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Gene expression values

Differential expression results

Supplementary Figure 1: Log-transformed Quantile-Quantile plots of the Univariate Survival Analysis p-values. P-values derived from the univariate survival analysis of the effects of each individual gene was plotted for each fold in which the analysis took place. The horizontal line at 2.52 represents -log(0.003), which was the cutoff for variable selection in the final modeling of survival in the test cohort. Supplementary Figure 2: Abridged representation of the FOXM1 regulatory network. See references [2-5]

Mutation list

Patient characteristics

Mutation list

BackgroundPoly ADP-ribose glycohydrolase (PARG) is responsible for the catabolism of PARP-synthesized PAR to free ADP-ribose. Inhibition of PARG leads to DNA repair interruption and consequently induces cell death. This study aims to evaluate the effect of a PARG inhibitor (PARGi) on epithelial ovarian cancer (OC) cell lines, alone and in combination with a PARP inhibitor (PARPi) and/or Cisplatin.MethodsPARG mRNA levels were studied in three different OC datasets: TCGA, Hendrix, and Meyniel. PARG protein levels were assessed in 100 OC specimens from our bio-bank. The therapeutic efficacy of PARGi was assessed using cell migration and clonogenic formation assays. Flow cytometry was used to evaluate the cell apoptosis rate and the changes in the cell cycle.ResultsPARG protein was highly expressed in 34% of the OC tumors and low expression was found in another 9%. Similarly, Hendrix, Meyneil and TCGA databases showed a significant up-regulation in PARG mRNA expression in OC samples as compared to normal tissue (P=0.001, P=0.005, P=0.005, respectively). The use of PARGi leads to decreased cell migration. PARGi in combination with PARPi or Cisplatin induced decreased survival of cells as compared to each drug alone. In the presence of PARPi and Cisplatin, PARG knockdown cell lines showed significant G2/M cell cycle arrest and cell death induction.ConclusionsPARG inhibition appears as a complementary strategy to PARP inhibition in the treatment of ovarian cancer, especially in the presence of homologous recombination defects.

Severe tricuspid regurgitation (TR) is associated with significant mortality and morbidities. Currently, surgical tricuspid repair with annuloplasty is the gold standard treatment. However, the prohibitive risks of open surgery and increasing evidence that severe TR should be intervened on early has led to an outburst in the development and evolution of transcatheter tricuspid valve interventions (TTVI). These technologies are broadly categorized into direct suture annuloplasty devices, minimally invasive annuloplasty, direct ring annuloplasty devices, coaptation-based strategies, edge-to-edge repair devices, and transcatheter valve replacement. Each has its own set of advantages and limitations and have been tried, to varying degrees of success, in a myriad of pathoanatomic scenarios. Challenges faced in TTVI device and trial designs include heterogeneous patient populations, the need for quality imaging, variations of imaging requirements and anatomic criteria by device, hard-to-define clinical endpoints, and the poor prognosis carried by significant residual TR. Similar to tricuspid valve disease, pulmonic valve (PV) disease can occur on its own or secondary to a congenital heart defect, most commonly tetralogy of Fallot. Many patients with pulmonic stenosis or insufficiency often require repeat surgical interventions for other cardiac problems, highlighting the importance of developing transcatheter approaches to reduce the number of repeat open-heart surgeries required. Transcatheter PV replacement (TPVR) is growing in use and is the procedure of choice in patients with failed bioprostheses via valve-in-valve implantation. The Melody (Medtronic Inc., Minneapolis, Minnesota) and SAPIEN XT (Edwards Lifesciences Inc., Irvine, California) devices are the currently available TPVR technologies. Current limitations here include device kinking, the risk of stent fracture, anatomic difficulties, such as asymmetric right ventricular outflow tracts leading to poor landing zones and procedural risks of coronary artery and aortic root compression.

