Efficacy and safety of olaparib according to age in BRCA1/2-mutated patients with recurrent platinum-sensitive ovarian cancer: Analysis of the phase III SOLO2/ENGOT-Ov21 study.

BACKGROUND: Olaparib has significantly improved outcome and patient-centered endpoints in BRCA1/2-mutated patients with recurrent platinum-sensitive ovarian cancer (PSOC). Specific information on efficacy and safety of olaparib for older patients appears of special interest. METHODS: 295 patients from the SOLO2 trial randomly assigned to olaparib or placebo were categorized according to age-cutoff at 65 years. Efficacy, tolerability, and quality of life (QoL) of olaparib relative to placebo within in each age group was analyzed. RESULTS: Baseline characteristics were similar in patients ≥65 years (N = 62;21.0%) compared to patients <65 years (N = 233;78.9%). No significant difference in the magnitude of progression-free survival (PFS) benefit from olaparib for older patients (N = 40, hazard ratio [HR]≥65 0.43, 95%-confidence interval [CI] 0.24-0.81) as compared with younger patients (N = 155, HR<65 0.31 (95%-CI 0.22-0.43) was seen (interaction P = 0.33). The overall survival (OS)benefit seen in younger patients in the olaparib arm was not observed in older patients. Older and younger patients had comparable safety profiles and QoL scores although higher discontinuation rates for toxicity, and higher frequency of AML/MDS were noted in the older subset. TWiST analysis revealed clinically meaningful duration of good QoL on olaparib for both age groups (≥65: 13.5 vs <65: 18.4 months, P = 0.05). CONCLUSIONS: Results of this large phase III cohort of BRCA1/2-mutated PSOC patients treated with olaparib underline impressive efficacy of olaparib maintenance irrespective of age. Although toxicity and tolerability did not raise significant concerns, some caution, close monitoring, and follow-up needs to be exercised for older patients given higher discontinuation rates, frequency of AML/MDS, and no clear effects on OS.

Prognostic significance of pretreatment thrombocytosis in endometrial cancer: an Israeli Gynecologic Oncology Group study.

OBJECTIVE: Endometrial cancer prognosis is related to stage, histology, myometrial invasion, and lymphovascular space invasion. Several studies have examined the association between pretreatment thrombocytosis and patient outcomes with contrasting results regarding prognosis. Our aim was to evaluate the association of pretreatment platelet count with outcomes in endometrial cancer patients. METHODS: This is an Israeli Gynecologic Oncology Group multicenter retrospective cohort study of consecutive patients with endometrial cancer, who underwent surgery between January 2002 and December 2014. Patients were grouped as low risk (endometrioid G1-G2 and villoglandular) and high risk (endometrioid G3, uterine serous papillary carcinoma, clear cell carcinoma, and carcinosarcoma). Those with stage I disease were compared with stages II-IV. Disease stages were reviewed and updated to reflect International Federation of Gynecology and Obstetrics (FIGO) 2009 staging. All patients underwent pelvic washings for cytology and total abdominal or laparoscopic hysterectomy with bilateral salpingo-oophorectomy. Pelvic lymph node assessment was performed in patients with tumors of moderate-high risk histology or deep myometrial invasion. Para-aortic sampling was performed at the surgeon's discretion. Patients were categorized by pretreatment platelet count into two groups: ≤400×109/L and >400×109/L (defined as thrombocytosis). Clinical and pathological features were compared using Student t-test, χ2 or Fisher's exact test. Survival measures were plotted with the Kaplan-Meier method and compared using the log-rank test. A Cox proportional hazards model was used for multivariable comparison of associations. RESULTS: Of the 1482 patients included, most had stage I disease (961; 74.8%) and most had endometrioid histology (927; 64.1%). A total of 1392 patients (94%) had pretreatment platelet counts ≤400×109/L and 90 (6%) had pretreatment thrombocytosis. Patients with thrombocytosis had a significantly higher rate of high-grade malignancy, advanced stage, lymphovascular space invasion, low uterine segment involvement, and lymph node metastases. They also had shorter 5 year disease-free survival (65% vs 80%, p=0.003), disease-specific survival (63% vs 83%, p<0.05) and overall survival (59% vs 77%, p<0.05). On multivariate analysis, an elevated pretreatment thrombocyte count remained a significant independent predictor for disease-specific survival and overall survival. CONCLUSIONS: Pretreatment thrombocytosis is an independent prognostic factor for decreased disease-specific survival and overall survival among patients with endometrial cancer, and can serve as a predictor of poor outcome.

