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Background: Robotic-assisted laparoscopy has become a widely and increasingly used modality of minimally invasive surgery in the treatment of endometrial cancer. Due to its technical advantages, robotic-assisted laparoscopic surgery offers benefits, such as a lower rate of conversions compared to conventional laparoscopy. Yet, data on long-term oncological outcomes after robotic-assisted laparoscopy is scarce and based on retrospective cohort studies only., Objective: This study aimed to assess overall survival, progression-free survival, and long-term surgical complications in patients with endometrial cancer randomly assigned to robotic-assisted or conventional laparoscopy., Study Design: This randomized controlled trial was conducted at the Department of Gynecology and Obstetrics of Tampere University Hospital, Finland. Between 2010 and 2013, 101 patients with low-grade endometrial cancer scheduled for minimally invasive surgery were randomized preoperatively 1:1 either to robotic-assisted or conventional laparoscopy. All patients underwent laparoscopic hysterectomy, bilateral salpingo-oophorectomy, and pelvic lymphadenectomy. A total of 97 patients (49 in the robotic-assisted laparoscopy group and 48 in the conventional laparoscopy group) were followed up for a minimum of 10 years. Survival was analyzed using Kaplan-Meier curves, log-rank test, and Cox proportional hazard models. Binary logistic regression analysis was used to analyze risk factors for trocar site hernia., Results: In the multivariable regression analysis, overall survival was favorable in the robotic-assisted group (hazard ratio 0.39; 95% confidence interval [CI], 0.15-0.99, P=.047) compared to the conventional laparoscopy group. There was no difference in progression-free survival (log-rank test, P=.598). The 3-, 5-, and 10-year overall survival were 98.0% (95% CI, 94.0-100) vs 97.9% (93.8-100), 91.8% (84.2-99.4) vs 93.7% (86.8-100), and 75.5% (64.5-87.5) vs 85.4% (75.4-95.4) for the conventional laparoscopy and the robotic-assisted groups, respectively. Trocar site hernia developed more often for the robotic-assisted group compared to the conventional laparoscopy group 18.2% vs 4.1% (odds ratio 5.42, 95% CI, 1.11-26.59, P=.028). The incidence of lymphocele, lymphedema, or other long-term complications did not differ between the groups., Conclusion: The results of this randomized controlled trial suggest a minor overall survival benefit in endometrial cancer after robotic-assisted laparoscopy compared to conventional laparoscopy. Hence, the use of robotic-assisted technique in the treatment of endometrial cancer seems safe, though larger randomized controlled trials are needed to confirm any potential survival benefit. No alarming safety signals were detected in the robotic-assisted group since the rate of long-term complications differed only in the incidence of trocar site hernia., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: Plasma, but also urine sample could represent a simple liquid biopsy for ovarian cancer biomarker detection. The miRNA-200 family has been shown to be dysregulated in ovarian cancer. The aim of this study was to isolate three members of miR-200 family from tumor tissue, plasma and urine of high-grade serous ovarian cancer patients in comparison with samples from patients with benign ovarian tumors. This is a methodological pilot study of a prospective ovarian cancer patient cohort investigating the potential of liquid biopsies and the role of miRNAs in ovarian cancer treatment., Results: MiR-200a, miR-200b and miR-200c were isolated from samples of nine ovarian cancer patients and seven patients with benign ovarian tumor. The most significant finding is that all three miRNAs were detectable in all sample types. Tumor tissue and plasma, but not urine analysis was able to discriminate malignant and benign samples. A correlation between the miRNA-200 expression in urine and plasma was observed in malignant samples only. Plasma and urine with respect to miRNA detection show potential according to this study, but larger studies are needed to clarify the usefulness of these liquid biopsies in ovarian cancer., Trial Registration: ClinicalTrials.gov NCT02758652, May 2, 2016.

To prevent endometrial carcinoma in Lynch syndrome (LS), regular gynecological surveillance visits and prophylactic surgery are recommended. Previous data have shown that prophylactic hysterectomy is an effective means of cancer prevention, while the advantages and disadvantages of surveillance are somewhat unclear. We aimed to evaluate female LS carriers' attitudes towards regular gynecological surveillance and factors influencing their decision-making on prophylactic surgery that have not been well documented. Pain experienced during endometrial biopsies was also evaluated. Postal questionnaires were sent to LS carriers undergoing regular gynecological surveillance. Questionnaires were sent to 112 women with LS, of whom 76 responded (68%). Forty-two (55%) had undergone prophylactic hysterectomy by the time of the study. The majority of responders (64/76; 84.2%) considered surveillance appointments beneficial. Pain level during endometrial biopsy was not associated with the decision to undergo prophylactic surgery. The level of satisfaction the women had with the information and advice provided during surveillance was significantly associated with the history of prophylactic hysterectomy (satisfaction rate of 73.2% versus 31.8% of nonoperated women, p = 0.003). The women who had undergone prophylactic surgery were older than the nonoperated women both at mutation testing (median of 42.3 years versus 31.6 years, p < 0.001) and at the time of the study (median of 56.9 years versus 46.0 years, respectively, p < 0.001). Women with LS pathogenic variants have positive experiences with gynecological surveillance visits, and their perception of the quality of the information and advice obtained plays an important role in their decision-making concerning prophylactic surgery.

