Does vaginal bacterial colonization contribute to preterm birth in women with asymptomatic shortened cervix?

PURPOSE: The aim of this study is to describe the typical microbial spectrum and the influence of distinct vaginal infections on preterm birth in pregnancies affected by cervical incompetence. METHODS: 327 patients were admitted because of asymptomatic shortening of the cervix in the second and third trimester of pregnancy. Clinical data such as age, cervical length, gestational age at admission and at delivery and vaginal microbiologic findings were collected and analyzed. RESULTS: The spectrum of germs in the vagina revealed seven different distinct species; the most common bacteria were Ureaplasma spp. and E. coli. In 327 included patients, 217 revealed a bacterial colonization, 110 did not. Most common bacteria in women with preterm birth before 34 weeks were Ureaplasma spp., while E. coli was most common in women undergoing preterm birth after 34 weeks. Nevertheless, the rates of occurrence of these bacterial taxa were not significantly different between who underwent preterm birth to those who did not. CONCLUSIONS: This study gives an overview over the vaginal bacterial colonization in pregnant women with cervical incompetence. The clinical relevance of vaginal bacterial colonization remains unclear.

Depression and anxiety in women with malignant ovarian germ cell (MOGCT) and sex cord stromal tumors (SCST): an analysis of the AGO-CORSETT database.

INTRODUCTION: The intention of this study was to evaluate the level of anxiety and depression of malignant ovarian germ cell (MOGCT) and sex cord stromal tumors (SCST) survivors and to identify possible alterable cofactors. METHODS: CORSETT was an observational, multicenter, mixed retrospective/prospective cohort study of the AGO Studygroup. Women who had been diagnosed with MOGCTs and SCSTs between 2001 and 2011 were asked to complete the Hospital Anxiety and Depression Scale (HADS) to evaluate distress. Predictors of distress (type of surgery, chemotherapy, time since diagnosis, recurrence, second tumor, pain) were investigated using multivariate linear regression analysis. RESULTS: 150 MOGCT and SCST patients with confirmed histological diagnosis completed the questionnaire median seven years after diagnosis. They had a HADS total score ≥ 13 indicating severe mental distress in 34% of cases. Patients after fertility-conserving surgery had lower probability of severe mental distress than those without fertility-conserving treatment (ß = - 3.1, p = 0.04). Pain was associated with the level of distress in uni- and multivariate analysis (coef 0.1, p < 0.01, coef. Beta 0.5). DISCUSSION: Severe mental distress was frequent in patients with MOGCT and SCST and the level of pain was associated with the level of distress. Fertility conserving therapy, however, was associated with less mental distress. Screening and treatment of pain and depression is required to improve mental well-being in survivors of MOGCT and SCST.

Post-traumatic stress disorder following childbirth: prevalence and associated factors-a prospective cohort study.

OBJECTIVE: Traumatic experiences during or after childbirth are subject of intense discussions in mainstream and social media as well as in scientific literature. Aim of this evaluation is to estimate the prevalence of post-traumatic stress disorder (PTSD) following childbirth in postpartum women and to evaluate the influence of maternal, obstetrical and neonatal characteristics on the degree of PTSD symptoms measured by the Impact of Events Scale questionnaire (IES-R). METHODS: In total, 589 women who gave birth in the University Medical Center Mainz, Germany in 2016, participated in a survey within the first days after birth. Of these, 278 also participated 6 months later. All participants received the validated Impact of Events Scale questionnaire (IES-R). The influence of maternal, obstetric and fetal parameters on PTSD score was evaluated. RESULTS: PTSD overall prevalence was 2.9%. Patients with PTSD had significantly less often personal support during labor (p < 0.001). Maternal age (p < 0.001), parity (p < 0.001), migration background (p < 0.001), mode of delivery (p < 0.001) and assistance during labor (p < 0.001) were parameters significantly influential on the PTSD symptom level measured by the IES-R. CONCLUSIONS: Maternal PTSD prevalence after childbirth seems to be quite rare with 2.9%. Nevertheless, recent findings assume that this prevalence may only represent the "tip of the iceberg". PTSD after childbirth should not be underestimated. As PTSD depends on personal vulnerability and existing risk factors, patients at risk have to be detected before childbirth, which appears to be challenging especially for obstetric and family care professionals.