Age is an independent predictor of outcome in endometrial cancer patients: An Israeli Gynecology Oncology Group cohort study.

INTRODUCTION: Advanced age is considered an adverse factor in endometrial cancers but may be a surrogate for other conditions that impact outcomes. The study objective was to assess the association of age with endometrial cancer features, treatment and prognosis. MATERIAL AND METHODS: In this multicenter cohort study, consecutive women with endometrial cancer treated at 10 Israeli institutions between 2000 and 2014 were accrued in an assimilated database. Postmenopausal women were stratified into age groups with a cut-off of 80. Clinical, pathological and treatment data were compared using t test or Mann-Whitney test for continuous variables, and Chi-square Test or Fisher's Exact test for categorical variables. Main outcome measures included disease recurrence and disease-specific and overall survival; these were plotted using the Kaplan-Meier method and compared using the log-rank test. The association between age and recurrence and survival, adjusted for other clinical and pathological factors, was assessed using multivariable Cox regression modeling. RESULTS: A total of 1764 postmenopausal women with endometrial cancer were identified. Adverse pathological features were more prevalent in older women, including high-risk histologies (35% vs 27%, P = .025), deep myoinvasion (44% vs 29%, P = .001) and lymphovascular involvement (22% vs 15%, P = .024). Surgical staging was performed less frequently among older women (33% vs 56%; P < .001). Chemotherapy was less often prescribed, even for non-endometrioid histologies (72% vs 45%; P < .001). On multivariable analysis, age remained a significant predictor for recurrence (HR = 1.75, P = .007), death of disease (HR = 1.89, P = .003) and death (HR = 2.4, P < .001). CONCLUSIONS: Older age in women with endometrial cancer is associated with more adverse disease features, limited surgery and adjuvant treatment, and worse outcomes. On multivariable analysis, age remains an independent prognosticator in this population.

Raynaud's phenomenon as a presenting manifestation of ovarian cancer: A case report.

Raynaud's phenomenon (RP) is characterized by episodes of vasospasm affecting the hands and feet. Paraneoplastic RP, as a single presenting symptom is rarely seen in cases of ovarian cancer (OC), and thus may lead to misdiagnosis. We present a case of paraneoplastic RP in a patient with high-grade serous OC. A 66-year-old female presented with dyspnea and bilateral peripheral cyanosis involving her fingers. CA125 was elevated (423 U/mL). CT revealed a pleural effusion on the left side, suspicious omental lesions and ascites. Omental biopsy and pleural cytology demonstrated high-grade serous OC. Neoadjuvant chemotherapy (carboplatin/paclitaxel) resulted in objective improvement in finger ischemia and complete regression of vasospastic features. However, the patient's disease was refractory to post-surgical treatment and eventually she deceased of multiple organ failure. To conclude, RP may be a presenting symptom of OC. It is important to determine the underlying disease and develop an effective treatment strategy.

Robotic laparoendoscopic single-site compared with robotic multi-port sacrocolpopexy for apical compartment prolapse.

