Association between Antenatal Vaginal Bleeding and Adverse Perinatal Outcomes in Placenta Accreta Spectrum.

Background and Objectives: Placenta accreta spectrum (PAS) disorders are placental conditions associated with significant maternal morbidity and mortality. While antenatal vaginal bleeding in the setting of PAS is common, the implications of this on overall outcomes remain unknown. Our primary objective was to identify the implications of antenatal vaginal bleeding in the setting of suspected PAS on both maternal and fetal outcomes. Materials and Methods: We performed a case-control study of patients referred to our PAS center of excellence delivered by cesarean hysterectomy from 2012 to 2022. Subsequently, antenatal vaginal bleeding episodes were quantified, and components of maternal morbidity were assessed. A maternal composite of surgical morbidity was utilized, comprised of blood loss ≥ 2 L, transfusion ≥ 4 units of blood, intensive care unit (ICU) admission, and post-operative length of stay ≥ 4 days. Results: During the time period, 135 cases of confirmed PAS were managed by cesarean hysterectomy. A total of 61/135 (45.2%) had at least one episode of bleeding antenatally, and 36 (59%) of these had two or more bleeding episodes. Increasing episodes of antenatal vaginal bleeding were associated with emergent delivery (p < 0.01), delivery at an earlier gestational age (35 vs. 34 vs. 33 weeks, p < 0.01), and increased composite maternal morbidity (76, 84, and 94%, p = 0.03). Conclusions: Antenatal vaginal bleeding in the setting of PAS is associated with increased emergent deliveries, earlier gestational ages, and maternal composite morbidity. This important antenatal event may aid in not only counseling patients but also in the coordination of multidisciplinary teams caring for these complex patients.

Implementation and outcomes of a uterine artery embolization and tranexamic acid protocol for placenta accreta spectrum.

BACKGROUND: Placenta accreta spectrum disorders are a continuum of placental pathologies with significant maternal morbidity and mortality. Morbidity is related to the overall degree of placental adherence, and thus patients with placenta increta or percreta represent a high-risk category of patients. Hemorrhage and transfusion of blood products represent 90% of placenta accreta spectrum morbidity. Both tranexamic acid and uterine artery embolization independently decrease obstetrical hemorrhage. OBJECTIVE: This study aimed to provide an evidence-based intraoperative protocol for placenta accreta spectrum management. STUDY DESIGN: This study was a pre- and postimplementation analysis of concomitant uterine artery embolization and tranexamic acid in cases of patients with antenatally suspected placenta increta and percreta over a 5-year period (2018-2022). For comparison, a 5-year (2013-2017) preimplementation group was used to assess the impact of the uterine artery embolization and tranexamic acid protocol for placenta accreta spectrum. Patient demographics and clinically relevant outcomes were obtained from electronic medical records. RESULTS: A total of 126 cases were managed by the placenta accreta spectrum team, of which 66 had suspected placenta increta/percreta over the 10-year time period. Two patients were excluded from the postimplementation cohort because they did not undergo both interventions. Thus, 30 (30/64; 47%) were treated after implementation of the uterine artery embolization and tranexamic acid protocol for placenta accreta spectrum, and 34 (34/64; 53%) preimplementation patients did not undergo uterine artery embolization or tranexamic acid infusion. With the uterine artery embolization and tranexamic acid protocol, operative times were longer (416 vs 187 minutes; P<.01), and patients were more likely to receive general anesthesia (80% vs 47%; P<.01). However, blood loss was reduced by 33% (2000 vs 3000 cc; P=.03), overall blood transfusion rates decreased by 51% (odds ratio, 0.05 [95% confidence interval, 0.001-0.20]; P<.01), and massive blood transfusion (>10 units transfused) was reduced 5-fold (odds ratio, 0.17 [95% confidence interval, 0.02-0.17]; P=.02). Postoperative complication rates remained unchanged (4 vs 10 events; P=.14). Neonatal outcomes were equivalent. CONCLUSION: The uterine artery embolization and tranexamic acid protocol for placenta accreta spectrum is an effective approach to the standardization of complex placenta accreta spectrum cases that results in optimal perioperative outcomes and reduced maternal morbidity.

Importance of the gynecologic oncologist in management of cesarean hysterectomy for Placenta Accreta Spectrum (PAS).

