Durvalumab Plus Carboplatin/Paclitaxel Followed by Maintenance Durvalumab With or Without Olaparib as First-Line Treatment for Advanced Endometrial Cancer: The Phase III DUO-E Trial.

PURPOSE: Immunotherapy and chemotherapy combinations have shown activity in endometrial cancer, with greater benefit in mismatch repair (MMR)-deficient (dMMR) than MMR-proficient (pMMR) disease. Adding a poly(ADP-ribose) polymerase inhibitor may improve outcomes, especially in pMMR disease. METHODS: This phase III, global, double-blind, placebo-controlled trial randomly assigned eligible patients with newly diagnosed advanced or recurrent endometrial cancer 1:1:1 to: carboplatin/paclitaxel plus durvalumab placebo followed by placebo maintenance (control arm); carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab plus olaparib placebo (durvalumab arm); or carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab plus olaparib (durvalumab + olaparib arm). The primary end points were progression-free survival (PFS) in the durvalumab arm versus control and the durvalumab + olaparib arm versus control. RESULTS: Seven hundred eighteen patients were randomly assigned. In the intention-to-treat population, statistically significant PFS benefit was observed in the durvalumab (hazard ratio [HR], 0.71 [95% CI, 0.57 to 0.89]; P = .003) and durvalumab + olaparib arms (HR, 0.55 [95% CI, 0.43 to 0.69]; P < .0001) versus control. Prespecified, exploratory subgroup analyses showed PFS benefit in dMMR (HR [durvalumab v control], 0.42 [95% CI, 0.22 to 0.80]; HR [durvalumab + olaparib v control], 0.41 [95% CI, 0.21 to 0.75]) and pMMR subgroups (HR [durvalumab v control], 0.77 [95% CI, 0.60 to 0.97]; HR [durvalumab + olaparib v control] 0.57; [95% CI, 0.44 to 0.73]); and in PD-L1-positive subgroups (HR [durvalumab v control], 0.63 [95% CI, 0.48 to 0.83]; HR [durvalumab + olaparib v control], 0.42 [95% CI, 0.31 to 0.57]). Interim overall survival results (maturity approximately 28%) were supportive of the primary outcomes (durvalumab v control: HR, 0.77 [95% CI, 0.56 to 1.07]; P = .120; durvalumab + olaparib v control: HR, 0.59 [95% CI, 0.42 to 0.83]; P = .003). The safety profiles of the experimental arms were generally consistent with individual agents. CONCLUSION: Carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab with or without olaparib demonstrated a statistically significant and clinically meaningful PFS benefit in patients with advanced or recurrent endometrial cancer.

FAK PROTAC Inhibits Ovarian Tumor Growth and Metastasis by Disrupting Kinase Dependent and Independent Pathways.

Focal adhesion kinase (FAK) is highly expressed in a variety of human cancers and is a target for cancer therapy. Since FAK kinase inhibitors only block the kinase activity of FAK, they are not highly effective in clinical trials. FAK also functions as a scaffold protein in a kinase-independent pathway. To effectively target FAK, it is required to block both FAK kinase-dependent and FAK-independent pathways. Thus, we tested a new generation drug FAK PROTAC for ovarian cancer therapy, which blocks both kinase and scaffold activity. We tested the efficacy of FAK PROTAC and its parent kinase inhibitor (VS-6063) in ovarian cancer cell lines in vitro by performing cell functional assays including cell proliferation, migration, invasion. We also tested in vivo activity in orthotopic ovarian cancer mouse models. In addition, we assessed whether FAK PROTAC disrupts kinase-dependent and kinase-independent pathways. We demonstrated that FAK PROTAC is highly effective as compared to its parent FAK kinase inhibitor VS-6063 in inhibiting cell proliferation, survival, migration, and invasion. FAK PROTAC not only inhibits the FAK kinase activity but also FAK scaffold function by disrupting the interaction between FAK and its interaction protein ASAP1. We further showed that FAK PROTAC effectively inhibits ovarian tumor growth and metastasis. Taken together, FAK PROTAC inhibits both FAK kinase activity and its scaffold protein activity by disrupting the interaction between FAK and ASAP1 and is highly effective in inhibiting ovarian tumor growth and metastasis.

