Developing a fit-for-purpose composite symptom score as a symptom burden endpoint for clinical trials in patients with malignant pleural mesothelioma.

We developed a composite symptom score (CSS) representing disease-related symptom burden over time in patients with malignant pleural mesothelioma (MPM). Longitudinal data were collected from an open-label Phase IIB study in which 239 patients completed the validated MD Anderson Symptom Inventory for MPM (MDASI-MPM). A blinded, independent review committee of external patient-reported outcomes experts advised on MDASI-MPM symptoms to include in the CSS. Through iterative analyses of potential symptom-item combinations, 5 MPM symptoms (pain, fatigue, shortness of breath, muscle weakness, coughing) were selected. The CSS correlated strongly with the full MDASI-MPM symptom set (0.92-0.94) and the Lung Cancer Symptom Scale-Mesothelioma (0.79-0.87) at each co-administration of the scales. The CSS also had good sensitivity to worsening disease and global quality-of-life ratings. The MDASI-MPM CSS can be used as an outcome in MPM clinical trials, including in responder analyses and at the individual patient level. It is brief enough to administer frequently, including electronically, to better capture symptom trajectories during and after a trial and in clinical practice. As a single score, the CSS addresses multiplicity issues that can arise when several symptoms increase due to worsening disease. Our process can be adapted to produce a CSS for other advanced-cancer trials.

Sharing Medical Big Data While Preserving Patient Confidentiality in Innovative Medicines Initiative: A Summary and Case Report from BigData@Heart.

Sharing individual patient data (IPD) is a simple concept but complex to achieve due to data privacy and data security concerns, underdeveloped guidelines, and legal barriers. Sharing IPD is additionally difficult in big data-driven collaborations such as Bigdata@Heart in the Innovative Medicines Initiative, due to competing interests between diverse consortium members. One project within BigData@Heart, case study 1, needed to pool data from seven heterogeneous data sets: five randomized controlled trials from three different industry partners, and two disease registries. Sharing IPD was not considered feasible due to legal requirements and the sensitive medical nature of these data. In addition, harmonizing the data sets for a federated data analysis was difficult due to capacity constraints and the heterogeneity of the data sets. An alternative option was to share summary statistics through contingency tables. Here it is demonstrated that this method along with anonymization methods to ensure patient anonymity had minimal loss of information. Although sharing IPD should continue to be encouraged and strived for, our approach achieved a good balance between data transparency while protecting patient privacy. It also allowed a successful collaboration between industry and academia.

Accuracy of Breast Ultrasonography and Mammography in Comparison with Postoperative Histopathology in Breast Cancer Patients after Neoadjuvant Chemotherapy.

INTRODUCTION: Nowadays chemotherapy in breast cancer patients is optionally applied neoadjuvant, which allows for testing of tumor response to the chemotherapeutical treatment in vivo, as well as allowing a greater number of patients to benefit from a subsequent breast-conserving surgery. MATERIAL AND METHODS: We compared breast ultrasonography, mammography, and clinical examination (palpation) results with postoperative histopathological findings after neoadjuvant chemotherapy, aiming to determine the most accurate prediction of complete remission and tumor-free resection margins. To this end, clinical and imaging data of 184 patients (193 tumors) with confirmed diagnosis of breast cancer and neoadjuvant therapy were analyzed. RESULTS: After chemotherapy, tumors could be assessed by palpation in 91.7%, by sonography in 99.5%, and by mammography in 84.5% (chi-square p < 0.0001) of cases. Although mammography proved more accurate in estimating the exact neoadjuvant tumor size than breast sonography in total numbers (136/163 (83.44%) vs. 142/192 (73.96%), n.s.), 29 tumors could be assessed solely by means of breast sonography. A sonographic measurement was feasible in 192 cases (99.48%) post-chemotherapy and in all cases prior to chemotherapy. CONCLUSIONS: We determined a superiority of mammography and breast sonography over clinical palpation in predicting neoadjuvant tumor size. However, neither examination method can predict either pCR or tumor margins with high confidence.