OBJECTIVE: Placenta Accreta Spectrum (PAS) is an invasive placental disorder characterized by significant maternal and fetal morbidity. Utilization of multidisciplinary teams has been shown to optimize patient outcomes. Our objective was to assess the impact of cesarean hysterectomy performed by gynecologic oncologists versus Ob/Gyn specialists in maternal morbidity. METHODS: A retrospective cohort study was performed of singleton, non-anomalous pregnancies complicated by PAS University of Texas Health San Antonio Placenta Accreta program from 2010 to 2021. Our primary outcome was a maternal morbidity composite of any of the following: estimated blood loss >2 L, ICU admission, intraoperative acidosis and post-operative length of stay >4 days. In addition, demographic and pregnancy data were obtained. Univariate and multivariate analyses were performed to identify the individual impact of variables such as general anesthesia, episodes of vaginal bleeding, uterine artery embolization, emergent delivery and placenta percreta pathology. RESULTS: 122 pregnancies complicated by PAS who underwent cesarean hysterectomy were identified from 2010 to 2021. Gynecologic oncologists were the primary surgeons for 62 (50.8%) of these cases. The involvement of gynecologic oncologists increased over the time period from 16% to 80%. Gynecologic oncologists were more like to be involved in cases with an antenatal diagnosis of placenta percreta (11.7 vs 37.1%, p = 0.001) and these cases were characterized by increased composite maternal morbidity (65 vs 83.9%, p = 0.02). These cases were also significantly longer (151 vs 271 min, p < 0.0001), involved greater usage of urinary stents (36.7 vs 66.1%, p = 0.002) and had longer post-operative lengths of stay (3 vs 4 days, p < 0.0001). PAS cesarean hysterectomies by gynecologic oncologists were less likely to be supracervical (25 vs 3.2%, p = 0.0005). Multivariate analysis controlling for placenta percreta, uterine artery embolization, vaginal bleeding and emergent delivery showed no difference in composite maternal morbidity (aOR = 0.95, 95%CI [0.35-2.52]) and lower rates of intraoperative acidosis (aOR = 0.36, 95%CI [0.14-0.93]) or post-operative length of stay >4 days (aOR = 0.37, 95%CI [0.15-0.91]). CONCLUSIONS: Gynecologic oncologists play a critical role in the surgical management of PAS cesarean hysterectomies. When compared to Ob/Gyn specialists, gynecologic oncologists are more likely to act as primary surgeons in complex cases similar morbidity and greater post-operative outcomes.

Less radical surgery for early-stage cervical cancer: Can conization specimens help identify patients at low risk for parametrial involvement?

OBJECTIVE: Radical hysterectomy for cervical cancer is associated with increased morbidity over an extrafascial hysterectomy. The goal of this study was to determine incidence of and risk factors for parametrial involvement (PI) based on conization specimen (CS) and to potentially identify candidates for less radical surgery. METHODS: Patients with FIGO IA2-IIA cervical cancer treated with radical hysterectomy and pelvic lymph node dissection (RH) from 2000 to 2010 were retrospectively identified. Data was extracted from operative and pathology reports. Statistical analyses were performed using Fisher's exact test, t-test, and asymptotic logistic regression. RESULTS: Of 267 RH patients identified, 118 (44%) had conization prior to RH. The incidence of PI was 15.7% overall and 7.5% in patients treated with conization prior to RH. There was no association between PI and histology, stage, grade, or tumor size. Conization patients with PI were more likely to have LVSI on CS (77.8% vs. 29.4%) and positive lymph nodes (LNP) (66.7% vs. 8.3%). Of patients with positive endocervical curettage, a modest 12% had PI, which was not statistically significant. Tumor size, depth of invasion, and margin status on CS were not statistically associated with PI. In logistic regression analysis, LNP alone or LNP+LVSI were predictive of PI. CONCLUSIONS: The incidence of PI in early-stage cervical cancer is significant. Only LVSI on CS and LNP were predictors of PI in the current study. While there may be select patients with early stage cervical cancer who can be spared parametrectomy, additional research is warranted.

Perceptions of weight management counseling among gynecologic cancer survivors: opportunities for enhancing survivorship care.