Intergenerational gestational surrogacy in a patient with ovarian dysgerminocarcinoma.

A 20-year-old woman was diagnosed with an ovarian dysgerminoma on the right ovary and underwent fertility-preserving right salpingo-oophorectomy and staging. Eight months later she was found to have a left ovarian solid mass. She underwent controlled ovarian hyperstimulation and oocyte cryopreservation before total abdominal hysterectomy, left salpingo-oophorectomy, and exploratory surgery were performed. The patient was optimally debulked, with no recurrent cancer to date. Thirty-six oocytes were mature and cryopreserved using vitrification. Now, the patient's mother has undergone embryo transfer that resulted in a clinical pregnancy, acting as a gestational carrier, for her daughter. To our knowledge, this is the first case describing the uterine transfer of embryos into a gestational carrier where the embryos were generated using oocytes obtained through controlled ovarian hyperstimulation in the context of active ovarian cancer. In the appropriate clinical setting, women desiring future fertility with a diagnosis of ovarian cancer without the option of ovarian-sparing surgery may be candidates for controlled ovarian hyperstimulation for the purposes of fertility preservation, especially if altruistic gestational carriers are available and willing.

Celecoxib versus ketorolac following robotic hysterectomy for the management of postoperative pain: An open-label randomized control trial.

OBJECTIVE: Compare postoperative pain scores following hysterectomy in patients receiving perioperative celecoxib versus postoperative ketorolac as part of a multimodal pain regimen. METHODS: Patients undergoing hysterectomy were randomized to receive scheduled intravenous ketorolac in the immediate postoperative period or oral celecoxib prior to surgery and continued for a total seven days. All patients received a common multimodal pain protocol consisting of scheduled acetaminophen, gabapentin, and opioids as needed. Inpatient pain scores and postoperative opioid use were analyzed. A questionnaire regarding outpatient opioid use and return to normal activities of daily living (ADLs) was returned two weeks postoperatively. RESULTS: 192 patients were assessed for eligibility and 170 patients were randomized. Enrollment of patients undergoing open hysterectomy was closed prematurely for poor accruement (n = 32). 138 patients undergoing robotic hysterectomy were included were analyzed. There were no differences for inpatient pain scores (2.7 ±â€¯1.9 v. 2.4 ±â€¯1.6, p = 0.21). Average length of stay was similar between the two arms (11.6 ±â€¯8.1 h v. 11.9 ±â€¯7.6 h, p = 0.41). Patients in the celecoxib arm used less prescription opioids (6.0 ±â€¯3.6 v. 8.1 ±â€¯4.0, p = 0.001) and stopped using oral opioids earlier (3.8 ±â€¯2.6 days v. 5.7 ±â€¯2.8 days, p < 0.001). No differences were seen in inpatient opioid or anti-emetic usage, perioperative complications, or days to return to ADLs. CONCLUSIONS: There was no difference in inpatient pain scores between patients who received celecoxib or ketorolac as part of multimodal pain control following robotic hysterectomy. Patients who received scheduled celecoxib for seven days after surgery used less prescription narcotics.

Use of a web-based app to improve postoperative outcomes for patients receiving gynecological oncology care: A randomized controlled feasibility trial.

OBJECTIVE: Nearly 1 in 5 patients hospitalized for ovarian cancer surgery are readmitted for complications that may have been prevented with monitoring. We conducted a randomized controlled feasibility trial to evaluate a postoperative web-based app intervention to provide real-time symptom monitoring among patients diagnosed or with suspected gynecological cancer who had open bilateral salpingo-oophorectomy surgery. METHODS: Participants were randomized into two groups: (1) App + Reminder: had access to the app, and use was encouraged with daily and/or weekly reminders; (2) app: had access to the app but received no reminders. The app displayed discharge instructions and queried symptoms. Patients' self-reported health information was integrated into their electronic health records. Outcomes above a predetermined threshold triggered alerts that indicated a patient may need medical intervention. Participants completed a questionnaire at baseline and 30-day follow-up. They were also invited to provide qualitative, post-intervention feedback. RESULTS: We screened 35 patients, with high rates of recruitment (74%, N = 26) and completion (93%, N = 24). Participants in the App + Reminder group had more frequent app use relative to the app group (p = 0.05). Using differences-in-differences (DID) analysis for quality of life, the App + Reminder group had relative increase in the mental health score (DID = 7.51, p = 0.15) but decrease in the physical health score (DID = -7.49, p = 0.13). Participant feedback suggested the relative decrease in physical quality of life was attributable to the app activating patients' focus on physical symptoms, not the intervention. CONCLUSION: The pilot established feasibility, acceptability, and some potential benefits of a new web-based app intervention for gynecological oncology postoperative care.

