Immunohistochemical assessment of PD-L1 expression using three different monoclonal antibodies in triple negative breast cancer patients.

BACKGROUND: PD-L1 receptor expression in breast cancer tissue can be assessed with different anti-human PD-L1 monoclonal antibodies. The performance of three specific monoclonal antibodies in a head-to-head comparison is unknown. In addition, a potential correlation of PD-L1 expression and clinico-pathological parameters has not been investigated. METHODS: This was a retrospective study on tissue samples of patients with histologically confirmed triple negative breast cancer (TNBC). PD-L1 receptors were immune histochemically stained with three anti-human PD-L1 monoclonal antibodies: 22C3 and 28-8 for staining of tumor cell membranes (TC) and cytoplasm (Cyt), SP142 for immune cell staining (IC). Three different tissue samples of each patient were evaluated separately by two observers in a blinded fashion. The percentage of PD-L1 positive tumor cells in relation to the total number of tumor cells was determined. For antibodies 22C3 and 28-8 PD-L1 staining of 0 to < 1% of tumor cells was rated "negative", 1-50% was rated "positive" and > 50% was rated "strong positive". Cyt staining was defined as "negative" when no signal was observed and as "positive", when any positive signal was observed. For IC staining with SP142 all samples with PD-L1 expression ≥ 1% were rated as "positive". Finally, the relationship between PD-L1 expression and clinico-pathological parameters was analyzed. RESULTS: Tissue samples from 59 of 60 enrolled patients could be analyzed. Mean age was 55 years. Both the monoclonal antibodies 22C3 and 28-8 had similar properties, and were positive for both TC in 13 patients (22%) and for Cyt staining in 24 patients (40.7%). IC staining with antibody SP142 was positive in 24 patients (40.7%), who were also positive for Cyt staining. The differences between TC and Cyt staining and TC and IC staining were significant (p = 0.001). Cases with positive TC staining showed higher Ki67 expression compared to those with negative staining, 40 vs 30%, respectively (p = 0.05). None of the other clinico-pathological parameters showed any correlation with PDL1 expression. CONCLUSIONS: Antibodies 22C3 and 28-8 can be used interchangeably for PD-L1 determination in tumor cells of TNBC patients. Results for Cyt staining with 22C3 or 28-8 and IC staining with SP142 were identical. In our study PD-L1 expression correlates with Ki67 expression but not with OS or DFS.

Clinical Efficacy of Reduced-Dose Gadobutrol Versus Standard-Dose Gadoterate for Contrast-Enhanced MRI of the CNS: An International Multicenter Prospective Crossover Trial (LEADER-75).

BACKGROUND. Gadobutrol and gadoterate are widely used macrocyclic gadolinium-based contrast agents. Given gadobutrol's higher T1 relaxivity, a reduced gadobutrol dose should achieve essentially equivalent diagnostic efficacy as a standard dose of gadoterate. OBJECTIVE. The purpose of our study was to show efficacy of a 25% reduced dose of gadobutrol is noninferior to 100% standard dose of gadoterate for contrast-enhanced MRI of the CNS. METHODS. In this international prospective multicenter open-label crossover trial (LEADER-75 [Lower Administered Dose With Higher Relaxivity: Gadovist vs Dotarem]), adult patients with known or suspected CNS pathology underwent contrast-enhanced brain MRI with standard-dose gadoterate (0.1 mmol/kg); if an enhancing lesion was identified, a second MRI with reduced-dose gadobutrol (0.075 mmol/kg) was performed within 15 days of the first MRI. Three radiologists independently reviewed images to score three primary efficacy measures: subjective lesion enhancement, lesion border delineation, lesion internal morphology. A noninferiority analysis used readers' mean scores of the primary efficacy measures. Noninferiority of reduced-dose gadobutrol to standard-dose gadoterate for primary efficacy measures was defined as the difference in score between reduced-dose gadobutrol images and unenhanced images achieving at least 80% of the difference in score between standard-dose gadoterate images and unenhanced images. A post hoc analysis was performed to directly compare contrast-enhanced images for equivalence. Secondary efficacy variables included the number of lesions detected, reader confidence, diagnostic performance for malignancy, and reader preference in side-by-side comparison. RESULTS. The efficacy analysis included 141 patients (78 men, 63 women; mean age, 58.5 ± 13.5 [SD] years). Improvement of reduced-dose gadobutrol over unenhanced images was noninferior to improvement of standard-dose gadoterate over unenhanced images using a 20% noninferiority margin for all three primary efficacy measures using mean readings (p ≤ .025). In the post hoc analysis, the mean reading for the three primary efficacy measures differed by less than 1% between reduced-dose gadobutrol and standard-dose gadoterate, supporting equivalence of all measures using a narrow ± 5% margin (p ≤ .025). The total number of lesions detected by mean reading was 301 for reduced-dose gadobutrol versus 291 for standard-dose gadoterate. Mean reader confidence was 3.3 ± 0.6 for reduced-dose gadobutrol versus 3.3 ± 0.6 for standard-dose gadoterate. Sensitivity (58.7%), specificity (91.8%), and accuracy (70.2%) for malignancy from majority reading were identical for reduced-dose gadobutrol and standard-dose gadoterate. Reader preference was not different (95% CI, -0.10 to 0.11). CONCLUSION. A 25% reduced dose of gadobutrol is noninferior to standard-dose gadoterate for contrast-enhanced brain MRI. CLINICAL IMPACT. Use of reduced-dose gadobutrol should be considered for brain MRI, particularly in patients undergoing multiple contrast-enhanced examinations. TRIAL REGISTRATION. ClinicalTrials.gov NCT03602339; EU Clinical Trials Register EudraCT 2018-00690-78.

