Electronic data review, client reminders, and expanded clinic hours for improving cervical cancer screening rates after the COVID-19 pandemic shutdowns: A multicomponent quality improvement program.

Background: To improve cervical cancer screening (CCS) rates, the East Boston Neighborhood Health Center implemented a quality improvement initiative from March to August 2021. Methods: Staff training was provided. A 21-provider team validated overdue CCS indicated by electronic medical record data. To improve screening, CCS-only sessions were created during regular clinic hours (n = 5) and weekends/evenings (n = 8). Patients were surveyed on their experience. Results: A total of 6126 charts were reviewed. Of the list of overdue patients, outreach was performed on 1375 patients to schedule the 13 sessions. A total of 459 (33%) patients completed screening, 622 (45%) could not be reached, and 203 (15%) canceled or missed appointments. The proportion of total active patients who were up to date with CCS increased from 68% in March to 73% in August 2021. Survey results indicated high patient satisfaction, and only 42% of patients would have scheduled CCS without outreach. Conclusions: The creation of a validated patient chart list and extra clinical sessions devoted entirely to CCS improved up-to-date CCS rates. However, high rates of unsuccessful outreach and cancelations limited sustainability. This information can be used by other community health centers to optimize clinical workflows for CCS. Funding: All funding was internal from the EBNHC Adult Medicine, Family Medicine, and Women's Health Departments.

Connective tissue growth factor as a novel therapeutic target in high grade serous ovarian cancer.

Ovarian cancer is the most common cause of death among women with gynecologic cancer. We examined molecular profiles of fibroblasts from normal ovary and high-grade serous ovarian tumors to identify novel therapeutic targets involved in tumor progression. We identified 2,300 genes that are significantly differentially expressed in tumor-associated fibroblasts. Fibroblast expression of one of these genes, connective tissue growth factor (CTGF), was confirmed by immunohistochemistry. CTGF protein expression in ovarian tumor fibroblasts significantly correlated with gene expression levels. CTGF is a secreted component of the tumor microenvironment and is being pursued as a therapeutic target in pancreatic cancer. We examined its effect in in vitro and ex vivo ovarian cancer models, and examined associations between CTGF expression and clinico-pathologic characteristics in patients. CTGF promotes migration and peritoneal adhesion of ovarian cancer cells. These effects are abrogated by FG-3019, a human monoclonal antibody against CTGF, currently under clinical investigation as a therapeutic agent. Immunohistochemical analyses of high-grade serous ovarian tumors reveal that the highest level of tumor stromal CTGF expression was correlated with the poorest prognosis. Our findings identify CTGF as a promoter of peritoneal adhesion, likely to mediate metastasis, and a potential therapeutic target in high-grade serous ovarian cancer. These results warrant further studies into the therapeutic efficacy of FG-3019 in high-grade serous ovarian cancer.

TGF-ß modulates ovarian cancer invasion by upregulating CAF-derived versican in the tumor microenvironment.

TGF-ß has limited effects on ovarian cancer cells, but its contributions to ovarian tumor growth might be mediated through elements of the tumor microenvironment. In the present study, we tested the hypothesis that TGF modulates ovarian cancer progression by modulating the contribution of cancer-associated fibroblasts (CAF) that are present in the microenvironment. Transcriptome profiling of microdissected stromal and epithelial components of high-grade serous ovarian tumors and TGF-ß-treated normal ovarian fibroblasts identified versican (VCAN) as a key upregulated target gene in CAFs. Functional evaluations in coculture experiments showed that TGF-ß enhanced the aggressiveness of ovarian cancer cells by upregulating VCAN in CAFs. VCAN expression was regulated in CAFs through TGF-ß receptor type II and SMAD signaling. Upregulated VCAN promoted the motility and invasion of ovarian cancer cells by activating the NF-κB signaling pathway and by upregulating expression of CD44, matrix metalloproteinase-9, and the hyaluronan-mediated motility receptor. Our work identified a TGF-ß-inducible gene signature specific to CAFs in advanced high-grade serous ovarian tumors, and showed how TGF-ß stimulates ovarian cancer cell motility and invasion by upregulating the CAF-specific gene VCAN. These findings suggest insights to develop or refine strategies for TGF-ß-targeted therapy of ovarian cancer.