Objective: Evaluation of the impact of lower uterine segment involvement (LUSI) in type II endometrial cancer, and mutational profile of uterine papillary serous carcinomas (UPSC). Methods: Retrospective cohort study comparing patients with type II endometrial cancer with LUSI to patients without LUSI. Genes commonly implicated in carcinogenesis were analyzed in a subgroup of 42 patients with UPSC using next generation sequencing. Results: 83 patients with type II endometrial cancer were included in the study, of these, LUSI was diagnosed in 31.3%. During a median follow-up of 45.5 months, patients with LUSI developed more local and distant recurrences (local: 19.2% vs. 3.5%, P = .03; distant: 50% vs. 17.5%, P = .004) and progression events (73.1% vs. 26.3%, P

Objective The expression of homologous recombination (HR) genes in high grade ovarian cancer (HGOC) samples from debulking surgeries were correlated to outcomes in patients selected for chemotherapy treatment regimens. Study design RNA was extracted from 96 fresh frozen tumor samples from debulking surgeries from chemotherapy naive patients with HGOC (primary derived surgeries (PDS), n = 55) or following neoadjuvant chemotherapy treatment (NACT), n = 41). The samples were selected for high tumor content by a gynecological pathologist, and cancer cell content was further confirmed using a percent tumor content covariate, and mutation score covariate analysis. Gene expression analysis was performed using a tailored NanoString-based Pancancer Pathway Panel. Cox proportional hazard regression models were used to assess the associations between the expression of 19 HR genes and survival. Results In the PDS group, over-expression of six HR genes (C11orf30, NBN, FANCF, FANCC, FANCB, RAD50) was associated with improved outcome, in contrast to the NACT group where four HR genes (BRCA2, TP53, FANCB, RAD51) were associated with worse outcome. With the adding extent of debulking as a covariate, three HR genes (NBN, FANCF, RAD50), and only one HR gene (RAD51) remained significantly associated with survival in PDS and NACT groups, respectively. Conclusion Distinct HR expression profiles define subgroups associated with overall outcome in patients that are exposed to neoadjuvant chemotherapy and not only chemotherapy-naive patients.

Objective Pilot study to assess the value of weekly paclitaxel plus carboplatin every 3weeks (dose dense regimen, DD) compared to the standard 3-weekly protocol in the adjuvant setting for endometrial cancer. Methods Retrospective cohort study comparing consecutive patients with high and intermediate-high risk endometrial cancer, undergoing DD protocol (from 2011 to 2015) to a non-overlapping historical cohort with similar characteristics who received treatment every three weeks (2008–2011). Results 122 patients with endometrial cancer were included in the study, of these, 61 patients received the dose dense protocol and 61 were treated with the standard 3-weekly protocol. After a median follow-up of 61.6months in the 3-weekly cohort, compared with 41.6months in the DD cohort, 40 progressions were recorded. 29 progressions were observed in women treated in the standard protocol, with a three years progression free survival (PFS) of 57.4%, compared to 11 progressions observed in patients in the DD schedule, with a three years PFS of 79.5% ( P =0.03). Patients who were treated with the DD protocol were less likely to have progression events compared to the standard cohort with a hazard ratio of 0.4 on multivariate analysis (CI 95%, 0.2–0.8, P =0.01), had significantly less distant metastases ( P =0.01), and had improved overall survival when diagnosed with advanced stage disease ( P =0.02). Complaints of musculoskeletal pain were more frequent in the standard cohort ( n =17, 27.9%) compared to the dose dense cohort ( n =4, 6.6%), P =0.005. Conclusion Preliminary data suggests that dose dense chemotherapy might be a reasonable and superior option for adjuvant treatment of endometrial cancer, compared to standard chemotherapy.