Objective: To evaluate the relationship between cesarean scar defect and abnormal uterine bleeding at one year after cesarean section (CS)., Study Design: A prospective observational cohort study was conducted in 401 women who delivered by CS between January 2016 and January 2017. Women were screened for isthmocele with sonohysterography six months after CS and followed by electronic questionnaires at 12, 13 and 14 months after CS. The main outcome measure was the prevalence of postmenstrual spotting. Secondary outcome measures were the duration of menstrual bleeding, prevalence of postcoital bleeding, dyspareunia or dysmenorrhea, usage of painkillers, and absence from work or other activities., Results: The response rate was 88 %. In the isthmocele group, the prevalence of postmenstrual spotting was 20.0 % compared to 8.3 % in women without isthmocele (OR 2.75 [95 % CI 1.39-5.44]; P = 0.004). Additionally, women with isthmocele reported more frequently postcoital bleeding (8.3 % vs. 2.4 %; OR 3.73 [95 % CI 1.18-11.83]; P = 0.026). The prevalence of postmenstrual spotting was even higher in the subgroup of large isthmoceles, (25.9 % vs. 9.5 %; (OR 3.34 [95 % CI 1.72-6.49]; P < 0.001)., Conclusion: The prevalence of postmenstrual spotting among isthmocele patients was 20.0 %. Additionally, postmenstrual spotting was associated with the presence of isthmocele inquired at 1 year after CS., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Platinum-based chemotherapy is the foundation of treatment for platinum-sensitive recurrent ovarian cancer, but has substantial toxicity. Bevacizumab and maintenance poly(ADP-ribose) polymerase (PARP) inhibitors both significantly improve efficacy versus standard therapy, primarily in terms of progression-free survival, and offer the potential for chemotherapy-free treatment. AVANOVA2 compared niraparib and bevacizumab versus niraparib alone as definitive treatment for platinum-sensitive recurrent ovarian cancer., Methods: This open-label, randomised, phase 2, superiority trial in 15 university hospitals in Denmark, Sweden, Finland, Norway, and the USA enrolled women aged 18 years or older with measurable or evaluable high-grade serous or endometrioid platinum-sensitive recurrent ovarian cancer. Patients had to have an Eastern Cooperative Oncology Group performance status of 0-2, and had to have previously received platinum-containing therapy for primary disease but ≤1 prior non-platinum-containing regimen for recurrent disease. Previous treatment with bevacizumab or first-line maintenance PARP inhibitors was permitted. Eligible patients were randomly assigned 1:1 (by random permuted blocks with block sizes of two and four, no masking), stratified by homologous recombination deficiency status and chemotherapy-free interval, to receive once-daily oral niraparib 300 mg alone or with intravenous bevacizumab 15 mg/kg once every 3 weeks until disease progression. The primary endpoint was progression-free survival, assessed by the investigators in the intention-to-treat population after events in at least 62 patients. Safety was analysed in all patients who received at least one dose of study drug. This ongoing trial is registered with ClinicalTrials.gov, number NCT02354131., Findings: Between May 23, 2016, and March 6, 2017, 97 patients were enrolled and randomly assigned: 48 to niraparib plus bevacizumab and 49 to single-agent niraparib. Median follow-up was 16·9 months (IQR 15·4-20·9). Niraparib plus bevacizumab significantly improved progression-free survival compared with niraparib alone (median progression-free survival 11·9 months [95% CI 8·5-16·7] vs 5·5 months [3·8-6·3], respectively; adjusted hazard ratio [HR] 0·35 [95% CI 0·21-0·57], p<0·0001). Grade 3 or worse adverse events occurred in 31 (65%) of 48 patients who received niraparib plus bevacizumab and 22 (45%) of 49 who received single-agent niraparib. The most common grade 3 or worse adverse events in both groups were anaemia (7 [15%] of 48 vs 9 [18%] of 49) and thrombocytopenia (5 [10%] vs 6 [12%]), and hypertension in the combination group (10 [21%] vs 0). Niraparib plus bevacizumab was associated with increased incidences of any-grade proteinuria (10 [21%] of 48 patients vs 0) and hypertension (27 [56%] of 48 vs 11 [22%] of 49) compared with niraparib alone. No treatment-related deaths occurred., Interpretation: The efficacy observed with this chemotherapy-free combination of approved agents in women with platinum-sensitive recurrent ovarian cancer warrants further evaluation. A randomised phase 3 trial investigating niraparib plus bevacizumab versus chemotherapy plus bevacizumab in platinum-sensitive recurrent ovarian cancer is planned., Funding: Nordic Society of Gynaecological Oncology and Tesaro., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Purpose: The two main etiological factors for vulvar squamous cell carcinoma (vSCC) are the vulvar dermatosis lichen sclerosus (LS) and high-risk human papillomavirus (hrHPV). Serpin A1 (α1-antitrypsin) is a serine protease inhibitor, which plays a role in the tumorigenesis of various cancer types. The aim of the study was to evaluate the expressions of Serpin A1 in LS, premalignant vulvar lesions, and vSCC using immunohistochemistry (IHC) and serum analysis, and to compare Serpin A1 stainings to the tumor markers p53 and p16., Methods: In total, 120 samples from 74 patients were studied with IHC for Serpin A1, p53 and p16: 18 normal vulvar skin, 53 LS, 9 premalignant vulvar lesions (dVIN/HSIL) and 40 vSCC samples. Serum concentrations of Serpin A1 were analyzed from 30 LS, 44 vSCC and 10 control patients. Expressions were compared to clinical data., Results: Tumor cell-specific Serpin A1 overexpression was detected in 88% of vSCC samples, independent of the etiology. The intensity of Serpin A1 expression was significantly higher in vSCC than in healthy vulvar skin, LS, or premalignant vulvar lesions. Serpin A1 showed an association with p53 positivity. No difference in overall survival was found between Serpin A1-, p53-, or p16-positive vSCC patients. Serum concentrations of Serpin A1 were equal in the LS, vSCC, and control groups., Conclusion: Tumor cell-specific Serpin A1 overexpression is a potential biomarker in vSCC.