Biomarker-based early detection of epithelial ovarian cancer based on a five-protein signature in patient's plasma - a prospective trial.

BACKGROUND: Trial on five plasma biomarkers (CA125, HE4, OPN, leptin, prolactin) and their possible role in differentiating benign from malignant ovarian tumors. METHODS: In this unicentric prospective trial preoperative blood samples of 43 women with ovarian masses determined for ovarian surgery were analyzed. 25 patients had pathologically confirmed benign, 18 malignant ovarian tumors. Blood plasma was analyzed for CA125, HE4, OPN, leptin, prolactin and MIF by multiplex immunoassay analysis. Each single protein and a logistical regression model including all the listed proteins were tested as preoperative predictive marker for suspect ovarian masses. RESULTS: Plasma CA125 was confirmed as a highly accurate tumor marker in ovarian cancer. HE4, OPN, leptin and prolactin plasma levels differed significantly between benign and malignant ovarian masses. With a logistical regression model a formula including CA125, HE4, OPN, leptin and prolactin was developed to predict malignant ovarian tumors. With a discriminatory AUC of 0.96 it showed to be a highly sensitive and specific diagnostic test for a malignant ovarian tumor. CONCLUSIONS: The calculated formula with the combination of CA125, HE4, OPN, leptin and prolactin plasma levels surpasses each single marker in its diagnostic value to discriminate between benign and malignant ovarian tumors. The formula, applied to our patient population was highly accurate but should be validated in a larger cohort. TRIAL REGISTRATION: Clinical Trials.gov under NCT01763125 , registered Jan. 8, 2013.

Genetic findings in miscarriages and their relation to the number of previous miscarriages.

PURPOSE: Early pregnancy loss leads to a devastating situation for many couples. Genetic disorders found in the pregnancy tissue are a frequent cause of miscarriages. It is unclear whether maternal age or previous miscarriages are associated with a higher chromosomal anomaly rate. This study aimed to determine the cytogenetical distribution of chromosomal disorders in couples after one or more previous miscarriages as well as the influence of maternal age. METHODS: 406 fetal tissue samples obtained after spontaneous abortion between 2010 and 2014 were successfully karyotyped. This included 132 couples with at least two losses and 274 couples with sporadic miscarriage. Normal and abnormal karyotype rate was determined for age, parity, gravidity, gestational week and number of previous miscarriages by logistic regression analysis. RESULTS: 145 (35.71%) fetal tissue samples had a normal karyotype, and 261 (64.8%) did not. After adjusting for age, older patients have a statistically significantly higher probability of genetic disorders in the pregnancy tissue (p < 0.001, OR 1.064, 95% CI 1.03-1.11). With each additional year, the probability of finding chromosomal abnormalities in a miscarriage increased by 6.4%. Patients younger than 35 years have a lower probability of having chromosomal disorders in the aborted material after two or more miscarriages than after sporadic miscarriages (50.7 vs. 58.9%) (p = 0.014, OR 0.67, 95% CI 0.48-0.914). Nevertheless, the risk of embryonic chromosomal disorders in patients aged 35 and above increased from 75.5% in sporadic miscarriages to 82.4% after more than one pregnancy losses (p = 0.59, OR 1.14, 95% CI - 0.72 to 1.92). CONCLUSION: Chromosomal disorders found after one or more previous miscarriages are related to patients' age. Couples suffering two or more miscarriages should be further researched, especially in younger patients.

Low-dose metronomic chemotherapy as an efficient treatment option in metastatic breast cancer-results of an exploratory case-control study.