PURPOSE: Oncology practice guidelines recommend incorporating weight management efforts throughout survivorship care; however, some oncologists raise concerns about implementing weight management counseling without damaging patient-provider relationships. This study explores cancer survivors' receptivity to weight management counseling and examines whether views of counseling effectiveness are associated with individual characteristics including health-related perceptions or psychological distress. METHODS: Patients presenting to a NCI Comprehensive Cancer Center gynecologic oncology ambulatory clinic were asked to complete a survey assessing health and weight history, health perceptions, psychological distress, provider preferences, and weight management counseling perceptions. RESULTS: Two hundred forty-four gynecologic cancer patients (38% endometrial, 37% ovarian, 16% cervical, 8% other) completed surveys. Mean participant BMI was 31.6 (SD = 9.6); 69% were overweight/obese. Most survivors (≥85%) agreed that oncologists should discuss healthy eating, exercise, and weight loss; only 14% reported receiving weight management counseling from their oncologist. 79% reported being more likely to attempt weight loss if counseled by a physician; 59% reported counseling would not be offensive. Regression results indicated that viewing weight management counseling as effective was associated with fewer depressive symptoms and greater enjoyment of physical activity, while viewing counseling unfavorably was associated with a history of attempting multiple weight loss strategies and an overall view of healthy behaviors as less beneficial (ps < .05). CONCLUSIONS: Most gynecologic cancer survivors want weight management counseling from oncologists and believe counseling is effective rather than deleterious, yet obesity remains inadequately addressed. Results from this study highlight important topics to be incorporated into weight management counseling.

Lymphatic mapping and sentinel lymph node dissection compared to complete lymphadenectomy in the management of early-stage vulvar cancer: A cost-utility analysis.

OBJECTIVE: Sentinel lymph node biopsy (SLNB) is an acceptable method of evaluating groin lymph nodes in women with vulvar cancer. The purpose of this study is to assess the cost and effectiveness of SLNB compared to universal inguinofemoral lymphadenectomy (LND) for vulvar cancer. METHODS: A modified Markov decision model was generated to compare two surgical approaches for newly diagnosed, early-stage vulvar cancer: (1) radical vulvectomy+LND and (2) radical vulvectomy+SLNB. Published data were used to estimate survival outcomes, probability of positive lymph nodes and lymphedema. Costs of surgery and radiation and lymphedema therapies were estimated from published data. Lymphedema's effect on quality of life (QOL) was extrapolated from other disease sites and assigned a utility score of 0.84. Multiple sensitivity analyses were performed. RESULTS: SLNB was less costly ($13,449 versus $14,261) and more effective (4.16 quality-adjusted life years (QALYs) versus 4.00 QALYs) than LND. The model was sensitive to the impact of lymphedema on QOL. Unless the impact of lymphedema on QOL was minimal (utility score>0.975) SLNB dominated LND. Variations in the rate of positive SLNB and probability of lymphedema over clinically reasonable ranges did not alter the results. CONCLUSIONS: SLNB is a cost-effective strategy for the treatment of newly diagnosed vulvar cancer, mainly due to the impact of lymphedema on QOL.

Hereditary cancer syndromes with high risk of endometrial and ovarian cancer: surgical options for personalized care.

Cancer genomics has increased our recognition of specific hereditary cancer mutations. Hereditary breast and ovarian cancer (HBOC) syndrome and Lynch syndrome are two such entities in which women carrying specific mutations may be at high risk for developing breast, ovarian, and/or endometrial cancers. Risk reducing surgery such as prophylactic mastectomy, oophorectomy, and/or hysterectomy may allow women to decrease these risks after completing childbearing. Background, indications, and consequences of these procedures are reviewed.

Robotic Hysterectomy for Endometrial Cancer in Obese Patients With Comorbidities: Evaluating Postoperative Complications.

OBJECTIVES: The objective of this study is to determine (1) if there is a relationship between increasing body mass index (BMI) and postoperative complications in patients undergoing robotic hysterectomy for endometrial cancer and (2) if there are additional patient characteristics, specifically preoperative comorbidities, which increase the risk of postoperative complication METHODS: A retrospective chart review was conducted on women who underwent a robotic staging surgery for endometrial cancer from 2006 to 2012. Basic demographics and preoperative and postoperative complications were extracted from the medical records. Obesity was divided into 4 categories, and complication rates were compared across these subgroups. Patients were also divided by the number of comorbidities and compared. RESULTS: The cohort included 543 patients. The BMI ranged from 17.3 to 69.5 kg/m. Three hundred eighty patients (70%) were obese (BMI >30 kg.m). One hundred ninety patients (35%) had no comorbidities other than obesity, and 180 patients (33%) had only 1 comorbidity other than obesity (Table 1).Postoperative complications occurred in 102 (18.7%) of the patients. Severe postoperative complications, including intensive care unit admission, reintubation, reoperation, and perioperative death, occurred in 14 patients (2.6%). Of the nonobese patients, 27 (16.5%) had postoperative complications; of the obese patients, 75 (19.7%) had a complication (P = 0.38). In patients with no comorbidities, 16.3% had a complication; 18% of patients with 1 to 2 comorbidities had a complication, and 28% of patients with 3 or more comorbidities had a complication (P = 0.08). CONCLUSIONS: The postoperative complication rate based on BMI or number of comorbidities was not statistically significant, but patients with greater number of comorbidities had an increased rate of postoperative complications. Patients with certain comorbidities, cardiac and renal specifically, had the highest rates of postoperative complications.