Aim: We hypothesized that field asymmetric waveform ion mobility spectrometry (FAIMS) as a novel artificial olfactory technology could differentiate urine of women with malignant ovarian tumors from controls and women with benign tumors, based on previous findings on the ability of canine olfactory system to "smell" cancer., Patients and Methods: Preoperative urine samples from 51 women with ovarian tumors, both benign and malignant, and from 18 women with genital prolapse, as controls, were collected. The samples were analyzed by FAIMS device. Data analysis was processed by quadratic data analysis (QDA) and linear discriminant analysis (LDA), and cross-validated using 10-fold cross-validation., Results: Thirty-three women had malignant ovarian tumors, of which 18 were high-grade cancers. FAIMS distinguished controls from malignancies with the accuracy of 81.3% (sensitivity 91.2% and specificity 63.1%), and benign tumors from malignancies with the accuracy of 77.3% (sensitivity 91.5% and specificity 51.4%). Moreover, low grade tumors were also separated from high grade cancers and benign ovarian tumors with accuracies of 88.7% (sensitivity 87.8% and specificity 89.6%) and 83.9% (sensitivity 73.1% and specificity 92.9%), respectively., Conclusions: This proof of concept-study indicates that the FAIMS from urine has potential to discriminate malignant ovarian tumors from no tumor-bearing controls and benign tumors., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Cesarean scar defect (isthmocele) is a known complication after cesarean delivery. It has become more common due to a rising cesarean delivery rate. Isthmocele has been associated with various gynecological and obstetric problems such as uterine rupture, cesarean scar pregnancy, and bleeding disorders., Objective: We sought to prospectively investigate factors associated with the risk for isthmocele assessed by sonohysterography., Study Design: A prospective observational cohort study was conducted in 401 nonpregnant women who were recruited within 3 days of cesarean delivery. Women were evaluated with sonohysterography 6 months after cesarean delivery to detect a possible isthmocele. The ultrasonographer was blinded to any clinical information. The main outcome measure was the presence of isthmocele. Type of surgery (elective vs emergency), maternal background variables, and factors related to pregnancy, labor, and postoperative recovery were analyzed in relation to isthmocele. A logistic regression model was used to assess independent risk factors from univariate analysis., Results: In all, 371 women were examined with sonohysterography resulting in a follow-up rate of 92.5%. The prevalence of isthmocele was 45.6%. Independent risk factors for isthmocele development were a history of gestational diabetes (odds ratio, 1.73; 95% confidence interval, 1.02-2.92; P = .042), previous cesarean delivery (odds ratio, 3.14; 95% confidence interval, 1.90-5.17; P < .001), and advanced maternal body mass index (odds ratio, 1.06; 95% confidence interval, 1.01-1.11; P = .012). Every additional unit of body mass index increased the risk of isthmocele by 6%. In the subgroup of emergency cesarean delivery, longer duration of active labor increased the risk for isthmocele (odds ratio, 1.06; 95% confidence interval, 1.01-1.11; P = .032). There was no statistically significant difference in prevalence between the groups of elective and emergency cesarean delivery (P = .898)., Conclusion: Based on sonohysterographic examination, maternal body mass index, gestational diabetes, and previous cesarean deliveries are associated with an increased risk for incomplete healing of the uterine incision., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Previous results obtained from serum samples of late-stage, high-grade serous ovarian carcinoma patients showed large alterations in lipid metabolism. To validate and extend the results, we studied lipidomic changes in early-stage ovarian tumours. In addition to serous ovarian cancer, we investigated whether these changes occur in mucinous and endometrioid histological subtypes as well., Methods: Altogether, 354 serum or plasma samples were collected from three centres, one from Germany and two from Finland. We performed lipidomic analysis of samples from patients with malignant (N = 138) or borderline (N = 25) ovarian tumours, and 191 controls with benign pathology. These results were compared to previously published data., Results: We found 39 lipids that showed consistent alteration both in early- and late-stage ovarian cancer patients as well as in pre- and postmenopausal women. Most of these changes were already significant at an early stage and progressed with increasing stage. Furthermore, 23 lipids showed similar alterations in all investigated histological subtypes., Conclusions: Changes in lipid metabolism due to ovarian cancer occur in early-stage disease but intensify with increasing stage. These changes occur also in other histological subtypes besides high-grade serous carcinoma. Understanding lipid metabolism in ovarian cancer may lead to new therapeutic and diagnostic alternatives.

Introduction: The aim of this study was to investigate the prevalence of post-cesarean isthmocele and to measure agreement between transvaginal ultrasonography and saline contrast sonohysterography in assessment of isthmocele., Material and Methods: A prospective observational cohort study was carried out at Tampere University Hospital, Finland. Non-pregnant women delivered by cesarean section (n = 371) were examined with transvaginal ultrasonography (TVUS) and sonohysterography (SHG) six months after cesarean section. The main outcome measure was the prevalence of isthmocele using TVUS and SHG. Secondary outcome measures were characteristics of isthmocele., Results: In all, 371 women were included. The prevalence of isthmocele was 22.4% based on TVUS and 45.6% based on SHG. Sensitivity and specificity for TVUS was 49.1 and 100%, respectively, when compared with SHG. Therefore, half of the defects (50.9%) diagnosed with SHG remained undiagnosed with TVUS. Bland-Altman analysis showed an underestimation of 1.1 mm (range 0.00-7.90) for TVUS compared with SHG, with 95% limits of agreement from -1.9 to 4.1 mm., Conclusions: This methodological study provides confirmatory data that TVUS and SHG are not in good agreement in the isthmocele diagnostics and the use of only TVUS may lead to an underestimation of the prevalence of isthmocele. Thus, SHG should be considered as a method of choice in diagnostics of isthmocele., (© 2018 Nordic Federation of Societies of Obstetrics and Gynecology.)

Objective: Mini-invasive surgery has essentially replaced open laparotomy in surgery for endometrial and cervical carcinoma. Of the procedures needed for a complete staging, especially para-aortic lymphadenectomy (PALND) is challenging to perform. The present study was undertaken to investigate the technical and surgical outcomes of robotic-assisted PALND for gynecological cancers in the setting of a tertiary university hospital in Finland., Methods: This was a retrospective chart review of 283 robotic-assisted para-aortic lymphadenectomies using the single-docking transperitoneal technique performed at the Department of Obstetrics and Gynecology of Tampere University Hospital, in 2009-2016. The primary outcome measure was the extent of the operation in terms of the height, that is, how often the level cranial to the inferior mesenteric artery (IMA) was achieved. The secondary outcome measures included operation time and surgical outcome., Results: The majority of operations (n = 239 [84.4%]) were performed for endometrial carcinoma. The most common operation type was robotic-assisted hysterectomy, bilateral salpingo-oophorectomy, and pelvic lymphadenectomy and PALND, which took a median of 3:38 hours or 218 minutes (range, 140-341 minutes) to perform. The high PALND (above the level of IMA) succeeded in 235 operations (83%). In the total cohort, the median number of para-aortic lymph nodes removed was 12 (range, 0-38), with a learning curve approximately more than 40 operations. Para-aortic lymph node metastases were found in 43 patients (15.2%). Seven conversions to laparotomy (2.5%) were done. The conversion and intraoperative complication rates were 2.5% and 3.5%, respectively, and postoperative complications was 18%, according to the classification of Clavien-Dindo. The median length of the postoperative hospital stay was 2 days (range, 1-8 days)., Conclusions: Using the transperitoneal technique for PALND, the area between IMA and the renal veins can be reached in more than 80% of the operations, with a very low or 2.5% conversion rate.

Objectives: The purpose of this study was to compare the costs of traditional laparoscopy and robotic-assisted laparoscopy in the treatment of endometrial cancer., Methods and Materials: A total of 101 patients with endometrial cancer were randomized to the study and operated on starting from 2010 until 2013, at the Department of Obstetrics and Gynecology of Tampere University Hospital, Tampere, Finland. Costs were calculated based on internal accounting, hospital database, and purchase prices and were compared using intention-to-treat analysis. Main outcome measures were item costs and total costs related to the operation, including a 6-month postoperative follow-up., Results: The total costs including late complications were 2160 &OV0556; higher in the robotic group (median for traditional 5823 &OV0556;, vs robot median 7983 &OV0556;, P < 0.001). The difference was due to higher costs for instruments and equipment as well as to more expensive operating room and postanesthesia care unit time. Traditional laparoscopy involved higher costs for operation personnel, general costs, medication used in the operation, and surgeon, although these costs were not substantial. There was no significant difference in in-patient stay, laboratory, radiology, blood products, or costs related to complications., Conclusions: According to this study, robotic-assisted laparoscopy is 37% more expensive than traditional laparoscopy in the treatment of endometrial cancer. The cost difference is mainly explained by amortization of the robot and its instrumentation.