BACKGROUND: Sacrocolpopexy is a commonly performed procedure for repair of apical compartment prolapse. A Y-shaped mesh is attached to the prolapsed cervix or vagina and suspended to the anterior longitudinal ligament of the sacrum. In addition to conventional laparoscopic and multi-port robotic routes, the robotic laparoendoscopic single-site approach has emerged as a viable, feasible, and widely applicable minimally invasive approach to sacrocolpopexy. OBJECTIVE: To compare robotic laparoendoscopic single-site with multi-port robotic sacrocolpopexy for women with either utero-vaginal or vaginal apical prolapse. MATERIALS AND METHODS: In this single-center randomized controlled trial, 70 women at Pelvic Organ Prolapse Quantitative stages 2-4 were assigned randomly to undergo sacrocolpopexy by robotic laparoendoscopic single-site or multi-port robotic approaches from August 2017 to November 2018. Of 35 women randomized to each group, 32 underwent sacrocolpopexy. Operating time was the primary outcome of the trial. Secondary outcomes included intraoperative bleeding, length of hospitalization, pain during the first postoperative 24 hours (according to a 0-10 visual analogue scale), need for analgesics, and intraoperative and postoperative adverse events. At 6 weeks and 6 months after surgery, patients underwent a physical examination according to Pelvic Organ Prolapse Quantitative measurements, to assess the anatomical success of the surgery. The Pelvic Floor Distress Inventory-20 and Pelvic Organ Prolapse/Urinary Incontinence Sexual-12 questionnaires were administered prior to surgery and at 6-month follow-up. The Patient Scar Assessment Questionnaire and the Activity Assessment Scale were administered at 6 weeks and 6 months after the surgery. Exclusion criteria included contraindication to general anesthesia, a history of prior sacrocolpopexy, suspicious adnexal masses, suspicious thickened endometrium, and morbid obesity (body mass index of 40 kg/m2 or more). RESULTS: The mean age of the patients was 58.4 years. More than half of the patients (54%) had stage III prolapse. Mean total operative times were 181.3 ± 32.6 and 157.5 ± 42 minutes for robotic laparoendoscopic single-site and multi-port robotic sacrocolpopexy, respectively; the difference was 23.8 minutes (95% confidence interval, 4.2-43.4, P = .018). The mean differences in duration between the procedures were as follows: 29.8 minutes, 95% confidence interval, 9.2-50.4, P = .005 for anesthesia time; 33.1 minutes, 95% confidence interval, 16.5-49.7, P < .0001 for console time; 8.6 minutes, 95% confidence interval, 1.1-16.3, P = .025 for supracervical hysterectomy time; 8.3 minutes, 95% confidence interval, 1.8-14.8, P = 0.03 for mesh suturing and fixation to the promontory; and 4.7 minutes, 95% confidence interval, 1.5-7.7, P = .004 for peritoneum suturing. Statistically significant differences were not observed between the groups in regard to estimated blood loss, intraoperative complications, and demand for analgesics during hospital stay. Quality-of-life parameters were similar. Patients' assessments of their scars were more favorable in the robotic laparoendoscopic single-site group. CONCLUSION: For sacrocolpopexy, the operative time was longer for the robotic laparoendoscopic single-site than for the multi-port robotic approach. Both approaches are feasible, and short-term outcomes, quality-of-life parameters, and anatomic repair are comparable. Our results are generalizable only to the specific robotic platforms used in the study.

Transvaginal Natural Orifice Transluminal Endoscopic (vNOTES) Hysterectomy Learning Curve: Feasibility in the Hands of Skilled Gynecologists.

BACKGROUND: During Transvaginal Natural Orifice Transluminal Endoscopic Surgery (vNOTES) the surgeon operates exclusively through a single vaginal entry point, leaving no external scarring. OBJECTIVES: To evaluate the learning curve of vNOTES hysterectomy by experienced gynecologists based on surgical times and short-term outcomes. METHODS: A retrospective study was conducted of the first 25 vNOTES hysterectomy surgeries performed from July to December 2018 at Rambam Health Care Campus by a single surgeon. The primary outcome was hysterectomy time. Secondary outcomes included intra-operative bleeding, length of hospitalization, postoperative pain, and need for analgesia. Socio-demographic and clinical data were retrieved from patient electronic medical charts. RESULTS: Median age was 64.5 years (range 40-79). Median hysterectomy time was 38 minutes (range 30-49) from the first cut until completion. Comparisons between median hysterectomy time in the first 10 hysterectomies and in the 15 subsequent procedures demonstrated a significant decrease in median total time: 45 minutes (range 41-49) vs. 32 minutes (range 30-38), respectively (P = 0.024). The median estimated intraoperative blood loss decreased from 100 ml (range 70-200) in the first 10 hysterectomies to 40 ml (range 20-100) in the subsequent procedures (P = 0.011). CONCLUSIONS: vNOTES hysterectomy is feasible by an experienced gynecologist, with an exponential improvement in surgical performance in a short period as expressed by the improvement in hysterectomy time, low complication rates, negligible blood loss, minimal post-surgical pain, fast recovery, and short hospitalization. vNOTES allows easier and safer access to adnexal removal compared to conventional vaginal surgery.

Is there a survival advantage in diagnosing endometrial cancer in asymptomatic postmenopausal patients? An Israeli Gynecology Oncology Group study.

