Olaparib plus bevacizumab first-line maintenance in ovarian cancer: final overall survival results from the PAOLA-1/ENGOT-ov25 trial.

BACKGROUND: In the PAOLA-1/ENGOT-ov25 primary analysis, maintenance olaparib plus bevacizumab demonstrated a significant progression-free survival (PFS) benefit in newly diagnosed advanced ovarian cancer patients in clinical response after first-line platinum-based chemotherapy plus bevacizumab, irrespective of surgical status. Prespecified, exploratory analyses by molecular biomarker status showed substantial benefit in patients with a BRCA1/BRCA2 mutation (BRCAm) or homologous recombination deficiency (HRD; BRCAm and/or genomic instability). We report the prespecified final overall survival (OS) analysis, including analyses by HRD status. PATIENTS AND METHODS: Patients were randomized 2 : 1 to olaparib (300 mg twice daily; up to 24 months) plus bevacizumab (15 mg/kg every 3 weeks; 15 months total) or placebo plus bevacizumab. Analysis of OS, a key secondary endpoint in hierarchical testing, was planned for ∼60% maturity or 3 years after the primary analysis. RESULTS: After median follow-up of 61.7 and 61.9 months in the olaparib and placebo arms, respectively, median OS was 56.5 versus 51.6 months in the intention-to-treat population [hazard ratio (HR) 0.92, 95% confidence interval (CI) 0.76-1.12; P = 0.4118]. Subsequent poly(ADP-ribose) polymerase inhibitor therapy was received by 105 (19.6%) olaparib patients versus 123 (45.7%) placebo patients. In the HRD-positive population, OS was longer with olaparib plus bevacizumab (HR 0.62, 95% CI 0.45-0.85; 5-year OS rate, 65.5% versus 48.4%); at 5 years, updated PFS also showed a higher proportion of olaparib plus bevacizumab patients without relapse (HR 0.41, 95% CI 0.32-0.54; 5-year PFS rate, 46.1% versus 19.2%). Myelodysplastic syndrome, acute myeloid leukemia, aplastic anemia, and new primary malignancy incidence remained low and balanced between arms. CONCLUSIONS: Olaparib plus bevacizumab provided clinically meaningful OS improvement for first-line patients with HRD-positive ovarian cancer. These prespecified exploratory analyses demonstrated improvement despite a high proportion of patients in the placebo arm receiving poly(ADP-ribose) polymerase inhibitors after progression, confirming the combination as one of the standards of care in this setting with the potential to enhance cure.

Bipolar vessel-sealing devices in laparoscopic hysterectomies: a multicenter randomized controlled clinical trial.

OBJECTIVE: To compare operating time and blood loss in patients undergoing total laparoscopic hysterectomies (TLH) for benign conditions with either the Marseal™ IQ 5 mm (MS) or the Ligasure™ 5 mm (LS) vessel-sealing device. DESIGN AND SETTING: A randomized controlled clinical trial (RCT) in two German gynecology departments. PATIENTS: 74 patients scheduled to undergo TLH for a symptomatic fibroid uterus, adenomyosis or severe meno-metrorrhagia. INTERVENTIONS: Patients were randomized to receive a TLH with either the MS or the LS device. 27 variables were prospectively collected to address potential confounding issues. MEASUREMENT AND MAIN RESULTS: Operating time, defined as the time period between the first (round ligament dissection) and the last (uterine vessels sealing) use of the device, estimated and calculated intraoperative blood loss. The mean operating time (95% confidence interval, CI) was 22.7 min (95% CI 17.6-27.7) for LS and 26.4 min (95% CI 20-32.8) for the MS device (p = .89). The estimated intraoperative blood loss was 164 ml (95% CI 110-217) for LS and 160 ml (95% CI 116-203) for the MS device (p = .36). The multivariate analyses accounting for BMI, endometriosis, uterine weight and appearance of fibroids did not reveal any significant effect of the type of device used on operating time and estimated blood loss. CONCLUSION: In this RCT, both devices provided reliable and effective sealing and dissection. The reusable MS showed non-inferiority against the disposable LS device with regard to operating time and estimated intraoperative blood loss.