Objectives: Elevated concentrations of polyamines have been found in urine of patients with malignant tumors, including ovarian cancer. Previous research has suffered from poorly standardized detection methods. Our liquid chromatography-tandem mass spectrometry (LC-MS/MS) method is capable of simultaneous standardized analysis of most known polyamines. Liquid chromatography-tandem mass spectrometry has not previously been used in the differential diagnostics of ovarian tumors in postmenopausal women., Materials and Methods: In this prospective study, postmenopausal women (n = 71) presenting with an adnexal mass and, as controls, women with genital prolapse or urinary incontinence scheduled for surgery (n = 22) were recruited in the study. For analysis of the polyamines, a morning urine sample was obtained before surgery. Preoperative serum CA125 concentrations were determined in the study group., Results: Twenty-three women with benign and 37 with malignant ovarian tumors were eligible. Of all analyzed polyamines, only urinary N,N-diacetylspermine showed statistically significant differences between all groups except controls versus benign tumors. N,N-diacetylspermine was elevated in malignant versus benign tumors (P < 0.001), in high-grade versus low malignant potential tumors (P < 0.001), in stage III to IV versus stage I to II cancers (P < 0.001), and even in early-stage cancer (stage I-II) versus benign tumors (P = 0.017). N,N-diacetylspermine had better sensitivity (86.5%) but lower specificity (65.2%) for distinguishing benign and malignant ovarian tumors than CA125 with a cut-off value of 35 kU/L (sensitivity, 75.7%; specificity, 69.6%)., Conclusions: Urinary N,N-diacetylspermine seems to be able to distinguish benign and malignant ovarian tumors as well as early and advanced stage, and low malignant potential and high-grade ovarian cancers from each other, respectively.

Objectives: Eight percent of women have vulvodynia (VD), a chronic pain disorder with unknown etiology. The aim of our study was to assess the efficacy of given VD treatments measured by numerical rating scale (NRS) for pain and patients' quality of life., Materials and Methods: Study material consisted of a retrospective VD patient cohort (N = 70). Data were collected by postal questionnaires and review of the medical records., Results: We report here a statistically significant reduction in NRS only with combination of therapies (median NRS before treatments 8 vs median NRS 4 after treatments, p < .001) but not with any individual therapy alone, i.e., physiotherapy, topical medications, oral pharmaceutical therapy, sexual counseling by a trained nurse, sacral neuromodulation, and laser treatment or surgery. Older age (>30) and frequent (≥6) outpatient clinic visits associated with a significantly minor reduction in NRS (p = .03 and p = .04, respectively)., Conclusions: The results of this retrospective study suggest that an effective, multimodality-based treatment is most beneficial for VD patients and VD at older age may represent a subtype more resistant to therapy.

Objective: Intraoperative detection of ovarian sentinel nodes has been shown to be feasible. We examined the detection rate and locations of sentinel nodes in patients with ovarian tumors. We also aimed to assess the reliability of sentinel node method in predicting regional lymph node metastasis., Methods: Twenty patients scheduled for laparotomy because of a pelvic mass were recruited to the study. In the beginning of the laparotomy, radioisotope and blue dye were injected under the serosa next to the junction of the ovarian tumor and suspensory ligament. The number and locations of the hot and/or blue nodes/spots were recorded during the operation. If the tumor was malignant according to the frozen section, systematic lymphadenectomies were performed, the sentinel nodes sampled separately, and their status compared with other regional lymph nodes., Results: Eleven patients had a right-sided ovarian tumor, 7 patients a left-sided tumor, and 2 patients had bilateral tumors. A median of 2 sentinel nodes/locations per patient (range, 1-3) were found. Sixty percent of all sentinel nodes were located in the para-aortic region only, compared with 30% in both para-aortic and pelvic areas and 10% in pelvic area only. Both unilateral and bilateral locations were found. In 83% of the cases with more than 1 sentinel node location, they were located in separate anatomical regions. In 3 patients, systematic lymphadenectomies were performed. One of them had nodal metastases in 2 regions and also a metastasis in 1 of her 2 sentinel nodes in 1 of those regions., Conclusions: In patients with ovarian tumor(s), the detection of sentinel nodes is feasible. They are located in different anatomic areas both ipsilaterally and contralaterally, although most of them are found in the para-aortic region. The reliability of the sentinel node concept should be evaluated in the framework of a multicenter trial.

Data available on lifestyle-associated hormonal and medical factors among endometrial cancer (EC)-affected women who carry the Lynch Syndrome (LS) mutation is limited. The aim of the present retrospective case study was to compare the reproductive and medical history, as well as lifestyle-associated factors, among patients with LS and sporadic EC. The study population consisted of 50 verified germline mismatch repair (MMR) gene mutation carriers diagnosed with EC, and 110 sporadic EC patients. Data were collected using postal questionnaires. Apart from the mean age at the time of the EC diagnosis (LS, 48.7 years compared with sporadic patients, 55.2 years; P<0.0001), the characteristics of sporadic and LS EC patients were similar with regard to body mass index (BMI) at age 18, 40 or at the time of the survey, and smoking and alcohol consumption. LS women reported a significantly lower rate of spontaneous abortion (P=0.043) and also more frequent use of contraceptives (P=0.004). The prevalence of co-morbidities, including diabetes, atherosclerosis, hypercholesterolemia and hypertension, was similar between the LS and the sporadic groups. A trend for a higher prevalence of endometriosis among mutation carriers was detected (16.0 vs. 8.1%, P=0.137). As anticipated, the prevalence of gastrointestinal tract, urinary tract and ovarian cancer was higher among the LS women (P<0.0001, P=0.006 and P=0.056, respectively). Co-morbidity and lifestyle-associated factors appeared to be comparable among patients with LS and sporadic EC. The reported difference in the use of contraceptives warrants further investigation. Future studies are also required to address the possible association between LS and endometriosis.

Background: Preoperative evaluation of ovarian tumors is challenging. This study was undertaken to evaluate the performance of conventional two-dimensional (2D) ultrasound and CA125 in predicting malignant or benign nature of pelvic masses, and to investigate if three-dimensional power Doppler (3DPD) ultrasound provides any added value. Ninety-six postmenopausal and four perimenopausal women with supposed ovarian tumors were examined by standardized 2D and 3DPD ultrasounds preoperatively. The tumors were evaluated using the risk of malignancy index (RMI), International Ovarian Tumors Analysis (IOTA) group simple rules, expert opinion, IOTA logistic regression model 2 (LR2) and 3D vascular indices, and were postoperatively compared to histopathological results., Results: Ninety-eight tumors turned out to be ovarian in origin. Of these, 66 were benign and 32 malignant. RMI (cut-off value 200), simple rules, expert opinion and LR2 (cut-off value 25) were used to predict malignant nature of the tumors and had sensitivities of 71.9, 90.6, 87.5 and 90.6%, and specificities of 80.3, 84.6, 92.4 and 77.3%, respectively. When the 3D vascularization flow index (VFI) was added to RMI and LR2, the accuracy of the test improved from 77.6 to 81.4% and from 81.6 to 86.5%, respectively, at the expense of sensitivity, while VFI gave no added benefit for simple rules and expert opinion. Agreement between two examiners using expert opinion was good (Cohen's kappa = 0.89)., Conclusions: The subjective opinion of an expert seems to be the most reliable method in assessing ovarian tumors, and the 3DPD indices seem to provide no significant added value.

