Integrative multi-omics analyses to identify the genetic and functional mechanisms underlying ovarian cancer risk regions.

To identify credible causal risk variants (CCVs) associated with different histotypes of epithelial ovarian cancer (EOC), we performed genome-wide association analysis for 470,825 genotyped and 10,163,797 imputed SNPs in 25,981 EOC cases and 105,724 controls of European origin. We identified five histotype-specific EOC risk regions (p value <5 × 10-8) and confirmed previously reported associations for 27 risk regions. Conditional analyses identified an additional 11 signals independent of the primary signal at six risk regions (p value <10-5). Fine mapping identified 4,008 CCVs in these regions, of which 1,452 CCVs were located in ovarian cancer-related chromatin marks with significant enrichment in active enhancers, active promoters, and active regions for CCVs from each EOC histotype. Transcriptome-wide association and colocalization analyses across histotypes using tissue-specific and cross-tissue datasets identified 86 candidate susceptibility genes in known EOC risk regions and 32 genes in 23 additional genomic regions that may represent novel EOC risk loci (false discovery rate <0.05). Finally, by integrating genome-wide HiChIP interactome analysis with transcriptome-wide association study (TWAS), variant effect predictor, transcription factor ChIP-seq, and motifbreakR data, we identified candidate gene-CCV interactions at each locus. This included risk loci where TWAS identified one or more candidate susceptibility genes (e.g., HOXD-AS2, HOXD8, and HOXD3 at 2q31) and other loci where no candidate gene was identified (e.g., MYC and PVT1 at 8q24) by TWAS. In summary, this study describes a functional framework and provides a greater understanding of the biological significance of risk alleles and candidate gene targets at EOC susceptibility loci identified by a genome-wide association study.

Characterization of innate lymphoid cell subsets infiltrating melanoma and epithelial ovarian tumors.

The innate lymphoid cell (ILC) family is composed of heterogeneous innate effector and helper immune cells that preferentially reside in tissues where they promote tissue homeostasis. In cancer, they have been implicated in driving both pro- and anti-tumor responses. This apparent dichotomy highlights the need to better understand differences in the ILC composition and phenotype within different tumor types that could drive seemingly opposite anti-tumor responses. Here, we characterized the frequency and phenotype of various ILC subsets in melanoma metastases and primary epithelial ovarian tumors. We observed high PD-1 expression on ILC subsets isolated from epithelial ovarian tumor samples, while ILC populations in melanoma samples express higher levels of LAG-3. In addition, we found that the frequency of cytotoxic ILCs and NKp46+ILC3 in tumors positively correlates with monocytic cells and conventional type 2 dendritic cells, revealing potentially new interconnected immune cell subsets in the tumor microenvironment. Consequently, these observations may have direct relevance to tumor microenvironment composition and how ILC subset may influence anti-tumor immunity.

Generation of an Inhibitory NK Cell Subset by TGF-ß1/IL-15 Polarization.

NK cells have been shown to exhibit inflammatory and immunoregulatory functions in a variety of healthy and diseased settings. In the context of chronic viral infection and cancer, distinct NK cell populations that inhibit adaptive immune responses have been observed. To understand how these cells arise and further characterize their immunosuppressive role, we examined in vitro conditions that could polarize human NK cells into an inhibitory subset. TGF-ß1 has been shown to induce regulatory T cells in vitro and in vivo; we therefore investigated if TGF-ß1 could also induce immunosuppressive NK-like cells. First, we found that TGF-ß1/IL-15, but not IL-15 alone, induced CD103+CD49a+ NK-like cells from peripheral blood NK cells, which expressed markers previously associated with inhibitory CD56+ innate lymphoid cells, including high expression of GITR and CD101. Moreover, supernatant from ascites collected from patients with ovarian carcinoma also induced CD103+CD49a+ NK-like cells in vitro in a TGF-ß-dependent manner. Interestingly, TGF-ß1/IL-15-induced CD103+CD56+ NK-like cells suppressed autologous CD4+ T cells in vitro by reducing absolute number, proliferation, and expression of activation marker CD25. Collectively, these findings provide new insight into how NK cells may acquire an inhibitory phenotype in TGF-ß1-rich environments.