Impact of concentration and dilution of three macrocyclic gadolinium-based contrast agents on MRI signal intensity at 1.5T and 3T and different pulse sequences: results of a phantom study in human plasma.

BACKGROUND: Many factors influence the increase in signal intensity (SI) provided by magnetic resonance imaging (MRI) contrast media. PURPOSE: To assess the impact of different gadolinium concentrations and dilutions of three macrocyclic gadolinium-based contrast agents (GBCA) on SI. MATERIAL AND METHODS: This phantom study investigated gadobutrol, gadoteridol, and gadoterate in human plasma of a healthy donor pool at 37 °C. Different molar concentrations served to mimic conditions typically relevant for steady-state imaging; different dilutions served to mimic influence on first-pass bolus imaging. For SI measurement at 1.5T and 3T, we used two Magnetom Scanners (Siemens), applying the T1-weighted sequences Flash 2D/3D and VIBE. Regions of interest were placed on the central slice of the test vials. RESULTS: In the concentration series, gadobutrol showed the highest SI of all three GBCAs up to 2 mM, followed by gadoteridol and gadoterate. No major differences were seen between 1.5T and 3T. In the dilution series, gadobutrol showed the highest SI of all three GBCAs up to 10 mL/L. The highest effect was recorded with Flash 3D and VIBE at 3T. CONCLUSION: SIs measured in phantoms using three macrocyclic GBCAs strongly depend on their relaxivity and on the local concentration. The latter can be influenced-when comparing dilutions-by their initial concentration in their formulation. Furthermore, the pulse sequences and the chosen parameters have essential influence. At steady-state concentrations (≤2 mM) and first-pass bolus dilutions (up to 10 ml/L), gadobutrol showed highest SIs, followed by gadoterate and gadoteridol.

Diagnostic efficacy of contrast-enhanced breast MRI versus X-ray mammography in women with different degrees of breast density.

BACKGROUND: Detection of breast cancer in women with high breast densities is a clinical challenge. PURPOSE: To study the influence of different degrees of breast density on the sensitivity of contrast-enhanced breast magnetic resonance imaging (CE-BMRI) versus X-ray mammography (XRM). MATERIAL AND METHODS: We performed an additional analysis of two large Phase III clinical trials (G1; G2) which included women with histologically proven breast cancers, called "index cancers." Additional cancers were detected during image reading. We compared the sensitivity of CE-BMRI and XRM in women with different breast densities (ACR A→D; Version 5). For each study, six blinded readers evaluated the images. Results are given as the "Median Reader." RESULTS: A total of 774 patients were included, 169 had additional cancers. While sensitivity of CE-BMRI for detecting all index cancers was independent of breast density (ACR A→D) (G1: 83%→83%; G2: 91%→91%) the sensitivity of XRM declined (ACR A→D) (G1: 79%→62%; G2: 82%→64%). Thus, the sensitivity difference between both imaging modalities in ACR A breasts of 3% (G1) and 9% (G2) increased to 21% (G1) and 26% (G2) in ACR D breasts. Sensitivity of CE-BMRI for detecting at least one additional cancer increased with increasing breast density (ACR A→D) (G1: 50%→73%, G2: 57%→81%). XRM's sensitivity decreased (G1: 34%→20%) or remained stable (G2: 24%→25%). CONCLUSION: CE-BMRI showed significantly higher sensitivity compared to XRM.