Substituting a randomised placebo control group with a historical placebo control in an endometriosis pain trial: a case study re-evaluating trial data using historical control data from another trial.

OBJECTIVE: The substitution of an in-study control population with a historical control (HC) population is considered a viable option for reducing the necessary recruitment of control patients. However, it is necessary to evaluate whether this method is applicable to studies on indications targeting endometriosis-associated pelvic pain (EAPP). This study aims to evaluate the potential bias in the results of an EAPP study with an HC arm. METHODS: For this case study, we re-evaluated data from a randomised, placebo-controlled trial using dienogest daily to treat EAPP with an HC arm based on data from a second randomised, placebo-controlled trial in the same indication. Propensity Score (PS) matching was used to match between the treatment and HC arm on all baseline variables. To evaluate the effect of matching on the introduced bias, we evaluated efficacy parameters with the full treatment and control group, as well as the matched group. RESULTS: The difference between means (placebo minus treatment) in change in pain, as measured on the Visual Analogue Scale from baseline to end of treatment, deviates in the comparison treatment/pool of HC (7.15 (0.22 to 14.08)) from the overall in-study group (reference: 11.89 (6.06 to 17.73)). After PS matching on the baseline variables, the difference between means (11.79 (4.09 to 19.5)) is close to the reference. CONCLUSIONS: Using HC with PS matching has proven to be useful in the setting of treating EAPP, while emphasis must be given to the selection mechanism and the underlying assumptions. This case study has shown that even for studies which are very similar in design, heterogeneity and between-study variations are present. With the use of an HC arm, it was possible to reproduce similar results than in the original study, while the PS matching improved the comparability considerably. For the main endpoint, PS matching could reproduce the original study results. TRIAL REGISTRATION NUMBER: NCT00225199, NCT00185341.

Sex differences in the generalizability of randomized clinical trials in heart failure with reduced ejection fraction.

AIMS: In order to understand how sex differences impact the generalizability of randomized clinical trials (RCTs) in patients with heart failure (HF) and reduced ejection fraction (HFrEF), we sought to compare clinical characteristics and clinical outcomes between RCTs and HF observational registries stratified by sex. METHODS AND RESULTS: Data from two HF registries and five HFrEF RCTs were used to create three subpopulations: one RCT population (n = 16 917; 21.7% females), registry patients eligible for RCT inclusion (n = 26 104; 31.8% females), and registry patients ineligible for RCT inclusion (n = 20 810; 30.2% females). Clinical endpoints included all-cause mortality, cardiovascular mortality, and first HF hospitalization at 1 year. Males and females were equally eligible for trial enrolment (56.9% of females and 55.1% of males in the registries). One-year mortality rates were 5.6%, 14.0%, and 28.6% for females and 6.9%, 10.7%, and 24.6% for males in the RCT, RCT-eligible, and RCT-ineligible groups, respectively. After adjusting for 11 HF prognostic variables, RCT females showed higher survival compared to RCT-eligible females (standardized mortality ratio [SMR] 0.72; 95% confidence interval [CI] 0.62-0.83), while RCT males showed higher adjusted mortality rates compared to RCT-eligible males (SMR 1.16; 95% CI 1.09-1.24). Similar results were also found for cardiovascular mortality (SMR 0.89; 95% CI 0.76-1.03 for females, SMR 1.43; 95% CI 1.33-1.53 for males). CONCLUSION: Generalizability of HFrEF RCTs differed substantially between the sexes, with females having lower trial participation and female trial participants having lower mortality rates compared to similar females in the registries, while males had higher than expected cardiovascular mortality rates in RCTs compared to similar males in registries.

Postpartum Assessment of the Correlation between Serum Hormone Levels of Estradiol, Progesterone, Prolactin and ß-HCG and Blood Pressure Measurements in Pre-Eclampsia Patients.