Sustainability of an enhanced recovery pathway after minimally invasive gynecologic oncology surgery.

OBJECTIVE: Same day discharge is safe after minimally invasive gynecology oncology surgery. Our quality improvement peri-operative program based on enhanced recovery after surgery principles led to an increase in same day discharge from 30% to 75% over a 12 month period. Twelve months after program implementation, we assessed the sustainability of same day discharge rates, determined post-operative complication rates, and evaluated factors affecting same day discharge rates. METHODS: A retrospective chart review was conducted of 100 consecutive patients who underwent minimally invasive surgery at an academic cancer center from January to 2021 to December 2021. This cohort was compared with the active intervention cohort (n=102) from the implementation period (January 2020 to December 2020). Same day discharge rates and complications were compared. Multivariable analysis was performed to assess which factors remained associated with same day discharge post-intervention. RESULTS: Same day discharge post-intervention was 72% compared with 75% during active intervention (p=0.69). Both cohorts were similar in age (p=0.24) and body mass index (p=0.27), but the post-intervention cohort had longer operative times (p=0.001). There were no significant differences in 30-day complications, readmission, reoperation, or emergency room visits (p>0.05). There was a decrease in 30-day post-operative clinic visits from 18% to 5% in the post-intervention cohort (p=0.007), and unnecessary bowel prep use decreased from 35% to 14% (p<0.001). On multivariable analysis, start time (second case of the day) (OR 0.06; 95% CI 0.01 to 0.35), and ward narcotic use (OR 0.12; 95% CI 0.03 to 0.42) remained associated with overnight admission. CONCLUSION: Same day discharge rate was sustained at 72%, 12 months after the implementation of a quality improvement program to optimize same day discharge rate after minimally invasive surgery, while maintaining low post-operative complications and reducing unplanned clinic visits. To maximize same day discharge, minimally invasive gynecologic oncology surgery should be prioritized as the first case of the day, and post-operative narcotic use should be limited.

Primary cytoreductive surgery compared with neoadjuvant chemotherapy in patients with BRCA mutated advanced high grade serous ovarian cancer: 10 year survival analysis.

OBJECTIVES: Given the high response to platinum based chemotherapy in BRCA 1/2 mutated high grade serous ovarian cancers, there is uncertainty about the relative benefits of primary cytoreductive surgery versus neoadjuvant chemotherapy in this population. We aimed to compare the survival outcomes for women with BRCA 1/2 mutated high grade serous ovarian cancers undergoing either primary cytoreductive surgery or neoadjuvant chemotherapy. METHODS: We conducted a retrospective cohort study of all stage III/IV BRCA mutated high grade serous ovarian cancers treated with primary cytoreductive surgery or neoadjuvant chemotherapy at a single tertiary cancer center between 1991 and 2020. Baseline demographics, initial disease burden, surgical complexity, and survival outcomes were examined. RESULTS: Of 314 women with germline or somatic BRCA mutations, 194 (62%) underwent primary cytoreductive surgery and 120 (38%) underwent neoadjuvant chemotherapy followed by interval cytoreductive surgery. Those undergoing primary cytoreductive surgery were younger (median age 53 years (range 47-59) vs 59 years (50-65), p<0.001), but there were no differences in functional status or underlying comorbidities. The initial disease burden was lower (disease score high (40% vs 44%; p<0.001) but surgical complexity was higher (surgical complexity score high (18% vs 3%; p<0.001) in the primary cytoreductive surgery cohort. The rate of optimal or complete cytoreduction was similar in both groups (89% vs 90%; p=0.23) as well as the rate of poly (ADP-ribose) polymerase inhibitor use (62% vs 68%; p=0.3). The 10 year overall survival and recurrence free survival were superior in the primary cytoreductive surgery cohort (overall survival 49% vs 25%, p<0.001 and progression free survival 25% vs 10%, p<0.001). After controlling for confounders, primary cytoreductive surgery remained a significant predictor of improved overall survival (hazard ratio (HR) 0.45; 95% confidence interval (CI) 0.27 to 0.74; p=0.002) and recurrence free survival (HR 0.55; 95% CI 0.37 to 0.80; p=0.002). CONCLUSIONS: Primary cytoreductive surgery was associated with improved survival in women with stage III/IV BRCA mutated high grade serous ovarian cancers compared with neoadjuvant chemotherapy.