PURPOSE: There is growing interest in low-dose metronomic chemotherapy (LDMC) in metastatic breast cancer (MBC). In this retrospective case-control analysis, we compared the efficacy of LDMC and conventional chemotherapy (CCT) in MBC. METHODS: Each LDMC patient receiving oral cyclophosphamide (CTX) (50 mg daily) and methotrexate (MTX) (2.5 mg every other day) was matched with two controls who received CCT. Age, number of chemotherapy lines and metastatic sites as well as hormone receptor (HR) status were considered as matching criteria. Primary endpoint was disease control rate longer than 24 weeks (DCR). Secondary endpoints were progression-free survival (PFS), duration of response (DoR) and subgroup analyses using the matching criteria. RESULTS: 40 cases and 80 controls entered the study. 30.0% patients with LDMC and 22.5% patients with CCT showed DCR (p = 0.380). The median PFS was 12.0 weeks in both groups (p = 0.218) and the median DoR was 31.0 vs. 20.5 weeks (p = 0.383), respectively. Among younger patients, DCR was 40.0% in LDMC vs. 25.0% in the CCT group (p = 0.249). DCR was achieved in 33.3% vs. 26.2% non-heavily pretreated patients (p = 0.568) and in 36.0% vs. 18.0% patients without multiple metastases (p = 0.096), respectively. In the HR-positive group, 30.0% LDMC vs. 28.3% CCT patients showed DCR (p = 1.000). Among triple-negative patients, DCR was achieved in 30.0% LDMC and 5.0% CCT patients (p = 0.095). CONCLUSIONS: We demonstrated a similar efficacy of LDMC compared to CCT in the treatment of MBC. Thus, LDMC may be a valuable treatment option in selected MBC patients.

EndoPredict® in early hormone receptor-positive, HER2-negative breast cancer.

PURPOSE: Evaluating consecutive early breast cancer patients, we analyzed both the impact of EndoPredict® on clinical decisions as well as clinico-pathological factors influencing the decision to perform this gene expression test. METHODS: Hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative early breast cancer patients treated between 2011 and 2016 were included in this study to investigate the role of EndoPredict® (EPclin) in the treatment of early breast cancer. A main study aim was to analyze the changes in therapy recommendations with and without EPclin. In addition, the impact of clinico-pathological parameters for the decision to perform EPclin was examined by Pearson's chi-squared test (χ2-test) and Fisher's exact test as well as univariate and multivariate logistic regressions. RESULTS: In a cohort of 869 consecutive early HR-positive, HER-negative breast cancer patients, EPclin was utilized in 156 (18.0%) patients. EPclin led to changes in therapy recommendations in 33.3% (n = 52), with both therapy escalation in 19.2% (n = 30) and de-escalation in 14.1% (n = 22). The clinico-pathological factors influencing the use of EPclin were age (P < 0.001, odds ratio [OR] 0.498), tumor size (P = 0.011, OR 0.071), nodal status (P = 0.021, OR 1.674), histological grade (P = 0.043, OR 0.432), and Ki-67 (P < 0.001, OR 3.599). CONCLUSIONS: EPclin led to a change in therapy recommendations in one third of the patients. Clinico-pathological parameters such as younger age, smaller tumor size, positive nodal status, intermediate histological grade and intermediate Ki-67 had a significant influence on the use of EndoPredict®.

Gynecologic cancers in pregnancy: guidelines based on a third international consensus meeting.

We aimed to provide comprehensive protocols and promote effective management of pregnant women with gynecological cancers. New insights and more experience have been gained since the previous guidelines were published in 2014. Members of the International Network on Cancer, Infertility and Pregnancy (INCIP), in collaboration with other international experts, reviewed existing literature on their respective areas of expertise. Summaries were subsequently merged into a manuscript that served as a basis for discussion during the consensus meeting. Treatment of gynecological cancers during pregnancy is attainable if management is achieved by collaboration of a multidisciplinary team of health care providers. This allows further optimization of maternal treatment, while considering fetal development and providing psychological support and long-term follow-up of the infants. Nonionizing imaging procedures are preferred diagnostic procedures, but limited ionizing imaging methods can be allowed if indispensable for treatment plans. In contrast to other cancers, standard surgery for gynecological cancers often needs to be adapted according to cancer type and gestational age. Most standard regimens of chemotherapy can be administered after 14 weeks gestational age but are not recommended beyond 35 weeks. C-section is recommended for most cervical and vulvar cancers, whereas vaginal delivery is allowed in most ovarian cancers. Breast-feeding should be avoided with ongoing chemotherapeutic, endocrine or targeted treatment. More studies that focus on the long-term toxic effects of gynecologic cancer treatments are needed to provide a full understanding of their fetal impact. In particular, data on targeted therapies that are becoming standard of care in certain gynecological malignancies is still limited. Furthermore, more studies aimed at the definition of the exact prognosis of patients after antenatal cancer treatment are warranted. Participation in existing registries (www.cancerinpregnancy.org) and the creation of national tumor boards with multidisciplinary teams of care providers (supplementary Box S1, available at Annals of Oncology online) is encouraged.