Sarcoma of the Uterus. Guideline of the DGGG (S2k-Level, AWMF Registry No. 015/074, August 2015).

Purpose: Official guideline published and coordinated by the German Society of Gynecology and Obstetrics (DGGG). Due to their rarity and their heterogeneous histopathology uterine sarcomas remain challenging tumors to manage and need a multidisciplinary approach. To our knowledge so far there is no evidence-based guideline on the appropiate management of these heterogeneous tumors. Methods: This S2k-guideline is the work of an representative committee of experts from a variety of different professions who were commissioned by the DGGG to carry out a systematic literature review of uterine sarcoma. Members of the participating scientific societies developed a structured consensus in a formal procedure. Recommendations: 1. The incidence and histopathologic classification of uterine sarcoma. 2. The clinical manifestations, diagnosis and staging of uterine sarcoma. 3. The management of leiomyosarcoma. 4. The management of endometrial stromal sarcoma and undifferentiated uterine sarcoma. 5. The management of adenosarcoma as well as carcinosarcomas. 6. The management of morcellated uterine sarcoma.

Surgical Methods for the Treatment of Uterine Fibroids - Risk of Uterine Sarcoma and Problems of Morcellation: Position Paper of the DGGG.

The appropriate surgical technique to treat patients with uterine fibroids is still a matter of debate as is the potential risk of incorrect treatment if histological examination detects a uterine sarcoma instead of uterine fibroids. The published epidemiology for uterine sarcoma is set against the incidence of accidental findings during surgery for uterine fibroids. International comments on this topic are discussed and are incorporated into the assessment by the German Society for Gynecology and Obstetrics (DGGG). The ICD-O-3 version of 2003 was used for the anatomical and topographical coding of uterine sarcomas, and the "Operations- und Prozedurenschlüssel" (OPS) 2014, the German standard for process codes and interventions, was used to determine surgical extirpation methods. Categorical qualifiers were defined to analyze the data provided by the Robert Koch Institute (RKI), the German Federal Bureau of Statistics (DESTATIS; Hospital and Causes of Death Statistics), the population-based Cancer Register of Bavaria. A systematic search was done of the MEDLINE database and the Cochrane collaboration, covering the period from 1966 until November 2014. The incidence of uterine sarcoma and uterine fibroids in uterine surgery was compared to the literature and with the different registries. The incidence of uterine sarcoma in 2010, standardized for age, was 1.53 for Bavaria, or 1.30 for every 100 000 women, respectively, averaged for the years 2002-2011, and 1.30 for every 100 000 women in Germany. The mean incidence collated from various surveys was 2.02 for every 100 000 women (0.35-7.02; standard deviation 2.01). The numbers of inpatient surgical procedures such as myoma enucleation, morcellation, hysterectomy or cervical stump removal to treat the indication "uterine myoma" have steadily declined in Germany across all age groups (an absolute decrease of 17 % in 2012 compared to 2007). There has been a shift in the preferred method of surgical access from an abdominal/vaginal approach to endoscopic or endoscopically assisted procedures to treat uterine fibroids, with the use of morcellation increasing by almost 11 000 coded procedures in 2012. Based on international statements (AAGL, ACOG, ESGE, FDA, SGO) on the risk of uterine sarcoma as an coincidental finding during uterine fibroid surgery and the associated risk of a deterioration of prognosis (in the case of morcellation procedures), this overview presents the opinion of the DGGG in the form of four Statements, five Recommendation and four Demands.

Erratum: Sarcoma of the Uterus. Guideline of the DGGG (S2k-Level, AWMF Registry No. 015/074, August 2015).

[This corrects the article DOI: 10.1055/s-0035-1558120.].

Sentinel lymph node detection in patients with vulvar carcinoma; Feasibility of intra-operative mapping with technetium-99m-labeled nanocolloid.