Targeted Mass Spectrometry of Longitudinal Patient Sera Reveals LTBP1 as a Potential Surveillance Biomarker for High-Grade Serous Ovarian Carcinoma.

High-grade serous ovarian carcinoma (HGSC) is the most prevalent subtype of epithelial ovarian cancer. The combination of a high rate of recurrence and novel therapies in HGSC necessitates an accurate assessment of the disease. Currently, HGSC response to treatment and recurrence are monitored via immunoassay of serum levels of the glycoprotein CA125. CA125 levels predictably rise at HGSC recurrence; however, it is likely that the disease is progressing even before it is detectable through CA125. This may explain why treating solely based on CA125 increase has not been associated with improved outcomes. Thus, additional biomarkers that monitor HGSC progression and cancer recurrence are needed. For this purpose, we developed a scheduled parallel reaction monitoring mass spectrometry (PRM-MS) assay for the quantification of four previously identified HGSC-derived glycopeptides (from proteins FGL2, LGALS3BP, LTBP1, and TIMP1). We applied the assay to quantify their longitudinal expression profiles in 212 serum samples taken from 34 HGSC patients during disease progression. Analyses revealed that LTBP1 best-mirrored tumor load, dropping as a result of cancer treatment in 31 out of 34 patients and rising at HGSC recurrence in 28 patients. Additionally, LTBP1 rose earlier during remission than CA125 in 11 out of 25 platinum-sensitive patients with an average lead time of 116.4 days, making LTBP1 a promising candidate for monitoring of HGSC recurrence.

Disturbed sleep is associated with reduced verbal episodic memory and entorhinal cortex volume in younger middle-aged women with risk-reducing early ovarian removal.

Introduction: Women with early ovarian removal (<48 years) have an elevated risk for both late-life Alzheimer's disease (AD) and insomnia, a modifiable risk factor. In early midlife, they also show reduced verbal episodic memory and hippocampal volume. Whether these reductions correlate with a sleep phenotype consistent with insomnia risk remains unexplored. Methods: We recruited thirty-one younger middleaged women with risk-reducing early bilateral salpingo-oophorectomy (BSO), fifteen of whom were taking estradiol-based hormone replacement therapy (BSO+ERT) and sixteen who were not (BSO). Fourteen age-matched premenopausal (AMC) and seventeen spontaneously peri-postmenopausal (SM) women who were ~10y older and not taking ERT were also enrolled. Overnight polysomnography recordings were collected at participants' home across multiple nights (M=2.38 SEM=0.19), along with subjective sleep quality and hot flash ratings. In addition to group comparisons on sleep measures, associations with verbal episodic memory and medial temporal lobe volume were assessed. Results: Increased sleep latency and decreased sleep efficiency were observed on polysomnography recordings of those not taking ERT, consistent with insomnia symptoms. This phenotype was also observed in the older women in SM, implicating ovarian hormone loss. Further, sleep latency was associated with more forgetting on the paragraph recall task, previously shown to be altered in women with early BSO. Both increased sleep latency and reduced sleep efficiency were associated with smaller anterolateral entorhinal cortex volume. Discussion: Together, these findings confirm an association between ovarian hormone loss and insomnia symptoms, and importantly, identify an younger onset age in women with early ovarian removal, which may contribute to poorer cognitive and brain outcomes in these women.

