neural networks (ANN) were used together with conventional logistic regression to predict continuous and binary LOS outcomes for HGSOC patients. The models were evaluated in a post-hoc internal validation set and a Graphical User Interface (GUI) was developed to demonstrate the clinical feasibility of sophisticated LOS predictions. (3) Results: For binary LOS predictions at differential time points, the accuracy ranged between 70-98%. Feature selection identified surgical complexity, pre-surgery albumin, blood loss, operative time, bowel resection with stoma formation, and severe postoperative complications (CD3-5) as independent LOS predictors. For the GUI numerical LOS score, the ANN model was a good estimator for the standard deviation of the LOS distribution by ± two days. (4) Conclusions: We demonstrated the development and application of both quantitative and qualitative AI models to predict LOS in advanced-stage EOC patients following their cytoreduction. Accurate identification of potentially modifiable factors delaying hospital discharge can further inform services performing root cause analysis of LOS.

Survival and Chemosensitivity in Advanced High Grade Serous Epithelial Ovarian Cancer Patients with and without a BRCA Germline Mutation: More Evidence for Shifting the Paradigm towards Complete Surgical Cytoreduction.

Background and Objectives: Approximately 10−15% of high-grade serous ovarian cancer (HGSOC) cases are related to BRCA germline mutations. Better survival rates and increased chemosensitivity are reported in patients with a BRCA 1/2 germline mutation. However, the FIGO stage and histopathological entity may have been confounding factors. This study aimed to compare chemotherapy response and survival between patients with and without a BRCA 1/2 germline mutation in advanced HGSOC receiving neoadjuvant chemotherapy (NACT). Materials and Methods: A cohort of BRCA-tested advanced HGSOC patients undergoing cytoreductive surgery following NACT was analyzed for chemotherapy response and survival. Neoadjuvant chemotherapy served as a vehicle to assess chemotherapy response on biochemical (CA125), histopathological (CRS), biological (dissemination), and surgical (residual disease) levels. Univariate and multivariate analyses for chemotherapy response and survival were utilized. Results: Thirty-nine out of 168 patients had a BRCA ½ germline mutation. No differences in histopathological chemotherapy response between the patients with and without a BRCA ½ germline mutation were observed. Survival in the groups of patients was comparable Irrespective of the BRCA status, CRS 2 and 3 (HR 7.496, 95% CI 2.523−22.27, p < 0.001 & HR 4.069, 95% CI 1.388−11.93, p = 0.011), and complete surgical cytoreduction (p = 0.017) were independent parameters for a favored overall survival. Conclusions: HGSOC patients with or without BRCA ½ germline mutations, who had cytoreductive surgery, showed comparable chemotherapy responses and subsequent survival. Irrespective of BRCA status, advanced-stage HGSOC patients have a superior prognosis with complete surgical cytoreduction and good histopathological response to chemotherapy.

Factors Predicting Surgical Effort Using Explainable Artificial Intelligence in Advanced Stage Epithelial Ovarian Cancer.

(1) Background: Surgical cytoreduction for epithelial ovarian cancer (EOC) is a complex procedure. Encompassed within the performance skills to achieve surgical precision, intra-operative surgical decision-making remains a core feature. The use of eXplainable Artificial Intelligence (XAI) could potentially interpret the influence of human factors on the surgical effort for the cytoreductive outcome in question; (2) Methods: The retrospective cohort study evaluated 560 consecutive EOC patients who underwent cytoreductive surgery between January 2014 and December 2019 in a single public institution. The eXtreme Gradient Boosting (XGBoost) and Deep Neural Network (DNN) algorithms were employed to develop the predictive model, including patient- and operation-specific features, and novel features reflecting human factors in surgical heuristics. The precision, recall, F1 score, and area under curve (AUC) were compared between both training algorithms. The SHapley Additive exPlanations (SHAP) framework was used to provide global and local explainability for the predictive model; (3) Results: A surgical complexity score (SCS) cut-off value of five was calculated using a Receiver Operator Characteristic (ROC) curve, above which the probability of incomplete cytoreduction was more likely (area under the curve [AUC] = 0.644; 95% confidence interval [CI] = 0.598−0.69; sensitivity and specificity 34.1%, 86.5%, respectively; p = 0.000). The XGBoost outperformed the DNN assessment for the prediction of the above threshold surgical effort outcome (AUC = 0.77; 95% [CI] 0.69−0.85; p < 0.05 vs. AUC 0.739; 95% [CI] 0.655−0.823; p < 0.95). We identified "turning points" that demonstrated a clear preference towards above the given cut-off level of surgical effort; in consultant surgeons with <12 years of experience, age <53 years old, who, when attempting primary cytoreductive surgery, recorded the presence of ascites, an Intraoperative Mapping of Ovarian Cancer score >4, and a Peritoneal Carcinomatosis Index >7, in a surgical environment with the optimization of infrastructural support. (4) Conclusions: Using XAI, we explain how intra-operative decisions may consider human factors during EOC cytoreduction alongside factual knowledge, to maximize the magnitude of the selected trade-off in effort. XAI techniques are critical for a better understanding of Artificial Intelligence frameworks, and to enhance their incorporation in medical applications.

