Nucleolar Localization of the RNA Helicase DDX21 Predicts Survival Outcomes in Gynecological Cancers.

Cancer cells with DNA repair defects (e.g., BRCA1/2 mutant cells) are vulnerable to PARP inhibitors (PARPi) due to induction of synthetic lethality. However, recent clinical evidence has shown that PARPi can prevent the growth of some cancers irrespective of their BRCA1/2 status, suggesting alternative mechanisms of action. We previously discovered one such mechanism in breast cancer involving DDX21, an RNA helicase that localizes to the nucleoli of cells and is a target of PARP1. We have now extended this observation in endometrial and ovarian cancers and provided links to patient outcomes. When PARP1-mediated ADPRylation of DDX21 is inhibited by niraparib, DDX21 is mislocalized to the nucleoplasm resulting in decreased rDNA transcription, which leads to a reduction in ribosome biogenesis, protein translation, and ultimately endometrial and ovarian cancer cell growth. High PARP1 expression was associated with high nucleolar localization of DDX21 in both cancers. High nucleolar DDX21 negatively correlated with calculated IC50s for niraparib. By studying endometrial cancer patient samples, we were able to show that high DDX21 nucleolar localization was significantly associated with decreased survival. Our study suggests that the use of PARP inhibitors as a cancer therapeutic can be expanded to further types of cancers and that DDX21 localization can potentially be used as a prognostic factor and as a biomarker for response to PARPi.

Risk factors for catheter-associated urinary tract infections following radical hysterectomy for cervical cancer.

BACKGROUND: Radical hysterectomy is the mainstay of treatment for early-stage cervical cancer. Urinary tract dysfunction is one of the most common complications after radical hysterectomy, and prolonged catheterization has previously been defined as a significant risk factor for catheter-associated urinary tract infections. OBJECTIVE: This study aimed to determine the rate of catheter-associated urinary tract infections after radical hysterectomy for cervical cancer, and to identify additional risk factors for developing catheter-associated urinary tract infections in this population. STUDY DESIGN: We reviewed patients who underwent radical hysterectomy for cervical cancer from 2004 to 2020 after institutional review board approval. All patients were identified from institutional Gynecologic Oncology surgical and tumor databases. The inclusion criterion was radical hysterectomy for early-stage cervical cancer. Exclusion criteria included inadequate hospital follow-up, insufficient records of catheter use in the electronic medical record, urinary tract injury, and preoperative chemoradiation. Catheter-associated urinary tract infection was defined as an infection diagnosed in a catheterized patient or within 48 hours of catheter removal, with significant bacteriuria (>103 cfu/mL) and symptoms or signs attributable to the urinary tract. Data analysis was performed using comparative analysis and univariate and multivariable logistic regression using Excel, GraphPad Prism, and IBM SPSS Statistics. RESULTS: Of the 160 included patients, 12.5% developed catheter-associated urinary tract infections. In univariate analysis, catheter-associated urinary tract infection was significantly associated with current smoking history (odds ratio, 3.76; 95% confidence interval, 1.39-10.08), minimally invasive surgical approach (odds ratio, 5.24; 95% confidence interval, 1.91-16.87), estimated surgical blood loss >500 mL (odds ratio, 0.18; 95% confidence interval, 0.04-0.57), operative time >300 minutes (odds ratio, 2.92; 95% confidence interval, 1.07-9.36), and increased duration of catheterization (odds ratio, 18.46; 95% confidence interval, 3.67-336). After adjusting for interactions and controlling for potential confounders with multivariable analysis, current smoking history and catheterization for >7 days were identified as independent risk factors for development of catheter-associated urinary tract infections (adjusted odds ratio, 3.94; 95% confidence interval, 1.28-12.37; adjusted odds ratio, 19.49; 95% confidence interval, 2.78-427). CONCLUSION: Preoperative smoking cessation interventions for current smokers should be implemented to decrease risk for postoperative complications, including catheter-associated urinary tract infections. In addition, catheter removal within 7 postoperative days should be encouraged in all women undergoing radical hysterectomy for early-stage cervical cancer in an effort to decrease infection risk.