Fertility Preservation Through Oocyte Cryopreservation in a Patient with Ovarian Dysgerminocarcinoma: A Case Report.

BACKGROUND: This case evaluates a 20-year-old patient diagnosed with recurrent dysgerminoma who desired fertility preservation. CASE: A 20-year-old woman, GOPO, with a history of fertility-preserving right salpingo-oophorectomy and staging for dysgerminoma presented with interval change of a 5-cm left ovarian solid mass on ultrasound evaluation concerning for recurrent carcinoma. She underwent controlled ovarian hyperstimulation with injectable gonadotropins followed by transvaginal oocyte retrieval immediately followed by laparotomy, at which time ovarian dysgerminoma was confirmed. Completion total abdominal hysterectomy, left salpingo-oophorectomy, and exploratory surgery were performed. Forty-five oocytes were obtained, of which 37 mature oocytes were isolated and cryopreserved. The patient had an unremarkable postoperative course and was discharged home. CONCLUSION: Oncofertility preservation through oocyte cryopreservation may be considered a viable option for young women with ovarian cancer.

In vitro chemoresponse analysis of cervical cancer patient specimens.

PURPOSE: The objective of this study was to report the results of in vitro chemoresponse analysis of primary, metastatic, and recurrent human cervical cancers. METHODS: There were 557 tumor specimens submitted for testing from August 2006 to June 2010. Single agents tested were cisplatin, carboplatin, paclitaxel, docetaxel, epirubicin, fluorouracil, 4-hydroxy ifosfamide (active metabolite of ifosfamide), SN-38 (active metabolite of irinotecan), topotecan, and vinorelbine. Doublets tested were carboplatin/paclitaxel and cisplatin/topotecan. Tumor response was determined from dose-response curves. Results were scored as responsive, intermediate, or nonresponsive. Chemoresponse was reported as the combined responsive and intermediate results. RESULTS: Three hundred fifty-three (63.4%) of 557 submitted specimens were successfully assayed. Confirmation of histology and tumor status (primary, metastatic, or recurrent) was available for 273 specimens. The chemoresponse of the most active agents in primary cancers (n = 151) was 75% for SN-38, 71% for 4-hydroxy ifosfamide, 62% for topotecan, and 73% for carboplatin/paclitaxel. The chemoresponse of metastatic cancers (n = 66) was 54% for SN-38, 51% for 4-hydroxy ifosfamide, 44% for epirubicin, and 53% for carboplatin/paclitaxel. The chemoresponse for recurrent cancers (n = 56) was 44% for epirubicin, 41% for 4-hydroxy ifosfamide, 39% for vinorelbine, 39% for paclitaxel, 36% for topotecan, 46% for carboplatin/paclitaxel, and 35% for cisplatin/topotecan. The overall chemoresponse was greater in primary cancers (58%) than in recurrent cancers (35%) (P < 0.0001). CONCLUSIONS: In vitro chemoresponse analysis of cervical cancer biospecimens is feasible. Chemoresponse results are variable depending on tumor status. Clinical studies of assay-directed therapy should be developed.

Guided outcomes in learned efficiency model in clinical medical education: a randomized controlled trial of self-regulated learning.