BACKGROUND: Incidental ultrasonographic findings in asymptomatic postmenopausal women, such as thickened endometrium or polyps, often lead to invasive procedures and to the occasional diagnosis of endometrial cancer. Data supporting a survival advantage of endometrial cancer diagnosed prior to the onset of postmenopausal bleeding are lacking. OBJECTIVE: To compare the survival of asymptomatic and bleeding postmenopausal patients diagnosed with endometrial cancer. STUDY DESIGN: This was an Israeli Gynecology Oncology Group retrospective multicenter study of 1607 postmenopausal patients with endometrial cancer: 233 asymptomatic patients and 1374 presenting with postmenopausal bleeding. Clinical, pathological, and survival measures were compared. RESULTS: There was no significant difference between the asymptomatic and the postmenopausal bleeding groups in the proportion of patients in stage II-IV (23.5% vs 23.8%; P = .9) or in high-grade histology (41.0% vs 38.4%; P = .12). Among patients with stage-I tumors, asymptomatic patients had a greater proportion than postmenopausal bleeding patients of stage IA (82.1% vs 66.2%; P < .01) and a smaller proportion received adjuvant postoperative radiotherapy (30.5% vs 40.6%; P = .02). There was no difference between asymptomatic and postmenopausal bleeding patients in the 5-year recurrence-free survival (79.1% vs 79.4%; P = .85), disease-specific survival (83.2% vs 82.2%; P = .57), or overall survival (79.7% vs 76.8%; P = .37). CONCLUSION: Endometrial cancer diagnosed in asymptomatic postmenopausal women is not associated with higher survival rates. Operative hysteroscopy/curettage procedures in asymptomatic patients with ultrasonographically diagnosed endometrial polyps or thick endometrium are rarely indicated. It is reasonable to reserve these procedures for patients whose ultrasonographic findings demonstrate significant change over time.

Evaluation of Microscopic Changes in Fallopian Tubes of BRCA Mutation Carriers by Morphometric Analysis of Histologic Slides: A Preliminary Pilot Study.

Mutations in BRCA genes increase the risk of ovarian cancer, yet no method for early diagnosis is available. Some serous ovarian tumors are hypothesized to stem from cells of the fallopian tube fimbria. Using a novel method of computerized morphometry of the fimbrial epithelium, this study aimed to detect morphologic differences in noncancerous fimbriae between BRCA mutation carriers and noncarriers, and between healthy and serous ovarian cancer patients. Twenty-four fimbriae from healthy women (13 BRCA+, 11 BRCA-) and 21 fimbriae from women with serous ovarian cancer (10 BRCA+, 11 BRCA-), all reported as "normal" by hematoxylin and eosin examination, were subjected to computerized histomorphometric analysis. A Fast Fourier Transformation was applied to images of fimbrial epithelium and the Fast Fourier Transformation 2-dimensional frequency maps were subsequently quantified for nuclear orientation and planar distribution by a cooccurrence matrix analysis. Additional analysis of nuclear contour was applied to the fimbriae of the healthy women. Among the healthy women, significant differences were found in morphometric characteristics between the BRCA mutation carriers and noncarriers. Among the women with ovarian cancer, no significant differences were found between BRCA mutation carriers and noncarriers. Between healthy women and those with ovarian cancer, significant differences were detected, regardless of BRCA mutational status. A novel method, which combined Fast Fourier Transformation with cooccurrence matrix analysis, demonstrated differences in morphometric characteristics in the fimbriae between healthy and ovarian cancer patients, and between BRCA mutation carriers and noncarriers. The clinical significance of these observations should be investigated.

Effects of Pneumoperitoneum and the Steep Trendelenburg Position on Heart Rate Variability and Cerebral Oxygenation during Robotic Sacrocolpopexy.

STUDY OBJECTIVE: The aim of this study was to investigate how steep Trendelenburg positioning with pneumoperitoneum modifies brain oxygenation and autonomic nervous system modulation of heart rate variability during robotic sacrocolpopexy. DESIGN: Prospective study (Canadian Task Force classification III). SETTING: Rambam Health Care Campus. PATIENTS: Eighteen women who underwent robotic sacrocolpopexy for treatment of uterovaginal or vaginal apical prolapse. INTERVENTIONS: Robotic sacrocolpopexy. MEASUREMENTS AND MAIN RESULTS: A 5-minute computerized electrocardiogram, cerebral O2 saturation (cSO2), systemic O2 saturation, heart rate (HR), diastolic blood pressure (BP), systolic BP, and end-tidal CO2 tension were recorded immediately after anesthesia induction (baseline phase) and after alterations in positioning and in intra-abdominal pressure. HR variability was assessed in time and frequency domains. Cerebral oxygenation was measured by the technology of near-infrared spectrometry. cSO2 at baseline was 73% ± 9%, with minor and insignificant elevation during the operation. Mean HR decreased significantly when the steep Trendelenburg position was implemented (66 ± 10 vs 55 ± 9 bpm, p < .05) and returned gradually to baseline with advancement of the operation and the decrease in intra-abdominal pressure. Concomitant with this decrease, the power of both arms of the autonomic nervous system increased significantly (2.8 ± .8 vs 3.3 ± .9 ms2/Hz and 2.5 ± 1.2 vs 3.2 ± .9 ms2/Hz, respectively, p < .05). All these effects occurred without any significant shifts in systolic or diastolic BP or in systemic or cerebral oxygenation. CONCLUSION: This study supports the safety of robotic sacrocolpopexy performed with steep Trendelenburg positioning with pneumoperitoneum. Only minor alterations were observed in cerebral oxygenation and autonomic perturbations, which did not cause clinically significant alterations in HR rate and HR variability.