Isolated para-aortic nodal recurrence after treatment of early stage cervical carcinoma.

OBJECTIVE: Surgical evaluation of lymph node metastasis is paramount in the treatment of cervical cancer. We sought to explore the outcomes of patients with and without para-aortic lymphadenectomy undergoing curative-intent radical hysterectomy for stage IA-IIA cervical cancer. METHODS: Institutional data were retrospectively reviewed to identify women undergoing curative-intent radical hysterectomy with concurrent lymphadenectomy for stage IA-IIA cervical carcinoma from 2004 to 2021. Any carcinoma histology was allowed. Clinical risk stratification was performed according to GOG 92 and GOG 109 protocols. Disease outcomes, patterns of recurrence, and survival were analyzed with Chi square, t-test, Kaplan-Meier, and Cox proportional hazards multivariable statistics. RESULTS: 300 patients were identified, 265 met inclusion criteria. Median follow up was 56 months. Pelvic lymphadenectomy (PLND) was performed in 71%, with the remainder undergoing combined para-aortic dissection (PPaLND). Baseline patient demographics and presence of clinical risk factors were well balanced between groups. PPaLND was more common in patients undergoing open surgery (OR 10.58, p <.0001), and tumors were larger in this group (2.96 vs 2.12 cm, p = .0002) and more likely non-squamous histology (OR 2.02, p = .017). Recurrence of disease was present in 13% of cases, with no difference between PLND and PPaLND regardless of histology. There were zero cases of isolated PaLN recurrence in either group. Neither progression free nor overall survival was different between groups. Prophylactic extended field radiation (EFRT) was not prescribed. CONCLUSION: Omission of PaLN dissection, in the absence of suspicious nodes, did not decrease survival. There were no isolated PaLN recurrences after PLND alone.

The Impact of Racial Disparities on Outcome in Patients With Stage IIIC Endometrial Carcinoma: A Pooled Data Analysis.

OBJECTIVE: To report the impact of race on clinical outcomes in patients with stage IIIC endometrial carcinoma. MATERIALS AND METHODS: A retrospective multi-institutional study included 90 black and 568 non-black patients with stage IIIC endometrial carcinoma who received adjuvant chemotherapy and radiation treatments. Overall survival (OS) and recurrence-free survival (RFS) were calculated by the Kaplan-Meier method. Propensity score matching (PSM) was conducted. Statistical analyses were conducted using SPSS version 27. RESULTS: The Median follow-up was 45.3 months. black patients were significantly older, had more nonendometrioid histology, grade 3 tumors, and were more likely to have >1 positive paraaortic lymph nodes compared with non-black patients (all P <0.0001). The 5-year estimated OS and RFS rates were 45% and 47% compared with 77% and 68% for black patients versus non-black patients, respectively ( P <0.001). After PSM, the 2 groups were well-balanced for all prognostic covariates. The estimated hazard ratios of black versus non-black patients were 1.613 ( P value=0.045) for OS and 1.487 ( P value=0.116) for RFS. After PSM, black patients were more likely to receive the "Sandwich" approach and concurrent chemoradiotherapy compared with non-black ( P =0.013) patients. CONCLUSIONS: Black patients have higher rates of nonendometrioid histology, grade 3 tumors, and number of involved paraaortic lymph nodes, worse OS, and RFS, and were more likely to receive the "Sandwich" approach compared with non-black patients. After PSM, black patients had worse OS with a nonsignificant trend in RFS. Access to care, equitable inclusion on randomized trials, and identification of genomic differences are warranted to help mitigate disparities.

Docetaxel treatment for widely metastatic invasive vulvar extramammary Paget's disease with multifocal bone metastasis.

•Invasive extramammary Paget's disease of the vulva is rare.•Distant metastasis has a very poor prognosis.•Given rarity of disease, no standardized treatment exists.•Single agent docetaxel is a viable treatment for metastatic invasive extramammary Paget's disease.

Clostridium and Bacteroides bacteremia as initial presentation of uterine carcinosarcoma.

