Psychological characteristics and structural brain changes in women with endometriosis and endometriosis-independent chronic pelvic pain.

STUDY QUESTION: Are there neurobiological changes induced by endometriosis? SUMMARY ANSWER: Women with endometriosis demonstrate specific neurobiological changes distinct from those in patients with chronic pelvic pain (CPP) in the absence of endometriosis. WHAT IS KNOWN ALREADY: Endometriosis is a chronic disease affecting women of reproductive age that presents with pain and infertility often accompanied by comorbid mental disorders. Only one study with a number of limitations has investigated changes in gray matter volumes and functional connectivity in a small group of patients with endometriosis. STUDY DESIGN, SIZE, DURATION: This prospective study recruited 53 women undergoing a laparoscopy due to suspicion of symptomatic endometriosis and 25 healthy, pain-free women. Clinical and psychological characteristics, thermal pain perception, and voxel- and surface-based morphology were assessed in all study participants. Thereafter, the patients underwent a laparoscopy, where endometriosis was either histologically confirmed and removed, or ruled out. Correspondingly, patients were assigned into the group with endometriosis (n = 27) or with endometriosis-independent CPP (n = 26) and compared to the pain-free controls. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study groups were generally representative for the population of women with endometriosis. Sociodemographic, medical, clinical, and psychological characteristics were collected using various questionnaires and a structured clinical interview. Thermal pain perception and voxel- and surface-based morphometry were assessed using thermode and MRI, respectively. MAIN RESULTS AND THE ROLE OF CHANCE: Despite comparable pain intensity and burden of mental disorders, both patient groups demonstrated distinct neurobiological patterns. Women with endometriosis exhibited increased gray matter volume (GMV) in the left cerebellum, lingual gyrus and calcarine gyrus, compared to those with endometriosis-independent CPP. Patients with CPP had decreased GMV in the right cerebellum as compared to controls. Dysmenorrhoea severity correlated positively with GMV in the left inferior parietal lobule, whereas depressive symptoms were associated with decreased GMV in the right superior medial gyrus across patient groups. Dyspareunia correlated negatively with cortical thickness in the left inferior temporal gyrus and left middle temporal gyrus. LIMITATIONS, REASONS FOR CAUTION: The study groups differed in a few baseline-characteristics, including educational levels, smoking and BMI. While measuring pain perception thresholds, we did not attempt to mimic CPP by placement of the thermode on the abdominal wall. WIDER IMPLICATIONS OF THE FINDINGS: Changes in gray matter volume associated with endometriosis differ from those observed in women with endometriosis-independent CPP. Our results underline an involvement of the cerebellum in pain perception and the pathogenesis of pain associated with endometriosis. STUDY FUNDING/COMPETING INTEREST(S): This work was funded by the START Program of the Faculty of Medicine, RWTH Aachen, Germany, and supported by the International Research Training Group (IRTG 2150) of the German Research Foundation (DFG)-269953372/GRK2150, Germany. S.T. was supported by postdoctoral fellowship of the Faculty of Medicine, RWTH Aachen, Germany. There are no conflicts of interest. TRIAL REGISTRATION NUMBER: DRKS00021236.

Endometriosis, psychiatric comorbidities and neuroimaging: Estimating the odds of an endometriosis brain.

Endometriosis is a chronic pain disorder that affects young women, impairing their physical, mental and social well-being. Apart from personal suffering, it imposes a significant economic burden on the healthcare system. We analyzed studies reporting comorbid mental disorders in endometriosis based on the ICD/DSM criteria, discussing them in the context of available neuroimaging studies. We postulate that at least one-third of endometriosis patients suffer from mental disorders (mostly depression or anxiety) and require psychiatric or psychotherapeutic support. According to three neuroimaging studies involving patients with endometriosis, brain regions related not only to pain processing but also to emotion, cognition, self-regulation and reward likely constitute the so-called "endometriosis brain". It is not clear, however, whether the neurobiological changes seen in these patients are caused by chronic pain, mental comorbidities or endometriosis itself. Given the paucity of high-quality data on mental comorbidities and neurobiological correlates in endometriosis, further research is needed.

