Expression of the H19 Oncofetal Gene in Premalignant Lesions of Cervical Cancer: A Potential Targeting Approach for Development of Nonsurgical Treatment of High-Risk Lesions

Background. Recent data suggest a role for H19 gene in promoting cancer transformation and progression. Cervical cancer, progresses from high-grade lesions (CIN3). At present, it is unclear if CIN lesions express H19. Objectives. To determine H19 expression in patient samples of CIN3 as well as the ability of a construct in which the promoter from the H19 gene drives expression of the diphtheria toxin A chain (DTA) to inhibit cervical cancer cell growth in vitro. Methods. H19 transcript levels were evaluated on 10 biopsies of CIN3 using in situ hybridization. PCR was used to examine H19 expression in cervical cancer cell lines and in two samples from a patient with cervical carcinoma. Cell lines were transfected with H19-DTA to determine its impact on cell number. Results. H19 gene was expressed in the area of CIN3 in 9 out of 10 samples. RT-PCR indicated expression of H19 in cervical cancer samples and in one of the three cell lines examined. Transfection of all cell lines with H19-DTA vector resulted in inhibited cell growth. Conclusions. H19 is expressed in the majority of CIN3 samples. These results suggest that most CIN3 lesions could be targeted by H19-DTA. Further in vivo preclinical studies are thus warranted.Peer Reviewe

Identifying Borderline Ovarian Tumor Recurrence Using Routine Ultrasound Follow-Up

Borderline ovarian tumors (BOTs) are non-invasive tumors frequently diagnosed in young patients. Surgical removal of the uterus, fallopian tubes, ovaries, and omentum is considered definitive management, however fertility-sparing approach is a recognized option. Surveillance is important due to known recurrence, but there is controversy over the effectiveness of follow-up modalities. The objective is to determine the efficacy of ultrasound screening in identifying tumor recurrence. This retrospective chart review evaluated all patients consulted and/or treated surgically at our institution from January 2015 to June 2020 diagnosed with BOT. Patients were excluded if concurrently diagnosed with another gynecologic malignancy, did not have yearly ultrasound follow-up, or were lost to follow-up. This study included 56 patients, 17 of whom underwent fertility preserving surgery. The overall rate of recurrence was 10.7%; with recurrence rates of 23.5% for the fertility preserving surgery population and 5.1% for the definitive surgery population. Ultrasound first identified 5 of the 6 (83.3%) recurrences. Overall time to recurrence was 51.5 months. In conclusion, recurrences were identified on routine ultrasound screening prior to symptom onset or detection via physical exam in 83.3% of cases. While the best modality of follow-up remains controversial, this review provides evidence supporting the use of routine ultrasound follow-up for early detection of BOT recurrence

Bevacizumab Treatment for Low-Grade Serous Ovarian Cancer: A Systematic Review

Serous epithelial ovarian cancer, classified as either high-grade (90%) or low-grade (10%), varies in molecular, histological, and clinicopathological presentation. Low-grade serous ovarian cancer (LGSOC) is a rare histologic subtype that lacks disease-specific evidence-based treatment regimens. However, LGSOC is relatively chemo-resistant and has a poor response to traditional treatments. Alternative treatments, including biologic therapies such as bevacizumab, have shown some activity in LGSOC. Thus, the objective of this systematic review is to determine the effect and safety of bevacizumab in the treatment of LGSOC. Following PRISMA guidelines, Medline ALL, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Embase all from the OvidSP platform, ClinicalTrials.gov, International Clinical Trials Registry Platform, International Standard Randomised Controlled Trial Number Registry were searched from inception to February 2022. Articles describing bevacizumab use in patients with LGSOC were included. Article screening, data extraction, and critical appraisal of included studies were completed by two independent reviewers. The effect of bevacizumab on the overall response rate, progression-free survival, overall survival, and adverse effects were summarized. The literature search identified 3064 articles, 6 of which were included in this study. A total of 153 patients were analyzed; the majority had stage IIIC cancer (56.2%). The overall median response rate reported in the studies was 47.5%. Overall, bevacizumab is a promising treatment for LGSOC, with response rates higher than traditional treatment modalities such as conventional chemotherapy, and is often overlooked as a treatment tool. A prospective clinical trial evaluating the use of bevacizumab in LGSOC is necessary to provide greater evidence and support these findings

Molecular Profiling and Clinical Outcome of High-Grade Serous Ovarian Cancer Presenting with Low- versus High-Volume Ascites