Impact of body mass index, smoking habit, alcohol consumption, physical activity and parity on disease course of women with triple-negative breast cancer.

OBJECTIVE: To evaluate the potential impact of body mass index (BMI), smoking habit, alcohol consumption, physical activity and parity on disease course of women with triple-negative breast cancer (TNBC). MATERIAL AND METHODS: This was a retrospective chart analysis of patients with TNBC. Primary target parameters were overall survival (OS) and disease-free survival (DFS) depending on BMI, smoking habit, alcohol consumption, physical activity and parity. Results were descriptively evaluated and plotted as Kaplan-Meier curves. The null hypothesis was tested using the non-parametric log-rank test. All patients were treated at the University Medical School of Saarland, Dept of Gynecology, Obstetrics and Reproductive Medicine. RESULTS: A total of 197 patients were analyzed. More than 50% of women were 40-60 years old (mean 57 years) and had a normal BMI. More than 88% of patients had either a T1 or T2 tumor, 64% were N0 and 66.5% had a G3 cancer. Thirty-four of 84 patients (40.38%) on neo-adjuvant chemotherapy reached a pathology-confirmed complete remission. During the follow-up (median 41.43 months), 34 (17.3%) patients had recurrent disease and 51 (25.9%) suffered from metastases. A total of 51 (25.9%) finally deceased. OS and DFS were not significantly impacted by BMI (OS: p = 0.4720; DFS: p = 0.2272), smoking habit (p = 0.9892; p = 0.6040), alcohol consumption (p = 0.6515; p = 0.7460), physical activity (p = 0.3320; p = 0.5991) or parity (p = 0.5929; 0.1417). CONCLUSION: BMI, smoking habit, alcohol consumption, physical activity and parity had no impact on OS or DFS in women with TNBC.

Muscle mass loss in patients with metastatic breast cancer.

PURPOSE: To assess the change of body mass index (BMI), muscle mass, visceral and subcutaneous fat in patients with metastatic breast cancer. METHODS: In this retrospective chart analysis, patients with metastatic breast cancer as initial diagnosis between 2012 and 2016 were analyzed. Patients had received either chemotherapy (CTH) or endocrine therapy (ETH) according to the German S3 Guideline. BMI was calculated from the patients' weight and height. Change of muscle mass, visceral and subcutaneous fat was determined by comparing the surface area of these tissues on transverse CT images at the level of the third lumbar vertebrae (L3) at baseline and during treatment. RESULTS: A total of 45 patients were included in the study, 29 on CTH and 16 on ETH. BMI, visceral and subcutaneous fat remained stable over time for both treatment groups. When taking both treatment groups together, muscle mass decreased significantly by 5.0 ± 2.5 cm2 per year (p < 0.05). CONCLUSION: In patients with metastatic breast cancer, a slight reduction of muscle mass was observed, independent of therapy regimes.

Cross design analysis of randomized and observational data - application to continuation rates for a contraceptive intra uterine device containing Levonorgestrel in adolescents and adults.

BACKGROUND: To combine results from a randomized controlled study (RCT) and an observational study (OS) to evaluate discontinuation rate of a levonorgestrel-containing intrauterine contraceptive device (LNG IUD) in a real-life setting. METHODS: We included 253 parous and nulliparous women aged 21-40 years from our own phase II RCT. A total of 1607 women of all ages (including adolescents, < 20 years) were recruited from an OS. We applied the cross design synthesis (CDS) method recommended by the United States General Accounting Office. This method combines the different strengths of RCTs and OSs into one single estimate. RESULTS: Combined continuation rates for parous vs nulliparous women could be estimated more precisely as well as overall continuation rates after one (86.6%) and two years (78.5%), irrespective of age and parity. CONCLUSION: Cross design synthesis allowed more precise estimation of continuation rates of an intrauterine device.

Safety profile of gadoxetate disodium in elderly patients (≥65 years).