Subtype-specific prognostic impact of different immune signatures in node-negative breast cancer.

BACKGROUND: The role of different subtypes of immune cells is still a matter of debate. METHODS: We compared the prognostic relevance for metastasis-free survival (MFS) of a B-cell signature (BS), a T-cell signature (TS), and an immune checkpoint signature (CPS) in node-negative breast cancer (BC) using mRNA expression. Microarray-based gene-expression data were analyzed in six previously published cohorts of node-negative breast cancer patients not treated with adjuvant therapy (n = 824). The prognostic relevance of the individual immune markers was assessed using univariate analysis. The amount of independent prognostic information provided by each immune signature was then compared using a likelihood ratio statistic in the whole cohort as well as in different molecular subtypes. RESULTS: Univariate Cox regression in the whole cohort revealed prognostic significance of CD4 (HR 0.66, CI 0.50-0.87, p = 0.004), CXCL13 (HR 0.86, CI 0.81-0.92, p < 0.001), CD20 (HR 0.76, CI 0.64-0.89, p = 0.001), IgκC (HR 0.81, CI 0.75-0.88, p < 0.001), and CTLA-4 (HR 0.67, CI 0.46-0.97, p = 0.032). Multivariate analyses of the immune signatures showed that both TS (p < 0.001) and BS (p < 0.001) showed a significant prognostic information in the whole cohort. After accounting for clinical-pathological variables, TS (p < 0.001), BS (p < 0.05), and CPS (p < 0.05) had an independent effect for MFS. In subgroup analyses, the prognostic effect of immune cells was most pronounced in HER2+ BC: BS as well as TS showed a strong association with MFS when included first in the model (p < 0.001). CONCLUSION: Immune signatures provide subtype-specific additional prognostic information over clinical-pathological variables in node-negative breast cancer.

How common is ballooning? Hiatal area on 3D transperineal ultrasound in urogynecological patients and its association with lower urinary tract symptoms.

INTRODUCTION: Pelvic floor ultrasound plays a major role in urogynecologic diagnostics. Using 3D ultrasound we can identify integrity of levator ani and measure hiatal area in the axial plane. The main goal of our study was to measure hiatal area on Valsalva in a cohort of urogynecological patients. Furthermore, we aimed to correlate hiatal area with urogynecological symptoms, levator integrity and evaluate cut-off values for pelvic organ prolapse. MATERIALS AND METHODS: In a retrospective analysis, we included 246 patients seen for urogynecological problems in our tertiary urogynecological unit. After a standardized interview and physical examination, a 3D pelvic floor ultrasound was performed. According to the cardinal urogynecological symptoms and signs, patients were categorized into three groups: pelvic organ prolapse, stress urinary incontinence and overactive bladder symptoms. RESULTS: Median age of our study population was 66 (range 29-94) years, median parity was 2.1 (range 0-9) with 17 (6.9 %) nulliparous women. Symptoms of overactive bladder in 71.1 % were most common, followed by 54.5 % symptoms of stress incontinence and 32.1 % symptoms of prolapse. On examination 49.2 % showed signs of prolapse. Levator avulsions on 3D ultrasound were detected in 20.7 %. Hiatal area was normally distributed with a median of 28.7 cm2 (range 10.4-50.0 cm2). Patients with levator avulsion had a significantly larger hiatal area (p < 0.001). Also patients with signs of prolapse had a significantly larger hiatal area (p < 0.001). There was no correlation between hiatal area and symptoms of overactive bladder (p = 0.374). Although not reaching statistical significance there was evidence of a smaller hiatal area for patients with stress incontinence (p = 0.016). In our cohort there were 33.7 % (83) women without ballooning, 27.2 % (67) showed mild, 18.3 % (45) moderate, 12.3 % (30) marked and 8.5 % (21) severe ballooning. The ROC curve analysis for hiatal area on patients with prolapse yielded an AUC of 0.755 [95 % CI (0.696-0.814)]. Using the Youden-Index we obtained 27.53 cm2 as a cut-off with a sensitivity of 0.70 and a specificity of 0.69. DISCUSSION: Hiatal area is a new repeatable diagnostic parameter. Its clinical application could improve our understanding of the pathophysiology of pelvic organ prolapse as a form of hiatal hernia.