AIMS: Sentinel lymph node (SLN) mapping appears to be feasible in patients with primary vulvar cancer. Previous protocols describe the injection of the technetium-99m-nanocolloid at least 3 h before surgery which involves two invasive procedures for the patient. In this study, we assessed the feasibility, safety, and accuracy of an intra-operative rather than preoperative SLN mapping in patients with primary vulvar cancer. METHODS: Patients with histologically confirmed squamous cell vulvar cancer and clinically FIGO stage Ib disease underwent intra-operative SLN mapping by intradermal injection of the nanocolloid around the tumor. SLN were identified and removed before a complete inguinofemoral lymphnode dissection was performed. Surgical and pathologic data on all patients were prospectively entered into a database. RESULTS: An SLN procedure was performed in 16 patients; 3 patients received unilateral lymphadenectomy, and 13 women underwent surgery on both groins. In all groins but 4 at least one SLN was clearly identified (detection rate 25/29, 86%). A median number of 2 SLN and 4 non-SLN per groin were removed. 3 of 16 patients (19%) had metastatic disease in the lymph nodes. There was no false negative SLN result. CONCLUSION: Intra-operative SLN detection seems feasible in patients with early stage vulvar cancer. More patients need to be enrolled in this ongoing study before this more convenient technique can be considered safe.

Evaluation of FDG-PET for detecting lymph node metastasis in uterine corpus cancer.

BACKGROUND: In order to decrease surgery-related morbidity, we evaluated the reliability of the evaluation of lymph node metastasis in patients with uterine corpus cancer by positron-emission tomography (PET) with 2-[(18)F]fluoro-2-deoxy-D-glucose (FDG) before surgical staging. MATERIALS AND METHODS: Patients with newly diagnosed uterine corpus cancer scheduled for surgical staging, including lymphadenectomy, underwent PET imaging within 30 days before surgery. PET results and postoperative histopathology were compared for each patient and each nodal site. Sensitivity, specificity, positive and negative predictive value (PPV/NPV) as well as accuracy of FDG-PET in predicting nodal disease was determined by joined meta-analysis of the present data and the data available in the literature. RESULTS: Of 21 patients examined, 13 patients were eligible to enter this pilot study. Only one patient had lymph node metastasis, which was preoperatively detected by FDG-PET scan. Additionally, another patient was considered to have lymph node metastasis according to increased focal FDG uptake; however, all lymph nodes were free of malignant disease upon final pathology. In contrast, all other patients without lymph node metastasis upon final pathology showed negative preoperative FDG-PET scans. The meta-analysis yielded a sensitivity, specificity, PPV, NPV and accuracy of 0.53, 0.91, 0.57, 0.90 and 0.84, respectively. CONCLUSION: In patients with uterine corpus cancer, FDG-PET had an insufficient positive predictive value in detecting lymph node metastases, indicating that this method cannot replace surgical staging. However, due to its high NPV, FDG-PET might be beneficial in selected patients who are poor candidates for surgical staging.

Estrogen replacement therapy after endometrial cancer: a survey of physicians' prescribing practice.

OBJECTIVE: To determine whether the prescribing practice of physicians with regard to estrogen replacement therapy (ERT) in symptomatic women with previous endometrial cancer is consistent with the available evidence. METHODS: A descriptive survey was conducted among physicians in Germany, using a questionnaire containing two hypothetical cases of endometrial cancer patients ('low-risk' and 'high-risk' disease) and menopausal symptoms. Physicians were asked about their prescribing practice concerning moderate to severe menopausal symptoms. RESULTS: Four hundred and twenty questionnaires were sent out, with an overall response rate of 39.8%; 45.6% in the 'low-risk' case and 75.4% in the 'high-risk' case (p < 0.0001) stated that ERT is contraindicated. Only 12.9% were willing to prescribe ERT; 81.9% preferred to prescribe non-estrogenic alternatives (44.8% phytoestrogens, 29.0% selective serotonin reuptake inhibitors). CONCLUSION: Despite the evidence that ERT does not increase the risk of recurrence of endometrial cancer, many physicians are reluctant to prescribe ERT in women suffering from moderate to severe menopausal symptoms.