Highlights • Preoperative diagnosis of endometrioid carcinoma is common in finally diagnosed serous endometrial cancer. • Endometrioid preoperative sample is associated with better outcome in women finally diagnosed with serous uterine cancer. • Endometrioid preoperative sample is reflected in the mutational profile of final pathology., The aim of this study was to evaluate the impact of discordant endometrial sampling on the prognosis of patients finally diagnosed with uterine papillary serous carcinoma (UPSC) and to analyze UPSC mutational profile. Retrospective cohort study comparing outcomes of patients post-operatively diagnosed with UPSC and preoperatively diagnosed with endometrioid endometrial cancer (EEC) or UPSC. Genes commonly implicated in carcinogenesis were analyzed in a subgroup of 40 patients post-operatively diagnosed with UPSC, using next generation sequencing. 61 patients with UPSC on post-surgical, final pathology were included in the study. Prior to surgery, 15 were diagnosed with EEC (discordant) and 46 were correctly diagnosed with UPSC (concordant). After a median follow-up of 41.6 months [5.4–106.7], a preoperative diagnosis of EEC was associated with better 3-year progression-free survival (100% vs. 60.9%, P = 0.003) and longer disease free interval (63.5 versus 15 months, P = 0.026) compared to patients with an initial diagnosis of UPSC. Patients with a concordant diagnosis of UPSC were 5 times more likely to progress or die compared to those with a discordant EEC diagnosis (P = 0.02, P = 0.03, respectively), and their tumors were associated with higher rates of TP53 (88.9% vs. 61.5%, P = 0.04), and a lower rate of PTEN (14.8% vs. 38.5%, P = 0.09) and ARID1A (3.7% vs. 23.1%, P = 0.05) mutations. A pre-surgical diagnosis of EEC is associated with improved prognosis in patients with UPSC. Some histologically defined UPSC tumors contain endometrioid-like molecular characteristics that may confer a survival advantage, suggesting a possible need for molecular approaches to better stratify patients into risk groups.

Recent advances in device design have resulted in a wide variety of transcatheter treatment options for patients with symptomatic mitral valve disease. Surgery remains the gold standard for patients with symptomatic, primary mitral regurgitation, while transcatheter devices can be considered in higher-risk patients. For secondary mitral regurgitation, optimal medical therapy and cardiac resynchronization are recommended. Recent evidence suggests that transcatheter alternatives may be considered as well. This review will provide an overview of current transcatheter mitral repair and replacement technologies. These include those that mimic open surgical procedures such as edge-to-edge repair, choral replacement, direct annuloplasty, and valve replacement.

Objectives Evaluation of the impact of discordant endometrial sampling on the prognosis of patients finally diagnosed with uterine papillary serous carcinoma (UPSC) and analysis of UPSC mutational profile. Methods Retrospective cohort study comparing outcomes of patients with UPSC preoperatively diagnosed with endometrioid endometrial cancer (EEC) or UPSC. Genes commonly implicated in carcinogenesis were analyzed in a subgroup of 40 patients, using next generation sequencing. Results 61 patients with UPSC on post-surgical, final pathology were included in the study. Prior to surgery, 15 were diagnosed with EEC (discordant) and 46 were correctly diagnosed with UPSC (concordant). After a median follow-up of 41.6 months [5.4–106.7], a preoperative diagnosis of EEC was associated with better 3-year progression-free survival (100% vs. 60.9%, P=0.003) and longer disease free interval (63.5 versus 15 months, P=0.026) compared to patients with an initial diagnosis of UPSC. Patients with a concordant diagnosis of UPSC were 5 times more likely to progress or die compared to those with a discordant EEC diagnosis (P=0.02, P=0.03, respectively ), and their tumors were associated with higher rates of TP53 (88.9% vs. 61.5%, P=0.04), and a lower rate of PTEN (14.8% vs. 38.5%, P=0.09)and ARID1A (3.7% vs. 23.1%, P=0.05) mutations. Conclusions A pre-surgical diagnosis of EEC is associated with improved prognosis in patients with UPSC. Some histologically defined UPSC tumors contain endometrioid-like molecular characteristics that may confer a survival advantage.