Should the Risk of Invasive Cancer in Pregnancy and the Safety of Loop Electrosurgical Excision Procedure During the First 15 Weeks Change Our Practice?

OBJECTIVE: The aim of this article was to describe the outcome of women diagnosed with cervical intraepithelial neoplasia (CIN) grades 2 or 3 in pregnancy either observed or treated by loop electrosurgical excision procedure (LEEP) in the first 15 weeks of gestation. METHODS: Loop electrosurgical excision procedure during the first 15 gestational weeks compared with observation of CIN2/3. This is a retrospective analysis of a nonrandomized study at tertiary, academic, and referring centers in Israel. Ninety-three pregnant women diagnosed with CIN2/3 between 2006 and 2016 were included in this study. Fifty patients with CIN2/3 on cervical biopsy were conservatively followed-up, and 43 patients have undergone LEEP during the first 15 gestational weeks. Main outcome measures were ultimate diagnosis of invasive cancer or CIN, pregnancy outcome, and complications. RESULTS: In 5.4% of CIN2/3 during pregnancy, the final diagnosis was invasive cancer. The postpartum results of 50 women who were conservatively observed were as follows: 3 (6.0%) had cervical cancer and undergone radical hysterectomy, 33 (66.6%) had CIN2/3, and 14 (28%) had CIN1 or normal histology. The diagnoses of the 43 patients who have undergone LEEP were invasive cancer in 2 patients (4.6%) but did not undergo hysterectomy, CIN2/3 or adenocarcinoma in situ (AIS) in 38 patients (88.4%), and 3 women (7%) had CIN1 or normal histology. None of them suffered severe bleeding. Thirty-seven women continued their pregnancy, 34 (91.9%) had term deliveries, 2 (5.4%) gave birth at 34 and 36 weeks, and 1 patient had missed abortion (2.7%). CONCLUSIONS: The LEEP procedure during the first 15 weeks of pregnancy is safe. A total of 5.4% of the women with CIN2/3 during pregnancy were diagnosed with invasive cancer. It is time to reconsider the recommendations about CIN2/3 in early gestation.

Liposome-encapsulated doxorubicin citrate (Myocet) for treatment of recurrent epithelial ovarian cancer: a retrospective analysis.

The aim of this study was to assess the clinical activity and toxicity of liposome-encapsulated doxorubicin citrate (Myocet) in a retrospective multicenter cohort of epithelial ovarian, primary peritoneal, and tubal cancer patients. Records of patients with recurrent epithelial ovarian, primary peritoneal, and tubal cancer treated with liposome-encapsulated doxorubicin citrate (60 mg/m on day 1 of a 21-day cycle) after failure of more than one previous regimen were reviewed. Fifty-three patients were evaluated for efficacy and toxicity. The median age of the patients was 59 (range 39-73). The median follow-up was 6 months (range 1-17). One patient (1.9%) showed a complete response and 13 patients (24.5%) showed a partial response, yielding an overall response rate of 26.4% (14/53 patients). Clinical benefit was achieved in 36 patients (67.9%). The median progression-free survival (PFS) for the entire study population was 4.0 months (range 1.0-14.8). The median PFS for platinum-sensitive and platinum-resistant patients was 4.0 months (ranges 1.0-14.8 and 1.0-9.4, respectively; P=0.652). The median overall survival from the start of liposome-encapsulated doxorubicin citrate was 10.0 months. Multivariate survival analysis showed no association between the liposome-encapsulated doxorubicin citrate line of treatment or platinum sensitivity to PFS in age and BRCA status-adjusted models. Only 11.3% of patients experienced grade 3-4 hematologic toxicities, 80% grade-2 alopecia, and 50% grade-1-2 fatigue. No other grade-4 toxicities, no significant cardiac events, or hand and foot syndromes were reported. Liposome-encapsulated doxorubicin citrate was well tolerated, with a good response and high clinical benefit rate. Further evaluation in a larger prospective cohort is warranted.