OBJECTIVE: The guided outcomes in learned efficiency (GOLE) model emphasizes the use of evidence-based resources to understand the diagnosis, treatment, follow-up, and prevention of disease. We seek to determine whether presentations created using the GOLE model are superior to an unstructured approach in achieving Accreditation Council for Graduate Medical Education (ACGME) Core Competencies. STUDY DESIGN: Consenting medical students were randomized to GOLE or control groups to individually research a self-selected clinical topic. A validated survey instrument was used prepresentation and postpresentation to assess perceived improvement in knowledge. Subjects completed self-evaluations at enrollment and after presentation of their chosen clinical topic. Other students, residents, and a faculty member also completed evaluations after each student presentation. Standard statistical methods (analysis of variance, 2-tailed t test) were used to determine if a statistically significant difference existed between intervention and control groups. RESULTS: Self-assessments were similar in the GOLE and control groups. Externally perceived presentation scores were greater in the GOLE group (ACGME global P < .0001, presentation global P = .07), which demonstrated a significant improvement in 5 core competencies. Time spent preparing the presentation and resources utilized did not differ between groups. CONCLUSION: The presentations prepared using the GOLE model were rated higher by observers than those prepared using traditional techniques.

Live full-term ovarian ectopic pregnancy: a case report.

BACKGROUND: Ovarian ectopic pregnancy is rare, with an incidence of 1/7,000 to 1/40,000. Only a few of them progress to full term and survive. Most of them rupture in the first trimester and require emergency surgical intervention. CASE: An African American woman at 38 4/7 weeks' gestation presented to labor thd delivery with decreased smaal movement. Fetal presentation was vertex by ultrasound, which failed to detect ectopic pregnancy. The patient underwent cesarean section for nonreassuring fetal status. Dense pelvic adhesions and an unexpected, live, left ovarian ectopic pregnancy were encountered during laparotomy. CONCLUSION: This case stresses the importance of starting prenatal care early and having a routine first trimester transvaginal ultrasound, which could enhance

Combination metronomic oral topotecan and pazopanib: a pharmacokinetic study in patients with gynecological cancer.

BACKGROUND: Combination metronomic topotecan plus pazopanib is active against preclinical models of gynecological cancer. Both agents are substrates for ATP-binding cassette family transporters so there is an increased likelihood for pharmacokinetic (PK) drug-drug interactions. PATIENTS AND METHODS: PK analyses of topotecan were performed during three cycles of a phase I dose-escalation study of metronomic topotecan and pazopanib in consenting adult patients with gynecological cancer. Concentration time data were analyzed using a population PK approach. RESULTS: Twenty-one patients were evaluable for serial PK studies. Considerable inter- and intra-patient variability was observed in the PK parameters, attributable primarily to highly variable oral bioavailability. No difference in topotecan disposition was detected between administration cycles, nor between the off- versus on-pazopanib studies. CONCLUSION: The lack of a statistically significant drug-drug interaction agrees with preclinical findings suggesting that pazopanib does not influence the PK of metronomic topotecan. No adjustment of low dose metronomic topotecan dosing is merited when used in conjunction with pazopanib.

Phase II clinical trial of bevacizumab with albumin-bound paclitaxel in patients with recurrent, platinum-resistant primary epithelial ovarian or primary peritoneal carcinoma.

OBJECTIVE: We examined the safety and efficacy of combining bevacizumab with albumin-bound (ab-) paclitaxel to treat patients with recurrent, platinum-resistant primary epithelial ovarian or peritoneal carcinoma. METHODS: Patients had measurable disease per RECIST guidelines, progressing within 6 months after a prior course of platinum-based treatment. Patients received ab-paclitaxel 100mg/m(2) given by intravenous infusion over 30 min on days 1, 8, and 15 of a 28-day cycle with bevacizumab 10mg/kg given on days 1 and 15. RESULTS: Forty-eight patients with an average 1.8 prior lines of treatment participated. The overall response rate was 50% (24/48) (95% CI, 34.8% - 65.1%), with 4 complete and 20 partial responses. Fourteen patients (29%) had stable disease, whereas eight (17%) had progressive disease, and two (4%) were not evaluable. Patients received a median of 6 treatment cycles (range, 1 - 31 cycles). The median progression-free survival was 8.08 months (95% CI, 5.78 - 10.15 months); 6 month progression-free rate was 62.5% (95% CI, 47.8%-77.2%); median overall survival was 17.15 months (95% CI, 13.57 - 23.82 months). Grade 3-4 adverse events included gastrointestinal disorders (18.8%), neutropenia (8.3%), and hypertension (6.3%). CONCLUSIONS: Ab-paclitaxel with bevacizumab clearly demonstrates antitumor activity and manageable toxicity profile in patients with recurrent, platinum-resistant ovarian carcinoma. This regimen should be evaluated in a larger randomized trial.