Background Safety data on routine clinical use of gadoxetate disodium in elderly patients is not reported yet. Purpose To assess the safety of liver specific gadoxetate disodium in contrast enhanced magnetic resonance imaging in elderly patients (≥65 years) in comparison to adults (18-64 years). Material and Methods Safety data on gadoxetate disodium were analyzed from 12 clinical phase II-III studies and from our pharmacovigilance database. A comparison between elderly (≥65 years) versus adults (18-64 years) was performed with respect to the frequency of drug-related adverse events (AEs) in clinical phase II-III studies and adverse drug reactions (ADRs) in the pharmacovigilance database. Results In clinical studies, 1989 patients were enrolled: 675 elderly and 1314 adults. Twenty-three elderly patients (3.4%) suffered at least one drug-related AE in contrast to 58 patients (4.4%) in the group of adults (odds ratio = 0.76; 95% confidence interval = 0.45-1.27). Since marketing authorization in 2004, more than 3.5 million patients have been exposed to gadoxetate disodium worldwide: 1.7 million (48.6%) in elderly and 1.8 million (51.4%) in adults. The number of patients with post-marketing ADRs (total n = 793) was 354 (0.021%) in the elderly group and 439 (0.024%) in the adult group. Thus, there were significantly fewer patients with ADRs reported in the group of elderly versus adults ( P = 0.028). Hypersensitivity/immune system disorders, gastrointestinal disorders, and respiratory disorders were the most frequent ADRs in both groups, elderly and adults. Conclusion The incidence of drug-related AEs in clinical studies was similar and that of patients with ADRs in the post-marketing setting was lower in elderly (≥65 years) compared with younger adults aged 18-64 years. Overall, gadoxetate disodium shows a favorable safety profile in both age groups.

Safety of gadoxetate disodium: results from six clinical phase IV studies in 8194 patients.

Background Safety data on routine clinical use of gadoxetate disodium for liver magnetic resonance imaging (MRI) is not reported yet. Purpose To assess the safety profile of gadoxetate disodium for liver MRI in the routine clinical setting. Material and Methods Six multicenter studies were performed in Europe, USA, Australia, and Asia to evaluate the safety and efficacy of gadoxetate disodium (Primovist®/Eovist®) enhanced liver MRI. Patients received a single intravenous bolus injection of the standard approved dose of 0.025 mmol/kg body weight (0.1 mL/kg). The number of patients, the characteristics of adverse events, related adverse events, and serious adverse events were analyzed. Results A total of 8194 patients were included in the database. A total of 141 patients (1.7%) reported 230 AEs of which 129 were considered being related to the use of gadoxetate disodium by the investigators. None of the AEs in the pediatric population ( n = 52) were related. The most frequent AEs independent of relationship to the drug included dyspnea (25/0.31%), nausea (22/0.27%), liver disorders (13/0.16%), and renal disorders (9/0.11%). Nine related SAEs were recorded. No patient died during the studies. Conclusion Gadoxetate disodium for liver MRI is safe and well tolerated in the routine clinical setting.

Safety of gadoxetate disodium: Results from the clinical phase II-III development program and postmarketing surveillance.

PURPOSE: To summarize the safety data of gadoxetate disodium, reported in 12 Phase II and III clinical development studies and in the postmarketing surveillance database. MATERIALS AND METHODS: Patients with liver lesions received gadoxetate disodium-enhanced liver magnetic resonance imaging (MRI). Adverse events (AEs) were recorded and evaluated with regard to a potential drug relationship. Subgroup analyses were run on patients with special medical history. Worldwide spontaneous AEs and adverse drug reactions (ADRs) from postmarketing safety surveillance were analyzed. RESULTS: A total of 1989 patients were included in the clinical development program. A total of 1581/1989 (79.5%) patients received the finally approved dose of 0.025 mmol/kg body weight. 10.1% of patients reported AEs, 4.1% were classified as related AEs. Nausea and headache were the most frequently reported related AEs, with 1.1% each. Age, history of contrast media allergy, liver cirrhosis, or impaired liver or renal function did not significantly impact the frequency and type of AEs. The postmarketing safety surveillance database encompassed more than 2.2 million patients. Nausea was the most frequent ADR, with a reporting rate of 0.00652%; all other symptoms were below 0.004%. CONCLUSION: Gadoxetate disodium for liver MRI has an excellent safety profile.

Does the Risk of Hypersensitivity Reactions to Iopromide Differ by Sex, Race or across Regions/Countries? An Analysis of 152,233 Patients from Four Observational Studies and the Company's Pharmacovigilance Database.