Cervical intraepithelial neoplasia 2, 3 in pregnancy: time to consider loop cone excision in the first trimester of pregnancy?

OBJECTIVES: To report the outcome of patients diagnosed with cervical intraepithelial neoplasia 2, 3 (CIN 2, 3) during pregnancy, who were treated by large loop excision of the transformation zone (LLETZ) in the first trimester or were followed up conservatively and treated after delivery. METHODS: Patients diagnosed with CIN 2, 3 during pregnancy who were treated with LLETZ or were conservatively followed up were included. Complications of the LLETZ, pathologic results, and pregnancy outcome of both groups were examined after delivery. RESULTS: Thirty-one patients were included in the study. Eighteen were conservatively followed up and 13 underwent LLETZ during the first 14 weeks of pregnancy. Four patients (12.9%) in the study group were diagnosed with invasive cervical cancer. From women who underwent LLETZ, 9 patients continued their pregnancy, 7 of which had term normal deliveries and 2 had late preterm deliveries. No complications of severe bleeding or miscarriage were reported in any of the treated patients. CONCLUSIONS: Large loop excision of the transformation zone procedure in the first trimester of pregnancy is a safe procedure, with the advantage of treating definitively CIN 2, 3 lesions and preventing the devastating consequences of undiagnosed cervical cancer. We suggest that LLETZ should be performed more liberally in the first trimester of pregnancy.

Tolerance of the vaginal vault to high-dose rate brachytherapy and concomitant chemo-pelvic irradiation: Long-term perspective.

AIM/BACKGROUND: We sought to determine the tolerance level and complication rates of the vaginal vault to combined high-dose-rate intra-cavitary brachytherapy with concomitant chemo-radiotherapy. PATIENTS AND METHODS: A retrospective review of medical records of all the patients who received definitive chemo-radiotherapy for cervical cancer between 1998 and 2002 was undertaken. The records were reviewed for doses and for radiation-associated early and late sequelae of the vagina, rectum and bladder. Cumulative biological effective dose was calculated for two reference vaginal surface points. RESULTS: Fifty patients were included. Average age at diagnosis was 54 years. Median follow-up was 59 months. There were no recorded instances of acute grade IV toxicity. Maximal high-dose-rate vaginal surface dose (upper central point) was 103 Gy, and maximal brachytherapy lateral surface dose was 70 Gy. Maximal cumulative biological effective dose for the lateral surface reference point was 465.5 Gy3, and the maximal cumulative biological effective dose for the superior reference point was 878.6 Gy3. There were no cases of vaginal necrosis or fistulas, and no cases of grade IV late vaginal, rectal or bladder toxicity. No correlation was found between the maximal vaginal surface dose and vaginal, rectal or bladder toxicity. CONCLUSIONS: The maximal surface HDR brachytherapy dose of 103 Gy and the maximal cBED of 878.6 Gy3 were not associated with fistula or necrosis or other grade 3-4 vaginal complications. Concomitant chemo-radiotherapy, including pelvic radiotherapy and high-dose-rate intracavitary brachytherapy, is relatively safe for cervical cancer patients.

Assessment of oncological safety and utility of hysteroscopy in high grade endometrial cancers: Results from an Israel gynecologic oncology group study.

OBJECTIVE: To compare survival measures of women with Stage I high-grade endometrial cancer who underwent either hysteroscopy or a non-hysteroscopic procedure as a diagnostic procedure. STUDY DESIGN: 298 patients with stage I high grade endometrial cancer who underwent surgery between 2002 and 2014. Patients were divided into two groups: hysteroscopy and non-hysteroscopy (curettage or office endometrial biopsy). Clinical, pathological, and survival measures were compared between the groups. High grade histology included endometroid grade -3, uterine serous papillary carcinoma, clear cell carcinoma, and carcinosarcoma. RESULTS: There were 71 patients in the hysteroscopy group and 227 patients in the non-hysteroscopy group. The median follow-up was 52 months (range 12-120 months). There were no differences between the groups in the 5-year recurrence-free survival (73.9 % vs. 79.7 %; p = 0.65), disease-specific survival (79.3 % vs. 83.6 %; p = 0.87), and overall survival (65.7 % vs. 80.3 %; p = 0.35). CONCLUSION: Hysteroscopic diagnosis in women with early-stage and high-grade endometrial cancer does not adversely affect the survival outcomes.