The impact of chemotherapy for breast cancer on sexual function and health-related quality of life.

PURPOSE: In this prospective trial, we evaluated the influence of chemotherapy for breast cancer on women's health-related quality of life (HR-QoL), sexual function, and mental status. METHODS: The patients completed validated questionnaires on HR-QoL, sexual function, and depression before, during, and at the end and finally 6 months after chemotherapy. Special attention was paid to possible differences between pre- and postmenopausal patients. RESULTS: Between 2008 and 2012, 79 patients were enrolled in the trial (mean age 47.46 years). Premenopausal participants were 63.3 %. Sexual activity dropped from 71.9 % before chemotherapy to a minimum of 47 % at the end of chemotherapy. A similar effect was seen for pleasure and discomfort. Depression values were the highest at the beginning of chemotherapy, with spontaneous improvement in many patients during the course of time. HR-QoL and global health status both increased 6 months after therapy. For almost all parameters, changes were more obvious in pre- than in postmenopausal patients. CONCLUSIONS: In a close monitoring, we observed significant changes in HR-QoL, depression, and sexual function in breast cancer patients. Special attention needs to be paid to premenopausal patients. The knowledge of effective recovery and spontaneous improvement of HR-QoL in spite of still impaired sexuality are important information in counseling both pre- and postmenopausal patients with diagnosis of breast cancer prior to upcoming therapy.

Customized treatment of recurrent gynaecological cancer--the need for intraoperative radiation therapy.

OBJECTIVE: The objective of this retrospective study was to analyze the experience with intraoperative radiation therapy (IORT) at the present institution and to evaluate its contribution to the management of patients with recurrent gynecological cancer. Materials and METHODS: Retrospectively this study reviewed data of patients with a gynecological malignancy considered for treatment with IORT at Freiburg University Medical Center between 2005 and 2012. For this purpose, an analysis of medical records, radiation oncology records, operation reports, and follow-up data was conducted. RESULTS: During the period of this study, 31 women with gynecological cancer underwent tumor resection in combination with IORT. The median age of the patients at the time of IORT was 62 years (range 38-85). Most patients had undergone surgery at the time of initial diagnosis (87%). More than one-third of the patients received prior radiation therapy. In addition to that, 52% of the patients had already received chemotherapy. The majority of patients suffered from the first relapse of their disease. The local recurrence was predominantly located at the pelvic side wall (32%) or in intra-abdominal lymph nodes (32%). In 12 patients the authors did not apply the planned IORT. Intraoperative complications were rare and IORT was tolerated without severe side-effects. Follow-up was 14 months (range 1-65), progression free survival (PFS) was five months (range 3-31). CONCLUSIONS: In carefully selected patients, IORT and cytoreductive surgery contributed to local control and disease palliation. The authors therefore consider IORT an important aspect of modern cancer treatment.

Surgical staging and prognosis in serous borderline ovarian tumours (BOT): a subanalysis of the AGO ROBOT study.

BACKGROUND: Incomplete surgical staging is a negative prognostic factor for patients with borderline ovarian tumours (BOT). However, little is known about the prognostic impact of each individual staging procedure. METHODS: Clinical parameters of 950 patients with BOT (confirmed by central reference pathology) treated between 1998 and 2008 at 24 German AGO centres were analysed. In 559 patients with serous BOT and adequate ovarian surgery, further recommended staging procedures (omentectomy, peritoneal biopsies, cytology) were evaluated applying Cox regression models with respect to progression-free survival (PFS). RESULTS: For patients with one missing staging procedure, the hazard ratio (HR) for recurrence was 1.25 (95%-CI 0.66-2.39; P=0.497). This risk increased with each additional procedure skipped reaching statistical significance in case of two (HR 1.95; 95%-CI 1.06-3.58; P=0.031) and three missing steps (HR 2.37; 95%-CI 1.22-4.64; P=0.011). The most crucial procedure was omentectomy which retained a statistically significant impact on PFS in multiple analysis (HR 1.91; 95%-CI 1.15-3.19; P=0.013) adjusting for previously established prognostic factors as FIGO stage, tumour residuals, and fertility preservation. CONCLUSION: Individual surgical staging procedures contribute to the prognosis for patients with serous BOT. In this analysis, recurrence risk increased with each skipped surgical step. This should be considered when re-staging procedures following incomplete primary surgery are discussed.