Validation of the Integrated Prediction Model algorithm for outcome of cytoreduction in advanced ovarian cancer.

BACKGROUND: We previously developed the Integrated Prediction Model using a 4-step algorithm of unresectable stage IVB, patient factors, surgical resectability, and surgical complexity to predict outcome of <1 cm cytoreduction in advanced epithelial ovarian cancer, and triaged patients to neoadjuvant chemotherapy or primary cytoreductive surgery. OBJECTIVE: To validate the Integrated Prediction Model on a retrospective cohort of patients. METHODS: A retrospective cohort study of 107 patients with advanced ovarian cancer treated between January 2017 and September 2018 was carried out. The above mentioned 4-step algorithm determined cut-off points using the Youden Index. This validation study reports sensitivity, specificity, negative and positive predictive value on an external cohort. RESULTS: Among 107 patients, 61 had primary surgery and 46 had neoadjuvant chemotherapy. Compared with primary surgery, patients treated with neoadjuvant chemotherapy were significantly older (63.5 vs 61, p=0.037), more likely to have stage IV disease (52% vs 18%, p<0.001), Eastern Cooperative Oncology Group (ECOG) score >1 (30% vs 11%, 0.045), lower pre-operative albumin (37 vs 40, p<0.001), and higher CA-125 (970 vs 227.5, p<0.001). They also had higher patient factors (2 vs 0, p=0.013), surgical resectability (4 vs 1, p<0.001), and anticipated surgical complexity (8 vs 5, p<0.001). There was no significant difference in outcome of cytoreduction (<1 cm residual disease: 85% for primary surgery vs 87% interval surgery, p=0.12)In this validation cohort, triaging patients with patient factors ≤2, surgical resectability score ≤5, and surgical complexity score ≤9 to primary surgery had a sensitivity of 91% for optimal cytoreduction <1 cm and a specificity of 81%. The positive predictive value, negative predictive value, and accuracy were 83%, 90%, and 86%, respectively. Application of the Integrated Prediction Model would have prevented five patients from receiving suboptimal cytoreduction and triaged them to neoadjuvant chemotherapy. CONCLUSIONS: We validated the proposal that a triage algorithm integrating patient factors, surgical complexity, and surgical resectability in advanced ovarian cancer had high sensitivity and specificity to predict optimal cytoreduction <1 cm.

Identification of antigenic epitopes recognized by tumor infiltrating lymphocytes in high grade serous ovarian cancer by multi-omics profiling of the auto-antigen repertoire.

Immunotherapeutic strategies aimed at enhancing tumor cell killing by tumor-specific T cells hold great potential for reducing tumor burden and prolonging survival of cancer patients. Although many potential tumor antigens have been described, identifying relevant targets when designing anti-cancer vaccines or targeted cell therapies remains a challenge. To identify novel, potentially immunogenic candidate tumor antigens, we performed integrated tumor transcriptomic, seromic, and proteomic analyses of high grade serous ovarian cancer (HGSC) patient tumor samples. We identified tumor neo-antigens and over-expressed antigens using whole exome and RNA sequencing and examined these in relation to patient-matched auto-antibody repertoires. Focusing on MHC class I epitopes recognized by CD8+ T cells, HLA-binding epitopes were identified or predicted from the highly expressed, mutated, or auto-antibody target antigen, or MHC-associated peptides (MAPs). Recognition of candidate antigenic peptides was assessed within the tumor-infiltrating T lymphocyte (TIL) population expanded from each patient. Known tumor-associated antigens (TAA) and cancer/testis antigens (CTA) were commonly found in the auto-antibody and MAP repertoires and CD8+ TILs recognizing epitopes from these antigens were detected, although neither expression level nor the presence of auto-antibodies correlated with TIL recognition. Auto-antibodies against tumor-mutated antigens were found in most patients, however, no TIL recognition of the highest predicted affinity neo-epitopes was detected. Using high expression level, auto-antibody recognition, and epitope prediction algorithms, we identified epitopes in 5 novel antigens (MOB1A, SOCS3, TUBB, PRKAR1A, CCDC6) recognized by HGSC patient TILs. Furthermore, selection of epitopes from the MAP repertoire identified 5 additional targets commonly recognized by multiple patient TILs. We find that the repertoire of TIL specificities includes recognition of highly expressed and immunogenic self-antigens that are processed and presented by tumors. These results indicate an ongoing autoimmune response against a range of self-antigens targeted by HGSC TILs.