Ofranergene Obadenovec (Ofra-Vec, VB-111) With Weekly Paclitaxel for Platinum-Resistant Ovarian Cancer: Randomized Controlled Phase III Trial (OVAL Study/GOG 3018).

PURPOSE: To evaluate the addition of ofranergene obadenovec (ofra-vec, VB-111), a novel gene-based anticancer targeted therapy, to once a week paclitaxel in patients with recurrent platinum-resistant ovarian cancer (PROC). METHODS: This placebo-controlled, double-blind, phase III trial (ClinicalTrials.gov identifier: NCT03398655) randomly assigned patients with PROC 1:1 to receive intravenous ofra-vec every 8 weeks with once a week IV paclitaxel or placebo with paclitaxel until disease progression. The dual primary end points were overall survival (OS) and progression-free survival (PFS) as assessed by Blinded Independent Central Review. RESULTS: Between December 2017 and March 2022, 409 patients were randomly assigned. The median PFS was 5.29 months in the ofra-vec arm and 5.36 months in the control arm, hazard ratio (HR) 1.03 (CI, 0.83 to 1.29; P = .7823). The median OS with ofra-vec was 13.37 months versus 13.14 months, HR 0.97 (CI, 0.75 to 1.27; P = .8440). Objective response rates (ORRs) per RECIST 1.1 were similar in both arms: 28.9% with ofra-vec versus 29.6% with control. In both treatment arms, response to CA-125 was a substantial prognostic factor for both PFS and OS. In the ofra-vec arm, the HR in CA-125 responders compared with that in nonresponders for PFS was 0.2428 (CI, 0.1642 to 0.3588), and for OS, the HR was 0.3343 (CI, 0.2134 to 0.5238). Safety profile was characterized by common transient flu-like symptoms such as fever and chills. CONCLUSION: The addition of ofra-vec to paclitaxel did not improve PFS or OS. The PFS and ORR in the control arm exceeded the results that were anticipated on the basis of the AURELIA chemotherapy control arm. CA-125 response was a substantial prognostic biomarker for PFS and OS in patients with PROC treated with paclitaxel.

Niraparib Population Pharmacokinetics and Exposure-Response Relationships in Patients With Newly Diagnosed Advanced Ovarian Cancer.

PURPOSE: Niraparib is a poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitor approved for the maintenance treatment of advanced ovarian cancer (OC). Niraparib was originally approved in recurrent OC at a fixed starting dose (FSD) of 300 mg once daily (QD). This analysis characterized the population pharmacokinetics (PK) of niraparib and evaluated the relationships between exposure, efficacy, and safety to support clinical use of an individualized dosing strategy, in which the starting dose of niraparib was adjusted based on patient characteristics to improve the benefit-risk profile. METHODS: A population PK model was developed by pooling data from four niraparib clinical trials (PN001 [n = 104], QUADRA [n = 455], NOVA [n = 403], and PRIMA [n = 480]) in patients with solid tumors, including OC. Exposure-response analyses were conducted to explore the relationships of niraparib exposure with progression-free survival (PFS) and adverse events in the PRIMA study. A multivariate logistic regression model was also developed to estimate the probability of grade ≥3 thrombocytopenia, using data from patients enrolled in PRIMA and NOVA. The impact of an individualized starting dose (ISD) regimen (200 mg QD in patients with body weight [BW] <77 kg or platelet count [PLT] <150,000/µL, or 300 mg QD in patients with BW ≥77 kg and PLT ≥150,000/µL) on systemic exposure, efficacy, and safety was assessed. FINDINGS: Niraparib disposition was best described by a 3-compartment model with linear elimination. Key covariates included baseline creatinine clearance, BW, albumin, and age, all of which had minor effects on niraparib exposure. Comparable model-predicted exposure up to the time of disease progression/death or censoring in the 300-mg FSD and 200-/300-mg ISD groups was consistent with the lower rate of dose reduction in the ISD groups. No consistent niraparib exposure-response relationship was observed for efficacy in all PRIMA patients (first-line OC), and no statistically significant difference was seen in PFS curves for patients receiving a niraparib dose of 200 mg versus 300 mg. In the multivariate regression model, performed using combined data from PRIMA and NOVA, higher niraparib exposure (area under the concentration-time curve at steady-state [AUCss]), lower BW, and lower PLT were associated with an increased risk of grade ≥3 thrombocytopenia. IMPLICATIONS: Population PK and exposure-response analyses support use of an ISD to improve the safety profile of niraparib, including reducing the rate of grade ≥3 thrombocytopenia, without compromising efficacy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT01847274 (NOVA), NCT00749502 (PN001), NCT02655016 (PRIMA), NCT02354586 (QUADRA), www. CLINICALTRIALS: gov.

