Short-term outcomes of uterine artery embolization for urgent or emergent abnormal uterine bleeding.

PURPOSE: To evaluate the outcomes of uterine artery embolization (UAE) for patients with urgent or emergent abnormal uterine bleeding (AUB). MATERIALS AND METHODS: Retrospective review of all patients from 1/2009-12/2020 who were treated urgently or emergently with UAE for AUB. Urgent and emergent cases were defined as those requiring inpatient admissions. Demographic data were collected for each patient including hospitalizations related to bleeding and length of stay (LOS) for each hospitalization. Hemostatic interventions other than UAE were collected. Hematologic data were collected before and after UAE including hemoglobin, hematocrit, and transfusion products. Data specific to the UAE procedure included complication rates, 30-day readmission, 30-day mortality, embolic agent, site of embolization, radiation dose, and procedure time. RESULTS: 52 patients (median age: 39) underwent 54 urgent or emergent UAE procedures. The most common indications for UAE were malignancy (28.8%), post-partum hemorrhage (21.2%), fibroids (15.4%), vascular anomalies (15.4%), and post-operative bleeding (9.6%). There were no procedure-related complications. Following UAE, 44 patients (84.6%) achieved clinical success and required no additional intervention. Packed red blood cell transfusion decreased from a mean of 5.7 to 1.7 units (p < 0.0001). Fresh frozen plasma transfusion decreased from a mean of 1.8 to 0.48 units (p = 0.012). 50% of patients received a transfusion prior to UAE, while only 15.4% were transfused post-procedure (p = 0.0001). CONCLUSIONS: Emergent or urgent UAE is a safe and effective procedure to control AUB hemorrhage secondary to a variety of etiologies.

Systematic Next Generation Sequencing is feasible in clinical practice and identifies opportunities for targeted therapy in women with uterine cancer: Results from a prospective cohort study.

BACKGROUND: Both incidence and mortality of uterine cancer are on the rise and mortality is higher for African American women. The aim of our study was to evaluate how Next Generation Sequencing (NGS) may facilitate identification of and intervention for treatment disparities when integrated into clinical workflows. RESULTS: Our cohort included 159 uterine cancer patients with recurrent/progressive and newly diagnosed advanced stage and/or high-risk histology. The most common tumor histological subtypes included EEC (n = 67), SEC (n = 34), UCS (n = 20), and mixed (n = 14). Black patients were most likely to present with aggressive histology: (SEC, 34.0%) and carcinosarcoma (UCS, 14.0%). The four most common mutations across all subtypes were TP53, PIK3CA, PTEN, and ARID1A. There was racial disparity between Black versus non-Black patients who were initiated on targeted therapy (28.2% vs. 38.2%, respectively) and clinical trial (15% vs. 22.6%, respectively). Compared to non-Black patients, Black patients had a significantly higher percentage TP53 mutations (p < 0.05) and a significantly lower percentage ARID1A mutations (p < 0.05). CONCLUSIONS: NGS for uterine malignancies provides actionable information for targetable mutations and/or clinical trial enrollment in most patients; further investigation is necessary to identify potentially modifiable factors contributing to current disparities that may improve targeted therapy uptake and clinical trial participation.

Neutralization of TGFß Improves Tumor Immunity and Reduces Tumor Progression in Ovarian Carcinoma.

The immunosuppressive effects of TGFß promotes tumor progression and diminishes response to therapy. In this study, we used ID8-p53-/- tumors as a murine model of high-grade serous ovarian cancer. An mAb targeting all three TGFß ligands was used to neutralize TGFß. Ascites and omentum were collected and changes in T-cell response were measured using flow. Treatment with anti-TGFß therapy every other day following injection of tumor cells resulted in decreased ascites volume (4.1 mL vs. 0.7 mL; P < 0.001) and improved the CD8:Treg ratio (0.37 vs. 2.5; P = 0.02) compared with untreated mice. A single dose of therapy prior to tumor challenge resulted in a similar reduction of ascites volume (2.7 vs. 0.67 mL; P = 0.002) and increased CD8:Tregs ratio (0.36 vs. 1.49; P = 0.007), while also significantly reducing omental weight (114.9 mg vs. 93.4 mg; P = 0.017). Beginning treatment before inoculation with tumor cells and continuing for 6 weeks, we observe similar changes and prolonged overall survival (median 70 days vs. 57.5 days). TGFß neutralization results in favorable changes to the T-cell response within the tumor microenvironment, leading to decreased tumor progression in ovarian cancer. The utilization of anti-TGFß therapy may be an option for management in patients with ovarian cancer to improve clinical outcomes and warrants further investigation.

Inhibiting WNT Ligand Production for Improved Immune Recognition in the Ovarian Tumor Microenvironment.

