The Poor Prognosis of Acquired Secondary Platinum Resistance in Ovarian Cancer Patients.

OBJECTIVE: The goal of this study was to evaluate response to treatment and survival in epithelial ovarian cancer patients with acquired secondary platinum resistance (SPR) compared to patients with primary platinum resistance (PPR). METHODS: Patients were categorized as PPR (patients with disease recurrence occurring during or <6 months after completing first-line platinum-based chemotherapy) and SPR (patients with previously platinum-sensitive disease that developed platinum resistance on subsequent treatments). Clinico-pathological variables and treatment outcomes were compared. RESULTS: Of the 118 patients included in this study, 60 had PPR and 58 developed SPR. The SPR women had a significantly higher rate of optimal debulking during their upfront and interval operations, significantly lower CA-125 levels during their primary treatment, and a significantly higher complete and partial response rate to primary chemotherapy. Once platinum resistance appeared, no significant difference in survival was observed between the two groups. The median PFS was 2 months in the PPR group and 0.83 months in the SPR group (p = 0.085). Also, no significant difference was found in post-platinum-resistant relapse survival, with a median of 17.63 months in the PPR and 20.26 months in the SPR group (p = 0.515). CONCLUSIONS: Platinum resistance is an important prognostic factor in women with EOC. Patients with SPR acquire the same poor treatment outcome as with PPR. There is a great need for future research efforts to discover novel strategies and biological treatments to reverse resistance and improve survival.

Age Disparities in End of Life Symptom Management Among Patients with Epithelial Ovarian Cancer.

OBJECTIVE: To evaluate the symptoms of women with epithelial ovarian cancer (EOC) during their last admission before death and analyze invasive palliative management administered in relation to symptom control and survival. MATERIALS & METHODS: A retrospective review of Israeli patients with EOC, primary peritoneal cancer (PPC) and tubal cancer, admitted to our department prior to death between 2008-2018. Basic palliative treatment was defined as administration of IV fluids, analgesics, oxygen, antiemetics, antibiotics and/or blood transfusions. Procedures regarded as invasive included: peritoneal or pleural fluid drainage; placement of an indwelling catheter, administration of total parenteral nutrition (TPN), chemotherapy and ventilation. RESULTS: 82 patients were included. Most suffered from weakness and fatigue, gastrointestinal complaints, pain and shortness of breath. 34 patients (41.5%) required only basic palliative treatment to alleviate their symptoms; however, in 48 patients (58.5%) invasive interventions were needed. Patients treated with invasive procedures were younger at death by almost 9 years (mean age of 65.73 ± 9.5 vs. 74.78 ± 9.8; p = 0.001). There were significantly more women with platinum sensitive disease in the invasive interventions group compared to the basic palliative care (60.42% vs. 32.35%; p = 0.012). No survival difference was found between the groups from diagnosis to death, relapse to death, last chemotherapy to death and last admission to death. CONCLUSIONS: EOC patients suffer from high disease burden and multiple symptoms before death. We found that physicians tend to use more invasive care in dying younger patients. However, this aggressive treatment does not prolong survival. Futile treatments influencing quality of life should be avoided.

Ovarian Cancer Therapy: Homologous Recombination Deficiency as a Predictive Biomarker of Response to PARP Inhibitors.

Poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors have revolutionised the management of patients with high-grade serous and endometrioid ovarian cancer demonstrating significant improvements in progression-free survival. Whilst the greatest benefit is seen with BRCA1/2 mutant cancers, it is clear that the benefit extends beyond this group. This sensitivity is thought to be due to homologous recombination deficiency (HRD), which is present in up to 50% of the high-grade serous cancers. Several different HRD assays exist, which fall into one of three main categories: homologous recombination repair (HRR)-related gene analysis, genomic "scars" and/or mutational signatures, and real-time HRD functional assessment. We review the emerging data on HRD as a predictive biomarker for PARP inhibitors and discuss the merits and disadvantages of different HRD assays.

Frontline Maintenance Treatment for Ovarian Cancer.

PURPOSE OF REVIEW: Advanced epithelial ovarian cancer remains the most lethal gynaecological cancer. Most patients with advanced disease will relapse within 3 years after primary treatment with surgery and chemotherapy. Recurrences become increasing difficult to treat due to the emergence of drug resistance and 5-year survival has changed little over the last decade. Maintenance treatment, here defined as treatment given beyond primary chemotherapy, can both consolidate the response and prolong the control of disease which is an approach to improve survival. RECENT FINDINGS: Here we review maintenance strategies such as targeting angiogenesis, interference of DNA repair through inhibition of PARP, combinations of targeting agents, and immunotherapy and hormonal therapy. Much has been learnt from the success and challenges of these treatments that have in the last few years which led to significant reduction in disease recurrence, changed the guidelines for treatment, and established a new paradigm for the treatment of ovarian cancer.