Background: Previous studies comparing robotic-assisted laparoscopic surgery to traditional laparoscopic or open surgery in gynecologic oncology have been retrospective. To our knowledge, no prospective randomized trials have thus far been performed on endometrial cancer., Objective: We sought to prospectively compare traditional and robotic-assisted laparoscopic surgery for endometrial cancer., Study Design: This was a randomized controlled trial. From December 2010 through October 2013, 101 endometrial cancer patients were randomized to hysterectomy, bilateral salpingo-oophorectomy, and pelvic lymphadenectomy either by robotic-assisted laparoscopic surgery or by traditional laparoscopy. The primary outcome measure was overall operation time. The secondary outcome measures included total time spent in the operating room, and surgical outcome (number of lymph nodes harvested, complications, and recovery). The study was powered to show at least a 25% difference in the operation time using 2-sided significance level of .05. The differences between the traditional laparoscopy and the robotic surgery groups were tested by Pearson χ 2 test, Fisher exact test, or Mann-Whitney test., Results: In all, 99 patients were eligible for analysis. The median operation time in the traditional laparoscopy group (n = 49) was 170 (range 126-259) minutes and in the robotic surgery group (n = 50) was 139 (range 86-197) minutes, respectively (P < .001). The total time spent in the operating room was shorter in the robotic surgery group (228 vs 197 minutes, P < .001). In the traditional laparoscopy group, there were 5 conversions to laparotomy vs none in the robotic surgery group (P = .027). There were no differences as to the number of lymph nodes removed, bleeding, or the length of postoperative hospital stay. Four (8%) vs no (0%) patients (P = .056) had intraoperative complications and 5 (10%) vs 11 (22%) (P = .111) had major postoperative complications in the traditional and robotic surgery groups, respectively., Conclusion: In patients with endometrial cancer, robotic-assisted laparoscopic surgery was faster to perform than traditional laparoscopy. Also total time spent in the operation room was shorter in the robotic surgery group and all conversions to laparotomy occurred in the traditional laparoscopy group. Otherwise, the surgical outcome was similar between the groups. Robotic surgery offers an effective and safe alternative in the surgical treatment of endometrial cancer., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: ERRs (estrogen-related receptors) regulate energy metabolism, the cell cycle and inflammatory processes in both normal and cancer cells. Chronic inflammation induced by lichen sclerosus (LS) or human papilloma virus (HPV) precedes vulvar squamous cell carcinoma (vulvar SCC). We investigated the expression of ERRα, ERRβ and ERRγ in normal vulvar skin, LS as well as LS-dependent and LS-independent/HPV-related vulvar SCC., Methods: A total of 203 samples were analyzed for ERRα, ERRβ and ERRγ by using immunohistochemistry. These included 37 normal vulvar skin samples, 110 LS samples, 6 vulvar intraepithelial neoplasia (VIN) samples and 50 vulvar SCC samples., Results: A substantial reduction in or disappearance of ERRα was detected in all vulvar SCC samples. A total of 79% of childhood-onset LS and 51% of adulthood-onset LS lesions showed decreases in ERRα staining. A gradual reduction in ERRα cytoplasmic staining was observed from healthy vulvar skin to precursor lesions and further to SCC. Nuclear ERRα staining was observed in 8/33 (24%) LS-dependent and 10/17 (59%) LS-independent SCC samples., Conclusions: ERRα, a key regulator of cell energy metabolism, may play a role in the pathogenesis of both LS and vulvar SCC., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: To investigate the initial experience with robotic-assisted laparoscopic surgery in gynecologic oncology., Design: A retrospective survey., Setting: Tertiary referral center., Population: The first 300 patients operated on using robotic assistance at the Department of Obstetrics and Gynecology of Tampere University Hospital, from March 2009 through January 2013., Methods: Retrospective patient chart review., Main Outcome Measures: The primary outcome measure was the learning curve events, and the complication and conversion rates were secondary outcome measures., Results: The commonest type of operation was hysterectomy, bilateral salpingoophorectomy and pelvic lymphadenectomy (LH + BSO + PLND, n = 89), followed by the same procedure amended by para-aortic lymphadenectomy (PALND, n = 74), type II radical hysterectomy (n = 24), and PLND + PALND ± omentectomy (n = 15). A learning curve was most evident for LH + BSO + PLND: whereas the median operative time of all 89 operations was 167 min (range 403-104), it was 260 (range 403-135) and 153 (range 247-104) min in the case of the first and last 20 operations, respectively. The learning curve was short, or 10 procedures. A learning curve was also seen for the preoperative time in the operation room and for the number of lymph nodes harvested. The median blood loss during all 300 operations was 100 mL (range 5-3200). The median postoperative hospital stay was 1 day. The conversion rate was 4.0%, and the complication rate 19.3% (major in 9%)., Conclusion: The learning curve of robotic-assisted laparoscopic surgery appears to be short, or 10 operations. Robotic-assisted procedures seem to offer a safe and useful alternative to traditional techniques., (© 2015 Nordic Federation of Societies of Obstetrics and Gynecology.)

Preoperative evaluation of the risk for metastases in endometrial carcinoma is challenging. The growth of new vessels, angiogenesis, is important for tumor growth and purported to be involved in the metastatic process. The aim of this study was to evaluate the significance of preoperative serum levels and immunohistochemical expression of angiogenic markers in predicting a metastasized disease. Preoperative sera from 98 consecutive women presenting with endometrial carcinoma were collected. Serum concentrations of VEGF, sFLT1, and CD105 were assessed by enzyme-linked immunosorbent assay (ELISA). Immunohistochemistry was used to assess the expression of CD105, VEGF, FLT1, and KDR. The results were correlated to the presence of metastases, presence of deep (≥50%) myometrial invasion, and the histological grade of the tumor. Tumors with other than endometrioid histology were excluded. Of the 80 evaluable patients, 11 had a metastasized disease. The serum concentration of VEGF was higher in the group with metastases than in the group without metastases (median [range], 743 pg/mL [546-1,183 pg/mL] vs. 383 pg/mL [31-1,524 pg/mL], p < 0.001, respectively). In the multivariable analysis, the concentration of VEGF was the sole independent, albeit weak predictive factor for the presence of metastases (odds ratio, 1.004, 95% confidence interval, 1.002-1.007; p = 0.001). The immunohistochemical expression of the markers was not associated with any of the clinicopathological features of the tumors. The results of the present study suggest that preoperative serum VEGF concentration correlates with the presence of metastases in endometrioid endometrial carcinoma.