In ovarian cancer, upregulation of the Wnt/ß-catenin pathway leads to chemoresistance and correlates with T cell exclusion from the tumor microenvironment (TME). Our objectives were to validate these findings in an independent cohort of ovarian cancer subjects and determine whether inhibiting the Wnt pathway in a syngeneic ovarian cancer murine model could create a more T-cell-inflamed TME, which would lead to decreased tumor growth and improved survival. We preformed RNA sequencing in a cohort of human high grade serous ovarian carcinoma subjects. We used CGX1321, an inhibitor to the porcupine (PORCN) enzyme that is necessary for secretion of WNT ligand, in mice with established ID8 tumors, a murine ovarian cancer cell line. In order to investigate the effect of decreased Wnt/ß-catenin pathway activity in the dendritic cells (DCs), we injected ID8 cells in mice that lacked ß-catenin specifically in DCs. Furthermore, to understand how much the effects of blocking the Wnt/ß-catenin pathway are dependent on CD8+ T cells, we injected ID8 cells into mice with CD8+ T cell depletion. We confirmed a negative correlation between Wnt activity and T cell signature in our cohort. Decreasing WNT ligand production resulted in increases in T cell, macrophage and dendritic cell functions, decreased tumor burden and improved survival. Reduced tumor growth was found in mice that lacked ß-catenin specifically in DCs. When CD8+ T cells were depleted, CGX1321 treatment did not have the same magnitude of effect on tumor growth. Our investigation confirmed an increase in Wnt activity correlated with a decreased T-cell-inflamed environment; a relationship that was further supported in our pre-clinical model that suggests inhibiting the Wnt/ß-catenin pathway was associated with decreased tumor growth and improved survival via a partial dependence on CD8+ T cells.

Novel Therapeutics for Recurrent Cervical Cancer: Moving Towards Personalized Therapy.

While screening programs and HPV vaccination have decreased the incidence of cervical cancer, still over 13,000 cases occur in the USA annually. Early-stage cervical cancer has an excellent long-term prognosis, with 5-year survival for localized disease being > 90%. Survival decreases markedly for both locally advanced and metastatic disease, and both are associated with a higher risk of recurrence. Few effective treatment options exist for persistent, recurrent, or metastatic cervical cancer. In 2014, the anti-VEGF antibody bevacizumab was approved in combination with chemotherapy based on the results of the Phase III GOG-240 study. As the majority of cervical cancers have a viral etiology, which impairs the immune system, immunotherapy using checkpoint inhibitors and other agents, appears to be a promising approach. In June 2018, the US FDA approved the anti-PD1 antibody pembrolizumab for recurrent or metastatic cervical cancer with PD-L1 expression that progressed after one or more lines of chemotherapy. Another anti-PD1 antibody, cemiplimab also shows potential in this setting, either as monotherapy or combined with radiotherapy, and it is currently being evaluated in a Phase III trial. Additional checkpoint inhibitors including nivolumab, durvalumab, atezolizumab, and camrelizumab are in different stages of clinical development for the disease. Finally, an additional targeted approach being pursued involves PARP inhibitors (rucaparib and olaparib are both in Phase II) based on earlier study results.

Neutrophilia and mortality in women with uterine carcinosarcoma.

OBJECTIVE: The objective of this study was to investigate the relationship between pre-treatment absolute neutrophil count and clinical outcomes in patients with uterine carcinosarcoma. METHODS: In an Institutional Review Board approved, retrospective cohort study of 103 patients with uterine carcinosarcoma, the pre-treatment absolute neutrophil count data were obtained from the medical records, along with clinical, pathologic, treatment, and outcome data. Kaplan-Meier survival estimates were calculated and compared by the log rank test. Univariable and multivariable Cox proportional hazard regression models were used to examine the relationship of pre-treatment absolute neutrophil count with progression-free survival and overall survival. RESULTS: Uterine carcinosarcoma patients in the highest quartile of pre-treatment absolute neutrophil count had significantly reduced progression-free survival (p<0.001, log rank test), and overall survival (p<0.001, log rank test), compared with patients in the lower absolute neutrophil count quartiles. On multivariable analysis, high absolute neutrophil count was an independent poor prognostic factor for disease recurrence, HR 2.97 (95% CI 1.35 to 6.53, p=0.007) for highest versus lowest quartile absolute neutrophil count, and for mortality, HR 4.43 (95% CI 1.64 to 12.00, p= 0.003). CONCLUSIONS: High pre-treatment absolute neutrophil count is an independent poor prognostic factor in patients with uterine carcinosarcoma and may be useful as a potential biomarker in clinical trials. The mechanistic relationship of neutrophilia and uterine carcinosarcoma progression merits further investigation.

Review: Targeting the Transforming Growth Factor-Beta Pathway in Ovarian Cancer.

Despite extensive efforts, there has been limited progress in optimizing treatment of ovarian cancer patients. The vast majority of patients experience recurrence within a few years despite a high response rate to upfront therapy. The minimal improvement in overall survival of ovarian cancer patients in recent decades has directed research towards identifying specific biomarkers that serve both as prognostic factors and targets for therapy. Transforming Growth Factor-ß (TGF-ß) is a superfamily of proteins that have been well studied and implicated in a wide variety of cellular processes, both in normal physiologic development and malignant cellular growth. Hypersignaling via the TGF-ß pathway is associated with increased tumor dissemination through various processes including immune evasion, promotion of angiogenesis, and increased epithelial to mesenchymal transformation. This pathway has been studied in various malignancies, including ovarian cancer. As targeted therapy has become increasingly prominent in drug development and clinical research, biomarkers such as TGF-ß are being studied to improve outcomes in the ovarian cancer patient population. This review article discusses the role of TGF-ß in ovarian cancer progression, the mechanisms of TGF-ß signaling, and the targeted therapies aimed at the TGF-ß pathway that are currently being studied.