Alternatives to commonly used pelvic reconstruction procedures in gynecologic oncology.

OBJECTIVES: The objective of this review is to discuss alternatives to commonly used methods of soft tissue reconstruction in patients with gynecologic malignancies, and in particular alternatives to skin grafts, local skin flaps, and rectus abdominis/gracilis flaps. METHODS: A review of the literature was performed on soft tissue reconstruction in patients with gynecologic malignancies. RESULTS: Soft tissue reconstruction is often necessary to achieve successful wound healing, minimize complications, and to restore anatomic form and function. Commonly used methods such as skin grafts, local skin flaps, and rectus abdominis/gracilis flaps are effective, but many scenarios exist where they may be suboptimal or unavailable for use. Situations faced by the gynecologic oncologist where this may be the case include patients in whom prior treatments and/or tumor involvement have affected the vascular supply and tissues of commonly used options, those with disease recurrence who have previously undergone tumor extirpation and reconstruction, and patients undergoing radical surgery where commonly used options alone are inadequate. Under these circumstances, there are several alternative options, and an understanding of the full spectrum of reconstructive techniques is essential. CONCLUSIONS: Many clinical scenarios exist where commonly used options for soft tissue reconstruction are suboptimal or unavailable. Current evidence supports use of alternative methods of reconstruction in these situations. However, further larger scale and comparative studies are needed to refine surgical decision-making.

Is bariatric surgery an option for women with gynecologic cancer? Examining weight loss counseling practices and training among gynecologic oncology providers.

OBJECTIVE: The objective of this study was to evaluate gynecologic oncology provider (GOP) practices regarding weight loss (WL) counseling, and to assess their willingness to initiate weight loss interventions, specifically bariatric surgery (WLS). METHODS: Members of the Society of Gynecologic Oncology were invited to complete an online survey of 49 items assessing knowledge, attitudes, and behaviors related to WL counseling. RESULTS: A total of 454 participants initiated the survey, yielding a response rate of 30%. The majority of respondents (85%) were practicing GOP or fellows. A majority of responders reported that >50% of their patient population is clinically obese (BMI ≥ 30). Only 10% reported having any formal training in WL counseling, most often in medical school or residency. Providers who feel adequate about WL counseling were more likely to offer multiple WL options to their patients (p<.05). Over 90% of responders believe that WLS is an effective WL option and is more effective than self-directed diet and medical management of obesity. Providers who were more comfortable with WL counseling were significantly more likely to recommend WLS (p<.01). Approximately 75% of respondents expressed interest in clinical trials evaluating WLS in obese cancer survivors. CONCLUSIONS: The present study suggests that GOP appreciate the importance of WL counseling, but often fail to provide it. Our results demonstrate the paucity of formal obesity training in oncology. Providers seem willing to recommend WLS as an option to their patients but also in clinical trials examining gynecologic cancer outcomes in women treated with BS.

Aberrantly activated pSTAT3-Ser727 in human endometrial cancer is suppressed by HO-3867, a novel STAT3 inhibitor.

