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.

Phosphatase and Tensin Homolog Is a Potential Target for Ovarian Cancer Sensitization to Cytotoxic Agents.

OBJECTIVES: The phosphatase and tensin homolog (PTEN) tumor suppressor protein has been found to be inactivated or mutated in various human malignancies and to play a role in cisplatin and poly(ADP-ribose) polymerase inhibitor sensitivity. In this study, we assessed the association of PTEN loss with homologous recombination (HR) deficiency and increased chemosensitivity. MATERIALS AND METHODS: The PTEN knockdown models were created using MISSION shRNA lentiviral transduction particles in cell lines derived from normal ovarian surface epithelium and a mixed endometrioid/clear-cell carcinoma. Sensitivity to common therapeutics was assessed using sulforhodamine B assay. Twenty-eight unselected primary epithelial ovarian cancer cultures derived from ascitic fluid collected at the time of surgery and matched genomic DNA were assessed for PTEN mutations using polymerase chain reaction amplification and Sanger sequencing and for mRNA expression using quantitative reverse transcription-polymerase chain reaction; HR was determined using γH2AX/RAD51 assay. The Cancer Genome Atlas data were analyzed using cBioPortal. RESULTS: In the carcinoma cell line, the PTEN knockdown enhanced sensitivity to cisplatin, rucaparib, doxorubicin, camptothecin, paclitaxel, and irradiation. In the primary ovarian cancer cultures, 2 point mutations were found (1105T>TG, 25L>L in 6 cultures and 1508G>GA, 159R>R in 4 cultures). The PTEN mRNA expression varied over 40-fold between the cultures, but did not correlate with HR status or in vitro sensitivity to cisplatin or rucaparib. The Cancer Genome Atlas data showed a rate of 8% alteration in PTEN and a trend toward improved survival in PTEN-mutated cases. CONCLUSIONS: These data indicate that although PTEN mutations in ovarian cancer are rare, PTEN inhibition results in therapeutic sensitization. Therefore, PTEN may be an important therapeutic target, in at least some cancers.

Advanced Ovarian Cancer Displays Functional Intratumor Heterogeneity That Correlates to Ex Vivo Drug Sensitivity.

INTRODUCTION: Epithelial ovarian cancer is recognized to be heterogeneous but is currently treated with a single treatment strategy. Successful patient stratification of emerging chemotherapy agents is dependent upon the availability of reliable biomarkers indicative of the entire tumor. AIM: The aim of this study was to evaluate intertumor and intratumor heterogeneity within a series of epithelial ovarian cancer using homologous recombination (HR) DNA repair status. METHODS: Primary cultures generated from ascites and solid tumor from multiple intra-abdominal sites were characterized by their morphology and expression of protein markers. Results were compared with Formalin fixed paraffin embedded tissue pathology.Homologous recombination function was determined by quantification of nuclear Rad51 foci. Growth inhibition (sulforhodamine B) assays were used to calculate the GI50 for cisplatin and rucaparib. RESULTS: Ascites with matched solid tumor were cultured from 25 patients.Concordance in functional HR status between ascites and solid tumor subcultures was seen in only 13 (52%) of 25 patients. Heterogeneity in HR status was seen even in patients with homogeneous histological subtype. Homologous recombination defective cultures were significantly more sensitive to cisplatin and rucaparib.Additionally, intertumor and intratumor heterogeneity was seen between the expression of epithelial and ovarian markers (EpCAM, cytokeratin, CA125, MOC-31, and vimentin). There was no relationship between heterogeneity of HR functional status and antigen expression. CONCLUSIONS: Intertumor and intratumor functional HR heterogeneity exists that cannot be detected using histological classification. This has implications for biomarker-directed treatment.

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.

Evaluation of safety and efficacy of single-incision mid-urethral short tape procedure (MiniArc™ tape) for stress urinary incontinence under local anaesthesia.