Mucin 13 (MUC13) as a candidate biomarker for ovarian cancer detection: potential to complement CA125 in detecting non-serous subtypes.

OBJECTIVES: Ovarian cancer is the most lethal gynecological malignancy in developed countries. One of the key associations with the high mortality rate is diagnosis at late stages. This clinical limitation is primarily due to a lack of distinct symptoms and detection at the early stages. The ovarian cancer biomarker, CA125, is mainly effective for identifying serous ovarian carcinomas, leaving a gap in non-serous ovarian cancer detection. Mucin 13 (MUC13) is a transmembrane, glycosylated protein with aberrant expression in malignancies, including ovarian cancer. We explored the potential of MUC13 to complement CA125 as an ovarian cancer biomarker, by evaluating its ability to discriminate serous and non-serous subtypes of ovarian cancer at FIGO stages I-IV from benign conditions. METHODS: We used our newly developed, high sensitivity ELISA to measure MUC13 protein in a large, well-defined cohort of 389 serum samples from patients with ovarian cancer and benign conditions. RESULTS: MUC13 and CA125 serum levels were elevated in malignant compared to benign cases (p<0.0001). Receiver-operating characteristic (ROC) curve analysis showed similar area under the curve (AUC) of 0.74 (MUC13) and 0.76 (CA125). MUC13 concentrations were significantly higher in mucinous adenocarcinomas compared to benign controls (p=0.0005), with AUC of 0.80. MUC13 and CA125 showed significant elevation in early-stage cases (stage I-II) in relation to benign controls (p=0.0012 and p=0.014, respectively). CONCLUSIONS: We report the novel role of MUC13 as a serum ovarian cancer biomarker, where it could complement CA125 for detecting some subtypes of non-serous ovarian carcinoma and early-stage disease.

Using a machine learning algorithm to predict outcome of primary cytoreductive surgery in advanced ovarian cancer.

OBJECTIVE: To develop a machine learning (ML) algorithm to predict outcome of primary cytoreductive surgery (PCS) in patients with advanced ovarian cancer (AOC) METHODS: This retrospective cohort study included patients with AOC undergoing PCS between January 2017 and February 2021. Using radiologic criteria, patient factors (age, CA-125, performance status, BRCA) and surgical complexity scores, we trained a random forest model to predict the dichotomous outcome of optimal cytoreduction (<1 cm) and no gross residual (RD = 0 mm) using JMP-Pro 15 (SAS). This model is available at https://ipm-ml.ccm.sickkids.ca. RESULTS: One hundred and fifty-one patients underwent PCS and randomly assigned to train (n = 92), validate (n = 30), or test (n = 29) the model. The median age was 58 (27-83). Patients with suboptimal cytoreduction were more likely to have an Eastern Cooperative Oncology Group 3-4 (11% vs. 0.75%, p = 0.004), lower albumin (38 vs. 41, p = 0.02), and higher CA125 (1126 vs. 388, p = 0.012) than patients with optimal cytoreduction (n = 133). There were no significant differences in age, histology, stage, or BRCA status between groups. The bootstrap random forest model had AUCs of 99.8% (training), 89.6%(validation), and 89.0% (test). The top five contributors were CA125, albumin, diaphragmatic disease, age, and ascites. For RD = 0 mm, the AUCs were 94.4%, 52%, and 84%, respectively. CONCLUSION: Our ML algorithm demonstrated high accuracy in predicting optimal cytoreduction in patients with AOC selected for PCS and may assist decision-making.