Robotic surgical management of endometrial cancer in octogenarians and nonagenarians: analysis of perioperative outcomes and review of the literature.

The primary aim of this article is to report the outcomes of octogenarians and nonagenarians who have undergone robotic surgery for endometrial cancer. A multi-institutional research consortium was created to evaluate the utility of robotics for gynecologic surgery (benign and malignant). IRB approval was obtained at each institution. A multi-institutional HIPPA compliant database was then created and analyzed for all patients that underwent robotic-assisted surgery with staging for endometrial cancer between the April 2003 and January 2009. In total, 395 patients were identified. A subset of patients between the ages of 80 and 95 years were then identified and analyzed for demographic data and perioperative outcomes. Twenty-seven patients in this age group were identified who underwent robotic-assisted hysterectomy and staging. The median age was 84, and median body mass index was 28. Comorbidities such as diabetes mellitus and hypertension were identified in 22 and 74% of patients, respectively. Over one-half (56%) of the patients reported a prior abdominal surgery. Final pathological analysis demonstrated that 88% of all patients had either Stage I or II disease. The median operative time was 192 min. The median estimated blood loss was 50 cc, and the median lymph node count was 16. The median hospital stay was 1.0 day. The overall intraoperative and postoperative complication rate was 7.4 and 33%, respectively. No patient received a blood transfusion. There was one conversion to laparotomy (3.7%). A comparison of the outcomes of the elderly cohort to those of all patients in the database (control group) revealed that there was no statistically significant difference between the groups in terms of operative time, blood loss, hospital stay, nodal yield, or conversion rate. Intraoperative complications were statistically similar between the groups; however, postoperative complications were significantly higher in the elderly cohort. We conclude that robotic surgery is safe, feasible, and expands surgical options for octogenarians and nonagenarians diagnosed with endometrial cancer. Age should not be considered a contraindication for robotic surgical management of patients with endometrial cancer.

A multiinstitutional experience with robotic-assisted hysterectomy with staging for endometrial cancer.

OBJECTIVE: To report perioperative outcomes and learning curve characteristics from a multiinstitutional experience with robotic-assisted surgical staging for endometrial cancer. METHODS: A multiinstitutional robotic surgical consortium was created to evaluate the usefulness of robotics for gynecologic oncology surgery. An analysis of a multiinstitutional database of all patients who underwent robotic surgery for endometrial carcinoma between April 2003 and January 2009 was performed. Records were reviewed for demographic data and perioperative outcomes. Individual surgeon outcomes were analyzed as well in an attempt to evaluate characteristics of learning with incorporation of robotic technology. RESULTS: Four hundred five patients were identified who underwent robotic surgery for endometrial cancer. Mean age was 62.2 years and mean body mass index was 32.4. Fifty-five percent of patients reported a prior abdominal surgery. Final pathologic analysis demonstrated that 89.6% of all patients had stage I and II disease. Mean operative time was 170.5 minutes. Mean estimated blood loss was 87.5 mL. Mean lymph node count was 15.5. Mean hospital stay was 1.8 days. Intraoperative complications occurred in 3.5% of the patients and conversion to laparotomy occurred in 6.7%. Postoperative complications were reported in 14.6% of the patients. For the group, fewer than 10 cases were required to achieve proficiency with the procedure. CONCLUSION: Robotic technology may level the playing field between the novice and expert laparoscopist for endometrial cancer staging. Prospective trials should be undertaken to compare robotic and laparoscopic approaches to treat endometrial cancer. LEVEL OF EVIDENCE: III.

A multi-institutional experience with robotic-assisted radical hysterectomy for early stage cervical cancer.