Up-regulation of stromal versican expression in advanced stage serous ovarian cancer.

OBJECTIVE: The purpose of this study is to examine the role of versican (VCAN) in advanced stage serous ovarian cancer by investigating its expression, its function, and its correlation with clinical outcomes. METHODS: Microarray analysis was performed on RNA isolated from tumor and stromal components of advanced stage serous ovarian cancer and normal ovarian epithelial tissue to identify genes up-regulated in ovarian tumor stroma. Validation studies using immunohistochemistry and quantitative real-time PCR (Q-RT-PCR) was performed on one of the up-regulated genes, VCAN. Immunolocalization of VCAN (n=111) and CD31 (n=56) was done on serous ovarian tumors. CD31 staining was performed to examine microvessel density (MVD). Q-RT-PCR was performed on 65 samples to evaluate the differential expression of VCAN isoforms. Cell proliferation and invasion assays were performed to examine how V1-treated ovarian cancer cell lines and an endothelial cell line would differ from controls. Univariate survival analyses were done with VCAN expression. Correlation analysis was done with CD31, platinum resistance, and clinical data. RESULTS: Validation studies using Q-RT-PCR and immunohistochemistry showed significantly higher VCAN V1 isoform expression in ovarian cancer stroma compared with normal ovarian stroma and ovarian cancer cells. Correlation studies showed stromal VCAN expression was associated with poorer overall and progression-free survival, platinum resistance, and increased MVD. VCAN-treated ovarian cancer and endothelial cells showed increased invasion potential. CONCLUSIONS: VCAN overexpression is associated with increased MVD and invasion potential, which may lead to poorer overall and progression-free survival and platinum resistance.

The evolving role of hysterectomy in gestational trophoblastic neoplasia at the New England Trophoblastic Disease Center.

OBJECTIVE: To identify indications for hysterectomy in patients with gestational trophoblastic neoplasia (GTN) and to evaluate outcomes of hysterectomy in those patients. STUDY DESIGN: Patients who underwent hysterectomy were identified utilizing hospital medical records and the New England Trophoblastic Disease Center (NETDC) database from January 1, 1959-January 1, 2009. Demographic data as well as indication for hysterectomy, stage, World Health Organization score, chemotherapeutic regimens and outcomes were recorded. We further stratified our population into patients with hysterectomies before and after 1980 to assess how indications for and outcomes after hysterectomy may have changed at our institution over time. RESULTS: A total of 98 patients were identified to have undergone hysterectomy for GTN. In the entire cohort 85% (n = 83) achieved remission and 48% (n = 47) required chemotherapy after hysterectomy. Among the patients in the early cohort (n = 49), indications for hysterectomy included 15 (31%) for primary definitive management, 14 (29%) for chemotherapy resistant disease, 14 (29%) for bleeding and 6 (11%) for other reasons. Of the patients with hysterectomy for chemotherapy resistance, 9 (64%) achieved remission. In the more recent cohort (n = 49) indications for hysterectomy included 24 (49%) for primary definitive management, 19 (39%) for drug-resistant disease, 4 (8%) for bleeding and 2 (4%) for other reasons. Of the patients with hysterectomy for chemotherapy resistance, 16 (84%) achieved remission. There was a statistically significant decline in the number of hysterectomies performed for bleeding. Hysterectomy was performed for bleeding in the early cohort (1959-1980) in 14 (29%) of 49 patients but in only 4 (8%) of 49 patients in the later cohort (1981-2009) (p = 0.02). CONCLUSION: During the years 1959-2009 the number of hysterectomies performed for GTN at the NETDC has remained stable. However, at our center there has been a decline in the incidence of hysterectomy for life-threatening hemorrhage. Overall 83 (84.7%) patients with hysterectomy for GTN obtained remission. In patients who underwent hysterectomy to treat chemotherapy-resistant disease, 25 of 33 (75.8%) subsequently achieved complete remission. Hysterectomy continues to play an important role in the management of selected patients with GTN.