OBJECTIVE: Constitutive activation of STAT3 is a hallmark of various human cancers, however an increased pSTAT3 expression in high grade human endometrial cancer has not been reported. In the present study, we examine the expression of STAT family of proteins in endometrial cancer cell lines and the efficacy of HO-3867, a novel STAT3 inhibitor designed in our lab. METHODS: Expression of STAT family proteins was evaluated via Western blot. The cell viability, post-treatment with HO-3867, was assessed using MTT, cell-cycle profile and Annexin assay. In vivo efficacy of HO-3867 was evaluated using xenograft mice. RESULTS: Expression of activated STATs was inconsistent among the cell lines and 18 human endometrial cancer specimens tested. While pSTAT3 Tyr705 was not expressed in any of the cell lines, pSTAT3 Ser727 was highly expressed in endometrial cancer cell lines and tumor specimens. HO-3867 decreased the expression of pSTAT3 Ser727 while total STAT3 remained constant; cell viability decreased by 50-80% and induced G2/M arrest in 55% of Ishikawa cells at the G2/M cell cycle checkpoint. There was an increase in p53, a decrease in Bcl2 and Bcl-xL, and cleavage of caspase-3, caspase-7 and PARP. HO-3867 mediated a dosage-dependent inhibition of the growth of xenografted endometrial tumors. CONCLUSIONS: HO-3867 treatment decreases the high levels of pSTAT3 Ser727 in endometrial cancer cells by inducing cell cycle arrest and apoptosis. This suggests a specific role of serine-phosphorylated STAT3, independent of tyrosine phosphorylation in the oncogenesis of endometrial cancer. HO-3867 could potentially serve as an adjunctive targeted therapy.

Training the next generation of robotic surgeons using guided mentorship: a randomized controlled trial.

STUDY OBJECTIVE: To evaluate the effect of expert guided mentorship on technical score and time for a set of robotic training drills. DESIGN: Prospective randomized controlled trial (Canadian Task Force classification I). SETTING: Academic institution. SUBJECTS: Fifty trainees in robotic surgery. INTERVENTION: Inexperienced trainees underwent either a 20-minute expert guided mentorship session or no intervention. The primary outcomes were technical score and time-to-drill completion for a set of dry lab robotic training drills evaluated at an initial and final skills assessment. The t-test, including paired analyses, was used to evaluate outcomes. MEASUREMENTS AND MAIN RESULTS: Forty-nine of 50 trainees (98%) completed the study. There were no significant differences in participant characteristics or initial performance between the 2 groups. During the final skills assessment, the intervention group demonstrated significantly better performance on 1 of 8 objective measures. They had a higher mean score for the bead transfer drill when compared with the control group (21.6 vs 19.9; p = .03). No differences in time-to-drill completion were noted between the 2 groups. Regardless of randomization, all participants had significantly improved scores for each of the drills on the final compared with the initial skills assessment (p < .01). CONCLUSIONS: Although expert guided mentorship in a dry lab simulation environment seems feasible, further investigation is warranted before its widespread use because it may be more resource intensive than other teaching methods, without consistent objective improvements in technical performance.

Risk factors for intensive care unit admission after cesarean hysterectomy for placenta accreta spectrum.

OBJECTIVE: Placenta accreta spectrum (PAS) is a complex disorder of uterine wall disruption with significant morbidity and mortality, particularly at time of delivery. Both physician and physical hospital resource allocation/utilization remains a challenge in PAS cases including intensive care unit (ICU) beds. The primary objective of the present study was to identify preoperative risk factors for ICU admission and create an ICU admission prediction model for patient counseling and resource utilization decision making in an evidence-based manner. METHODS: This was a case-control study of 145 patients at our PAS referral center undergoing cesarean hysterectomy for PAS. Final confirmation by histopathology was required for inclusion. Patient disposition after surgery (ICU vs post-anesthesia care unit) was our primary outcome and pre-/intra-/postoperative variables were obtained via electronic medical records with an emphasis on the predictive capabilities of the preoperative variables. Uni- and multivariate analysis was performed to identify independent predictive factors for ICU admission. RESULTS: In this large cohort of 145 patients who underwent cesarean hysterectomy for PAS, with histopathologic confirmation, 63 (43%) were admitted to the ICU following delivery. These patients were more likely to be delivered at an earlier gestational age (34 vs 35 weeks, P < 0.001), have had >2 episodes of vaginal bleeding and emergent delivery compared to patients admitted to patients with routine recovery care (44% vs 18.3%, P = 0.009). Uni- and multivariate logistic regression showed an area under the curve of 0.73 (95% CI: [0.63, 0.81], P < 0.001) for prediction of ICU admission with these three variables. Patients with all three predictors had 100% ICU admission rate. CONCLUSION: Resource prediction, utilization and allocation remains a challenge in PAS management. By identifying patients with preoperative risk factors for ICU admission, not only can patients be counseled but this resource can be requested preoperatively for staffing and utilization purposes.