Epithelial ovarian cancer consists of multiple histotypes differing in etiology and clinical course. The most prevalent histotype is high-grade serous ovarian cancer (HGSOC), which often presents at an advanced stage frequently accompanied with high-volume ascites. While some studies suggest that ascites is associated with poor clinical outcome, most reports have not differentiated between histological subtypes or tumor grade. We compared genome-wide gene expression profiles from a discovery cohort of ten patients diagnosed with stages III-IV HGSOC with high-volume ascites and nine patients with low-volume ascites. An upregulation of immune response genes was detected in tumors from patients presenting with low-volume ascites relative to those with high-volume ascites. Immunohistochemical studies performed on tissue microarrays confirmed higher expression of proteins encoded by immune response genes and increased tumorinfiltrating cells in tumors associated with low-volume ascites. Comparison of 149 advanced-stage HGSOC cases with differential ascites volume at time of primary surgery indicated low-volume ascites correlated with better surgical outcome and longer overall survival. These findings suggest that advanced stage HGSOC presenting with low-volume ascites reflects a unique subgroup of HGSOC, which is associated with upregulation of immune related genes, more abundant tumor infiltrating cells and better clinical outcomes.Peer Reviewe

BRCA1 Mutation Status and Follicular Fluid Exposure Alters NFκB Signaling and ISGylation in Human Fallopian Tube Epithelial Cells

Germline BRCA1 or BRCA2 mutations (mtBRCA1 and mtBRCA2) increase risk for high-grade serous ovarian cancer (HGSOC), the most commonly diagnosed epithelial ovarian cancer histotype. Other identified risk factors for this cancer, which originates primarily in the distal fallopian tube epithelium (FTE), implicate ovulation, during which the FTE cells become transiently exposed to follicular fluid (FF). To test whether mtBRCA1 or mtBRCA2 nonmalignant FTE cells respond differently to periovulatory FF exposure than control patient FTE cells, gene expression profiles from primary FTE cultures derived from BRCA1 or BRCA2 mutation carriers or control patients were compared at baseline, 24 hours after FF exposure, and 24 hours after FF replacement with culture medium. Hierarchical clustering revealed both FF exposure and BRCA mutation status affect gene expression, with BRCA1 mutation having the greatest impact. Gene set enrichment analysis revealed increased NFκB and EGFR signaling at baseline in mtBRCA1 samples, with increased interferon target gene expression, including members of the ISGylation pathway, observed after recovery from FF exposure. Gene set enrichment analysis did not identify altered pathway signaling in mtBRCA2 samples. An inverse relationship between EGFR signaling and ISGylation with BRCA1 protein levels was verified in an immortalized FTE cell line, OE-E6/E7, stably transfected with BRCA1 cDNA. Suppression of ISG15 and ISGylated protein levels by increased BRCA1 expression was found to be mediated by decreased NFκB signaling. These studies indicate that increased NFκB signaling associated with decreased BRCA1 expression results in increased ISG15 and protein ISGylation following FF exposure, which may be involved in predisposition to HGSOC

Oncologic Outcomes of Surgically Treated Cervical Cancer with No Residual Disease on Hysterectomy Specimen: A 4C (Canadian Cervical Cancer Collaborative) Working Group Study

Minimally invasive surgery for the treatment of macroscopic cervical cancer leads to worse oncologic outcomes than with open surgery. Preoperative conization may mitigate the risk of surgical approach. Our objective was to describe the oncologic outcomes in cases of cervical cancer initially treated with conization, and subsequently found to have no residual cervical cancer after hysterectomy performed via open and minimally invasive approaches. This was a retrospective cohort study of surgically treated cervical cancer at 11 Canadian institutions from 2007 to 2017. Cases initially treated with cervical conization and subsequent hysterectomy, with no residual disease on hysterectomy specimen were included. They were subdivided according to minimally invasive (laparoscopic/robotic (MIS) or laparoscopically assisted vaginal/vaginal hysterectomy (LVH)), or abdominal (AH). Recurrence free survival (RFS) and overall survival (OS) were estimated using Kaplan–Meier analysis. Chi-square and log-rank tests were used to compare between cohorts. Within the total cohort, 238/1696 (14%) had no residual disease on hysterectomy specimen (122 MIS, 103 AH, and 13 VLH). The majority of cases in the cohort were FIGO 2018 stage IB1 (43.7%) and underwent a radical hysterectomy (81.9%). There was no statistical difference between stage, histology, and radical vs simple hysterectomy between the abdominal and minimally invasive groups. There were no significant differences in RFS (5-year: MIS/LVH 97.7%, AH 95.8%, p = 0.23) or OS (5-year: MIS/VLH 98.9%, AH 97.4%, p = 0.10), although event-rates were low. There were only two recurrences. In this large study including only patients with no residual cervical cancer on hysterectomy specimen, no significant differences in survival were seen by surgical approach. This may be due to the small number of events or due to no actual difference between the groups. Further studies are warranted