Prognostic factors and outcome in women with uterine sarcoma.

OBJECTIVES: A retrospective analysis of patients with uterine sarcoma was undertaken to assess prognostic factors and treatment related outcomes. PATIENTS AND METHODS: Ninety-four patients (median age: 60years, range: 20-93years) with a histologically verified uterine sarcoma treated at the McGill University Health Centre (MUHC) between 1989 and 2004 were identified from the tumor registry and pathology database. RESULTS: Twenty-eight patients had an endometrial stromal sarcoma (ESS), 30 had a leiomyosarcoma (LMS), and 36 had mixed muellerian tumors (MMT). According to FIGO classification, Stage I, II, III, and IV tumors were identified in 49, 7, 20, and 18 patients, respectively. At the time of analysis, 55.5% of patients (52/94) were dead due to progressive sarcoma disease; 8.5% of the patients (8/94) were alive with disease recurrence, and 36.2% (34/94) were alive without disease recurrence, with a median survival of 35months. Univariate analysis demonstrated a statistically significant association between overall survival and histology in favor of patients with ESS (p<0.001). Analyzing each of the histological subtypes separately, adjuvant treatment with chemotherapy and/or hormonal treatment had no demonstrable impact on overall survival. In multivariate analysis age and advanced stage, remained a significant predictor for overall survival in patients with LMS and MMT, but not in patients with ESS. Regarding adjuvant treatment, radiotherapy had a significant impact on overall survival only in patients with MMT (p=0.002). CONCLUSIONS: In patients with uterine sarcoma, in comparison to LMS and MMT, ESS tends to present as a less aggressive disease with a favorable outcome. Furthermore, reflected by an improved overall survival after radiotherapy only in patients with MMT, it seems to be mandatory to differentiate between these histological subtypes.

Cytochrome P2A13 and P1A1 gene polymorphisms are associated with the occurrence of uterine leiomyoma.

PROBLEM: To investigate the association between the occurrence of uterine leiomyoma and two SNPs of the CYP 2A13 and CYP 1A1 genes. METHOD OF STUDY: Prospective case control study with 132 women with clinically and surgically diagnosed uterine leiomyoma and 260 controls. Genotyping was performed by polymerase chain reaction (PCR) based amplification of CYP 2A13 and CYP 1A1 genes, and restriction fragment length polymorphism (RFLP) analysis. RESULTS: Comparing women with uterine leiomyoma and controls, we demonstrate statistical significant differences of allele frequency and genotype distribution for the CYP 1A1 polymorphism (P = 0.025 and P = 0.046, respectively). Furthermore, for the CYP 2A13 polymorphism we found a significant difference concerning allele frequency (P = 0.033). However, for the genotype distribution, only borderline significance was observed (P = 0.064). CONCLUSIONS: The CYP 2A13 and CYP 1A1 SNPs are associated with uterine leiomyoma in a Caucasian population and may contribute to the understanding of the pathogenic mechanisms of uterine leiomyoma.

Evaluation of patients after extraperitoneal lymph node dissection for cervical cancer.