Background: Preeclampsia is a pregnancy-related hypertensive disease. Aberrant hormone levels have been implicated in blood pressure disorders. This study investigated the association of postpartum maternal serum hormone levels of estradiol, progesterone, prolactin, and ß-HCG with poorer PE-related complications including arterial hypertension. Methods: Thirty patient women with preeclampsia, and twenty women with uncomplicated pregnancy were included in this study. Serum levels of estradiol, progesterone, prolactin, and ß-HCG were determined immediately after delivery, and on the first and third postpartum days by means of ECLIA. Results: Compared with normal pregnancy cases, preeclampsia cases had higher serum levels of ß-HCG levels on Day-0 (319%), of progesterone on Day-0 (207%) and Day-1 (178%), and of estradiol on Day-1 (187%) and Day-3 (185%). Increased prolactin levels were positively associated with disease severity and estradiol and progesterone levels were decreased in poorer preeclampsia features including disease onset and IUGR diagnosis. No significant correlation between different hormone levels and blood pressure measurements was reported. Conclusions: This study is the first that detected postpartum maternal serum hormone levels and their correlation with blood pressure measurements in preeclampsia. We believe that the persistent arterial hypertension in the puerperium in preeclampsia as well as poorer disease specifications are most likely not of hormonal origin. Larger, well-defined prospective studies are recommended.

Risk of Hypersensitivity Reactions to Iopromide in Children and Elderly: An Analysis of 132,850 Patients From 4 Observational Studies and Pharmacovigilance Covering >288 Million Administrations.

PURPOSE: The aim of this study was to analyze the risk of hypersensitivity reactions (HSRs) to iopromide in children and elderly patients in comparison to adults. MATERIALS AND METHODS: Four observational studies were pooled and analyzed (analysis I). In addition, spontaneous reports from 1985 to 2020 from the pharmacovigilance database were evaluated (analysis II). All patients received iopromide for angiographic procedures or contrast-enhanced computed tomography in various indications. In analysis I, a nested case-control analysis, including a multivariable logistic regression model, based on pooled observational study data, was performed. Cases were defined as patients with a typical and unequivocal HSR; controls were patients without any recorded reaction. In analysis II, all spontaneous reports on HSRs after iopromide administration recorded in the pharmacovigilance database were descriptively analyzed. Exposure estimates on the size of the exposed age groups were derived from sales data and data from market research. The primary target variable was the risk of HSR to iopromide in children (<18 years) and elderly patients (≥65 years) compared with adults (≥18 to <65 years). RESULTS: In analysis I, a total of 132,850 patients were included (2978 children, 43,209 elderly, and 86,663 adults). Hypersensitivity reactions were significantly less frequent in children (0.47%) and elderly (0.38%) compared with adults (0.74%). The adjusted odds ratio (vs adults) for children was 0.58 (95% confidence interval, 0.34-0.98; P < 0.043), and that for the elderly was 0.51 (95% confidence interval, 0.43-0.61; P < 0.001), indicating a lower risk for both subpopulations as compared with adults. In analysis II, of the overall >288 million iopromide administrations, 5.87, 114.18, and 167.97 million administrations were administered to children, elderly, and adults, respectively. The reporting rate for HSRs in children (0.0114%) and elderly (0.0071%) was significantly lower as compared with adults (0.0143%) (P < 0.0001). CONCLUSIONS: Hypersensitivity reactions to iopromide were significantly less frequent in children and elderly compared with adults.

Generalizability of randomized controlled trials in heart failure with reduced ejection fraction.