OBJECTIVE: To analyze the potential impact of patients' sex, race and region/country on the risk of hypersensitivity reactions after intra-venous or intra-arterial administration of iopromide. METHODS: Two analyses were performed. 1.) The "Phase-IV-Analysis" evaluated an integrated pooled database of 4 non-interventional studies. 2.) The "GPV-Analysis" evaluated case reports from the company's pharmacovigilance database.The Phase-IV-Analysis was a nested case-control analysis of patients who received an injection of iopromide 300/370 mg iodine/mL. Cases had typical/unequivocal HSRs as defined by the ACR Committee on Drugs and Contrast Media 2018.The GPV-Analysis was based on HSR case reports in the company database. Exposure estimates were derived from sales/market research data. RESULTS: The Phase-IV-Analysis comprised 152,233 patients from 37 countries. In the full-analysis-set 145,033, 59,412 and146,649 patients were included in the sex, race and region/country cohort, respectively. The GPV-Analysis was based on 78.72 million administrations for sex and 118.56 million administrations for region/country. No GPV exposure data by race was available. SEX: Phase-IV-Analysis: The HSR-incidence was significantly higher for women (0.72%) vs. men (0.55%) (p ≤ 0.0001). The unadjusted odds ratio (OR) was 1.3 (CI 1.154; 1.499), the adjusted OR was 1.156 (CI 1.006; 1.328) (p = 0.04).GPV-Analysis: Reporting rates were 0.0102% for women and 0.0075% for men (p < 0.0001). OR: 1.36 (CI 1.3; 1.43). RACE: Phase-IV-Analysis: No significantly different HSR incidences for white (0.70%) and Asian (0.61%) patients (p = 0.3094) were detected. REGION/COUNTRY: Phase-IV-Analysis: The overall world HSR-incidence was 0.62%. Europe: 0.52%, Asia: 0.70%, USA: 0.75%, Germany: 0.51%, China: 0.41%, South Korea: 0.76%.GPV-Analysis: The overall world HSR-reporting rate was 0.015%, varying across regions/countries. CONCLUSION: Women showed a slightly higher risk for HSRs than men. Impact of race was not found. HSR-reporting varied by region/country. ADVANCES IN KNOWLEDGE: Risk for HSRs was increased by female sex but not by race or region/country.

Clinical Efficacy of Gadobutrol: Review of Over 25 Years of Use Exceeding 100 Million Administrations.

BACKGROUND: Gadobutrol has been administered more than 100 million times worldwide, since February 1998, that is, over the last 25 years. Numerous clinical studies in a broad range of indications document the long-term experience with gadobutrol. OBJECTIVE: The aim of this study was to provide a literature-based overview on gadobutrol's efficacy in 9 approved indications and use in children. MATERIALS AND METHODS: Efficacy results in patients of all age groups including sensitivity, specificity, accuracy, and positive/negative predictive values were identified by a systematic literature search on Embase until December 31, 2022. Nine approved indications were considered: central nervous system (CNS), magnetic resonance angiography (MRA), breast, heart, prostate, kidney, liver, musculoskeletal, whole body, and various indications in children. RESULTS: Sixty-five publications (10 phase III, 2 phase IV, 53 investigator-initiated studies) reported diagnostic efficacy results obtained from 7806 patients including 271 children, at 369 centers worldwide. Indication-specific sensitivity ranges were 59%-98% (CNS), 53%-100% (MRA), 80%-100% (breast), 64%-90% (heart), 64%-96% (prostate), 71-85 (kidney), 79%-100% (liver), 53%-98% (musculoskeletal), and 78%-100% (children). Indication-specific specificity ranges were 75%-100% (CNS), 64%-99% (MRA), 58%-98% (breast), and 47%-100% (heart). CONCLUSIONS: The evaluated body of evidence, consisting of 65 studies with 7806 patients, including 271 children and 7535 adults, showed that gadobutrol is an efficacious magnetic resonance imaging contrast agent for all age groups in various approved indications throughout the whole body.

Awareness of Breast Cancer Risk Factors in Women with vs. Without High Breast Density.