INTRODUCTION AND HYPOTHESIS: The aim of this study was to assess complications and short-term results (3 months and 1 year) from a single-incision mid-urethral tape for stress urinary incontinence. METHODS: Seventy-four women underwent single-incision mid-urethral tape under local anaesthesia, 59 of whom completed a 1-year follow-up. Thirty-seven (50%) suffered urodynamic stress urinary incontinence. The International Consultation on Incontinence Questionnaire--Short Form (ICIQ-SF) was completed in the context of the case history pre-operatively and post-operatively. The duration of follow-up ranged from 91 to 466 days. RESULTS: The use of MiniArc™ tape in our study resulted in the objective cure rate (negative cough stress test) of 74% and 66% at 3 months and 1 year, respectively. Scores with ICIQ-SF questionnaire improved significantly at 3 months and 1 year (p < 0.0001). No major intra-operative complication was reported in our study. CONCLUSIONS: Despite the advantage of being done under local anaesthetic, the overall cure rate is 66% at 1 year.

Machine Learning-Based Risk Prediction of Critical Care Unit Admission for Advanced Stage High Grade Serous Ovarian Cancer Patients Undergoing Cytoreductive Surgery: The Leeds-Natal Score.

Achieving complete surgical cytoreduction in advanced stage high grade serous ovarian cancer (HGSOC) patients warrants an availability of Critical Care Unit (CCU) beds. Machine Learning (ML) could be helpful in monitoring CCU admissions to improve standards of care. We aimed to improve the accuracy of predicting CCU admission in HGSOC patients by ML algorithms and developed an ML-based predictive score. A cohort of 291 advanced stage HGSOC patients with fully curated data was selected. Several linear and non-linear distances, and quadratic discriminant ML methods, were employed to derive prediction information for CCU admission. When all the variables were included in the model, the prediction accuracies were higher for linear discriminant (0.90) and quadratic discriminant (0.93) methods compared with conventional logistic regression (0.84). Feature selection identified pre-treatment albumin, surgical complexity score, estimated blood loss, operative time, and bowel resection with stoma as the most significant prediction features. The real-time prediction accuracy of the Graphical User Interface CCU calculator reached 95%. Limited, potentially modifiable, mostly intra-operative factors contributing to CCU admission were identified and suggest areas for targeted interventions. The accurate quantification of CCU admission patterns is critical information when counseling patients about peri-operative risks related to their cytoreductive surgery.

Exploring the Frequency of Homologous Recombination DNA Repair Dysfunction in Multiple Cancer Types.

Dysfunctional homologous recombination DNA repair (HRR), frequently due to BRCA mutations, is a determinant of sensitivity to platinum chemotherapy and poly(ADP-ribose) polymerase inhibitors (PARPi). In cultures of ovarian cancer cells, we have previously shown that HRR function, based upon RAD51 foci quantification, correlated with growth inhibition ex vivo induced by rucaparib (a PARPi) and 12-month survival following platinum chemotherapy. The aim of this study was to determine the feasibility of measuring HRR dysfunction (HRD) in other tumours, in order to estimate the frequency and hence wider potential of PARPi. A total of 24 cultures were established from ascites sampled from 27 patients with colorectal, upper gastrointestinal, pancreatic, hepatobiliary, breast, mesothelioma, and non-epithelial ovarian cancers; 8 were HRD. Cell growth following continuous exposure to 10 µM of rucaparib was lower in HRD cultures compared to HRR-competent (HRC) cultures. Overall survival in the 10 patients who received platinum-based therapy was marginally higher in the 3 with HRD ascites (median overall survival of 17 months, range 10 to 90) compared to the 7 patients with HRC ascites (nine months, range 1 to 55). HRR functional assessment in primary cultures, from several tumour types, revealed that a third are HRD, justifying the further exploration of PARPi therapy in a broader range of tumours.

Standardized Digital Colposcopy with Dynamic Spectral Imaging for Conservative Patient Management.