Large-scale genomic studies have detailed the molecular landscape of tumors from patients with high-grade serous ovarian cancers (HGSC) who underwent primary debulking surgery and correlated the identified subgroups to survival. In recent years, there is increased use of neoadjuvant chemotherapy (NACT) for patients with HGSC and while abundant data exist for patients who underwent primary debulking, little data are available on the cancer cells remaining after NACT that could lead to recurrences. We aimed to analyze gene expression profiles of NACT-treated HGSC tumor samples, and correlate them to treatment response and outcome. Tumor samples were collected from patients with stage III or IV HGSC (NACT cohort, N = 57) at the time of surgery and diagnosis (biopsy samples N = 8). Tumor content was validated by histologic examination and bioinformatics. Gene expression analysis was performed using a tailored NanoString-based assay, while sequencing was performed using MiSeq. A cross-validated survival classifier revealed patient clusters with either a “Better” or “Worse” prognostic outcome. The association with overall survival remained significant after controlling for clinical variables, and differential gene expression, gene set enrichment analyses, and the appropriate survival models were used to assess the associations between alterations in gene expression in cancer cells remaining after NACT and outcome. Pathway-based analysis of the differentially expressed genes revealed comparatively high levels of cell cycle and DNA repair gene expression in the poor outcome group. Implications: Our work suggests mRNA expression patterns in key genes following NACT may reflect response to treatment and outcome in patient with HGSC.

In view of the recent controversy concerning the use of minimally invasive radical hysterectomy as primary treatment for early stage cervical cancer, this study compared the survival and perioperative outcomes in a cohort of patients who underwent radical hysterectomy either by laparotomy or by robotics.This retrospective study compared all consecutive patients with early stage cervical cancer since the beginning of the Division of Gynecologic Oncology at the Jewish General Hospital in 2003, who underwent robotic radical hysterectomy (n = 74) with a cohort of all consecutive patients from the immediate past who underwent open radical hysterectomy (n = 24) for early stage cervical cancer. All patients were treated at the Jewish General Hospital in Montréal (Canadian Task Force Classification II-2).The median follow-up time for the robotic group was 46 months. During that time, 7% and 17% of patients in the robotic group and the laparotomy group had disease recurrence, respectively (P = 0.12). Cox multivariate regression showed no statistically significant effect of surgical approach on overall survival (hazard ratio 1.50, P = 0.63) or on progression-free survival (hazard ratio 0.29, P = 0.07). Patients in the robotic cohort had significantly shorter median hospital stays (1 day vs. 7 days, P 0.001), and their overall incidence of postoperative complications was lower (13% vs. 50%, P 0.001). Median estimated blood loss for robotics was also significantly lower (82 mL vs. 528 mL, P 0.001).Based on the data on a limited number of patients in a Canadian context, robotic radical hysterectomy did not lead to worse oncologic outcomes and was associated with improved short-term surgical outcomes. One might consider the evaluation of more personalized surgical decision making.