Time dependence of biomarkers: non-proportional effects of immunohistochemical panels predicting relapse risk in early breast cancer.

BACKGROUND: We investigated the impact of follow-up duration to determine whether two immunohistochemical prognostic panels, IHC4 and Mammostrat, provide information on the risk of early or late distant recurrence using the Edinburgh Breast Conservation Series and the Tamoxifen vs Exemestane Adjuvant Multinational (TEAM) trial. METHODS: The multivariable fractional polynomial time (MFPT) algorithm was used to determine which variables had possible non-proportional effects. The performance of the scores was assessed at various lengths of follow-up and Cox regression modelling was performed over the intervals of 0-5 years and >5 years. RESULTS: We observed a strong time dependence of both the IHC4 and Mammostrat scores, with their effects decreasing over time. In the first 5 years of follow-up only, the addition of both scores to clinical factors provided statistically significant information (P<0.05), with increases in R(2) between 5 and 6% and increases in D-statistic between 0.16 and 0.21. CONCLUSIONS: Our analyses confirm that the IHC4 and Mammostrat scores are strong prognostic factors for time to distant recurrence but this is restricted to the first 5 years after diagnosis. This provides evidence for their combined use to predict early recurrence events in order to select those patients who may/will benefit from adjuvant chemotherapy.

Age-dependent differences in borderline ovarian tumours (BOT) regarding clinical characteristics and outcome: results from a sub-analysis of the Arbeitsgemeinschaft Gynaekologische Onkologie (AGO) ROBOT study.

BACKGROUND: Approximately one-third of all borderline ovarian tumours (BOT) are diagnosed in patients with child-bearing potential. Detailed information regarding their specific characteristics and prognostic factors is limited. METHODS: Clinical parameters of BOT patients treated between 1998 and 2008 in 24 German centres were retrospectively investigated. Central pathology review and prospective follow-up were carried out. Patients <40 versus ≥40 years were analysed separately and then compared regarding clinico-pathological variables and prognosis. RESULTS: A total of 950 BOT patients with a median age of 49.1 (14.1-91.5) years were analysed [280 patients <40 years (29.5%), 670 patients ≥40 years (70.5%)]. Fertility-preserving surgery was carried out in 53.2% (149 of 280) of patients <40 years with preservation of the primarily affected ovary in 32 of these 149 cases (21.5%). Recurrence was significantly more frequent in patients <40 years (19.0% versus 10.1% 5-year recurrence rate, P < 0.001), usually in ovarian tissue, whereas disease-specific overall survival did not differ between the subgroups. In case of recurrent disease, malignant transformation was less frequent in younger than in older patients (12.0% versus 66.7%, P < 0.001), mostly presenting as invasive peritoneal carcinomatosis. Multivariate analysis for patients <40 years identified advanced International Federation of Gynecology and Obstetrics (FIGO) stage and fertility-sparing approach as independent prognostic factors negatively affecting progression-free survival (PFS) while, for patients ≥40 years, higher FIGO stage and incomplete staging was associated with impaired PFS. CONCLUSIONS: Despite favourable survival, young BOT patients with child-bearing potential are at higher risk for disease recurrence. However, relapses usually remain BOT in the preserved ovaries as opposed to older patients being at higher risk for malignant transformation in peritoneal or distant localisation. Therefore, fertility-sparing approach can be justified for younger patients after thorough consultation.

Do type 1 receptor tyrosine kinases inform treatment choice? A prospectively planned analysis of the TEAM trial.