Risk factors of massive blood transfusion (MTP) in cesarean hysterectomy for placenta accreta spectrum.

BACKGROUND: Placenta Accreta Spectrum (PAS) represents a particularly morbid condition for which blood transfusion is the leading cause. Delivery by cesarean hysterectomy is recommended for the management of PAS. Massive Transfusion Protocols (MTP) in obstetrics vary in definition and implementation. Given the significant blood loss during PAS cesarean hysterectomy, this is particularly important for surgeons and blood banks. Our objective was to identify risk factors for MTP in patients with antenatally suspected PAS. METHODS: We performed a case-control study over a 11-year period from 2012 to 2022 at our center for Placenta Accreta Spectrum. MTP was defined by two methods, >4 units or > 10 units of red blood cells/whole blood transfused over 24 h. Antenatal, operative and post-operative outcomes were obtained from electronic medical records of these cases. RESULTS: During the study time frame, 142 cases were managed by our PAS team and met all criteria. 85 % (120/142) of patients were transfused at least 1 unit of blood, 64 patients (45 %) received 0-3 units of blood, 50 patients (35 %) received 4-9 units of blood and 28 patients (19.7 %) were transfused > 10 units of blood. Pre-delivery vaginal bleeding, preterm labor and delivery < 34 weeks were independently significant in transfused patients. ROC analysis revealed an area under the curve (AUC) of 0.79 (p < 0.0001) in patients transfused > 10 units, showing predictive capability for this subgroup. DISCUSSION: We here report pre-operative risk factors for MTP in patients undergoing cesarean hysterectomy for PAS. This allows for both resource utilization and patient counseling for this morbid maternal condition.

Neuroendocrine carcinoma of the uterine cervix: the role of multimodality therapy in early-stage disease.

BACKGROUND: Neuroendocrine carcinomas (NECs) of the cervix comprise only 2% of all cervical cancers. Prospective data is limited and treatment guidelines rely on retrospective reviews and literature from lung NEC. The objective of this study was to report our experience in the management of this rare disease. METHODS: This was an IRB-approved retrospective review. Study criteria included patients with cervical NEC diagnosed between 1990 and 2012. Demographic, treatment and survival data was collected. Progression free survival (PFS) and overall survival (OS) were assessed. RESULTS: Twenty-six patients met inclusion criteria. Advanced-stage disease (II-IV) was diagnosed in 58% (n=15) of patients. Of the eleven patients with stage I disease, five were treated with platinum-based neoadjuvant chemotherapy (NACT), six with initial radical surgery, and seven received adjuvant therapy including chemotherapy and/or radiation. Nine patients (82%) are currently without evidence of disease (NED). Patients with stage I disease had significantly improved PFS and OS compared to stages II-IV with a median OS that was not reached and 12.1 months, respectively (p=0.0013). The majority of stage I patients with lymph node metastasis and large tumors achieved durable remission with triple-modality therapy including NACT and surgery followed by adjuvant therapy. CONCLUSIONS: Cervical NEC is an aggressive disease associated with a high mortality rate. Patients with advanced-stage disease have a poor prognosis regardless of therapy. However, multimodality with consideration of triple-modality therapy in early-stage disease has the potential for complete response and long-term survival, supporting the goal of curative intent in these patients.

The impact of close surgical margins after radical hysterectomy for early-stage cervical cancer.

OBJECTIVE: While it is known that positive surgical margins increase the risk of cervical cancer recurrence, little is known about the effect of close surgical margins (CSM). Therefore, we set out to determine the impact of margin status on recurrence and survival in patients with early-stage cervical cancer. METHODS: A retrospective review was conducted of patients undergoing radical hysterectomy from 2000 to 2010 with Stage IA2-IIA cervical cancer. CSM were defined as ≤5mm; association with other clinicopathologic factors as well as recurrence and survival was evaluated. RESULTS: Of the 119 patients, 75 (63%) with CSM had a recurrence rate of 24% compared to 9% without CSM. Though not independently associated with recurrence, CSM were significantly associated with positive lymph nodes (44% vs. 18%), positive parametria (33.3% vs. 2.3%), larger tumors (3.5 vs. 2.5cm), greater depth of stromal invasion (DOI) (84% vs. 33%), and lymphovascular space invasion (LVSI) (61.3% vs. 34.1%). We failed to find an association between adjuvant therapy and recurrence in those with CSM. Exploratory analysis revealed that a surgical margin of ≤2mm was significantly associated with an increased risk of overall recurrence (36% vs. 9%, p=0.009) as well as loco-regional recurrence (22% vs. 4%, p=0.0034). CONCLUSIONS: Surgical margins of ≤5mm on radical hysterectomy specimens are often associated with other high or intermediate risk factors for recurrence. While not a proven independent risk factor, the distance to surgical margin may warrant further investigation as an intermediate risk factor along with tumor size, DOI and LVSI.