BACKGROUND: Colposcopy is subjective and management of young patients with high-grade disease is challenging, as treatments may impair subsequent pregnancies and adversely affect obstetric outcomes. Conservative management of selected patients is becoming more popular amongst clinicians; however it requires accurate assessment and documentation. Novel adjunctive technologies for colposcopy could improve patient care and help individualize management decisions by introducing standardization, increasing sensitivity, and improving documentation. CASE: A nulliparous 27-year-old woman planning pregnancy underwent colposcopy following high-grade cytology. The colposcopic impression was of low-grade changes, whilst the Dynamic Spectral Imaging (DSI) map of the cervix suggested potential high-grade. A DSI-directed biopsy confirmed CIN2. At follow-up, both colposcopy and DSI were suggestive of low-grade disease only, and image comparison confirmed the absence of previously present acetowhite epithelium areas. Histology of the transformation zone following excisional treatment, as per patient's choice, showed no high-grade changes. CONCLUSION: Digital colposcopy with DSI mapping helps standardize colposcopic examinations, increase diagnostic accuracy, and monitor cervical changes over time, improving patient care. When used for longitudinal tracking of disease and when it confirms a negative colposcopy, it can help towards avoiding overtreatment and hence decrease morbidity related to cervical excision.

Ovarian Cancers Harbor Defects in Nonhomologous End Joining Resulting in Resistance to Rucaparib.

Purpose: DNA damage defects are common in ovarian cancer and can be used to stratify treatment. Although most work has focused on homologous recombination (HR), DNA double-strand breaks are repaired primarily by nonhomologous end joining (NHEJ). Defects in NHEJ have been shown to contribute to genomic instability and have been associated with the development of chemoresistance.Experimental Design: NHEJ was assessed in a panel of ovarian cancer cell lines and 47 primary ascetic-derived ovarian cancer cultures, by measuring the ability of cell extracts to end-join linearized plasmid monomers into multimers. mRNA and protein expression of components of NHEJ was determined using RT-qPCR and Western blotting. Cytotoxicities of cisplatin and the PARP inhibitor rucaparib were assessed using sulforhodamine B (SRB) assays. HR function was assessed using γH2AX/RAD51 foci assay.Results: NHEJ was defective (D) in four of six cell lines and 20 of 47 primary cultures. NHEJ function was independent of HR competence (C). NHEJD cultures were resistant to rucaparib (P = 0.0022). When HR and NHEJ functions were taken into account, only NHEJC/HRD cultures were sensitive to rucaparib (compared with NHEJC/HRC P = 0.034, NHEJD/HRC P = 0.0002, and NHEJD/HRD P = 0.0045). The DNA-PK inhibitor, NU7441, induced resistance to rucaparib (P = 0.014) and HR function recovery in a BRCA1-defective cell line.Conclusions: This study has shown that NHEJ is defective in 40% of ovarian cancers, which is independent of HR function and associated with resistance to PARP inhibitors in ex vivo primary cultures. Clin Cancer Res; 23(8); 2050-60. ©2016 AACR.

Bilirubin influences the clinical presentation of pre-eclampsia.

OBJECTIVES: Pre-eclampsia is a placental, inflammatory disease modified by maternal anti-oxidant status to give a syndrome. In its most severe forms pre-eclampsia is followed by maternal and neonatal mortality and morbidity. Bilirubin is a known antioxidant and as such is associated with a reduced risk of cardiovascular and respiratory disease. Hence we aimed to find an association between maternal bilirubin levels and the clinical severity of the disease. STUDY DESIGN: A retrospective observational study of 50,712 pregnancies, 925 of which had pre-eclampsia (1999-2010), to examine the association between bilirubin level and perinatal outcome. RESULTS: In women with pre-eclampsia, those with bilirubin levels in the lowest quintile were more likely to require caesarean section (p=0.001, aOR 2.59 (1.52-5.72)). The lowest quintile of bilirubin levels is associated with an increased risk of poor maternal (p=0.002, aOR 3.52 (95%CI 1.6-7.7)) and infant/fetal (p=0.001, OR=3.05 (95%CI=1.63-5.72)) outcome. CONCLUSIONS: Low levels of bilirubin were associated with poor maternal and infant outcomes in women diagnosed with pre-eclampsia. Bilirubin may act as an anti-oxidant in this condition and thus modify the disease.