Integrated prediction model of patient factors, resectability scores and surgical complexity to predict cytoreductive outcome and guide treatment plan in advanced ovarian cancer.

OBJECTIVE: To report performance of an integrated predictive model (IPM) algorithm based on patient factors, surgical resectability and surgical complexity to predict outcome of primary cytoreductive surgery (PCS) and guide treatment plan in patients with advanced epithelial ovarian cancer (AEOC). METHODS: Patients with AEOC between October 2018 and October 2020 were enrolled into a dedicated AEOC program and decision for PCS or neoadjuvant chemotherapy (NACT) was based on multidisciplinary consensus. Data of unresectable stage IVb, patient factors (PF), surgical resectability scores (SRS) and surgical complexity scores (SCS) was prospectively documented. An integrated prediction model (IPM) was developed to predict outcome of optimal (RD < 1 cm) cytoreduction. Retrospective analysis was performed to assess the performance of the IPM. Cut-offs were selected using the Youden Index. RESULTS: Of 185 eligible patients, 81 underwent PCS and 104 were treated with NACT. Patients undergoing PCS had significantly lower median PF (0 vs 2, p < 0.01), SRS (2 vs 4, p < 0.01) and pre-operative SCS (6 vs 8.5, p = 0.01) compared to NACT. In patients undergoing PCS, 88% had optimal cytoreduction and 34.5% had grade 3-4 post-operative complications. A model triaging patients with unresectable Stage IVb, PF > 2, SRS > 5 and SCS > 9 to NACT had 85% sensitivity, 75% specificity and 85% accuracy for outcome of optimal cytoreduction. Our model would have improved triage of 3/10 sub-optimally cytoreduced patients to NACT. For outcome of no-gross residual disease (RD = 0 mm) using the same cut-offs sensitivity and specificity were 85% and 76% respectively. CONCLUSION: The 4-step IPM algorithm had high sensitivity and specificity for optimal cytoreduction with acceptable morbidity without delay to adjuvant therapy. This algorithm may be used to triage patients to PCS or NACT once it is further validated.

A Pan-Canadian Consensus Statement on First-Line PARP Inhibitor Maintenance for Advanced, High-Grade Serous and Endometrioid Tubal, Ovarian, and Primary Peritoneal Cancers.

The majority of patients with advanced, high-grade epithelial-tubo ovarian cancer (EOC) respond well to initial treatment with platinum-based chemotherapy; however, up to 80% of patients will experience a recurrence. Poly(ADP-ribose) Polymerase (PARP) inhibitors have been established as a standard of care maintenance therapy to prolong remission and prevent relapse following a response to first-line platinum-chemotherapy. Olaparib and niraparib are the PARP inhibitors currently approved for use in the first-line maintenance setting in Canada. Selection of maintenance therapy requires consideration of patient and tumour factors, presence of germline and somatic mutations, expected drug toxicity profile, and treatment access. This paper discusses the current clinical evidence for first-line PARP inhibitor maintenance therapy in patients with advanced, high-grade EOC and presents consensus statements and a treatment algorithm to aid Canadian oncologists on the selection and use of PARP inhibitors within the Canadian EOC treatment landscape.

Oncologic and pregnancy outcomes after fertility-sparing surgery for stage I, low-grade endometrioid ovarian cancer.