Should bevacizumab be continued after progression on bevacizumab in recurrent ovarian cancer?

OBJECTIVE: The optimal role of bevacizumab (Bev) in the treatment of ovarian cancer has not yet been established. Furthermore, it is unclear whether there is a benefit of Bev after progression on a Bev-containing regimen in ovarian cancer. The objective of this study was to compare response rates, progression-free survival (PFS), and overall survival between patients who were treated with chemotherapy and Bev after progression on Bev (BAB) versus patients who were treated with chemotherapy without Bev (CWOB). METHODS: We conducted a retrospective chart review of all patients who received treatment with Bev (with or without cytotoxic chemotherapy) for recurrent ovarian cancer at a single institution. Patients who received additional therapy after progression while on Bev were included. RESULTS: Forty-six patients were included (16 CWOB group and 30 BAB). The median number of previous chemotherapy regimens was 2.5 for CWOB compared with 4 for BAB (P = 0.11). Fifty-two percent of patients had an objective response to the first Bev regimen before progressing on Bev. Response rates for the regimen after progression on Bev were 19% (3/16) in the CWOB group and 23% (7/30) in the BAB group (P = 1). Twenty-five percent of the patients who responded to the first Bev regimen and 18% of those who did not respond to the first Bev regimen responded to the second Bev regimen (P = 0.72). The median PFS for patients in the CWOB group was 2.6 months (95% confidence interval [CI], 1.3-5 months), compared with 5.0 months (95% CI, 3.5-7.3 months) for patients in the BAB group (P = 0.01). Overall survival was similar, 9.4 months (95% CI, 5.0-12.0 months) for CWOB versus 8.6 months (95% CI, 5.8-15.5 months) for BAB (P = 0.19). One patient in the BAB group died of a bowel perforation. CONCLUSIONS: In patients previously treated with Bev for recurrent ovarian cancer, the subsequent addition of Bev to cytotoxic chemotherapy increased the PFS compared with patients not receiving a second course of Bev, but did so without an impact on overall survival. The response to the first Bev regimen did not predict whether a patient would respond again to the next Bev regimen. Randomized, larger studies will have to be performed to confirm this observation.

Recurrent ovarian cancer: is there a role for re-treatment with bevacizumab after an initial complete response to a bevacizumab-containing regimen?

OBJECTIVE: To compare the progression free survival (PFS) and overall survival (OS) in patients with epithelial ovarian cancer (EOC) who received Bev after Bev (BAB) vs. those who were not re-treated with Bev (NOTBev) after initially experiencing a complete response (CR) to a Bev-containing regimen (BCR). METHODS: We performed a retrospective chart review of patients with EOC that received Bev in either the front-line or recurrent setting. Patients who received additional therapy after achieving a CR to BCR were analyzed. RESULTS: 36 patients who had a CR to a BCR were included, 17 who received Bev at the time of their subsequent recurrence vs. 19 that did not. More patients in the NOTBev group received Bev as primary therapy (21% vs. 6%, p=0.2), but this was not statistically significant. Patients in the BAB group had significantly higher mean PFS compared to the NOTBev group (20 vs. 6 months, p=0.0019). On adjusting for covariates, there was a 78% improvement in their PFS (HR 0.22, p=0.0048). No difference in overall survival was noted between the groups (23 vs. 26 months, p=0.7244). CONCLUSIONS: Re-treatment with Bev after a prior Bev response is associated with a significantly improved PFS. This is the first of such reports in this patient population. The 14-month improvement in PFS strongly supports the re-use of Bev in patients who demonstrate an initial response to Bev. This strategy should be formally tested in future clinical trials and further investigation should include evaluation of predictors of response to Bev therapy.

Addition of bevacizumab to weekly paclitaxel significantly improves progression-free survival in heavily pretreated recurrent epithelial ovarian cancer.