BACKGROUND: Poly(ADP-ribose) glycohydrolase (PARG) is responsible poly(ADP-ribose) (PAR) catabolism, which is synthesized by poly(ADP-ribose) polymerases (PARPs) at the site of DNA single-strand breaks (SSB). Faulty PAR formation or disintegration inhibits SSB repair. PARP inhibitors (PARPi) exploit the synthetic lethality between SSB repair and homologous recombination (HR) double strand break (DSB) repair. The most effective PARPi traps PARP at the SSB site, causing a double strand break during DNA synthesis that the cell cannot repair. The trapping of PARP can also be achieved through PARG inhibition. Due to the high rate of HR defects in epithelial ovarian cancer, the aim of this study is to evaluate the effect of a PARG inhibitor (PARGi) on epithelial ovarian cancer cell lines, alone and in combination with PARPi or cisplatin. METHODS: PARG protein levels were assessed in 74, unselected, snap-frozen, tumors kept in our bio-bank by western blotting and immuno-histochemistry (IHC), as well as in the TCGA database. PARG was knocked down in two cell lines resistant to PARP inhibition, OVCAR3 and SKOV3. The knockdowns were subjected to cell migration and cell proliferation assays, as well as single cell analysis. BRCA1 mutated and BRCA1 wild-type cell lines were exposed to clinically relevant doses of PARGi, PARPi, or cisplatin, separately or in various combination. Therapeutic efficacy was assessed using colony formation assay. Western Blotting was used to detect the levels of PARG and PARP proteins in the cell lines. RESULTS: PARG mRNA was expressed in 30% of tumors in TCGA. PARG protein was also detected in 30% of the biobank tumors analyzed. PARG knockdowns exhibited reduced rates of cellular proliferation and significant G2/M cell cycle arrest. In PARG over expressed ovarian cancer cell lines, PARG inhibitor similarly reduced cell migration (OVCAR3 and SKOV3: 75% reduction, SNU-251: 48% reduction). CONCLUSION: PARG inhibition appears to be a viable, complementary strategy to PARP inhibition in HR-deficient cancers. The effect of BRCA1 on the efficacy of PARG inhibition, as well as various treatment combinations, are currently under investigation. Citation Format: Emad Matanes, Tahira Baloch , David Octeau, Roy Kessous, Liron Kogan, Ido Laskov, Walter Gotlieb, Amber Yasmeen. INHIBITION OF PARG, SENSITIZES OVARIAN CANCER CELLS TO PARP INHIBITORS AND DNA DAMAGING AGENTS [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr NT-117.

BACKGROUND: Ovarian cancer is the most lethal gynecologic cancer. High grade serous ovarian cancer (HGSC) is the most common and deadly histological subtype. The current standard treatment protocol involves primary debulking surgery followed by platinum-based combination chemotherapy. PARP inhibitors(PARPi) are the first approved personalized treatments used in BRCA1-mutated recurrent ovarian cancer patients and have shown promising clinical results. Previously published data in collaboration with Dr. Witcher's lab, we described a significant reduction in PARP1 protein levels in patients after giving standard carboplatinum-paclitaxel chemotherapy that is effecting the clinical efficacy of PARP inhibitors in clinical trials. PARP inhibitors are currently administered after standard chemotherapy, when PARP levels are the lowest which was clearly shown in the previous published paper. Applying novel strategy and following the sequence of administration, giving PARP inhibitors first followed by standard chemotherapy might improve response rates. This study aims to evaluate this strategy (in vitro) in the pre-clinical models. METHODS: BRCA1 mutated (UWB1.287, SNU-251), epigenetically silenced (OVCAR8), and wild-type BRCA1 (OVCAR3, SKOV3, A2780P & A2780R) cell lines were exposed to clinically relevant doses of PARPi, either followed by standard chemotherapy, or the inverse sequence. Therapeutic efficacy was assessed using colony formation assay. Apoptotic index was evaluated by cell cycle analysis and apoptotic assays using flow cytometry. Western Blotting was used to detect the levels of relevant apoptotic and cell cycle proteins. RESULTS: Exposure to PARPi prior to standard chemotherapy sensitized BRCA1 mutated or epigenetically silenced BRCA1 cell lines to lower doses of Cisplatin (CP) or Paclitaxel (PT). Similarly, pre-treatment with PARPi prior to chemotherapy induced apoptosis more effectively in the same cell lines. Similar results were observed in BRCA1 wild-type cell lines and cell lines in which BRCA1 functionality was restored. CONCLUSION: Pre-treatment of cell lines with PARPi followed by standard chemotherapy is more efficient (in vitro) in inhibiting growth and inducing apoptosis than the present sequence of chemotherapy followed by PARPi. Citation Format: Tahira Baloch, Roy Kessous, David Octeau , Liron Kogan, Ido Laskov, Michael Witcher, Walter H. Gotlieb and Amber Yasmeen. SEQUENTIAL THERAPEUTIC TARGETING OF OVARIAN CANCER HARBORING DYSFUNCTIONAL BRCA1 [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr NT-118.