Objective: The purpose of this study was to evaluate the performance of preoperative serum levels of human epididymis protein 4 (HE4) and cancer antigen 125 (CA125) in the prediction of the presence of metastases in endometrial carcinoma., Study Design: Preoperative sera were collected from 98 women with a diagnosis of endometrial carcinoma. The concentrations of HE4 and CA125 were assessed by enzyme-linked immunosorbent assay and correlated with the results of the final histopathologic report., Results: Fourteen patients had metastases (≥stage IIIA, International Federation of Gynecology and Obstetrics 2009 classification). The serum concentrations of HE4 and CA125 were higher in the group with metastases than in the group without metastases (median [interquartile range], 148.6 pmol/L [71.6-219.1 pmol/L] vs 77.2 pmol/L [52.9-99.3 pmol/L]; P = .001; and 20.0 U/mL [10.1-70.8 U/mL] vs 4.3 U/mL [2.9-10.4 U/mL]; P < .001, respectively). By a multivariate analysis, the combination of HE4 and CA125 (a risk score algorithm) was the only predictive factor for the presence of metastases (odds ratio, 21.562; 95% confidence interval, 5.472-84.963; P < .001), and the grade was the predictor for a deep (≥50%) myometrial invasion by the tumor (odds ratio, 2.005; 95% confidence interval, 1.123-3.581; P = .019). The sensitivity, specificity, positive predictive value, and negative predictive value for the combination of the markers to predict the presence of metastases were 71.4%, 89.5%, 55.6%, and 94.4%, respectively., Conclusion: A combination of preoperative HE4 and CA125 seems to be a better predictor of metastatic disease than either 1 alone in endometrial carcinoma., (Copyright © 2013 Mosby, Inc. All rights reserved.)

Objective: To evaluate the usefulness of three-dimensional ultrasound (3D US), magnetic resonance imaging (MRI) and three-dimensional power Doppler angiography (3D-PDA) in the preoperative assessment of myometrial invasion in endometrial carcinoma., Design: A prospective observational study., Setting: University hospital., Population: Twenty consecutive patients diagnosed with endometrial carcinoma., Methods: Preoperative 3 T MRI and 3D US examinations were performed, and the depth of myometrial invasion was assessed. The vascularity indices, vascularization index, flow index and vascularization flow index, were calculated by 3D-PDA., Main Outcome Measures: The results were compared with the final histopathology report after a surgical staging., Results: In detecting deep myometrial invasion, the sensitivity of 3D US, MRI and their combination was 50, 91.7 and 100%, respectively. The specificity was 87.5, 50 and 50%, respectively. There were no significant differences in the 3D-PDA vascularity indices between the two groups., Conclusions: MRI appears to be more sensitive than 3D US in detecting deep invasion, while 3D US has a better specificity., (© 2012 The Authors Acta Obstetricia et Gynecologica Scandinavica© 2012 Nordic Federation of Societies of Obstetrics and Gynecology.)

Objective: Preoperative evaluation of the depth of myometrial invasion in endometrial carcinoma is challenging. The objective of this study was to evaluate the usefulness of three-dimensional power Doppler angiography (3D-PDA) in this setting., Methods: Sonographic and histological data on 100 consecutive cases of endometrial carcinoma were analyzed. The endometrial and myometrial vascular indices VI (vascularization index), FI (flow index) and VFI (vascularization flow index) were calculated by 3D-PDA. The results were compared with a complete surgical staging., Results: The mean ( ± SD) age of patients was 67.1 ± 8.8 (range, 33-87) years. Forty-six patients had deep (≥ 50%) myometrial invasion. Eight patients had metastases, seven of them with deep invasion. Three patients were found to have carcinomas of non-uterine origin on histology, and these were excluded from further statistical analysis. The median endometrial and myometrial vascular indices were higher in the group with deep invasion than in the group without. Following multivariable analysis of the indices only the endometrial FI was independently associated with deep invasion (OR, 1.061; 95% CI, 1.023-1.099; P = 0.001). However, a greater endometrial volume was also an independent predictor of deep invasion (OR, 1.109; 95% CI, 1.011-1.215; P = 0.028)., Conclusion: Our study suggests that endometrial and, to a lesser degree, myometrial vascular indices and endometrial volume correlate with the depth of myometrial invasion in endometrial carcinoma., (Copyright © 2012 ISUOG. Published by John Wiley & Sons, Ltd.)

Aims: To find out if there is any link between the therapeutic effect of toremifene on premenstrual mastalgia and luteal phase serum inhibin A and/or B levels., Methods: Forty-eight patients participating in a randomized cross-over trial on toremifene vs. placebo for premenstrual mastalgia gave three blood samples during the luteal phase of the menstrual cycle: the first at baseline, the second during the third toremifene/placebo cycle, and the third during the third placebo/toremifene cycle, respectively. The blood samples were analyzed for inhibin A and B with respective specific two-site enzyme-linked immunosorbent assays. Toremifene (20 mg/d) and placebo were administered during the luteal phase only., Results: When all the toremifene-treated cycles were compared with all the placebo cycles and with the baseline, the median inhibin A levels were 42, 38, and 40 pg/ml, respectively (baseline versus toremifene, p = 0.638; baseline versus placebo, p = 0.468; and toremifene versus placebo, p = 0.365). The median inhibin B levels were at baseline 19 ng/l, during placebo 20 ng/l, and during toremifene 17 ng/l (baseline versus toremifene, p = 0.983; baseline versus placebo, p = 0.519; and toremifene versus placebo, p = 0.880)., Conclusion: A luteal administration of toremifene does not seem to result in any changes in mid-luteal concentrations of inhibin A or B in serum.

We analyzed retrospectively the outcome of 15 patients treated with pelvic exenteration (nine total and six anterior) for gynecological cancer (six vaginal, four endometrial, three cervical, one vulvar, and one ovarian) from 1987 through 2008. Four operations were for primary tumors and 11 for recurrences. Eight patients had received prior radiotherapy. Median operation time was 310 (range 180-520) min, and median blood loss was 2,500 (range 600- 8,000) mL. Thirteen patients had altogether 59 postoperative complications, 25 (42%) early and 34 (58%) late. One patient each died of complications during the early and late postoperative phases, respectively. Both had received previous radiotherapy. By 31 January 2009, six patients had died, while five and four patients were alive with or without disease, respectively. Only one pelvic recurrence was found. The median progression-free survival was 8.9 months. Although pelvic exenteration was not totally devoid of mortality, the procedure provided a good local control, with mostly manageable complications.