Purpose: Women with high breast density (HBD) carry an increased risk for breast cancer (BC). The aim of the study was to provide data on awareness and knowledge gaps among women with vs w/o HBD about BC risk factors (BCRFs), which is the basis for effective communication about screening. Patients and Methods: This was a web-based survey of 3000 women aged ≥30 and ≤70 from six countries. It comprised of 45 questions. T-tests and chi-square tests with False Discovery Rate adjustments were conducted as applicable, with significant differences reported at α=0.05. Results: Three-thousand women were included in the analysis, 733 (24.4%) had HBD. Overall, 39% of women were familiar with the concept of HBD in the context of BC. Thirty-one percent of women were aware of HBD as BCRF and for 24% of women HBD was personally applicable. A significantly higher proportion of women with HBD were aware of almost all BCRFs compared to women w/o HBD (p ≤ 0.05). Similarly, a significantly higher proportion of women with HBD have undergone screening procedures compared to women w/o HBD (p ≤ 0.05). Women with HBD were significantly better aware of basic facts about BC (p ≤ 0.05). A total of 1617 women underwent mammography, 904 ultrasound and 150 MRI during their last screening. The most relevant source of information about BC was the health care professional, as reported by 63% of women. Conclusion: Overall 39% of women were familiar with HBD as BCRF. Lack of BCRF awareness may contribute to delayed screenings, missed opportunities for early detection, and potentially poorer outcomes for individuals with dense breast tissue. Thus, this information should be communicated more widely.

Clinical Safety of Gadobutrol: Review of Over 25 Years of Use Exceeding 100 Million Administrations.

BACKGROUND: The macrocyclic gadolinium-based contrast agent gadobutrol was introduced to the market in February 1998. Over the last 25 years, gadobutrol has been administered more than 100 million times worldwide providing a wealth of data related to safety. OBJECTIVE: The aim of this study was to perform a thorough review and status update on gadobutrol's safety. MATERIALS AND METHODS: Safety data from the clinical phase II-IV program and postmarketing surveillance were descriptively analyzed from February 1998 until December 31, 2022. Literature on special at-risk populations and specific safety aspects was critically summarized. RESULTS: Forty-five clinical phase II-IV studies recruited 7856 patients receiving gadobutrol. Drug-related adverse events (AEs) were reported in 3.4% and serious AEs in <0.1% of patients. Nausea (0.7%) and dysgeusia (0.4%) were the most reported AEs. All other drug-related AEs occurred ≤0.3%. After more than 100 million gadobutrol administrations, overall adverse drug reactions (ADRs) from postmarketing surveillance (including clinical trials) were rare with an overall reporting rate of 0.0356%, hypersensitivity reactions (0.0147%), nausea (0.0032%), vomiting (0.0025%), and dyspnea (0.0010%). All other ADRs were <0.001%. No trend for higher rates of AEs was found in patients with reduced renal or liver function. Seven clinical studies reported safety findings in 7292 children ≤18 years, thereof 112 newborns/toddlers younger than 2 years. Overall, 61 ADRs (0.84%) were reported, including 3 serious ones. Adverse events in patients ≥65 years of age ("elderly") were significantly less frequent than in younger patients. A total of 4 reports diagnostic of or consistent with nephrogenic systemic fibrosis have been received. No causal relationship has been established between clinical signs and symptoms and the presence of small amounts of gadolinium in the body in patients with normal renal function after use of gadobutrol. CONCLUSIONS: More than 100 million administrations worldwide have shown gadobutrol's well-established benefit-risk profile in any approved indication and populations.

Iopromide for Contrast-Enhanced Mammography: A Systemic Review and Meta-Analysis of Pertinent Literature.