Outcomes of ovarian transposition in cervical cancer; an updated meta-analysis.

BACKGROUND: Cervical cancer is the most common indication for ovarian transposition in reproductive-age women. Ovarian transposition should be performed in premenopausal women undergoing pelvic irradiation to preserve ovarian function, and prevent early menopause. As women become more knowledgeable about their fertility options, it is still unclear who will benefit from the intervention. We updated our previous meta-analysis of ovarian function preservation, symptomatic ovarian cysts, and metastases to the transposed ovaries following ovarian transposition in cervical cancer patients to further guide current clinical practice. METHODS: A systematic search of Medline, Embase, Web of Science, and The Cochrane Library databases, dating from January 1980 to July 2021, was conducted. We computed the summary proportions of women who had ovarian function preservation, non-ovarian cyst formation and metastases to the transposed ovaries following ovarian transposition by random-effects meta-analysis and we explored study heterogeneity by type of radiotherapy. RESULTS: There were 29 publications reporting on 1160 women with cervical cancer who underwent ovarian transposition. In the group that underwent surgery alone, 91% of the women had preserved ovarian function (95% CI 83-100), 89% (95% CI 80-99) of women who did not develop ovarian cysts, and 99% (95% CI 1-5) of women who did not suffer metastases to the transposed ovaries. In the surgery ± brachytherapy (BR) group, the proportion of women with the preserved ovarian function was 93% (95% CI 76-113), 84% (95% CI 69-103) of women who did not develop ovarian cysts, and 99% (95% CI 82-120) of women who did not suffer metastases to the transposed ovaries. In the external beam pelvic radiotherapy (EBRT) ± BR ± surgery group, the proportion of women with the preserved ovarian function was 61% (95% CI 55-69), and 95% (95% CI 85-107) of women who developed ovarian cysts. There were no metastases to the transposed ovaries in that group. CONCLUSIONS: In women with cervical cancer, ovarian transposition offers a significant preservation of the ovarian function. Despite an expected incidence of ovarian cyst formation, it carries almost no risk for metastases to the transposed ovaries.

Explainable Artificial Intelligence for Prediction of Complete Surgical Cytoreduction in Advanced-Stage Epithelial Ovarian Cancer.

Complete surgical cytoreduction (R0 resection) is the single most important prognosticator in epithelial ovarian cancer (EOC). Explainable Artificial Intelligence (XAI) could clarify the influence of static and real-time features in the R0 resection prediction. We aimed to develop an AI-based predictive model for the R0 resection outcome, apply a methodology to explain the prediction, and evaluate the interpretability by analysing feature interactions. The retrospective cohort finally assessed 571 consecutive advanced-stage EOC patients who underwent cytoreductive surgery. An eXtreme Gradient Boosting (XGBoost) algorithm was employed to develop the predictive model including mostly patient- and surgery-specific variables. The Shapley Additive explanations (SHAP) framework was used to provide global and local explainability for the predictive model. The XGBoost accurately predicted R0 resection (area under curve [AUC] = 0.866; 95% confidence interval [CI] = 0.8−0.93). We identified "turning points" that increased the probability of complete cytoreduction including Intraoperative Mapping of Ovarian Cancer Score and Peritoneal Carcinomatosis Index < 4 and <5, respectively, followed by Surgical Complexity Score > 4, patient's age < 60 years, and largest tumour bulk < 5 cm in a surgical environment of optimized infrastructural support. We demonstrated high model accuracy for the R0 resection prediction in EOC patients and provided novel global and local feature explainability that can be used for quality control and internal audit.