OBJECTIVE: The purpose of the study is to report a multi-institutional experience with robotic-assisted radical hysterectomy to treat patients with early stage cervical cancer with respect to perioperative outcomes. METHODS: A multi-institutional robotic surgical consortium consisting of five board-certified gynecologist oncologist in distinct geographical regions of the United States was created to evaluate the utility of robotics for gynecologic surgery (benign and malignant). Between April 2003 and August 2008, a total of 835 patients underwent robotic surgery for benign gynecologic disorders and/or gynecologic malignancies by a surgeon in the consortium. IRB approval was obtained and data was collected in a prospective fashion at each institution. For the purposes of the study, a multi-institutional HIPPA compliant database was then created for all patients that underwent robotic-assisted surgery between the April 2003 and August 2008. This database was queried for all patients who underwent a robotic-assisted type II or III radical hysterectomy for Stage IA1 (+vsi)-IB2 cervical carcinoma. Forty-two patients were identified. Records were then reviewed for demographic data, medical conditions, prior abdominal or pelvic surgeries, and follow-up. The perioperative outcomes analyzed included: operative time (skin-skin), estimated blood loss (EBL), length of hospital stay, total lymph node count, conversion to laparotomy, and operative complications. RESULTS: From a database of 835 patients who underwent robotic surgery by a gynecologic oncologist, a total of 42 patients who underwent a robotic-assisted type II (n=10) or type III (n=32) radical hysterectomy for early stage cervical cancer were identified. Demographic data demonstrated a median age of 41 and a median BMI of 25.1. With regard to stage, seven patients (17%) were Stage IA2, twenty-eight patients (67%) were Stage IB1 and six patients (14%) were Stage IB2. There was a single patient with Stage IA1 cervical cancer with vascular space invasion who underwent a type II radical hysterectomy. The overall median operative time was 215 min. The overall median estimated blood loss was 50 cc. No patient received a blood transfusion. The median lymph node count was 25. The median hospital stay was 1 day. Positive lymph nodes were detected in 12% of the patients. Pelvic radiotherapy or chemo-radiation was given to 14% of the patients based on final surgical pathology. Intraoperative complications occurred in 4.8% of the patients and included one conversion to laparotomy (2.4%) and one ureteral injury (2.4%). Postoperative complications were reported in 12% of the patients and included a DVT (2.4%), infection (7.2%), and bladder/urinary tract complication (2.4%) The conversion rate to laparotomy was 2.4%. CONCLUSIONS: Robotic-assisted radical hysterectomy is associated with minimal blood loss, a shortened hospital stay, and few operative complications. Operative time and lymph node yields are acceptable. This data suggests that robotic-assisted radical hysterectomy may offer an alternative to traditional radical hysterectomy. This series contributes to the growing literature on robotic-assisted radical hysterectomy and prospective comparisons with traditional radical hysterectomy are needed.

Lymph node counts in uterine cancer: a randomized double blind trial.

OBJECTIVE: Higher number of lymph nodes counts may suggest a more accurate cancer staging. We wish to study whether sending lymph nodes to pathologist in four containers, instead of a single container, yields a higher nodal count. METHODS: Patients with uterine cancer who underwent abdominal hysterectomy and lymphadenectomy were recruited. The right and left pelvic lymph nodes were collected from four locations (common, external and internal iliac, and obturator). Blinded randomization ex vivo allocated the side of the pelvic nodes specimen which was sent to pathology as one versus four containers. Each patient served as her own control by having the other side of her pelvic nodes sent as four different specimens. The surgeons and pathologists were blinded. RESULTS: 104 consecutive patients were enrolled. The average age was 61 years old. The patients were predominately Caucasians (69%). The average total pelvic and aortic nodes per patients was 17.8. 54 patients, whose right-sided pelvic nodes were randomized to be sent in a single container, yielded an average of 7.2 right pelvic nodes versus 8.6 left pelvic nodes (p=0.026). 50 patients, whose left-sided pelvic nodes were randomized to be sent in a single container, yielded an average 8.1 right pelvic nodes versus 6.9 left pelvic nodes (p=0.042). CONCLUSION: The lymph nodes count are higher when surgical nodes were sent as multiple separated instead of single specimens, regardless of the side of the pelvis.