•Anaerobic bacteremia with gynecologic pathology can lead to rapid deterioration.•Frequent physical examination and bedside assessment are critical in management.•Surgical intervention is often necessary for Clostridium and Bacteroides infection.

Combinatorial Treatment with PARP-1 Inhibitors and Cisplatin Attenuates Cervical Cancer Growth through Fos-Driven Changes in Gene Expression.

Cervical cancer continues to be a significant cause of cancer-related deaths in women. The most common treatment for cervical cancer involves the use of the drug cisplatin in conjunction with other therapeutics. However, the development of cisplatin resistance in patients can hinder the efficacy of these treatments, so alternatives are needed. In this study, we found that PARP inhibitors (PARPi) could attenuate the growth of cells representing cervical adenocarcinoma and cervical squamous cell carcinoma. Moreover, a combination of PARPi with cisplatin increased cisplatin-mediated cytotoxicity in cervical cancer cells. This was accompanied by a dramatic alteration of the transcriptome. The FOS gene, which encodes the transcription factor Fos, was one of the most highly upregulated genes in the dual treatment condition, leading to increased Fos protein levels, greater Fos binding to chromatin, and the subsequent induction of Fos target genes. Increased expression of Fos was sufficient to hinder cervical cancer growth, as shown by ectopic expression of Fos in cervical cancer cells. Conversely, Fos knockdown enhanced cell growth. Collectively, these results indicate that by inducing FOS expression, PARPi treatment in combination with cisplatin leads to inhibition of cervical cancer proliferation, likely through a Fos-specific gene expression program. IMPLICATIONS: Our observations, which link the gene regulatory effects of PARPi + cisplatin to the growth inhibitory effects of FOS expression in cervical cancer cells, strengthen the rationale for using PARPi with cisplatin as a therapy for cervical cancer.

Human Papillomavirus‒Positive and ‒Negative Vulvar Squamous Cell Carcinoma Are Biologically but Not Clinically Distinct.

Vulvar squamous cell carcinoma pathogenesis is traditionally defined by the presence or absence of human papillomavirus (HPV), but the definition of these groups and their molecular characteristics remain ambiguous across studies. In this study, we present a retrospective cohort analysis of 36 patients with invasive vulvar squamous cell carcinoma where HPV status was determined using RNA in situ hybridization and PCR. Clinical annotation, p16 immunohistochemistry, PD-L1 immunohistochemistry, HPV16 circular E7 RNA detection, and RNA sequencing of the cases were performed. A combination of in situ hybridization and PCR identified 20 cases (55.6%) as HPV positive. HPV status did not impact overall survival (hazard ratio: 1.36, 95% confidence interval = 0.307-6.037, P = 0.6857) or progression-free survival (hazard ratio: 1.12, 95% confidence interval = 0.388-3.22, P = 0.8367), and no significant clinical differences were found between the groups. PD-L1 expression did not correlate with HPV status, but increased expression of PD-L1 correlated with worse overall survival. Transcriptomic analyses (n = 23) revealed distinct groups, defined by HPV status, with multiple differentially expressed genes previously implicated in HPV-induced cancers. HPV-positive tumors showed higher global expression of endogenous circular RNAs, including several circular RNAs that have previously been implicated in the pathogenesis of other cancers.

Does Prophylactic Paraortic Lymph Node Irradiation Improve Outcomes in Women With Stage IIIC1 Endometrial Carcinoma?