The Uncertain Benefit of Adjuvant Chemotherapy in Advanced Low-Grade Serous Ovarian Cancer and the Pivotal Role of Surgical Cytoreduction.

In our center, adjuvant chemotherapy is routinely offered in high-grade serous ovarian cancer (HGSOC) patients but less commonly as a standard treatment in low-grade serous ovarian cancer (LGSOC) patients. This study evaluates the efficacy of this paradigm by analysing survival outcomes and by comparing the influence of different clinical and surgical characteristics between women with advanced LGSOC (n = 37) and advanced HGSOC (n = 300). Multivariate analysis was used to identify independent prognostic features for survival in LGSOC and HGSOC. Adjuvant chemotherapy was given in 99.7% of HGSOC patients versus in 27% of LGSOC (p < 0.0001). The LGSOC patients had greater surgical complexity scores (p < 0.0001), more frequent postoperative ICU/HDU admissions (p = 0.0002), and higher peri-/post-operative morbidity (p < 0.0001) compared to the HGSOC patients. The 5-year OS and progression-free survival (PFS) was 30% and 13% for HGSOC versus 57% and 21.6% for LGSOC, p = 0.016 and p = 0.044, respectively. Surgical complexity (HR 5.3, 95%CI 1.2-22.8, p = 0.024) and complete cytoreduction (HR 62.4, 95% CI 6.8-567.9, p < 0.001) were independent prognostic features for OS in LGSOC. This study demonstrates no clear significant survival advantage of chemotherapy in LGSOC. It highlights the substantial survival benefit of dynamic multi-visceral surgery to achieve complete cytoreduction as the primary treatment for LGSOC patients.

Feature Selection is Critical for 2-Year Prognosis in Advanced Stage High Grade Serous Ovarian Cancer by Using Machine Learning.

INTRODUCTION: Accurate prediction of patient prognosis can be especially useful for the selection of best treatment protocols. Machine Learning can serve this purpose by making predictions based upon generalizable clinical patterns embedded within learning datasets. We designed a study to support the feature selection for the 2-year prognostic period and compared the performance of several Machine Learning prediction algorithms for accurate 2-year prognosis estimation in advanced-stage high grade serous ovarian cancer (HGSOC) patients. METHODS: The prognosis estimation was formulated as a binary classification problem. Dataset was split into training and test cohorts with repeated random sampling until there was no significant difference (p = 0.20) between the two cohorts. A ten-fold cross-validation was applied. Various state-of-the-art supervised classifiers were used. For feature selection, in addition to the exhaustive search for the best combination of features, we used the-chi square test of independence and the MRMR method. RESULTS: Two hundred nine patients were identified. The model's mean prediction accuracy reached 73%. We demonstrated that Support-Vector-Machine and Ensemble Subspace Discriminant algorithms outperformed Logistic Regression in accuracy indices. The probability of achieving a cancer-free state was maximised with a combination of primary cytoreduction, good performance status and maximal surgical effort (AUC 0.63). Standard chemotherapy, performance status, tumour load and residual disease were consistently predictive of the mid-term overall survival (AUC 0.63-0.66). The model recall and precision were greater than 80%. CONCLUSION: Machine Learning appears to be promising for accurate prognosis estimation. Appropriate feature selection is required when building an HGSOC model for 2-year prognosis prediction. We provide evidence as to what combination of prognosticators leads to the largest impact on the HGSOC 2-year prognosis.

Adipocyte-like signature in ovarian cancer minimal residual disease identifies metabolic vulnerabilities of tumor-initiating cells.