OBJECTIVE: To evaluate oncologic outcomes in patients with stage I endometrioid ovarian cancer treated with fertility-sparing compared with conventional surgery and to describe reproductive outcomes. METHODS: A retrospective cohort study was carried out of patients aged 18-45 with stage I, grade 1 and 2 (low-grade) endometrioid ovarian cancer treated at two cancer centers between July 2001 and December 2019. Clinical and pathologic characteristics were compared using Fisher's exact test for categorical and the Mann-Whitney U test for continuous variables. Recurrence-free and overall survival were calculated from Kaplan-Meier curves and compared for fertility-sparing and conventional surgery using the log rank test. Pregnancy outcomes are described. RESULTS: There were 230 patients with endometrioid ovarian cancer. After exclusion of patients with stage greater than I and those older than 45 years, there were 31 patients with stage I cancer aged 18-45. Of these patients, 11 (35.5%) underwent fertility-sparing surgery and 20 (64.5%) underwent conventional surgery. The median follow-up was 6.0 years (range 1.8-17.3). The median age was 36 years (range 26-42) in the fertility-sparing group and 42 years (range 35-45) in the conventional surgery group (p=0.001), with no difference in other clinical and pathologic characteristics. The 5-year recurrence-free survival was 90.9% (95% CI 73.9% to 100%) for the fertility-sparing group and 84.0% (95% CI 67.3% to 100%) for the conventional surgery group (p=0.65). The 5-year overall survival was 100% for patients in the fertility-sparing group and 92.6% (95% CI 78.7% to 100%) for patients treated with conventional surgery (p=0.49). Four (12.9%) patients had disease recurrence: three (15%) after conventional surgery and one (9.1%) in the contralateral ovary after fertility-sparing surgery and embryo cryopreservation. After fertility-sparing surgery, seven (63.6%) patients attempted pregnancy, of which five (71.4%) conceived with four (57.1%) using in vitro fertilization. Of the five patients who conceived, there were three spontaneous abortions and five live births. CONCLUSION: Fertility-sparing surgery appears safe and may be considered in young women with stage I, low-grade endometrioid ovarian cancer when fertility preservation is desired.

Recurrent chromosomal translocations in sarcomas create a megacomplex that mislocalizes NuA4/TIP60 to Polycomb target loci.

Chromosomal translocations frequently promote carcinogenesis by producing gain-of-function fusion proteins. Recent studies have identified highly recurrent chromosomal translocations in patients with endometrial stromal sarcomas (ESSs) and ossifying fibromyxoid tumors (OFMTs), leading to an in-frame fusion of PHF1 (PCL1) to six different subunits of the NuA4/TIP60 complex. While NuA4/TIP60 is a coactivator that acetylates chromatin and loads the H2A.Z histone variant, PHF1 is part of the Polycomb repressive complex 2 (PRC2) linked to transcriptional repression of key developmental genes through methylation of histone H3 on lysine 27. In this study, we characterize the fusion protein produced by the EPC1-PHF1 translocation. The chimeric protein assembles a megacomplex harboring both NuA4/TIP60 and PRC2 activities and leads to mislocalization of chromatin marks in the genome, in particular over an entire topologically associating domain including part of the HOXD cluster. This is linked to aberrant gene expression-most notably increased expression of PRC2 target genes. Furthermore, we show that JAZF1-implicated with a PRC2 component in the most frequent translocation in ESSs, JAZF1-SUZ12-is a potent transcription activator that physically associates with NuA4/TIP60, its fusion creating outcomes similar to those of EPC1-PHF1 Importantly, the specific increased expression of PRC2 targets/HOX genes was also confirmed with ESS patient samples. Altogether, these results indicate that most chromosomal translocations linked to these sarcomas use the same molecular oncogenic mechanism through a physical merge of NuA4/TIP60 and PRC2 complexes, leading to mislocalization of histone marks and aberrant Polycomb target gene expression.

Scene memory and hippocampal volume in middle-aged women with early hormone loss.