PURPOSE: To evaluate the impact of prophylactic paraortic lymph node (PALN) radiation therapy (RT) on clinical outcomes in patients with International Federation of Obstetrics and Gynecology 2018 stage IIIC1 endometrial cancer (EC). METHODS AND MATERIALS: A multi-institutional retrospective study included patients with International Federation of Obstetrics and Gynecology 2018 stage IIIC1 EC lymph node assessment, status postsurgical staging, followed by adjuvant chemotherapy and RT using various sequencing regimens. Overall survival (OS) and recurrence-free survival (RFS) rates were estimated by the Kaplan-Meier method. Univariable and multivariable analysis were performed by Cox proportional hazard models for RFS/OS. In addition, propensity score matching was used to estimate the effect of the radiation field extent on survival outcomes. RESULTS: A total of 378 patients were included, with a median follow-up of 45.8 months. Pelvic RT was delivered to 286 patients, and 92 patients received pelvic and PALN RT. The estimated OS and RFS rates at 5 years for the entire cohort were 80% and 69%, respectively. There was no difference in the 5-year OS (77% vs 87%, P = .47) and RFS rates (67% vs 70%, P = .78) between patients treated with pelvic RT and those treated with pelvic and prophylactic PALN RT, respectively. After propensity score matching, the estimated hazard ratios (HRs) of prophylactic PALN RT versus pelvic RT were 1.50 (95% confidence interval, 0.71-3.19; P = .28) for OS and 1.24 (95% confidence interval, 0.64-2.42; P = .51) for RFS, suggesting that prophylactic PALN RT does not improve survival outcomes. Distant recurrence was the most common site of first recurrence, and the extent of RT field was not associated with the site of first recurrence (P = .79). CONCLUSIONS: Prophylactic PALN RT was not significantly associated with improved survival outcomes in stage IIIC1 EC. Distant metastasis remains the most common site of failure despite routine use of systemic chemotherapy. New therapeutic approaches are necessary to optimize the outcomes for women with stage IIIC1 EC.

Radiotherapy Versus Inguinofemoral Lymphadenectomy as Treatment for Vulvar Cancer Patients With Micrometastases in the Sentinel Node: Results of GROINSS-V II.

PURPOSE: The Groningen International Study on Sentinel nodes in Vulvar cancer (GROINSS-V)-II investigated whether inguinofemoral radiotherapy is a safe alternative to inguinofemoral lymphadenectomy (IFL) in vulvar cancer patients with a metastatic sentinel node (SN). METHODS: GROINSS-V-II was a prospective multicenter phase-II single-arm treatment trial, including patients with early-stage vulvar cancer (diameter < 4 cm) without signs of lymph node involvement at imaging, who had primary surgical treatment (local excision with SN biopsy). Where the SN was involved (metastasis of any size), inguinofemoral radiotherapy was given (50 Gy). The primary end point was isolated groin recurrence rate at 24 months. Stopping rules were defined for the occurrence of groin recurrences. RESULTS: From December 2005 until October 2016, 1,535 eligible patients were registered. The SN showed metastasis in 322 (21.0%) patients. In June 2010, with 91 SN-positive patients included, the stopping rule was activated because the isolated groin recurrence rate in this group went above our predefined threshold. Among 10 patients with an isolated groin recurrence, nine had SN metastases > 2 mm and/or extracapsular spread. The protocol was amended so that those with SN macrometastases (> 2 mm) underwent standard of care (IFL), whereas patients with SN micrometastases (≤ 2 mm) continued to receive inguinofemoral radiotherapy. Among 160 patients with SN micrometastases, 126 received inguinofemoral radiotherapy, with an ipsilateral isolated groin recurrence rate at 2 years of 1.6%. Among 162 patients with SN macrometastases, the isolated groin recurrence rate at 2 years was 22% in those who underwent radiotherapy, and 6.9% in those who underwent IFL (P = .011). Treatment-related morbidity after radiotherapy was less frequent compared with IFL. CONCLUSION: Inguinofemoral radiotherapy is a safe alternative for IFL in patients with SN micrometastases, with minimal morbidity. For patients with SN macrometastasis, radiotherapy with a total dose of 50 Gy resulted in more isolated groin recurrences compared with IFL.

Ribosome ADP-ribosylation inhibits translation and maintains proteostasis in cancers.