BACKGROUND: Heart failure (HF) trials have stringent inclusion and exclusion criteria, but limited data exist regarding generalizability of trials. We compared patient characteristics and outcomes between patients with HF and reduced ejection fraction (HFrEF) in trials and observational registries. METHODS AND RESULTS: Individual patient data for 16 922 patients from five randomized clinical trials and 46 914 patients from two HF registries were included. The registry patients were categorized into trial-eligible and non-eligible groups using the most commonly used inclusion and exclusion criteria. A total of 26 104 (56%) registry patients fulfilled the eligibility criteria. Unadjusted all-cause mortality rates at 1 year were lowest in the trial population (7%), followed by trial-eligible patients (12%) and trial-non-eligible registry patients (26%). After adjustment for age and sex, all-cause mortality rates were similar between trial participants and trial-eligible registry patients [standardized mortality ratio (SMR) 0.97; 95% confidence interval (CI) 0.92-1.03] but cardiovascular mortality was higher in trial participants (SMR 1.19; 1.12-1.27). After full case-mix adjustment, the SMR for cardiovascular mortality remained higher in the trials at 1.28 (1.20-1.37) compared to RCT-eligible registry patients. CONCLUSION: In contemporary HF registries, over half of HFrEF patients would have been eligible for trial enrolment. Crude clinical event rates were lower in the trials, but, after adjustment for case-mix, trial participants had similar rates of survival as registries. Despite this, they had about 30% higher cardiovascular mortality rates. Age and sex were the main drivers of differences in clinical outcomes between HF trials and observational HF registries.

Comparison of Maternal Serum Levels and Placental mRNA Levels of Dickkopf-1 in Preeclamptic and Normal Pregnant Women at Delivery.

Background Preeclampsia remains a major cause of perinatal and maternal mortality and morbidity worldwide. Wnt/ß-catenin signaling is known to be critically involved in placenta development processes. Dickkopf-1 (DKK1) is a key regulator of this transduction pathway. The aim of this study is to compare maternal serum DKK1 levels and placental mRNA levels of DKK1 and ß-catenin in preeclamptic and normal pregnant women at delivery. Methods The present study included 30 women with preeclampsia and 30 women with normal pregnancy. Maternal serum DKK1 levels were measured by ELISA. Placental mRNA levels of DKK1 and ß-catenin were detected using RT-PCR. Results Decreased maternal serum DKK1 levels were associated with worse maternal and fetal complications including HELLP syndrome, determination of one or more pathological symptom and IUGR diagnosis. No significant difference in maternal serum DKK1 levels was reported between preeclamptic women and women with normal pregnancy. Placental mRNA DKK1 levels were lower in preeclamptic women compared with normal pregnant women. Placental mRNA ß-catenin levels showed no significant difference between two groups. Conclusions Our findings reported the aberrant placental mRNA DKK1 levels in patients with preeclampsia. In addition, worse preeclampsia features were associated with decreased maternal serum DKK1 levels. Hence, aberrant Wnt/ß-catenin signaling might present a plausible mechanism in preeclampsia pathogenicity. Dysregulated expression of DKK1 at gene level in the placenta but not at protein level in the maternal serum might confirm the notion that preeclampsia is a type of placenta-derived disease.

Real world data on symptomology and diagnostic approaches of 27,840 women living with endometriosis.

Endometriosis is a chronic disease that requires a suitable, lifelong treatment. To our knowledge, the Visanne Post-approval Observational Study (VIPOS) is to date the largest real-world, non-interventional study investigating hormonal management of endometriosis. We describe women's experiences of endometriosis in the real world by considering their symptoms and the diagnostic process in their healthcare setting. Overall, 27,840 women were enrolled from six European countries via networks of gynecologists or specialized centers. Of these, 87.8% of women were diagnosed based on clinical symptoms; the greatest and lowest proportions of women were in Russia (94.1%) and Germany (61.9%), respectively. Most women (82.8%) experienced at least one of the triad of endometriosis-associated pain symptoms: pelvic pain, pain after/during sexual intercourse, and painful menstrual periods. The most frequently reported endometriosis-associated symptoms were painful periods (61.8%), heavy/irregular bleeding (50.8%), and pelvic pain (37.2%). Women reported that endometriosis impacted their mood; 55.6% reported feeling "down", depressed, or hopeless, and 53.2% reported feeling like a failure or having let down family/friends. VIPOS broadens our understanding of endometriosis based on real-world data by exploring the heterogeneity of symptoms women with endometriosis experience and the differences in diagnostic approaches between European countries.Trial registration: ClinicalTrials.gov, NCT01266421; registered 24 December 2010. Registered in the European Union electronic Register of Post-Authorisation Studies as number 1613.