Anatomic Asymmetry in Sentinel Lymph Node Detection in Endometrial Cancer.

STUDY OBJECTIVE: To determine whether the concomitant use of indocyanine green (ICG) with technetium-99m-filtered sulfur colloid (Tc99m-FSC) improves bilateral sentinel lymph node (SLN) detection rate in endometrial cancer and whether anatomic concordance of pelvic lymph nodes exists and can be used to predict SLN location in cases of unilateral mapping failure. DESIGN: Retrospective cohort study. SETTING: Tertiary academic medical center in Holon, Israel. PATIENTS: Patients diagnosed with endometrial cancer, who underwent SLN mapping with Tc99m-FSC, ICG, or both, at our center between 2014 and 2019. INTERVENTIONS: A total of 111 patients were included in the study. SLN mapping using Tc99m-FSC was performed in 101 (91.9%) patients, and ICG injection was given to 64 (57.6%) patients of whom 55 (49.5%) received both. We compared SLN detection rates (unilateral and bilateral) and anatomic symmetry for each method alone and for a combination of the 2. MEASUREMENTS AND MAIN RESULTS: The overall detection rate for unilateral SLNs was 96.4%; 96.9% with ICG, 93.1% with gamma-probe, and 98.2% by combining both methods. The total bilateral detection rate was 72.1%, with ICG performing better as a single tracer than Tc99m-FSC (75% vs 63.4%, respectively). In 55 women in whom both tracers were used, the bilateral detection rate was significantly higher compared with Tc99m-FSC alone. Symmetric pelvic anatomic concordance of SLN was found in only 35 of 80 patients with bilateral SLN detection (43.8%). CONCLUSION: The combination of preoperative radioisotope injection and intraoperative ICG administration may yield the best bilateral SLN detection rate. In cases of unilateral mapping failure, one cannot rely on the anatomic location of the ipsilateral SLN detected to harvest the complementary node because the symmetric concordance is poor.

ICON 9-an international phase III randomized study to evaluate the efficacy of maintenance therapy with olaparib and cediranib or olaparib alone in patients with relapsed platinum-sensitive ovarian cancer following a response to platinum-based chemotherapy.

BACKGROUND: Two novel biological agents-cediranib targeting angiogenesis, and olaparib targeting DNA repair processes-have individually led to an improvement in ovarian cancer control. The aim of ICON9 is to investigate the combination of cediranib and olaparib maintenance in recurrent ovarian cancer following platinum-based therapy. PRIMARY OBJECTIVE: To assess the efficacy of maintenance treatment with olaparib in combination with cediranib compared with olaparib alone following a response to platinum-based chemotherapy in women with platinum-sensitive ovarian, fallopian tube or peritoneal cancer during first relapse. STUDY HYPOTHESIS: Maintenance therapy with cediranib and olaparib in combination is associated with improved patient outcomes compared with olaparib alone. TRIAL DESIGN: International phase III randomized controlled trial. Following a response to platinum-based chemotherapy patients are randomized 1:1 to either oral olaparib and cediranib (intervention arm) or oral olaparib alone (control arm). MAJOR INCLUSION CRITERIA: Patients with a known diagnosis of high grade serous or endometrioid carcinoma of the ovary, fallopian tube or peritoneum, progressing more than 6 months after first-line platinum-based chemotherapy, who have responded to second-line platinum-based chemotherapy. PRIMARY ENDPOINTS: Progression-free and overall survival. Co-primary endpoints to be assessed using a fixed-sequence gatekeeping approach: (1) progression-free survival, all patients; (2) progression-free survival, BRCA wild type; (3) overall survival, all patients; (4) overall survival, BRCA wild type. SAMPLE SIZE: 618 patients will be recruited. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: Accrual is expected to be completed in 2024 with presentation of results in 2025. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03278717.

The Association of an Elevated Thrombocyte Count with Clinicopathological Prognostic Factors and Survival in Patients with Uterine Carcinosarcoma.