Defects in translation lead to changes in the expression of proteins that can serve as drivers of cancer formation. Here, we show that cytosolic NAD+ synthesis plays an essential role in ovarian cancer by regulating translation and maintaining protein homeostasis. Expression of NMNAT-2, a cytosolic NAD+ synthase, is highly upregulated in ovarian cancers. NMNAT-2 supports the catalytic activity of the mono(ADP-ribosyl) transferase (MART) PARP-16, which mono(ADP-ribosyl)ates (MARylates) ribosomal proteins. Depletion of NMNAT-2 or PARP-16 leads to inhibition of MARylation, increased polysome association and enhanced translation of specific mRNAs, aggregation of their translated protein products, and reduced growth of ovarian cancer cells. Furthermore, MARylation of the ribosomal proteins, such as RPL24 and RPS6, inhibits polysome assembly by stabilizing eIF6 binding to ribosomes. Collectively, our results demonstrate that ribosome MARylation promotes protein homeostasis in cancers by fine-tuning the levels of protein synthesis and preventing toxic protein aggregation.

A Multi-Institutional Analysis of Adjuvant Chemotherapy and Radiation Sequence in Women With Stage IIIC Endometrial Cancer.

PURPOSE: Our purpose was to evaluate the effect of sequence and type of adjuvant therapy for patients with stage IIIC endometrial carcinoma (EC) on outcomes. METHODS AND MATERIALS: In a multi-institutional retrospective cohort study, patients with stage IIIC EC who had surgical staging and received both adjuvant chemotherapy and radiation therapy (RT) were included. Adjuvant treatment regimens were classified as adjuvant chemotherapy followed by sequential RT (upfront chemo), which was predominant sequence; RT with concurrent chemotherapy followed by chemotherapy (concurrent); systemic chemotherapy before and after RT (sandwich); adjuvant RT followed by chemotherapy (upfront RT); or chemotherapy concurrent with vaginal cuff brachytherapy alone (chemo-brachy). Overall survival (OS) and recurrence-free survival (RFS) rates were estimated by the Kaplan-Meier method. RESULTS: A total of 686 eligible patients were included with a median follow-up of 45.3 months. The estimated 5-year OS and RFS rates were 74% and 66%, respectively. The sequence and type of adjuvant therapy were not correlated with OS or RFS (adjusted P = .68 and .84, respectively). On multivariate analysis, black race, nonendometrioid histology, grade 3 tumor, stage IIIC2, and presence of adnexal and cervical involvement were associated with worse OS and RFS (all P < .05). Regardless of the sequence of treatment, the most common site of first recurrence was distant metastasis (20.1%). Vaginal only, pelvic only, and paraortic lymph node (PALN) recurrences occurred in 11 (1.6%),15 (2.2 %), and 43 (6.3 %) patients, respectively. Brachytherapy alone was associated with a higher rate of PALN recurrence (15%) compared with external beam radiation therapy (5%) P < .0001. CONCLUSIONS: The sequence and type of combined adjuvant therapy did not affect OS or RFS rates. Brachytherapy alone was associated with a higher rate of PALN recurrence, emphasizing the role of nodal radiation for stage IIIC EC. The vast proportion of recurrences were distant despite systemic chemotherapy, highlighting the need for novel regimens.

Tumor Necrotic Debris and High Nuclear Grade: Newly Identified High-risk Factors for Early-stage Endocervical Adenocarcinoma.

OBJECTIVE: Invasive pattern of endocervical adenocarcinomas (EACs) is known to influence lymph node metastasis and cancer recurrence. In this study we describe the prognostic significance of necrotic tumor debris (NTD) and tumor nuclear grade on recurrence risk stratification of early-stage cervical adenocarcinoma. METHODS: Patients who underwent surgery from 2007 to 2018 for International Federation of Gynecology and Obstetrics (FIGO) stage IA1-IB2 EAC, for whom pathology was available for review were included in this study. Clinico-pathologic variables and clinical recurrence risk stratification (low, intermediate, or high risk) were correlated to intraluminal NTD and tumor nuclear grade (N3). RESULTS: Among 50 patients meeting inclusion criteria, all were managed surgically and clinically risk stratified as low (n=33), intermediate (n=13), and high risk (n=4). Twenty-three patients (46%) were NTD-N3 negative and 27 (54%) were NTD-N3 positive. NTD-N3 was significantly associated with higher stage, tumor grade, larger tumor size, positive lymphovascular space invasion, and recurrence of disease (P=0.025). Patients with stage IB1 EAC who were stratified as intermediate or high-risk for recurrence were positive for NTD-N3. Lack of NTD-N3 had 100% negative predictive value for disease recurrence. CONCLUSIONS: NTD-N3, a novel pathologic finding, may be used to further stratify overall recurrence risk, and may play a role in individualization of patient care in early-stage EAC.