FDG PET/CT in monitoring response to treatment in gynecological malignancies.

PURPOSE OF REVIEW: To evaluate the role of fluorodeoxyglucose (FDG) PET/CT as cancer response testing in gynecological malignancies. RECENT FINDINGS: The application of FDG PET/CT in patients with endometrial and ovarian cancer to evaluate treatment response was found to have no clinical benefits.Patients with cervical cancer seem to benefit from the use of PET/CT in estimation of treatment response. The influence of different treatments on FDG uptake, timing, frequency of examination, and survival advantage are evaluated and discussed. SUMMARY: Growing evidence supports an important role for functional imaging FDG PET/CT as a monitoring tool in patients with uterine-cervix carcinoma. Further studies are needed to establish the clinical benefits of this modality in this population.

Implementation of a new procedure: laparoscopic versus robotic sacrocolpopexy.

PURPOSE: The purpose of this study was to compare the implementation process and the learning curves of laparoscopic and robotic-assisted laparoscopic sacrocolpopexy (LSC and RSC, respectively) for vaginal apex prolapse. METHODS: A retrospective study of the first 40 LSC and first 40 RSC procedures performed at one medical center. The primary outcomes were intraoperative bleeding, operative time, and hospitalization. Secondary outcomes were surgical complications. The independent t test, paired t test, χ(2) test, Fisher's exact test and Pearson's correlation were used to analyze the data. We assumed that 34 participants were needed in each group to detect a 50 ml or more difference in estimated blood loss between laparoscopic and robotic surgeries, MAIN RESULTS: Age, preoperative pelvic organ prolapse quantification (POPQ) staging, and concomitant medical disorders did not differ significantly by procedure type. For LSC and RSC, the mean estimated intraoperative blood loss was 206 ± 107 and 48 ± 55 ml, P < 0.0001; mean operative times were 176 (110-380 min) and 186 (105-345 min), P = 0.34; and mean length of hospital stay, 3.8 ± 1 and 2.4 ± 1 days, P < 0.0001, respectively. Adverse events were rare, not severe, and did not differ significantly by procedure type. CONCLUSIONS: RSC and LSC are feasible procedures with acceptable complication rates. RSC enables operating more anatomically with less bleeding.

Fourier transformation based texture analysis for differentiating between hyperplastic polyps and sessile serrated adenomas.

Colorectal cancer (CRC) is the third most common type of cancer. One major pathway involved in the development of CRC is the serrated pathway. Colorectal polyps can be divided in benign, like small hyperplastic polyps and premalignant polyps, like the sessile serrated adenomas (SSA) that has a significant potential of malignant transformation. The morphological similarity between these types of polyp, not-infrequently raises diagnostic difficulties. This study aimed to morphologically differentiate between hyperplastic polyps (HP) and SSAs by using automated computerized texture analysis of Fourier transformed histological images. Thirty images of HP and 58 images of SSA were analyzed by computerized texture analysis. A fast Fourier transformation was applied to the images. The Fourier frequency plots were further transformed into gray level co-occurrence matrices and four textural variables were extracted: entropy, correlation, contrast, and homogeneity. Our study is the first to combine this type of analysis for automated classification of colonic neoplasia. The results were analyzed using statistical and neural network (NNET) classification models. The predictive values of these classifiers were compared. The statistical regression algorithm presented a sensitivity of 95% to detect the SSA and a specificity of 80% to detect the HP. The NNET analysis was superior to the statistical analysis displaying a classification accuracy of 100%. The results of this study have confirmed the hypothesis that Fourier based texture image analysis is helpful in differentiating between HP and SSA. RESEARCH HIGHLIGHTS: Colorectal polyps can be divided in benign, like hyperplastic polyps (HP) and premalignant, like the sessile serrated adenomas (SSA). There is a high morphologic similarity between these two types of polyp that not-infrequently raises diagnostic difficulties. The results of our morphometric analysis that were used to build a neural network based model of prediction of the polyp types, have a great clinical importance of identifying SSA polyps which have significant potential of malignant progression as compared to HP.