BACKGROUND: Uterine carcinosarcoma (UCS) is a rare tumor with a poor prognosis. An elevated thrombocyte count and thrombocytosis were found to be associated with poor prognosis in several gynecological tumors. Data regarding an elevated thrombocyte count and thrombocytosis, particularly in UCS, are scarce. OBJECTIVES: To assess the frequency of a preoperative elevated thrombocyte count and of thrombocytosis in UCS patients and their association with clinicopathological prognostic factors and survival. METHODS: The preoperative thrombocyte count of 29 consecutive verified USC patients diagnosed in our medical center from January 2000 to July 2015 was recorded, and clinicopathological data of these patients were abstracted from hospital files. RESULTS: Thrombocytosis was found in two patients (6.8 %) and both died of the disease. An elevated thrombocyte count was found in nine patients (31.0%). The percentage of patients with the poor prognostic factors who had a preoperative elevated thrombocyte count was not statistically different from those without these risk factors. The cumulative survival of patients with an elevated count was 22.1 months and that of those without an elevated count was 31.1 months. This difference was statistically not significant (P = 0.85). There was also no difference between the groups regarding the progression free survival. CONCLUSIONS: No association between an elevated thrombocyte count and prognosis was found. Larger studies are needed to clarify this issue.

Is There a Difference in the Outcome of Mid-Urethral Sling Operations Performed by Urogynecologists Compared with Supervised Residents?

STUDY OBJECTIVE: To compare the operative results of midurethral sling (MUS) surgeries for stress urinary incontinence (SUI) performed by residents under the guidance of an attending specialist in urogynecology and those performed by attendings. DESIGN: Retrospective chart review (Canadian Task Force classification II-2). SETTING: University hospital. PATIENTS: A retrospective analysis of all MUS surgeries performed at a single public tertiary medical center between January 2009 and December 2013 was carried out. A total of 257 patients underwent transobturator tape (TOT) placement during the study period, including 136 (52.9%) placed by an attending specialist in urogynecology (group A) and 121 (47.1%) placed by a resident, under the guidance of an attending (group B). MEASUREMENTS: The efficacy of treatment was evaluated in terms of early postoperative course, reoperation, and symptom improvement, as based on the Pelvic Floor Distress Inventory short form (PFDI-20) questionnaire. The primary outcome was patient-reported symptoms of SUI, as assessed with the PFDI-20 questionnaire, as well as absence of surgical retreatment for SUI. RESULTS: Immediate postoperative complications were comparable in the 2 groups, as were subjective failure and self-reported SUI. The primary outcome-moderate and severe symptoms of SUI-were reported by 23.7% of the patients in group A and 23.6% of those in group B (p = .91). At a mean follow-up of 40 months in both groups, symptoms, as assessed using the urinary scale and prolapse scale of the PFDI-20, were also similar in the 2 groups. The rate of reoperation with repeated sling for SUI was 5% in both groups. CONCLUSION: The operative results of TOT surgery for SUI performed by residents under the guidance of an attending specialist in urogynecology did not differ significantly from those performed by the attendings themselves.

Hysterscopic Resection of Premalignant and Malignant Endometrial Polyps: Is it a Safe Alternative to Hysterectomy?

STUDY OBJECTIVE: The standard treatment of endometrial cancer (EC) and complex atypical hyperplasia (CAH) is hysterectomy with or without adnexectomy. In the last decade several centers have attempted to perform hysteroscopic resection of malignant and premalignant polyps as an alternative to hysterectomy. In the present study we evaluated the safety of this procedure in regard to residual uterine pathology. DESIGN: Retrospective chart review (Canadian Task Force classification II-2). SETTING: University hospital. PATIENTS: Women (n = 1766) who underwent hysteroscopic polypectomy during the years 1998 to 2016. INTERVENTIONS: Patients with CAH and endometrioid type EC in the removed polyps who underwent hysterectomy were included in the study. Patients with nonendometrioid pathology were excluded. The operative and pathologic reports of the hysteroscopy and hysterectomy procedures were revised. MEASUREMENTS AND MAIN RESULTS: Forty-three women (2.4%) were diagnosed with premalignant and malignant polyps: 21 with EC and 22 with CAH. Thirty-four women (79.0%) underwent hysterectomy and were included in the study group. The median age was 62 years (range, 35-83). Most women (79.4%) presented with postmenopausal bleeding or menorrhagia. In 13 patients (38.2%) more than 1 polyp was removed. The median size of the polyps was 2 cm (range, 1-4). In 27 women there were no other visible endometrial findings during the hysteroscopy except for the removed polyp. However, in 24 women (88.9%) residual CAH or EC was present in the hysterectomy specimen, mostly (55.6%) as multifocal lesions. CONCLUSION: Our results indicate that hysteroscopic evaluation of the uterine cavity and polyp resection are not enough for the eradication of premalignant and malignant endometrial lesions. This alternative should be reserved for well-selected cases such as for fertility preservation and for patient with surgical risk factors that after the hysteroscopic polypectomy will receive further medical treatment.

The optimal angle of the mediolateral episiotomy at crowning of the head during labor.