Identification of PARP-7 substrates reveals a role for MARylation in microtubule control in ovarian cancer cells.

PARP-7 (TiPARP) is a mono(ADP-ribosyl) transferase whose protein substrates and biological activities are poorly understood. We observed that PARP7 mRNA levels are lower in ovarian cancer patient samples compared to non-cancerous tissue, but PARP-7 protein nonetheless contributes to several cancer-related biological endpoints in ovarian cancer cells (e.g. growth, migration). Global gene expression analyses in ovarian cancer cells subjected to PARP-7 depletion indicate biological roles for PARP-7 in cell-cell adhesion and gene regulation. To identify the MARylated substrates of PARP-7 in ovarian cancer cells, we developed an NAD+ analog-sensitive approach, which we coupled with mass spectrometry to identify the PARP-7 ADP-ribosylated proteome in ovarian cancer cells, including cell-cell adhesion and cytoskeletal proteins. Specifically, we found that PARP-7 MARylates α-tubulin to promote microtubule instability, which may regulate ovarian cancer cell growth and motility. In sum, we identified an extensive PARP-7 ADP-ribosylated proteome with important roles in cancer-related cellular phenotypes.

Cancer is a complex illness where changes inside healthy cells causes them to grow and reproduce rapidly. Specialized proteins called enzymes ­ which regulate chemical reactions in the cell ­ often help cancer develop and spread through the body. One such enzyme called PARP-7 labels other proteins by attaching a chemical group which changes their behavior. However, it was unknown which proteins PARP-7 modifies and how this tag alters the actions of these proteins. To investigate this, Parsons, Challa, Gibson et al. developed a method to find and identify the proteins labelled by PARP-7 in ovarian cancer cells taken from patients and cultured in the laboratory. This revealed that PARP-7 labels hundreds of different proteins, including adhesion proteins which affect the connections between cells and cytoskeletal proteins which regulate a cell's shape and how it moves. One of the cytoskeletal proteins modified by PARP-7 is α-tubulin, which joins together with other tubulins to form long, tube-like structures known as microtubules. Parsons et al. found that when α-tubulin is labelled by PARP-7, it creates unstable microtubules that alter how the cancer cells grow and move. They discovered that depleting PARP-7 or mutating the sites where it modifies α-tubulin increased the stability of microtubules and slowed the growth of ovarian cancer cells. Ovarian cancer is the fifth leading cause of cancer-related deaths among women in the United States. A new drug which suppresses the activity of PARP-7 has recently been developed, and this drug could potentially be used to treat ovarian cancer patients with high levels of PARP-7. Clinical trials are ongoing to see how this drug affects the behavior of cancer cells in patients.

Blood-based biomarkers of human papillomavirus-associated cancers: A systematic review and meta-analysis.