Similar to tumor-initiating cells (TICs), minimal residual disease (MRD) is capable of reinitiating tumors and causing recurrence. However, the molecular characteristics of solid tumor MRD cells and drivers of their survival have remained elusive. Here we performed dense multiregion transcriptomics analysis of paired biopsies from 17 ovarian cancer patients before and after chemotherapy. We reveal that while MRD cells share important molecular signatures with TICs, they are also characterized by an adipocyte-like gene expression signature and a portion of them had undergone epithelial-mesenchymal transition (EMT). In a cell culture MRD model, MRD-mimic cells showed the same phenotype and were dependent on fatty acid oxidation (FAO) for survival and resistance to cytotoxic agents. These findings identify EMT and FAO as attractive targets to eradicate MRD in ovarian cancer and make a compelling case for the further testing of FAO inhibitors in treating MRD.

Breast Cancer Patients at Increased Risk of Developing Type II Endometrial Cancer: Relative and Absolute Risk Estimation and Implications for Counseling.

Introduction Breast cancer (BC) is a recognized risk factor for endometrial cancer (EC). Emerging literature indicates that it confers a higher risk of type II EC (T2EC) than type I EC (T1EC). Although some surgeons offer a prophylactic hysterectomy to BC patients referred for risk-reducing bilateral salpingo-oophorectomy, insufficient evidence prevents this from being the standard practice. We aimed to quantify their absolute risk and relative risk (RR) of developing both EC subtypes and identify a higher-risk group that could be considered for prophylactic hysterectomy. Methodology This retrospective service evaluation compared patients diagnosed with BC between 2008 and 2014, who subsequently developed EC within 10 years to those who did not. Absolute risk and RR were calculated using the numbers of regional BC and EC cases within this group, alongside 2009 UK female population and EC incidence statistics. Binary logistic regression generated adjusted odds ratios (ORs) for patient- and disease-specific variables. Results A total of 45 BC patients developed EC, 24 had T1EC and 21 had T2EC. Their RR of developing EC was greater than that of the general population (RR: 12.44, p < 0.0001). Notably, this was higher for T2EC (RR: 33.96, p < 0.001) than T1EC (RR: 8.63, p < 0.0001). Nonetheless, the absolute risk remained low. Tamoxifen exposure was significantly more prevalent among T2EC patients (adjusted OR: 79.61, p = 0.003). Increased age at BC diagnosis was associated with T1EC (adjusted OR: 1.10, p = 0.043) and T2EC (adjusted OR: 1.13, p = 0.03). Neither smoking status nor family history of BC was significantly associated with any outcome. Conclusion Women with BC were more likely to develop T2EC than T1EC, and although the absolute risk was low, the cumulative risk was substantial enough to warrant vigilance. Tamoxifen exposure was significantly predictive of EC, particularly T2EC, and might facilitate risk estimation. Older women at BC diagnosis who receive tamoxifen treatment should be screened and closely monitored for EC. However, given the limitations of normal screening methods for the detection of T2EC, counseling for a prophylactic hysterectomy should also be considered. Clarification of the menopausal status will help make more meaningful recommendations.

Granulosa cell ovarian cancer with synchronous multiple bone metastases: case report of extreme rarity.

BACKGROUND: Adult granulosa cell tumor (AGCT) of the ovary generally has a good prognosis. Recurrences tend to be late and confined to the abdominopelvis. Bone metastases are extremely rare. We report an extremely rare case of AGCT with synchronous multiple bone metastases and discuss diagnostic procedures and management. CASE DESCRIPTION: A 35-year-old woman presented with abdominal bloating. On the day of surgery, acting on the complaint of right shoulder pain, an X-ray revealed a permeative lesion involving the neck of humerus, suggestive of a metastatic pathologic fracture. The patient underwent a full staging debulking surgery. Further imaging demonstrated multiple bone metastases. Histology confirmed an AGCT of the ovary. Diagnosis was established by a core bone biopsy from the left femur showing cells consistent with those seen with granulosa cell tumor. The patient received adjuvant chemotherapy with concurrent zoledronic acid as targeted therapy for her bone metastases. Endocrine systemic maintenance treatment was given. The patient rapidly deteriorated and died from her disease at 20 months from the initial diagnosis. CONCLUSION: Unpredictable biological behavior and clinical manifestations raise a high degree of suspicion for accurate AGCT diagnosis. Management of bone metastases often warrants input from the multidisciplinary team, and treatment may involve chemotherapy, palliative radiotherapy, or orthopaedic interventions.