Background: Contrast-enhanced mammography (CEM) is an emerging breast imaging modality. Clinical data is scarce. Objectives: To summarize clinical evidence on the use of iopromide in CEM for the detection or by systematically analyzing the available literature on efficacy and safety. Design: Systematic review and meta-analysis. Data sources and methods: Iopromide-specific publications reporting its use in CEM were identified by a systematic search within Bayer's Product Literature Information (PLI) database and by levering a recent review publication. The literature search in PLI was performed up to January 2023. The confirmatory-supporting review publication was based on a MEDLINE/EMBASE + full text search for publications issued between September 2003 and January 2019. Relevant literature was selected based on pre-defined criteria by 2 reviewers. The comparison of CEM vs traditional mammography (XRM) was performed on published results of sensitivity and specificity. Differences in diagnostic parameters were assessed within a meta-analysis. Results: Literature search: A total of 31 studies were identified reporting data on 5194 patients. Thereof, 19 studies on efficacy and 3 studies on safety. Efficacy: in 11 studies comparing iopromide CEM vs XRM, sensitivity was up to 43% higher (range 1%-43%) for CEM. Differences in specificity were found to be in a range of -4% to 46% for CEM compared with XRM. The overall gain in sensitivity for CEM vs XRM was 7% (95% CI [4%, 11%]) with no statistically significant loss in specificity in any study assessed. In most studies, accuracy, positive predictive value, and negative predictive value were found to be in favor of CEM. In 2 studies comparing CEM with breast magnetic resonance imaging (bMRI), both imaging modalities performed either equally well or CEM tended to show better results with respect to sensitivity and specificity. Safety: eight cases of iopromide-related adverse drug reactions were reported in 1022 patients (0.8%). Conclusions: Pertinent literature provides evidence for clinical utility of iopromide in CEM for the detection or confirmation of breast cancer. The overall gain in sensitivity for iopromide CEM vs XRM was 7% with no statistically significant loss in specificity.

Estimation of menstrual blood loss volume based on menstrual diary and laboratory data.

BACKGROUND: Abnormal uterine bleeding is often investigated in clinical studies and critical to identify during gynecological consultation. The current standard for quantification of menstrual blood loss is the alkaline-hematin-method. However, this method is expensive and inconvenient for patients. Bleeding diaries, although widely used, provide only qualitative information on menstrual blood loss. Other methods have been developed, but still do not provide reliable quantitative data. METHODS: We estimated blood loss volume using data from two clinical studies in women suffering abnormal menstrual bleeding. These estimations were derived from mixed linear models based on diary data, hematological parameters and age. To validate the models, we applied our results to data from a third study with a similar patient population. RESULTS: The resulting best fitting model uses diary entries on bleeding intensity at a particular day, information on occurrence and frequency of single bleeding intensities in defined time windows, hemoglobin and ferritin values and age of the patient all as predictors of menstrual blood loss volume. Sensitivity and specificity for the diagnosis of excessive bleeding were 87% and 70%, respectively. Our model-based estimates reflect the subjective assessment by physicians and patients in the same way as the measured values do.When applying the model to an independent study, we found a correlation of 0.73 between estimated and measured values for the blood loss in a single day. Further models with reduced number of parameters (simplified for easier practical use) still showed correlation values between 0.69 and 0.73. CONCLUSIONS: We present a method for estimating menstrual blood loss volume in women suffering from prolonged or excessive menstrual bleeding. Our statistical model includes entries from bleeding diaries, laboratory parameters and age and produces results which correlate well with data derived by the alkaline-hematin-method. Therefore, this model may be used to estimate menstrual blood loss volume in both routine gynecological counseling and clinical studies.

The levonorgestrel-releasing intrauterine system provides a reliable, long-term treatment option for women with idiopathic menorrhagia.

OBJECTIVES: Idiopathic menorrhagia (IM) is an important clinical challenge. The levonorgestrel-releasing intrauterine system (LNG IUS) provides an effective treatment option as shown by multiple small clinical studies. In this analysis of combined data, we describe the time course of relative change in menstrual blood loss (MBL) from baseline up to 5 years. The results of two different methods to assess MBL were merged. METHODS: We pooled and analyzed five prospective, randomized clinical studies investigating the effect of the LNG IUS on IM in a total of 230 women. Four studies assessed MBL by using the pictorial blood loss assessment chart (PBAC) and one study used the alkaline hematin method. We gathered data on percentage change from baseline after 3 and 6 months, and annually up to 5 years. In addition we analyzed results on hemoglobin (Hb) and serum ferritin (S-Fe). RESULTS: MBL data was available after 3 and 6 months from 165 and 152 patients, respectively, and after 1 year from 51 patients. Long-term data up to 3 and 5 years was available for 28 and 10 patients, respectively. Not all studies provided data for all time points. Median (interquartile range) MBL decreased from baseline by -84.5% (-93.3; -63.6%) after 3 months, by -92.9% (-97.6; -81.1%) and by -93.8% (-98.8; -81.1%) after 6 months and 1 year, respectively (P < 0.0001, all time points). After 2 and 5 years the decrease was more than 96%. In parallel, Hb and S-Fe increased significantly. CONCLUSION: The LNG IUS rapidly induced clinically and statistically significant long-term reductions in MBL, paralleled by increases in Hb and S-Fe levels.