BACKGROUND: Despite the significant societal burden of human papillomavirus (HPV)-associated cancers, clinical screening interventions for HPV-associated noncervical cancers are not available. Blood-based biomarkers may help close this gap in care. METHODS: Five databases were searched, 5687 articles were identified, and 3631 unique candidate titles and abstracts were independently reviewed by 2 authors; 702 articles underwent a full-text review. Eligibility criteria included the assessment of a blood-based biomarker within a cohort or case-control study. RESULTS: One hundred thirty-seven studies were included. Among all biomarkers assessed, HPV-16 E seropositivity and circulating HPV DNA were most significantly correlated with HPV-associated cancers in comparison with cancer-free controls. In most scenarios, HPV-16 E6 seropositivity varied nonsignificantly according to tumor type, specimen collection timing, and anatomic site (crude odds ratio [cOR] for p16+ or HPV+ oropharyngeal cancer [OPC], 133.10; 95% confidence interval [CI], 59.40-298.21; cOR for HPV-unspecified OPC, 25.41; 95% CI, 8.71-74.06; cOR for prediagnostic HPV-unspecified OPC, 59.00; 95% CI, 15.39-226.25; cOR for HPV-unspecified cervical cancer, 12.05; 95% CI, 3.23-44.97; cOR for HPV-unspecified anal cancer, 73.60; 95% CI, 19.68-275.33; cOR for HPV-unspecified penile cancer, 16.25; 95% CI, 2.83-93.48). Circulating HPV-16 DNA was a valid biomarker for cervical cancer (cOR, 15.72; 95% CI, 3.41-72.57). In 3 cervical cancer case-control studies, cases exhibited unique microRNA expression profiles in comparison with controls. Other assessed biomarker candidates were not valid. CONCLUSIONS: HPV-16 E6 antibodies and circulating HPV-16 DNA are the most robustly analyzed and most promising blood-based biomarkers for HPV-associated cancers to date. Comparative validity analyses are warranted. Variations in tumor type-specific, high-risk HPV DNA prevalence according to anatomic site and world region highlight the need for biomarkers targeting more high-risk HPV types. Further investigation of blood-based microRNA expression profiling appears indicated.

Current practice patterns in nodal evaluation and adjuvant treatment of advanced stage endometrioid endometrial cancer: An SGO survey.

The use of sentinel lymph node (SLN) mapping over full lymphadenectomy for endometrioid endometrial cancer (EC) has had varying uptake. Adjuvant therapy for advanced stage EC is also a debated topic globally. Two recent randomized controlled trials have attempted to clarify which treatment approach should be recommended. Our aims were to identify common practice patterns in the intraoperative lymph node evaluation as well as the practice patterns in the treatment of advanced stage (stage III-IV) endometrioid EC among gynecologic oncologists. A 16-question survey was distributed via email to all Society of Gynecologic Oncology members. Study data were collected anonymously and managed using REDCap electronic data tools. Respondents were asked questions regarding demographics, assessing nodal status, and choice of adjuvant treatment for each stage. Descriptive statistics, student's t-tests, and chi-squared analyses were performed. A total of 1531 surveys were distributed and 187 (12%) members responded. The majority (70%) of respondents identified nodal metastases by performing SLN mapping prior to nodal evaluation in grade 1-2 disease, however only half perform SLN mapping in grade 3 EC. Adjuvant chemotherapy was recommended by 90% of practitioners for advanced EC. However, external beam radiation or brachytherapy was combined with chemotherapy in 74% of stage III EC and 35% of stage IV EC. While 90% of practitioners recommend chemotherapy-based adjuvant treatment for women with stage IIIA-IVA endometrioid EC, decreasing local recurrence appears to be a factor in treatment planning as radiation combined with chemotherapy is used in 63% of cases.

Practice patterns using minimally invasive surgery for the treatment of ovarian cancer: A survey of physician members of the Society of Gynecologic Oncologists.

Retrospective studies suggest that minimally-invasive surgery may be safe and effective for the treatment of early-stage ovarian cancer as well as interval cytoreduction after neoadjuvant chemotherapy. Adoption rates and attitudes towards its use remain largely unknown. We aimed to determine the current use of minimally-invasive surgery for the treatment of ovarian cancer and identify perceived barriers towards further adoption of this method. Electronic survey was administered to physician members of the Society of Gynecologic Oncology. Chi-square analysis was used to determine if any correlation existed between variables and the current use of minimally invasive surgery in general practice and, specifically, for the treatment of ovarian cancer. There was a survey response rate of 15.1%. Sixty-five percent of respondents practiced in an academic setting, and 32.1% of respondents had completed fellowship training within the past 5 years. Ninety percent of respondents were performing >50% of their current procedures using minimally invasive surgery. Over seventy percent of respondents said that they performed minimally invasive surgery for primary staging and interval cytoreductive surgery for the treatment of ovarian cancer. Concern for residual disease and lack of scientific validation were the most frequently cited barriers to the implementation of minimally invasive surgery for the treatment of ovarian cancer. A majority of respondents have adopted the use of MIS for the management of early stage ovarian cancer. Advances in imaging to detect occult tumor deposits and a randomized trial to study and promote the use of minimally invasive surgery in ovarian cancer is warranted.