The present study explored whether early midlife bilateral salpingo-oophorectomy (BSO), a female-specific risk factor for dementia, is associated with reduced medial temporal lobe structure and function. Younger middle-aged women with the BRCA1/2 mutation and a BSO prior to spontaneous menopause (SM) were recruited. We determined the performance of women with BSO not taking estradiol-based hormone therapy (n = 18) on a task measuring object and scene recognition and quantified medial temporal lobe subregion volumes using manually segmented high-resolution T2-weighted MRI scans. Comparisons were made to those with BSO taking estradiol-based hormone therapy (n = 20), age-matched premenopausal controls (n = 28), and older women in SM not taking hormone therapy matched for duration of hormone deprivation (n = 17). Reduced hippocampal integrity specific to the BSO group not taking hormone therapy was observed, reflected by significantly smaller dentate gyrus/CA2/CA3 volumes and lower scene recognition memory performance. These findings show that hippocampal subfield volume may be useful for identifying early midlife changes in women at elevated risk for dementia.

Leiomyosarcoma: Current Clinical Management and Future Horizons.

Leiomyosarcomas are soft tissue tumors that are derived from smooth muscle mainly in the pelvis and retroperitoneum. Percutaneous biopsy is paramount to confirm diagnosis. Imaging is necessary to complete clinical staging. Multimodal treatment should be directed by expert sarcoma multidisciplinary teams that see a critical volume of these rare tumors. Surgery is the mainstay of curative intent treatment; however due to its high metastatic progression, there may be a benefit for neoadjuvant systemic treatment. Adjuvant systemic treatment has no proven disease-free survival, and its main role is in the palliative setting to potentially prolong overall survival.

Implementation of a standardized voiding protocol after minimally invasive surgery: A quality improvement initiative.

OBJECTIVES: To assess the effects of the implementation of a standardized voiding protocol in patients undergoing minimally invasive hysterectomy at a single cancer center in terms of the urinary tract infection (UTI) rate, time to first void, and overnight stays secondary to urinary retention. METHODS: We enrolled 102 consecutive patients undergoing minimally invasive hysterectomy at a single cancer center during a 12-month period. A pre-intervention cohort of 100 consecutive patients was identified for comparison. A multidisciplinary team developed and implemented a standardized voiding protocol using quality improvement methodology. We compared the demographics, time to first void, rate of urinary retention, and UTI rates between the pre- and post-intervention cohorts. RESULTS: Our intervention led to a significant reduction in the time to first void (289 min vs. 566 min; P < 0.001), rate of urinary retention (2% vs. 10%; P = 0.015), and postoperative UTI (4% vs. 8%; P = 0.249). There was a similar rate of patients going home with a Foley catheter (9% vs. 11%; P = 0.850). CONCLUSIONS: Implementation of a standardized voiding protocol was associated with a reduction in rate of UTI, time to first void, and overnight stays secondary to urinary retention.

Endometrial Cancer: Transitioning from Histology to Genomics.

Endometrial carcinoma (EC) is traditionally treated with surgery and adjuvant treatment depending on clinicopathological risk factors. The genomic analysis of EC in 2013 and subsequent studies using immunohistochemistry have led to the current EC molecular classification into: polymerase epsilon mutated (POLEmut), p53 abnormal (p53abn), mismatch repair deficient (MMRd), and no specific molecular profile (NSMP). The four groups have prognostic value and represent a promising tool for clinical decision-making regarding adjuvant treatment. Molecular classification was integrated into the recent European Society of Gynecologic Oncology (ESGO) management guidelines. POLEmut EC has favorable outcomes and retrospective studies found that omitting adjuvant treatment is safe in this group; two prospective clinical trials, PORTEC-4 and TAPER, are ongoing to assess this. p53 abn is associated with increased recurrence, decreased survival, and benefitted from chemotherapy in the PORTEC-3 subgroup molecular analysis. The clinical trials PORTEC-4a and CANSTAMP will prospectively assess this. MMRd and NSMP groups have intermediate prognosis and will likely continue to rely closely on clinicopathological features for adjuvant treatment decisions. In addition, the molecular classification has led to exploring novel treatments such as checkpoint inhibitors. Overall, the molecular perspective on EC and associated clinical trials will likely refine EC risk stratification to optimize care and avoid overtreatment.