INTRODUCTION AND HYPOTHESIS: The aim of the mediolateral episiotomy incision is to increase the diameter of the soft tissue of the vaginal outlet to facilitate birth and to prevent vaginal tears. Episiotomy angles that are too narrow and close to the midline increase the risk of obstetric anal sphincter injuries. In order to determine the optimal angle of the episiotomy, we assessed the changes in the angles of episiotomy lines marked during the first stage of labor and measured at the time of crowning of the head. METHODS: Incision lines for mediolateral episiotomy were marked on the perineal skin at angles of 30°, 45°, and 60° from the midline during the first stage of labor in women with a singleton pregnancy. The angles of the marked lines were measured at crowning of the head. Mediolateral episiotomy was performed only for obstetric indications. RESULTS: The study included 102 women with a singleton pregnancy. Of these women, 50 were primiparous and 52 were multiparous. All angles marked during the first stage of labor increased significantly (by more than 30°) at crowning of the head. Similar changes were observed in primiparous and multiparous women. CONCLUSIONS: The angle of the mediolateral episiotomy line was significantly greater at crowning of the head than when marked during the first stage of labor. To achieve the desired episiotomy angle, it is important to take into consideration the changes in mediolateral episiotomy angles that occur during labor.

Comparison between Three Methods of Fetal Weight Estimation during the Active Stage of Labor Performed by Residents: A Prospective Cohort Study.

OBJECTIVE: To compare the accuracy of ultrasonographic, calculated, and clinical methods for the estimation of fetal weight (EFW) performed during active labor by residents. METHODS: Parturients in active labor underwent prospectively EFW by 3 methods: ultrasonographic, clinical, and calculated (extrapolating EFW from a previous scan). Three different blinded residents evaluated each woman. Background variables were examined for their effect on the accuracy of each method. Comparison of the methods for the detection of macrosomia and small for gestational age (SGA) was also performed. RESULTS: Among the 405 women recruited, the rates of accuracy of ultrasonographic, clinical, and calculated EFW (within ±10%) was 72.5, 74.3, and 71.1%, respectively. The correlation coefficient between the methods and actual birth weight (ABW) were 0.702-0.611 (using 7 Hadlock formulas), 0.649, and 0.622, respectively (all p < 0.001). By logistic regression, epidural analgesia was associated with higher and second stage of labor with lower accuracy of ultrasonographic EFW. For the detection of macrosomia, clinical (p < 0.001) and calculated EFWs (p = 0.035) were superior to ultrasonographic EFW. For the detection of SGA, ultrasonographic EFW was superior to calculated (p < 0.001) and clinical (p < 0.001) EFWs. CONCLUSION: All 3 methods performed by residents during labor correlated well with ABW. Clinical and calculated EFWs were superior for macrosomia detection, whereas ultrasonographic EFW was superior for SGA detection.

Pregnancy outcome and placental findings in pregnancies complicated by fetal growth restriction with and without preeclampsia.

OBJECTIVE: To compare pregnancy outcome and placental pathology in pregnancies complicated by fetal growth restriction (FGR) with and without preeclampsia. METHODS: Labor, fetal/neonatal outcome, and placental pathology parameters from neonates with a birth weight below the 10 th percentile (FGR), born between 24 and 42 weeks of gestation, were reviewed. Results were compared between pregnancies complicated with preeclampsia (hypertensive FGR [H-FGR]) to those without preeclampsia (normotensive FGR [N-FGR]). Composite neonatal outcome, defined as 1 or more of early complication (respiratory distress, necrotizing enterocolitis, sepsis, transfusion, ventilation, seizure, hypoxic-ischemic encephalopathy, phototherapy, or death), Apgar score ≤ 7 at 5 minutes, and days of hospitalization, were compared between the groups. Placental lesions, classified as lesions related to maternal vascular supply, lesions consistent with fetal thrombo-occlusive disease and inflammatory lesions, maternal inflammatory response, and fetal inflammatory response, were also compared. RESULTS: Women in the H-FGR group (n = 72) were older, with higher body mass index (BMI) and higher rate of preterm labor (<34 weeks) than in the N-FGR group (n = 270), P < .001 for all. Composite neonatal outcome was worse in the H-FGR than in the N-FGR group, 50% versus 15.5%, P < .001. Higher rate of maternal placental vascular lesions was detected in H-FGR compared with N-FGR, 82% versus 57.7%, P < .001. Using a stepwise logistic regression model, maternal BMI (1.13 odds ratio [OR], confidence interval [CI] 1.035-1.227, P = .006) and neonatal birth weight (0.996 OR, CI 0.995-0.998, P < .001) were independently associated with worse neonatal outcome. CONCLUSION: Worse neonatal outcome and more maternal placental vascular lesions in pregnancy complicated by FGR with preeclampsia versus FGR without preeclampsia suggest different pathophysiology in these entities.