Background: There is growing interest to apply the sentinel node technique in the treatment of vulvar cancer., Methods: All charts of the patients operated on for vulvar cancer at Tampere University Hospital from January 1, 2001 through June 30, 2005 were retrospectively reviewed. Demographic, clinical, and histopathological information was collected from each patient. The sentinel lymph node mapping was done intraoperatively either with a combination of the radioisotope and dye techniques (40 patients) or with the dye technique alone (7 patients). The sentinel lymph node was dissected separately for histopathological evaluation, and then a routine inguinal lymphadenectomy was performed., Results: The final FIGO surgical Stage distribution was: Stage I, 11 (23%); Stage II, 14 (30%); Stage III, 21 (45%); and Stage IV, 1 (2%). Sentinel lymph node was identified in 46 (98%) women with either one or both of the methods. In Stage I-II, the sentinel lymph node identification rate was 25/25 (100%) with the combined method. The only patient with unidentified sentinel lymph node had lymphatic spread beyond inguinal area or Stage IV disease. Eighteen of the sentinel lymph nodes (39%) were positive for tumor cells, and in 5 cases additional metastatic nodes were found. One patient with macroscopically enlarged metastatic inguinal nodes and Stage III disease had a negative sentinel lymph node. In the 25 patients with Stage I-II disease, the false-negative rate of the sentinel lymph node method was 0/4, giving a negative predictive value of 1.00., Conclusions: A sentinel node identification rate of 98% with a false-negative rate of 0% in the patients with Stage I-II disease is an encouraging finding.

Objective: To determine the feasibility and efficacy of sequential gemcitabine-carboplatin followed by paclitaxel-carboplatin in the first-line treatment of advanced epithelial ovarian cancer, with the response rate as the primary endpoint., Methods: After primary laparotomy, 56 patients with FIGO Stages III-IV disease were given 4 cycles of gemcitabine 1000 mg/m2 d1,8 and carboplatin AUC5 (44 patients) or AUC6 (12 patients) d1 q3wk followed by 4 cycles of paclitaxel 175 mg/m2 d1 and carboplatin AUC5/6 q3wk. Of the tumors, 43 were serous, 6 clear cell, 4 endometrioid, and 3 anaplastic type. Thirty-seven (66.1%) of the patients were suboptimally debulked., Results: Forty-seven patients were evaluable for response by CA-125 criteria, and 46 (98%) responded. Thirty patients (after gemcitabine-carboplatin) and 24 (after paclitaxel-carboplatin) were evaluable for response by CT (RECIST criteria), respectively. After the four gemcitabine-carboplatin cycles, the objective response rate was 83% (6 CR, 19 PR). Following completion of the whole sequential regimen, 7 patients showed a CR and 15 a PR, respectively, giving a response rate of 92%. The median progression-free survival was 12.8 months after a median follow-up of 19 months (range 7-35 months). The median overall survival has not been reached yet. The main toxicity was neutropenia as 139/221 (62.9%) of the gemcitabine-carboplatin cycles and 92/181 (50.8%) of the paclitaxel-carboplatin cycles, respectively, were associated with Grades 3-4 neutropenia. Neutropenia was reported as a serious adverse event in 5.7% of the cycles, and G-CSF support was needed in 18.4% of the cycles. Only the gemcitabine-carboplatin cycles were associated with a marked thrombocytopenia (32.1% Grades 3-4). Of the other side effects, marked allergy occurred in 14/52 (27%) exposed to paclitaxel. A total of 14 patients discontinued the treatment prematurely: 3 due to lack of efficacy, 1 due to protocol violation, and 10 due to toxicity (4 allergic reactions to paclitaxel, 3 complicated neutropenias, 1 fever, and 2 unspecified toxicities). The mean relative dose intensities were: gemcitabine 84.0%, paclitaxel 85.4%, and carboplatin 96.5%. Of the gemcitabine-carboplatin cycles and paclitaxel-carboplatin cycles, 32% and 38% were delayed, respectively. Gemcitabine d8 dose had to be omitted in 8% of the cycles., Conclusion: The sequential regimen of gemcitabine-carboplatin followed by paclitaxel-carboplatin is feasible in chemotherapy-naive ovarian cancer. Although its use is associated with a marked neutropenia, the neutropenia is manageable.

Despite considerable progress over the past two decades in the management of advanced ovarian cancer, the majority of patients with this type of malignancy still die from their disease, and the search for new and improved first-line and salvage chemotherapy regimens continues. As part of this work, the antitumour activity and effect on survival of new chemotherapy combinations containing the novel taxane docetaxel are being explored. Dual therapy with docetaxel plus a camptothecin (a topoisomerase inhibitor) has shown promise in second-line treatment, and preliminary data indicate good activity of docetaxel in combination with gemcitabine. Triple-therapy studies have produced mixed results, but encouraging activity has been reported when the anthracycline, epirubicin, is added to docetaxel and carboplatin - sequential therapy with docetaxel, cisplatin and epirubicin is currently being assessed. Combinations of docetaxel, carboplatin and gemcitabine may also be of future interest. Early efficacy and tolerability results with novel combination chemotherapy regimens involving docetaxel thus offer the promise of additional progress in the chemotherapy of advanced ovarian cancer, and further trials should be encouraged.

The purpose of the present study was to evaluate the tissue distribution of toremifene (TOR) in baboons following intra-tissue injections and to examine the effectiveness of intratumoral TOR therapy of baboons with various spontaneous neoplasms. Five healthy baboons (Papio sp.) were used to examine the distribution of TOR following intra-tissue injections. Twenty-three different tissue specimens were collected for HPLC analysis. In addition, four baboons with various spontaneous neoplasms (myxoma, squamous cell carcinoma, lymphosarcoma and adenocarcinoma) were treated with intratumoral TOR and their responses were evaluated. Tissue TOR distribution was also examined in these animals. In the tissue distribution study, target tissue/serum TOR concentration ratios ranged from 138 to 8873 and the target tissue/other tissue ratios ranged from 1.2 to 2428. The distribution of TOR was very favorable, with the highest concentrations outside the injection sites noted in adjacent organs. A marked response was observed in the myxoma and partial responses were observed in the other three cases. Drug level analysis data from these four animals revealed tissue concentrations similar to those seen in the TOR tissue distribution study. Intratumoral administration of TOR can achieve effective local tumor and tissue concentrations, while systemic distribution via circulation to other organs is limited.