OBJECTIVE: The presence of nodal metastases is an important prognostic factor in patients with cervical cancer. To adjust our therapy to the anatomic extent of the disease, we performed a surgical staging with extraperitoneal lymph node dissection (EPLND). The goal of our study was to evaluate the clinical outcome and side effects of the combined treatment approach of EPLND and either radical hysterectomy in case of early stage cervical cancer (FIGO Ia/b and IIa) and negative nodes, or pelvic radiotherapy/extended field radiotherapy with concomitant chemotherapy in case of positive nodes or advanced stage cervical cancer (FIGO IIb, III, and IVa). PATIENTS AND METHODS: Fifty-nine patients with primarily diagnosed invasive cervical cancer underwent EPLND. The value of this procedure as a diagnostic tool for evaluating the extent of disease was determined. Additionally, treatment-related complications and clinical outcomes were monitored. RESULTS: A total of 983 lymph nodes were removed during EPLND (mean 16.7). According to the results of EPLND, radical hysterectomy was abandoned due to histopathologically confirmed lymph node involvement by frozen section in 11 out of 36 patients with early stage cervical cancer (31%). The most common adverse effects directly related to surgery in general (EPLND or combined EPLND and radical hysterectomy) were lymph cysts in seven patients (12%). Only in the group of patients who received EPLND followed by radical hysterectomy, 2 out of 25 patients (8%) developed a severe ileus postoperatively (WHO Grade 3 toxicity). The treatment approach of combined EPLND followed by radio- and chemotherapy was without major complications (WHO Grade 3 or 4 toxicity). After a mean follow up of 28 months (range 6-60), 44 out of 58 patients (one patient lost to follow up) are without evidence of disease (76%), 2 patients have progressive disease (3%), and 12 patients died of their disease (21%). Using Kaplan-Meier analysis, the estimated 5-year overall survival rate for all patients is 64% (SD +/- 9%). Performing the Cox proportional regression analysis, in contrast to clinical FIGO staging (P = 0.24; ns), lymph node involvement was the only significant independent predictor for overall survival (P = 0.04). CONCLUSION: Our data support the approach of pretherapeutic surgical staging by performing EPLND as a diagnostic tool with a low complication rate. This allows an individualized treatment for cervical cancer patients.

[Hystero-salpingo-contrast-sonography with 3-d-ultrasound -- a pilot study]. / Hystero-Salpingo-Kontrastsonographie mit 3D-Ultraschall: eine Pilotstudie.

UNLABELLED: Hystero-salpingo-contrast sonography (HyCoSy) is a sensitive method of assessing tubal patency but cannot completely substitute diagnostic laparoscopy with blue dye and hysteroscopy. Three-dimensional sonography has new imaging facilities which could lead to a reduction of invasive diagnostic procedures. AIM: The aim of this pilot study was to analyse the feasibility of HyCoSy by 3D- and 3D-Doppler-sonography. METHODS: In a prospective setting conventional (2D) HyCoSy was performed in 21 patients with an ultrasound device designed for 3D-ultrasound. After the completion of the 2D procedure, 3D-ultrasound was carried out. In five patients an additional 3D-Doppler-HyCoSy was performed. The generated 3D-volumina were then examined. Laparoscopy with blue dye was performed immediately after the ultrasound examination. RESULTS: A total of 42 Fallopian tubes was assessed. On 2D-ultrasound, visibility of the tubes was excellent in 28 and limited in seven tubes. Of the seven tubes not visible on 2D-ultrasound, four were not patent on laparoscopy. On 3D-ultrasound, visibility of the tubes was excellent in 15 and limited in twelve tubes. 15 tubes were not visible on 3D-ultrasound. 3D-Doppler-HyCoSy revealed excellent assessment in eight of ten tubes, even in one of those with limited visibility on 2D- and 3D-HyCoSy. In 19 patients the assessment of the uterine cavity was excellent by 2D- and 3D-HyCoSy, whereas it was limited in two patients. CONCLUSION: It is possible to visualise the full length of the tubes in a very detailed way from the uterine cavity to the fimbrial end in some patients, but the diagnostic power of HyCoSy is not improved by adding 3D-imaging. The accuracy of 3D-ultrasound seemed to be improved by 3D-Doppler-ultrasound.

Topotecan as a continuous infusion over 14 days in recurrent ovarian cancer patients.