BACKGROUND: Epidermal growth factor receptors contribute to breast cancer relapse during endocrine therapy. Substitution of aromatase inhibitors (AIs) may improve outcomes in HER-positive cancers. METHODS: Tissue microarrays were constructed. Quantitative analysis of HER1, HER2, and HER3 was performed. Data were analysed relative to disease-free survival and treatment using outcomes at 2.75 and 6.5 years. RESULTS: Among 4541 eligible samples, 4225 (93%) had complete HER1-3 data. Overall, 5% were HER1-positive, 13% HER2-positive, and 21% HER3-positive; 32% (n=1351) overexpressed at least one HER receptor. In the HER1-3-negative subgroup, the hazard ratio (HR) for upfront exemestane vs tamoxifen at 2.75 years was 0.67 (95% confidence interval (CI), 0.52-0.87), in the HER1-3-positive subgroup, the HR was 1.15 (95% CI, 0.85-1.56). A prospectively planned treatment-by-marker analysis demonstrated a significant interaction between HER1-3 and treatment at 2.75 years (HR=0.58; 95% CI, 0.39-0.87; P=0.008), as confirmed by multivariate regression analysis adjusting for prognostic factors (HR=0.55; 95% CI, 0.36-0.85; P=0.005). This effect was time dependent. CONCLUSION: In the 2.75 years prior to switching patients initially treated with tamoxifen to exemestane, a significant treatment-by-marker effect exists between AI/tamoxifen treatment and HER1-3 expression, suggesting HER expression could be used to select appropriate endocrine treatment at diagnosis to prevent or delay early relapses.

Correlation of treatment-emergent adverse events and clinical response to endocrine therapy in early breast cancer: a retrospective analysis of the German cohort of TEAM.

BACKGROUND: Previous studies have suggested a correlation between the occurrence of vasomotor or joint symptoms during tamoxifen or aromatase inhibitor treatment and improved clinical response. PATIENTS AND METHODS: A retrospective analysis of the German cohort of the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial was carried out to assess disease-free survival (DFS) and overall survival (OS) in patients with and without arthralgia/myalgia and/or menopausal symptoms during adjuvant endocrine treatment. RESULTS: A total of 1502 patients were included; 739 patients received tamoxifen followed by exemestane and 763 received exemestane. Patients reporting arthralgia/myalgia and patients reporting menopausal symptoms during endocrine treatment had significantly longer OS and DFS than those not reporting these events. The effect on OS was irrespective of treatment. DFS was significantly improved in exemestane-treated patients reporting arthralgia/myalgia or those reporting menopausal symptoms versus those not reporting these events. This effect on DFS was not observed in patients receiving sequential treatment. A combined analysis of patients reporting either menopausal symptoms or arthralgia/myalgia showed that OS and DFS were significantly improved in patients reporting one of these symptoms versus those not reporting either symptom. CONCLUSION: The occurrence of arthralgia/myalgia or menopausal symptoms during endocrine treatment is associated with significantly improved OS.

A phase II trial (AGO 2.11) in platinum-resistant ovarian cancer: a randomized multicenter trial with sunitinib (SU11248) to evaluate dosage, schedule, tolerability, toxicity and effectiveness of a multitargeted receptor tyrosine kinase inhibitor monotherapy.