Preoperative predictors of positive margins after loop electrosurgical excisional procedure-Cone.

OBJECTIVE: A LEEP-Cone may not be necessary for all patients with traditional cone indications. This study defines populations where a single pass technique with the LEEP is appropriate. METHODS: We retrospectively reviewed patients undergoing LEEP-Cone procedures performed at the University of Oklahoma Health Science Center from February of 1994 to July of 2002. Patients include those for LEEP-Cone with traditional excisional indications and those who underwent LEEP-Cone at the operating physician's discretion. Statistical analysis was used to compare preoperative factors with the resultant pathologic results. RESULTS: A total of 248 women underwent LEEP-Cone. 50.0% (33/66) of the patients with positive margins on the first pass had dysplasia or worse (CIN I-III or CA) in the second pass (top hat), compared to 6.6% (12/182) of the patients with a negative first pass (P < 0.0001). Univariate analysis found CIN III on histology and parity to be predictive of dysplasia in the top hat and two-step discrepancy to predict absence of dysplasia. On multivariate analysis, two-step discrepancy and parity remained predictive. Age >35 was the greatest percentile predictor of dysplasia in the top hat, and 91.5% of women <21 had normal top hat pathology. CONCLUSION: The retrospective data reported regarding LEEP-Cones reveal increased parity to predict dysplasia in the top hat and two-step discrepancy as a poor predictor of dysplasia in the top hat. Women under 21 years of age should have a single pass LEEP technique. The "top hat" is more appropriate as parity and age increase.

Sensitization of cervical cancer cell lines to low-dose radiation by retinoic acid does not require functional p53.

OBJECTIVE: Current therapy for cervical cancer includes radiation therapy. Retinoic acid (RA) can increase the sensitivity of cervical cancer cell lines to radiation. The mechanism of this sensitization may not involve the p53 protein because the human papillomavirus (HPV) E6 protein, which is present in the majority of cervical cancers, promotes p53 degradation. The objective of this study was to determine if p53 is involved in the mechanism of RA radiosensitization. METHOD: The effects of radiation on cervical (SiHa, CC-1, and C33a) and vulvar (SW962) cancer cell lines under various experimental conditions were evaluated using clonogenic, Coulter Counter, electrophoretic mobility shift (EMSA) and a multi-probe RNase protection assay of p53-inducible genes. RESULTS: RA (5 microM 9-cis-RA) radiosensitized the SiHa and CC-1 cell lines that contain HPV-degraded p53, but did not radiosensitize the SW962 cell line, which is HPV negative and contains wild-type p53, nor the C33a cell line, which contains mutant p53 (R273C). Expression of mutant p53 (R273H) in SiHa cells increased the growth rate, but did not prevent RA-induced differentiation or radiosensitization at clinically relevant doses. Inhibition of p53 transactivation with pifithirin alpha did not prevent RA radiosensitization of SiHa at 5 Gy. RA repressed c-fos mRNA expression in control and irradiated SiHa cultures, but did not repress bcl-x(L), p53, GADD45, p21, bax, bcl-2, or mcl-1 mRNA expression. CONCLUSIONS: The mechanism of RA radiosensitization does not require functional p53 and may involve c-fos in cervical cancer cell lines.

A comparison of stages IB1 and IB2 cervical cancers treated with radical hysterectomy. Is size the real difference?