ADP-Ribosylation Levels and Patterns Correlate with Gene Expression and Clinical Outcomes in Ovarian Cancers.

Inhibitors of nuclear PARP enzymes (e.g., PARP-1) have improved clinical outcomes in ovarian cancer, especially in patients with BRCA1/2 gene mutations or additional homologous recombination (HR) DNA repair pathway deficiencies. These defects serve as biomarkers for response to PARP inhibitors (PARPi). We sought to identify an additional biomarker that could predict responses to both conventional chemotherapy and PARPi in ovarian cancers. We focused on cellular ADP-ribosylation (ADPRylation), which is catalyzed by PARP enzymes and detected by detection reagents we developed previously. We determined molecular phenotypes of 34 high-grade serous ovarian cancers and associated them with clinical outcomes. We used the levels and patterns of ADPRylation and PARP-1 to distribute ovarian cancers into distinct molecular phenotypes, which exhibit dramatically different gene expression profiles. In addition, the levels and patterns of ADPRylation, PARP-1 protein, and gene expression correlated with clinical outcomes in response to platinum-based chemotherapy, with cancers exhibiting the highest levels of ADPRylation having the best outcomes independent of BRCA1/2 status. Finally, in cell culture-based assays using patient-derived ovarian cancer cell lines, ADPRylation levels correlated with sensitivity to the PARPi, Olaparib, with cell lines exhibiting high levels of ADPRylation having greater sensitivity to Olaparib. Collectively, our study demonstrates that ovarian cancers exhibit a wide range of ADPRylation levels, which correlate with therapeutic responses and clinical outcomes. These results suggest ADPRylation may be a useful biomarker for PARPi sensitivity in ovarian cancers, independent of BRCA1/2 or homologous recombination deficiency status.

Specimen Fragmentation and Loop Electrosurgical Excision Procedure and Cold Knife Cone Biopsy Outcomes.

OBJECTIVE: Surgical technique for loop electrosurgical excision procedure (LEEP) and cold knife cone (CKC) emphasizes a uniform specimen, but sequelae of specimen fragmentation are not established. We evaluated outcomes between fragmented and unfragmented excisional biopsy specimens. MATERIALS AND METHODS: Loop electrosurgical excision procedure and CKCs from January 2010 to October 2013 were reviewed. Intraepithelial lesion grade, fragmentation, margin, and Endocervical curettage status were analyzed. Adenocarcinoma in situ and cancer were excluded. Repeat procedures during the study period were included in follow-up. Loop electrosurgical excision procedures with top hat with no separate fragments were analyzed independently versus those with fragmented LEEP and/or top hat. Indeterminate margin was defined as inconclusive or unevaluable margin, or intraepithelial lesion in unidentifiable margin or fragment. Outcomes involved residual or recurrent disease and repeat procedures for intraepithelial lesion. χ was used for statistical analysis. RESULTS: Fragmented specimens were more likely to have any positive margin (p = .01), multiple positive margins (p < .001), and indeterminate margin (p < .001) than unfragmented specimens. There was no significant difference in rates of positive, insufficient, or high-grade Endocervical curettage (p = .74, 0.54, 0.92). Patients with fragmented specimens were more likely to have high-grade lesion recurrence in the following 3 years (p = .04) versus patients with index unfragmented specimens, though not compared with those with unfragmented LEEP + top-hat cases. Overall rates of repeat LEEP/CKC or hysterectomy for dysplasia were not different (p = .56). CONCLUSIONS: Fragmentation of LEEP and CKC specimens is associated with higher rates of positive margins, recurrent high-grade intraepithelial lesions, and indeterminate margins. These may cause diagnostic uncertainty, require closer follow-up, and increase cost with more visits and studies.