Incidence of and risk factors for vaginal cuff dehiscence following total laparoscopic hysterectomy: a monocentric hospital analysis.

PURPOSE: Vaginal cuff dehiscence (VCD) is one of the major surgical complications following hysterectomy with data on incidence rates varying largely and studies assessing risk factors being sparse with contradictive results. The aim of this study was to assess the incidence rate of and risk factors for VCD in a homogenous cohort of women treated for benign uterine pathologies via total laparoscopic hysterectomy (TLH) with standardized follow-up. METHODS: All patients undergoing TLH at the Department of Gynecology and Obstetrics, Saarland University Hospital between November 2010 and February 2019 were retrospectively identified from a prospectively maintained service database. RESULTS: VCD occurred in 18 (2.9%) of 617 patients included. In univariate and multivariate analyses, a lower level of surgeon laparoscopic expertise (odds ratio 3.19, 95% confidence interval (CI) 1.0-9.38; p = 0.03) and lower weight of removed uterus (odds ratio 0.99, 95% CI 0.98-0.99; p = 0.02) were associated positively with the risk of VCD. CONCLUSION: In this homogenous cohort undergoing TLH, laparoscopic expertise and uterine weight influenced the risk of postoperative VCD. These findings might help to further reduce the rate of this complication.

The use of external controls: To what extent can it currently be recommended?

With more and better clinical data being captured outside of clinical studies and greater data sharing of clinical studies, external controls may become a more attractive alternative to randomized clinical trials (RCTs). Both industry and regulators recognize that in situations where a randomized study cannot be performed, external controls can provide the needed contextualization to allow a better interpretation of studies without a randomized control. It is also agreed that external controls will not fully replace RCTs as the gold standard for formal proof of efficacy in drug development and the yardstick of clinical research. However, it remains unclear in which situations conclusions about efficacy and a positive benefit/risk can reliably be based on the use of an external control. This paper will provide an overview on types of external control, their applications and the different sources of bias their use may incur, and discuss potential mitigation steps. It will also give recommendations on how the use of external controls can be justified.

Urogynecology in obstetrics: impact of pregnancy and delivery on pelvic floor disorders, a prospective longitudinal observational pilot study.

PURPOSE: To assess changes in the pelvic floor anatomy that cause pelvic floor disorders (PFDs) in primigravidae during and after pregnancy and to evaluate their impact on women's quality of life (QoL). METHODS: POP-Q and translabial ultrasound examination was performed in the third trimester and 3 months after delivery in a cohort of primigravidae with singleton pregnancy delivering in a tertiary center. Results were analyzed regarding mode of delivery and other pre- and peripartal factors. Two individualized detailed questionnaires were distributed at 3 months and at 12 months after childbirth to determinate QoL. RESULTS: We recruited 45 women, of whom 17 delivered vaginally (VD), 11 received a vacuum extraction delivery (VE) and 17 a Cesarean section in labor (CS). When comparing third-trimester sonography to 3 months after delivery, bladder neck mobility increased significantly in each delivery group and hiatal area increased significantly in the VD group. A LAM avulsion was found in two women after VE. Connective tissue weakness (p = 0.0483) and fetal weight at birth (p = 0.0384) were identified as significant risk factors for the occurrence of PFDs in a multivariant regression analysis. Urinary incontinence was most common with 15% and 11% of cases at 3, respectively, 12 months after delivery. 42% of women reported discomfort during sexual intercourse, 3 months after delivery and 24% 12 months postpartum. Although 93% of women engage a midwife after delivery, only 56% participated in pelvic floor muscle training. CONCLUSION: Connective tissue weakness and high fetal weight at birth are important risk factors for the occurrence of PFDs. Nevertheless, more parturients should participate in postpartal care services to prevent future PFDs.

Patients' and clinicians' perspectives on item importance, scoring, and clinically meaningful differences for the Endometriosis Symptom Diary (ESD) and Endometriosis Impact Scale (EIS).