Hypoalbuminemia is a Predictive Factor for Fistula Formation in Recurrent Cervical Cancer.

OBJECTIVE: Antivascular endothelial growth factor monoclonal antibodies inhibit tumor angiogenesis, consequently impeding the recruitment of new vasculature to existing and new tumor lesions. We sought to evaluate toxicities in women with recurrent cervical cancer after receiving bevacizumab combination chemotherapy. METHODS: A review was conducted of women with recurrent and metastatic cervical cancer who were treated with salvage chemotherapy with or without bevacizumab between 2005 and 2015. Clinicopathologic data and reasons for treatment discontinuation were recorded. Patients that were excluded had other histology than squamous or adenocarcinoma, received 1 cycle of salvage chemotherapy, single agent bevacizumab, currently on treatment, or noncompliant. Statistical analysis was performed using the Fishers Exact Test, logistic regression, and Kaplan-Meier Survival Analysis. RESULTS: A total of 74 patients were included in analysis. Twenty-six patients were treated with bevacizumab (BEV) and chemotherapy and 48 patients with chemotherapy alone (chemotherapy). The progression free survival was significant with median 12 months versus 7 months for the BEV cohort (P<0.01) and the overall survival was a median 74 months versus 23 months for the BEV cohort (P=0.06). Cessation of treatment secondary to severe toxicities was seen in 46% (n=12) of BEV cohort versus 15% (n=7) of chemotherapy cohort (P<0.01). Twenty-seven percent (n=7) of patients in the BEV cohort stopped secondary because of fistula formations. Lower albumin levels and use of bevacizumab were identified as an independent predictor factors for fistula formation (P=0.004 and 0.024, respectively). CONCLUSIONS: Hypoalbuminemia and bevacizumab treatments are significant predictive factors of fistula formation in patients treated for recurrent cervical cancer.

Results of a pilot multicenter genotype-based randomized placebo-controlled trial of propranolol to reduce pain after major thermal burn injury.

BACKGROUND: Results of previous studies suggest that ß-adrenoreceptor activation may augment pain, and that ß-adrenoreceptor antagonists may be effective in reducing pain, particularly in individuals not homozygous for the catechol-O-methyltransferase (COMT) high-activity haplotype. MATERIALS AND METHODS: Consenting patients admitted for thermal burn injury at participating burn centers were genotyped; those who were not high-activity COMT homozygotes were randomized to propranolol 240 mg/d or placebo. Primary outcomes were study feasibility (consent rate, protocol completion rate) and pain scores on study days 5 to 19. Secondary outcomes assessed pain and posttraumatic stress disorder symptoms 6 weeks postinjury. RESULTS: Seventy-seven percent (61/79) of eligible patients were consented and genotyped, and 77% (47/61) were genotype eligible and randomized. Ninety-one percent (43/47) tolerated study drug and completed primary outcome assessments. In intention-to-treat and per-protocol analyses, patients randomized to propranolol had worse pain scores on study days 5 to 19. CONCLUSIONS: Genotype-specific pain medication interventions are feasible in hospitalized burn patients. Propranolol is unlikely to be a useful analgesic during the first few weeks after burn injury.

Catechol-O-methyltransferase genotype predicts pain severity in hospitalized burn patients.

Increasing evidence suggests that stress system activation after burn injury may contribute to burn-related pain. If this is the case, then genetic variations influencing the function of important stress system components, such as the enzyme catechol-O-methyltransferase (COMT), may predict pain severity after thermal burn injury. The authors evaluated the association between COMT genotype and pain intensity in 57 individuals hospitalized after thermal burn injury. Consenting participants at four burn centers were genotyped and completed daily 0 to 10 numeric rating scale pain assessments on 2 consecutive days including evaluation of waking, least, and worst pain. The association between COMT genotype and individual pain outcomes was calculated using a linear mixed model adjusting for sociodemographic and burn injury characteristics. Overall pain (combination of least, worst, and waking pain scores) was significantly higher in patients with a COMT pain vulnerable genotype (6.3 [0.4] vs 5.4 [0.4], P = .037). Individuals with a COMT pain vulnerable genotype also had significantly higher "least pain" scores (3.8 [0.5] vs 2.6 [0.4], P = .017) and significantly higher pain on awakening (6.8 [0.5] vs 5.3 [0.4], P = .004). Differences in worst pain according to genotype group were not significant. COMT pain vulnerable genotype was a stronger predictor of overall pain severity than burn size, burn depth, or time from admission to pain interview assessment. These findings suggest that genetic factors influencing stress system function may have an important influence on pain severity after burn injury. Further studies of genetic predictors of pain after burn injury are needed.