A current review of targeted therapeutics for ovarian cancer.

Difficult to detect, ovarian cancer typically presents at an advanced stage. Significant progress has been achieved in the treatment of ovarian cancer with therapeutics focused on DNA replication or cell division. However, despite sensitivity to induction chemotherapy the majority of patients will develop recurrent disease. Conventional agents for recurrent disease offer little in terms of long-term responses. Various targeted therapeutics have been explored in the management of ovarian cancer. These include monoclonal antibodies to epidermal growth factor receptors, small molecule tyrosine kinase inhibitors, monoclonal antibodies directed at the vascular endothelial growth factor (bevacizumab), and the small tyrosine kinase inhibitors that target the vascular endothelial growth factor receptor. Recently, several other agents have come forth as potential therapeutic agents in the management of ovarian cancer. These include monoclonal antibodies to the folate receptor, triple angiokinase inhibitors, PARP inhibitors, aurora kinase inhibitors, inhibitors of the Hedgehog pathway, folate receptor antagonists, and MTOR inhibitors.

The changing role of thoracotomy in gestational trophoblastic neoplasia at the New England Trophoblastic Disease Center.

OBJECTIVE: To review our experience with thoracotomy in gestational trophoblastic neoplasia (GTN). STUDY DESIGN: Nineteen thoracotomy patients from our database were identified. Thoracotomy was performed for therapeutic reasons in 11 patients and to clarify the diagnosis in eight. RESULTS: Among the 11 patients with chemotherapy-resistant pulmonary tumors, 10 of 11 (90.9%) achieved remission with thoracotomy. Thoracotomy was more likely to be done to clarify diagnosis before 1980 (83%) than after 1980 (23%) (p = 0.04), when it became more likely to be done for therapeutic indications. Ten patients had solitary lung lesions and 9 had multiple lesions. Four patients died (21%), with an average survival after thoracotomy of 149 days; patients had bilateral or multiple lung lesions, median preoperative hCG was 58,000 mIU/mL and all were stage IV. Survivors had lower stage disease, were more likely to have solitary lesions and had lower preoperative hCG levels. CONCLUSION: There have been several temporal changes in the indications for thoracotomy for GTN. In general, the optimal patient to achieve remission with thoracotomy will have stage III disease, a preoperative hCG of < 1,500 mIU/mL, and a solitary lung nodule resistant to chemotherapy. Likelihood of remission after thoracotomy is high in properly selected patients.

Vascular endothelial growth factor stimulates preantral follicle growth in the rat ovary.

The regulation of preantral follicle growth in mammals is poorly understood. The availability of an adequate vascular supply to provide endocrine and paracrine signals may be important during the early states of follicle growth as well as the later states of follicle selection and dominance. The objective of the present study was to investigate whether vascular endothelial growth factor (VEGF) plays a role in preantral follicular development in the rat ovary. Immature (age, 21 days) Sprague-Dawley rats were injected with 500 ng of VEGF in saline or 50 microg of diethylstilbestrol (DES) in oil under the bursa of one ovary. The contralateral ovary was injected with a corresponding volume of vehicle. Rats were killed 48 h later, and the ovaries were removed and analyzed histologically. Intrabursal administration of VEGF significantly increased the number of primary and small secondary, but not of large secondary, preantral follicles in the ovary, similar to the effect of DES (P < 0.05). The VEGF stimulated preantral follicle growth in a time- and dose-dependent manner. Subcutaneous DES administration increased the number of primary and secondary follicles, and both s.c. and intrabursal estrogen administration stimulated VEGF protein expression in the rat ovary. These data indicate that VEGF stimulates preantral follicular development in the rat ovary, is regulated by estrogen, and may be one of the factors that participate in the regulation of early follicle growth in the rat.