BACKGROUND: The Endometriosis Symptom Diary (ESD) and Endometriosis Impact Scale (EIS) are patient-reported outcome measures developed to evaluate efficacy in clinical trials and clinical practice. The ESD is a daily electronic diary assessing symptom severity; the EIS is a weekly electronic diary assessing symptom impact. This study explored the importance of symptoms (ESD items) and impacts (EIS domains), perspectives on scoring algorithms, and clinically important difference (CID) thresholds to inform clinical trial score interpretation. METHODS: Endometriosis patients in Germany (n = 8) and the US (n = 17), and expert clinicians (n = 4) in Germany, the US, Spain, and Finland participated in semi-structured qualitative interviews comprising structured tasks. Interview transcripts were analyzed using thematic analysis techniques. RESULTS: Quality and severity of endometriosis-associated pelvic pain varied considerably among patients; some experienced pelvic pain daily, others during menstrual bleeding (dysmenorrhea) only. Patients and clinicians ranked "worst pelvic pain" as the most meaningful pain concept assessed by the ESD, followed by constant and short-term pelvic pain. Preferences for summarizing daily pain scores over the 28-day menstrual cycle depended on individuals' experience of pain: patients experiencing pain daily preferred scores summarizing data for all 28 days; patients primarily experiencing pain during selected days, and their treating clinicians preferred scores based on the most severe pain days. Initial CID exploration for the "worst pelvic pain" 0-10 numerical rating scale (0-10 NRS) revealed that, for most patients, a 2- or 3-point reduction was considered meaningful, depending on baseline severity. Patients and clinicians ranked "emotional well-being" and "limitations in physical activities" as the most important EIS domains. CONCLUSIONS: This study informs the use of the ESD and EIS as clinically relevant measures of endometriosis symptoms and their impact. Findings from the ESD highlight the importance of individual-patient assessment of pain experience and identify "worst pelvic pain" as the most meaningful symptom assessed. Aggregating scores over the 28-day menstrual cycle may inform meaningful endpoints for clinical trials. Diverse EIS concepts (e.g. impact on emotional well-being and physical activities) are meaningful to patients and clinicians, emphasizing the importance of evaluating the impact on both to comprehensively assess treatment efficacy and decisions. TRIAL REGISTRATION: Not applicable. Qualitative, non-interventional study; registration not required.

Cervical and Lower Uterine Parameter Ultrasound and Elastographic Parameters for the Prediction of a Successful Induction of Labor.

PURPOSE: The prediction of successful induction of labor (IOL) has been the subject of a series of studies. The predictive role of cervical sonographic and elastographic parameters has been controversially discussed. Lower uterine segment (LUS) thickness and strain values have not been discussed yet in this regard. MATERIALS AND METHODS: A prospective cohort study was performed to examine the predictive power of Bishop score parameters, sonographic cervical length (CL), cervical funneling, cervical strain values, LUS thickness and its strain values regarding successful IOL within 24 hours and intervals to onset of labor, ROM and delivery of the fetus. A p-value of < 0.05 was considered statistically significant. RESULTS: 135 patients were examined. A cervical length of 25 mm, the presence of cervical funneling and digital shorter cervix was significant for the prediction of successful induction of labor (IOL) within 24 hours. There was weak correlation between the functional CL and the onset of labor (r2 = 0.10) and ROM (r2 = 0.13). There was also a weak correlation between the cervical funnel width and the time interval to the onset of labor (r2 = 0.25), ROM (r2 = 0.23) and delivery of the fetus (r2 = 0.22). Cervical elastography, LUS thickness and strain values were not significant for the prediction of a successful IOL. CONCLUSION: We were able to show that cervical structural changes at the level of the internal os, i. e., shortening through funneling, may be the determining factor for successful IOL.

Predicting menstrual bleeding patterns with levonorgestrel-releasing intrauterine systems.