Toremifene is a chlorinated tamoxifen analogue that is indicated for the treatment of postmenopausal hormone-dependent breast cancer. It competes with estradiol for estrogen receptors and has growth-inhibitory effects on MCF-7 breast cancer cells. At concentrations < 10(-6) mol/L, this growth inhibition can be reversed by estradiol, but at higher concentrations toremifene is cytotoxic. In dimethylbenzanthracene (DMBA)-induced mammary cancer in rats, toremifene has been shown to decrease the number of new tumours and to inhibit the growth of existing tumours. Toremifene causes growth inhibition by suppressing mitosis and inducing apoptosis. The mechanism by which these events occur may involve the induction of transforming growth factor-beta 1 and inhibition of insulin-like growth factor-1 (mecasermin). Toremifene is primarily an antiestrogen, but it has some estrogen agonist properties in postmenopausal women. The latter are reflected by the fall in luteinising hormone and follicle-stimulating hormone levels and the rise in sex hormone-binding globulin levels that are associated with its use in most women. After estrogen priming, toremifene 68mg administered orally has been found to exert a similar antiestrogenic effect on the vaginal epithelium in postmenopausal women as tamoxifen 60mg. The half-life of toremifene in plasma is 5 days, and the drug is > 99% bound to plasma proteins. The main metabolites of toremifene are N-demethyl-toremifene and deaminohydroxy-toremifene. Altered liver, but not kidney, function affects the pharmacokinetics of toremifene. Toremifene 60mg daily is as effective as tamoxifen 20mg daily in the treatment of postmenopausal hormone-dependent breast cancer, producing a response in about 50% of patients. Soft tissue and visceral metastases respond better to toremifene than bone metastases. Most of the adverse effects of toremifene are related to its activity at estrogen receptors and include hot flashes, vaginal discharge and nausea. Although toremifene decreases antithrombin III levels slightly, the incidence of thromboembolic complications is low. Thus far, no carcinogenic effects have been noted in humans, and preclinical data are mostly reassuring. Toremifene has favourable effects on serum lipids, and thus has potential in preventing coronary heart disease. Although toremifene is somewhat more expensive to use than tamoxifen, toremifene is an effective and well tolerated alternative to tamoxifen in the treatment of postmenopausal women with hormone-dependent breast cancer. No formal pharmacoeconomic comparisons of toremifene and tamoxifen have yet been published. Toremifene is potentially safer than tamoxifen in relation to carcinogenic effects and effects on serum lipids.

Purpose: Toremifene is an orally administered triphenylethylene derivative with antiestrogenic activity that is primarily used in the treatment of patients with metastatic breast cancer. The purpose of this study was to evaluate the therapeutic advantage of local (transdermal) administration of toremifene in several animal models. Local (subcutaneous and skin) versus systemic concentrations of toremifene were evaluated serially following transdermal application of the drug. With high local concentrations and minimal distribution to other organs via the circulation, topical toremifene may deliver maximal therapeutic effects to local tissue while avoiding the side effects seen with systemic therapy., Methods: Three animal models (nude mice, baboons, and a horse) were used to examine topically administered toremifene for kinetic measurements., Results: In nude mice implanted subcutaneously with MDA-MB-231 human breast tumors, topical toremifene (2.5 mg/day x 5 days) produced greater than 50-fold higher tumor concentrations compared with intraperitoneal (i.p.) administration (1.0 mg/day x 5 days). Systemic distribution in plasma, uterus, and liver was lower following topical than following i.p. administration. In nude mice inoculated subcutaneously with estrogen receptor-positive (ER +) MCF-7 human breast cancer cells, topical toremifene and 4-hydroxytoremifene (4-OH) prevented tumor growth in the presence of estradiol. In four nontumor-bearing baboons that were given transdermal toremifene, relatively high distribution of drug was noted in normal breast tissue and fat, compared with undetectable serum concentrations. Finally, a new topical formulation of toremifene (a gel preparation for human use, Orion-Farmos, Finland) achieved high local tumor toremifene concentrations in a horse melanoma, with minimal systemic distribution., Conclusions: Transdermal toremifene can achieve high local tissue concentrations with minimal systemic distribution.

In order to find out whether the response rate and survival in epithelial ovarian cancer can be improved by aid of sensitivity testing with the subrenal capsule assay (SRCA), 196 patients with FIGO Stage II-IV epithelial ovarian cancer were randomized to be treated with either cyclophosphamide-doxorubicin-cisplatin (CAP) or SRCA-guided chemotherapy. The drug combinations tested with the SRCA were (1) cyclophosphamide-doxorubicin-carboplatin (CACAR), (2) CAP, (3) carboquone-methotrexate-tegafur (CQ-MTX-TEG), (4) cisplatin-etoposide-hexamethyl-melamine (P-VP-HXM), and (5) bleomycin-epirubicin-cisplatin (BEP). A total of 132 patients (CAP, 69; SRCA, 63) were eligible for efficacy analysis based on relaparotomy findings. The overall response rate was 59% in the CAP arm and 62% in the SRCA arm. In the SRCA arm, 16 patients were treated with CACAR, 24 with CAP, 10 with CQ-MTX-TEG, 11 with P-VP-HXM, and 2 with BEP. The response rate to CACAR was 63% and to SRCA-CAP was 75%. The number of complete responses was higher when CAP was given as guided by the assay than when given at random (14/24 vs 23/69; P = 0.03, Pearson chi 2). Survival curves as estimated by Kaplan-Meier method gave a median survival of 24 (SE = 4) months to the SRCA arm and 28 (SE = 5) for the CAP arm (P = 0.7; log-rank test). Because no survival benefit was achieved, the SRCA obviously needs further development before it can be routinely recommended in the choice of first-line chemotherapy for patients with ovarian cancer.

The subrenal capsule assay (SRCA) was used to study the sensitivity of breast cancer to cytostatic drug combinations. The results were compared with steroid receptor status. Forty-five of 46 SRCAs (98%) were macroscopically evaluable. However, a histological study implied that the transplants should also be evaluated histologically, because in only 14/21 (67%) of the control SRCAs examined were histologically viable tumor cells seen. An inflammatory cell reaction was noticed in half of the cases. In the groups treated with cytostatics only 3/21 (14%) had vital tumor cells, whereas inflammation was evident in 4/21 (19%) of the cases. The rate of resistance to A + CTX was 30%. By testing several drug combinations against each tumor the rate of chemoresistance was reduced to 10%. The differences between A + CTX and the best combination were statistically significant (P less than 0.05). Of the tumors 79% were ER-positive and 67% PR-positive. Receptor-negative tumors tended to be more sensitive to cytostatics than receptor-positive tumors (100 vs 85%). The difference was not, however, statistically significant. It can be concluded that the SRCA under standardized conditions is a good method for studying the response of individual breast cancers to chemotherapy.