OBJECTIVE: In recurrent ovarian cancer the topoisomerase-1 inhibitor topotecan shows activity after prior treatment with platinum and taxanes. Overall response rates of up to 38% in combination with an acceptable toxicity profile have been reported. We performed a pilot study to evaluate the therapeutic efficacy and toxicity profile of a low-dose continuous infusion protocol of topotecan. PATIENTS AND METHODS: Twelve patients with recurrent ovarian cancer and a measurable lesion received a continuous infusion of topotecan (0.4 mg/m2/d) over 14 days, repeated every 28 days. All patients had at least one prior platinum-containing regimen of chemotherapy (range 1-7). Responses were evaluated by ultrasound, computed tomography (CT) scans and/or magnetic resonance imaging (MRI). RESULTS: A total of 57 (median 5, range 1-12) topotecan treatment cycles were administered. The overall response rate was 2/12 (17%). Four patients had stable disease (33%), among them two patients with platinum-refractory tumors. The median time to progression was 26 (range 20-100) weeks. No grade 3 or 4 hematological toxicities were observed. However, one patient developed a grade 2 allergy leading to discontinuation of topotecan. CONCLUSION: Treatment of recurrent ovarian cancer with low-dose continuous infusion of topotecan over 14 days demonstrated response rates comparable to other dosing schedules with minimal toxicity in a preliminary series of 12 patients.

The size of a microsatellite polymorphism of the haem oxygenase 1 gene is associated with idiopathic recurrent miscarriage.

Endothelial damage, impaired microvascularization and immune maladaptation have been described as aetiological factors in recurrent miscarriages. We investigated the relationship between idiopathic recurrent miscarriage (IRM) and a (GT)(n) repeat microsatellite polymorphism of the gene encoding haem oxygenase 1 (HO-1), known to modulate immune functions such as T-helper (TH) cell function and to be associated with cardiovascular disease. We investigated 162 women with IRM and 129 healthy, post-menopausal controls. The length of the HO-1 (GT)(n) microsatellite was assessed by PCR and direct sequencing in all women. Results were correlated with clinical data. The distribution of genotypes was in Hardy-Weinberg equilibrium. The HO-1 (GT)(n) microsatellite repeat numbers ranged from 13 to 37, with (GT)(23) and (GT)(30) being the most common alleles in both groups. We compared alleles consisting of < or =27 GT repeats, termed class S (short) alleles and alleles consisting of >28 GT repeats, termed class L (long) alleles. Seventy per cent of women with IRM had an S allele either in heterozygous (L/S) or homozygous (S/S) form, compared to 56% of controls (P = 0.02; OR 0.54; 95% CI 0.32-0.90). With respect to S allele frequencies, we found no significant difference among women with IRM and controls [P = 0.3; odds ratio (OR) 1.23, 95% confidence interval (CI) 0.86-1.76]. Comparing women with primary and secondary IRM, no difference with respect to the length of the HO-1 (GT)(n) microsatellite was ascertained. In summary, this is the first report on a HO-1 (GT)(n) microsatellite polymorphism among women with IRM, demonstrating that the investigated polymorphism is associated with IRM in a relatively large Caucasian population.

[The corpus luteum]. / Das Corpus Luteum.

The primary function of the corpus luteum is secretion of progesterone for maintenance of pregnancy. The development and function of the corpus luteum from residual follicular granulosa and theca cells after ovulation is induced by the midcyclic peak of LH secretion followed by further pulsatile LH release. Due to this stimulation the follicular granulosa and theca cells are converted to large and small luteinized cells with high proliferation rate. During this process Vascular-Endothelial-Growth Factor (VEGF) plays a major role as a potent stimulator of neo-angiogenesis. Formation of new blood vessels is essential to ensure supply of LDL-Cholesterol as substrate for steroidogenesis. If pregnancy does not occurs, the corpus luteum must regress to initiate another cycle. Luteal regression seems to be initiated by PGF2 alpha which is secreted from the uterus. PGF2 alpha, reduces luteal blood flow and progesterone synthesis. Furthermore it is a potent inducer of apoptosis. If pregnancy occurs, sustained secretion of progesterone and other substances like estradiol and relaxin are required to provide an appropriate uterine environment for maintenance of pregnancy. In that case the corpus luteum is further stimulated by hCG secreted by the blastocyst and the trophoblast-cells until 8/9 weeks of gestational age, when synthesis and secretion of steroids is taken over by the placenta.