PURPOSE: To develop a bleeding-pattern prediction model to inform counselling on amount and regularity of bleeding after levonorgestrel-releasing intrauterine system (LNG-IUS) placement. MATERIALS AND METHODS: Fixed-cluster and regression-tree models were developed using bleeding data pooled from two clinical trials of LNG-IUSs. Models were trained and cross-validated on LNG-IUS 12 data, then applied to LNG-IUS 20 and LNG-IUS 8 data. Three clusters were generated for the fixed-cluster model: predominantly amenorrhoea; predominantly spotting; and predominantly bleeding. A random-forest model predicted the future-bleeding cluster, then the probability of cycle regularity was calculated. In the regression-tree model, women were assigned by the model to less- or more-bleeding groups. RESULTS: With LNG-IUS 12 (n = 1351) in the fixed-cluster model, 70.4% of women were correctly classified. The correct classification rates for LNG-IUS 20 (n = 216) and LNG-IUS 8 (n = 1300) were 72.2% and 69.0%. The probability distribution for cycle regularity showed regular and irregular bleeding were best separated with LNG-IUS 12 data, and less well with LNG-IUS 20 and LNG-IUS 8 data. In the regression-tree model there was high variability in the more- and less-bleeding group distributions with LNG-IUS 12 data. CONCLUSIONS: A fixed-cluster model predicted bleeding patterns better than a regression-tree model in women using LNG-IUS, yielding understandable, informative output.

Validation of a menstrual pictogram and a daily bleeding diary for assessment of uterine fibroid treatment efficacy in clinical studies.

BACKGROUND: To evaluate the psychometric and measurement properties of two patient-reported outcome instruments, the menstrual pictogram superabsorbent polymer-containing version 3 (MP SAP-c v3) and Uterine Fibroid Daily Bleeding Diary (UF-DBD). Test-retest reliability, criterion, construct validity, responsiveness, missingness and comparability of the MP SAP-c v3 and UF-DBD versus the alkaline hematin (AH) method and a patient global impression of severity (PGI-S) were analyzed in post hoc trial analyses. RESULTS: Analyses were based on data from up to 756 patients. The full range of MP SAP-c v3 and UF-DBD response options were used, with score distributions reflecting the cyclic character of the disease. Test-retest reliability of MP SAP-c v3 and UF-DBD scores was supported by acceptable intraclass correlation coefficients when stability was defined by the AH method and Patient Global Impression of Severity (PGI-S) scores (0.80-0.96 and 0.42-0.94, respectively). MP SAP-c v3 and UF-DBD scores demonstrated strong and moderate-to-strong correlations with menstrual blood loss assessed by the AH method. Scores increased in monotonic fashion, with greater disease severities, defined by the AH method and PGI-S scores; differences between groups were mostly statistically significant (P < 0.05). MP SAP-c v3 and UF-DBD were sensitive to changes in disease severity, defined by the AH method and PGI-S. MP SAP-c v3 and UF-DBD showed a lower frequency of missing patient data versus the AH method, and good agreement with the AH method. CONCLUSIONS: This evidence supports the use of the MP SAP-c v3 and UF-DBD to assess clinical efficacy endpoints in UF phase III studies replacing the AH method.

Using Real-World Data to Predict Clinical and Economic Benefits of a Future Drug Based on its Target Product Profile.

INTRODUCTION: For a new drug to be developed, the desired properties are described in a target product profile. OBJECTIVE: We propose a framework for using real-world data to measure the disease-specific costs of the current standard of care and then to project the costs of the proposed new product for early data-driven portfolio decisions to select drug candidates for development. METHODS: We sampled from a cohort of patients representing the current standard of care to generate a hypothetical cohort of patients that fits a given target product profile for a new (hypothetical) treatment. The healthcare costs were determined and compared between standard of care and the new treatment. The approach differed according to the number of outcomes defined in the target product profile, and the cases for one, two, and three outcome variables are described. RESULTS: Based on assumed hypothetical treatment effect, absolute risk and cost reductions were estimated in a worked example. The median costs per day for one patient were estimated to be $10.37 and $8.39 in the original and hypothetical cohorts, respectively. This means that the assumed target product profile would result in cost savings of $1.98 per day and patient-not accounting for any additional drug costs. CONCLUSIONS: We present a simple approach to assess the potential absolute clinical and economic benefit of a new drug based on real-world data and its target product profile. The approach allows for early data-driven portfolio decisions to select drug candidates based on their expected cost savings.