BACKGROUND: Recurrent platinum-resistant ovarian cancer usually has a poor outcome with conventional chemotherapeutic therapy and new treatment modalities are warranted. This phase II study was conducted to evaluate sunitinib, an oral antiangiogenic multitargeted tyrosin kinase inhibitor, in this setting. MATERIAL AND METHODS: The primary end point of this randomized phase II trial was the objective response rate according to RECIST criteria and/or Gynecologic Cancer InterGroup CA125 response criteria to sunitinib in patients with recurrent platinum-resistant ovarian cancer who were pretreated with up to three chemotherapies. A selection design was employed to compare two schedules of sunitinib (arm 1: 50 mg sunitinib daily orally for 28 days followed by 14 days off drug; and arm 2: 37.5 mg sunitinib administered daily continuously). RESULTS: Of 73 patients enrolled, 36 patients were randomly allocated to the noncontinuous treatment arm (arm 1) and 37 patients were randomly allocated to the continuous treatment arm (arm 2). The mean age was 58.8 and 58.5 years, respectively. We observed six responders (complete response + partial response) in arm 1 (16.7%) and 2 responders in arm 2 (5.4%). The median progression-free survival (arm 1: 4.8 [2.9-8.1] months; arm 2: 2.9 [2.9-5.1] months) and the median overall survival (arm 1: 13.6 [7.0-23.2] months; arm 2: 13.7 [8.4-25.6] months) revealed no significant difference. Adverse events included fatigue as well as cardiovascular, gastrointestinal and abdominal symptoms, hematologic and hepatic laboratory abnormalities. Pattern and frequency of adverse events revealed no substantial differences between both treatment groups. CONCLUSIONS: Sunitinib treatment is feasible and moderately active in relapsed platinum-resistant ovarian cancer. The noncontinuous treatment schedule should be chosen for further studies in ovarian cancer.

Video-assisted thoracic surgery (VATS) evaluation of intrathoracic disease in patients with FIGO III and IV stage ovarian cancer.

OBJECTIVES: The aim of this study was to assess the influence of video-assisted thoracic surgery (VATS) on our treatment decisions in FIGO III and IV ovarian cancer patients. METHODS: Patients with ovarian cancer and suspected supra-diaphragmatic involvement (pleural effusions, pleural carcinomatosis, lung metastasis, or enlarged supra-diaphragmatic lymph nodes) at chest computer tomography (CT) scan underwent VATS with or without laparoscopy (LSC) to decide for primary cytoreduction or neoadjuvant chemotherapy. Operation time, VATS complications (intrapleural hematoma, secondary hemorrhage with intervention, pneumonia and empyema) and shift in the therapeutic strategy due to VATS were evaluated. RESULTS: 17 patients were included into this study (1 patient with FIGO stage IIIb, 1 with IIIc and 15 with stage IV). The median operation time for VATS only was 46.5 min (range: 20-50 min, n=3). Perioperatively, no complications occurred. After surgical staging, the tumor was confined to the abdomen in four patients in whom primary cytoreduction was attempted. All other 13 patients underwent neoadjuvant chemotherapy. VATS altered the therapeutic management in 6/17 ovarian cancer patients (3 times upstaging, 3 times downstaging). Negative predictive values (NPV) for local and diffuse pleural carcinomatosis ranged between 0.5 and 0.71. CONCLUSION: In this case series, VATS in addition to LSC showed negligible morbidity related to surgery and a short operation time. We were able to improve the accuracy of the FIGO staging and assessed operability more reliably in these patients than through imaging techniques alone.

Effects of exemestane and tamoxifen on hormone levels within the Tamoxifen Exemestane Adjuvant Multicentre (TEAM) trial: results of a German substudy.

AIM: The aim of this study was to compare the effects of exemestane and tamoxifen on hormone levels in postmenopausal patients with hormone receptor-positive breast cancer within a Germany substudy of the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial. METHODS: Within the TEAM trial, patients were randomized to receive adjuvant treatment with exemestane for 5 years or tamoxifen for 2.5-3 years followed by exemestane for 2-2.5 years. Serum levels of testosterone, dehydroepiandrosterone sulfate (DHEAS), sex hormone binding globulin (SHBG), follicle stimulating hormone (FSH) and parathyroid hormone (PTH)-intact were measured at screening and after 3, 6 and 12 months of treatment. RESULTS: Data on hormone levels were available from 63 patients in the tamoxifen arm and 68 patients in the exemestane arm. Treatment with exemestane resulted in decreases from baseline in SHBG and PTH-intact levels, and increases from baseline in testosterone, DHEAS and FSH levels. Tamoxifen treatment resulted in increases from baseline in SHBG and PTH-intact, whereas levels of testosterone and FSH decreased and DHEAS levels did not change. At all time points assessed, the absolute change from baseline was significantly different between tamoxifen and exemestane for testosterone, SHBG, FSH and PTH-intact (all p < 0.0001). CONCLUSIONS: Exemestane and tamoxifen had statistically significantly different effects on hormone levels, including testosterone, SHBG, FSH and PTH-intact.