OBJECTIVE: Weekly paclitaxel has been shown to be an effective cytotoxic regimen for recurrent epithelial ovarian cancer (EOC), and may act through inhibition of angiogenesis. Bevacizumab, a potent angiogenesis inhibitor, has also been shown to have activity in patients with EOC. Therefore, we sought to determine if the addition of bevacizumab to weekly paclitaxel led to an increased survival compared to weekly paclitaxel alone. METHODS: A single institutional review was conducted for patients with recurrent EOC treated with weekly paclitaxel (60-70mg/m(2)) on days 1, 8, 15, and 22 of a 28day cycle and those treated with weekly paclitaxel and bevacizumab (10-15mg/kg on day 1 and 15). Response rates (RR) were calculated, and progression-free survival (PFS), and overall survival (OS) were compared using Kaplan-Meier survival analysis. RESULTS: Twenty-nine patients treated with weekly paclitaxel and 41 patients treated with paclitaxel/bevacizumab were identified. The groups were similar in demographics, initial optimal cytoreduction, stage, histology, grade, platinum sensitivity, and median number of previous regimens (4 vs. 4, p=0.69).The overall response rate (ORR) was 63% (complete response (CR) 34% and partial response (PR) 29%) for paclitaxel/bevacizumab and 48% (CR 17% and PR 31%) for weekly paclitaxel (p=0.23). Improvement in PFS was seen in those treated with paclitaxel/bevacizumab in comparison to weekly paclitaxel alone (median PFS 13.2 vs. 6.2months, p<.01). There was a trend towards improved OS for paclitaxel/bevacizumab (median OS 20.6 vs. 9.1months; p=0.12). Toxicities were similar between the two regimens although more bowel perforations (2 vs. 0) were seen in the paclitaxel/bevacizumab group. CONCLUSION: A significant increase in PFS with a trend towards improved OS was demonstrated in this heavily pretreated population treated with paclitaxel/bevacizumab as compared to weekly paclitaxel alone. This data should be helpful in guiding future trials to determine the optimal care for women with recurrent EOC.

Rapid tumor vaccine using Toll-like receptor-activated ovarian cancer ascites monocytes.

BACKGROUND: Novel therapeutic strategies in ovarian cancer (OC) are needed as the survival rate remains dismally low. Although dendritic cell-based cancer vaccines are effective in eliciting therapeutic responses, their complex and costly manufacturing process hampers their full clinical utility outside specialized clinics. Here, we describe a novel approach of generating a rapid and effective cancer vaccine using ascites-derived monocytes for treating OC. METHODS: Using the ID8 mouse ovarian tumor model and OC patient samples, we isolated ascites monocytes and evaluated them with flow cytometry, Luminex cytokine and chemokine array analysis, ex vivo cocultures with T cells, in vivo tumor challenge and T cell transfer experiments, RNA-sequencing and mass spectrometry. RESULTS: We demonstrated the feasibility of isolating ascites monocytes and restoring their ability to function as bona fide antigen-presenting cells (APCs) with Toll-like receptor (TLR) 4 lipopolysaccharide and TLR9 CpG-oligonucleotides, and a blocking antibody to interleukin-10 receptor (IL-10R Ab) in the ID8 model. The ascites monocytes were laden with tumor antigens at a steady state in vivo. After a short 48 hours activation, they upregulated maturation markers (CD80, CD86 and MHC class I) and demonstrated strong ex vivo T cell stimulatory potential and effectively suppressed tumor and malignant ascites in vivo. They also induced protective long-term T cell memory responses. To evaluate the translational potential of this approach, we isolated ascites monocytes from stage III/IV chemotherapy-naïve OC patients. Similarly, the human ascites monocytes presented tumor-associated antigens (TAAs), including MUC1, ERBB2, mesothelin, MAGE, PRAME, GPC3, PMEL and TP53 at a steady state. After a 48-hour treatment with TLR4 and IL-10R Ab, they efficiently stimulated oligoclonal tumor-associated lymphocytes (TALs) with strong reactivity against TAAs. Importantly, the activated ascites monocytes retained their ability to activate TALs in the presence of ascitic fluid. CONCLUSIONS: Ascites monocytes are naturally loaded with tumor antigen and can perform as potent APCs following short ex vivo activation. This novel ascites APC vaccine can be rapidly prepared in 48 hours with a straightforward and affordable manufacturing process, and would be an attractive therapeutic vaccine for OC.