OBJECTIVE: To compare stages IB1 and IB2 cervical cancers treated with radical hysterectomy (RH) and to define predictors of nodal status and recurrence. METHODS: Patients with stage IB cervical cancers undergoing RH between 1990 and 2000 were evaluated and clinicopathological variables were abstracted. The perioperative complication rate, estimated blood loss (EBL), and OR time were also tabulated. Variables were analyzed using X(2) and t tests. Disease-free survival (DFS) was calculated by Kaplan-Meier method. Multivariate analysis was performed via stepwise logistic regression. Cox-proportional hazards were used to identify independent predictors of recurrence. RESULTS: RH was performed on 109 stage IB1 and 86 stage IB2 patients. Mean age, EBL, and perioperative complication rates were similar. Overall, 38 patients (14 IB1 vs. 24 IB2) had positive nodes (P = 0.01) including 9 patients with positive para-aortic nodes (2 IB1 and 7 IB2). Parametrial involvement (PI) and outer 2/3 depth of invasion (DOI) were significantly more common in the IB2 tumors as well. Patients with IB2 disease received adjuvant radiation more frequently than IB1 patients (52% vs. 37%, P = 0.04). Univariate predictors of nodal status included lymphovascular space involvement (LVSI) (P = 0.001), DOI (P = 0.011), PI (P = 0.001), and stage (P = 0.011). Multivariate analysis identified only LVSI (OR 6.4, CI 2.4-17, P = 0. 0002) and PI (OR 8, CI 3.1-20, P = 0. 0001) as independent predictors of positive nodes. With a median follow-up of 35 months, estimates of DFS revealed tumor size (P = 0.008), nodal status (P = 0.0004), LVSI (P = 0.002), PI (P = 0.004), and DOI (P = 0.0004) as significant univariate predictors. Neoadjuvant chemotherapy, age, grade, histology, and adjuvant radiation were not associated with recurrence. The significant independent predictors of DFS were LVSI (ROR 5.7, CI 2-16, P = 0.0064) and outer 2/3 DOI (OR 5.8, CI 2-20, P = 0.0029). Neither tumor size nor nodal status was a significant predictor of DFS. CONCLUSIONS: The prognosis in stage IB cervical cancer seems to be most influenced by presence of LVSI and DOI and not by tumor size as the staging criteria would suggest. These factors are best determined pathologically after radical hysterectomy. This report contains the largest comparison of IB1 and IB2 patients managed by RH. Tumor size failed to predict recurrence or nodal status when stratified by LVSI, DOI, and PI. Treatment decisions based on tumor size alone should be reconsidered.

Surgical-pathological predictors of disease-free survival and risk groupings for IB2 cervical cancer: do the traditional models still apply?

OBJECTIVE: To evaluate how the independent predictors of recurrence for stage IB2 cervical cancers treated with up-front radical hysterectomy apply to established risk models. METHODS: Patients with IB2 cervical cancers diagnosed from 1990 to 2000 were identified from tumor registries of two institutions. Patients were classified into risk groups: high-risk (HR) (positive nodes, parametria, or margins), intermediate-risk (IR) (positive lymph vascular space involvement (LVSI) with any cervical stromal invasion (CSI), or (-) LVSI and > middle- CSI), or low-risk (LR) (absence of HR or IR characteristics). Disease-free survival (DFS) was estimated by Kaplan-Meier method and comparisons between subgroups were studied by log rank. A Cox proportional hazards model was used to determine independent predictors of recurrence. RESULTS: We identified 86 patients with stage IB2 tumors treated by RH. We found 34% of patients to be HR, 60% IR, and 6% LR. Of the 52 IR patients, 28 had (+) LVSI with superficial, middle, and outer 1/3 CSI, and 24 had (-) LVSI with middle or outer 1/3 invasion. Overall, postoperative adjuvant radiation (PRT) was used in 52% of the 86 patients, including 0/5 LR, 16/52 IR, and 29/29 HR patients. Univariate predictors of recurrence were pelvic nodal disease, (+) LVSI, (+) parametria, outer 1/3 CSI, and tumor size > 6 cm. Age, grade, histology, and the use of postoperative radiation were not associated with recurrence. Multivariate analysis identified LVSI as the only independent predictor of recurrence (RR 5.2, P = 0.03). Two-year DFS for LR, IR, and HR patients was 100%, 83%, and 60%, respectively. Only 4/24 (17%) IR patients with (-) LVSI got PRT compared with 12/28 (43%) of IR patients with (+) LVSI. The 2-year DFS for IR patients with (-) LVSI was 96%. IR (+) patients recurred more frequently with a 2-year DFS of 71%. CONCLUSIONS: Overall, 66% of patients with IB2 disease were classified as having low or intermediate-risk disease. IR patients with (-) LVSI and all LR patients did well with surgery alone. This study defines the independent importance of LVSI and questions the utility of published IR models when applied to stage IB2 cervical cancer.