Safety of Dienogest and Other Hormonal Treatments for Endometriosis in Real-World Clinical Practice (VIPOS): A Large Noninterventional Study.

INTRODUCTION: Endometriosis is a common gynecologic disease associated with a significant burden on women's health and healthcare systems. Currently approved hormonal treatments for endometriosis can be effective in controlling symptoms, but may have clinically relevant side effects that limit their long-term use. Dienogest 2 mg (Visanne; Bayer AG, Berlin, Germany) is a 19-nortestosterone derivative that significantly reduces menstrual bleeding, dysmenorrhea, premenstrual pain, dyspareunia, and pelvic pain in women with endometriosis. Although dienogest 2 mg has demonstrated efficacy in clinical trials, data regarding long-term and real-world use are limited. METHODS: To our knowledge, the Visanne Post-approval Observational Study (VIPOS) is the largest real-world, noninterventional study performed examining the safety of dienogest and other hormonal treatments for the management of endometriosis in routine clinical practice. Patients self-reported medical and gynecologic history and symptoms and treatment information. Primary clinical outcomes were clinically validated and subject to independent blinded adjudication. Loss to follow-up was minimized through active contact with participating women at 6 months post-enrollment and annually thereafter to ensure almost all clinically relevant outcomes were captured. PLANNED OUTCOMES: VIPOS planned to enroll approximately 25,000 women initiating a new treatment for endometriosis, including those prescribed dienogest 2 mg/day and other hormonal medications for endometriosis (approved or nonapproved), from approximately 1000 centers in six European countries. The main clinical outcomes of interest for follow-up are anemia requiring medical intervention, de novo or clinically worsening depression, and treatment-failure patterns that result in drug discontinuation. Additional analyses will characterize the baseline risk factors of medically managed patients with endometriosis and assess treatment utilization patterns. VIPOS was designed to provide real-world information on endometriosis treatment and associated clinical outcomes, while not affecting the prescribing physician's decisions or the classification of patient diagnoses. TRIAL REGISTRATION: European Union Electronic Register of Post-Authorisation Studies (EU PAS) no. 1613, Clinicaltrials.gov: NCT01266421.

Is vimentin a potential prognostic factor for patients with triple-negative breast cancer?

OBJECTIVE: To evaluate the prognostic potential of vimentin, p53, EGFR, CK5/6, CK 14, and CK 17 in patients with triple-negative breast cancer (TNBC). MATERIAL AND METHODS: Tumor specimens of 60 patients with histologically confirmed TNBC were retrospectively analyzed. Formalin-fixed paraffin-embedded blocks of the tumor tissue were used to prepare tissue microarrays (TMAs). After immune-histochemical staining, protein expression of vimentin, p53, EGFR, CK5/6, CK 14, and CK 17 was determined and the immunoreactive score (IRS) was calculated. The protein expression was correlated to overall (OS) and disease-free survival (DFS). RESULTS: Ninety percent of patients suffered from an invasive ductal carcinoma T1 or T2, 66.7% were N0, and 70% had a G3 tumor with Ki67 of > 14%. Vimentin expression was found in 28/60 patients (46.7%), p53 expression in 30/60 patients (50%), and EGFR expression in 3/60 patients (5%). CK5/6, CK14, and CK17 expression was found in 60.0%, 63.3%, and 66.7%, respectively. Vimentin expression vs no expression was associated with significantly higher mean Ki67 values (52.5% vs. 31.1%; p = 0.0013) and significantly higher p53 expression (67.9% vs. 34.4%; p = 0.0097). No significant association between vimentin expression and OS (p = 0.7710) or DFS (p = 0.5558) was found during a mean follow-up of 92 months. CONCLUSION: None of the six proteins proved to be suitable prognostic factors for OS and DSF in patients with TNBC.