Treatment and outcome in metastatic lobular breast cancer in the prospective German research platform OPAL.

PURPOSE: Evidence about routine treatment and outcome of patients with invasive lobular cancer (ILC) is limited, especially regarding metastatic disease. Here we present prospective real-world data of patients with metastatic ILC (mILC) as compared to patients with metastatic invasive ductal cancer (mIDC) receiving systemic therapy in routine care in Germany. METHODS: Prospective data on patient and tumor characteristics, treatments, and outcomes of patients with mILC (n = 466) and mIDC (n = 2100), recruited between 2007 and 2021 into the Tumor Registry Breast Cancer/OPAL were analyzed. RESULTS: Compared to mIDCs, patients with mILC were older at start of first-line treatment (median 69 vs. 63 years) and had more often lower grade (G1/G2: 72.8% vs. 51.2%), hormone receptor (HR)-positive (83.7% vs. 73.2%) and less often HER2-positive (14.2% vs. 28.6%) tumors, which metastasized more frequently to the bone (19.7% vs. 14.5%) or peritoneum (9.9% vs. 2.0%), and less frequently to the lungs (0.9% vs. 4.0%). Median OS of patients with mILC (n = 209) and mIDC (n = 1158) was 30.2 months [95% confidence interval (CI) 25.3, 36.0] and 33.7 months [95% CI 30.3, 37.9], respectively. Multivariate survival analysis did not show a significant prognostic impact of the histological subtype [HR mILC vs. mIDC 1.18 (95% CI 0.97-1.42)]. CONCLUSION: Overall, our real-world data confirm clinicopathological differences between mILC and mIDC breast cancer patients. Despite patients with mILC presenting with some favorable prognostic factors, ILC histopathology was not associated with a better clinical outcome in multivariate analysis, suggesting the need for more tailored treatment strategies for patients with the lobular subtype.

Association of RAD51 with homologous recombination deficiency (HRD) and clinical outcomes in untreated triple-negative breast cancer (TNBC): analysis of the GeparSixto randomized clinical trial.

BACKGROUND: Current genetic and genomic tests measuring homologous recombination deficiency (HRD) show limited predictive value. This study compares the performance of an immunohistology-based RAD51 test with genetic/genomic tests to identify patients with HRD primary triple-negative breast cancer (TNBC) and evaluates its accuracy to select patients sensitive to platinum-based neoadjuvant chemotherapy (NACT). PATIENTS AND METHODS: This is a retrospective, blinded, biomarker analysis from the GeparSixto randomized clinical trial. TNBC patients received neoadjuvant paclitaxel plus Myocet®-nonpegylated liposomal doxorubicin (PM) or PM plus carboplatin (PMCb), both arms including bevacizumab. Formalin-fixed paraffin-embedded (FFPE) tumor samples were laid on tissue microarrays. RAD51, BRCA1 and γH2AX were quantified using an immunofluorescence assay. The predictive value of RAD51 was assessed by regression models. Concordance analyses were carried out between RAD51 score and tumor BRCA (tBRCA) status or genomic HRD score (Myriad myChoice®). Associations with pathological complete response (pCR) and survival were studied. Functional HRD was predefined as a RAD51 score ≤10% (RAD51-low). RESULTS: Functional HRD by RAD51-low was evidenced in 81/133 tumors (61%). RAD51 identified 93% tBRCA-mutated tumors and 45% non-tBRCA mutant cases as functional HRD. The concordance between RAD51 and genomic HRD was 87% [95% confidence interval (CI) 79% to 93%]. In patients with RAD51-high tumors, pCR was similar between treatment arms [PMCb 31% versus PM 39%, odds ratio (OR) 0.71, 0.23-2.24, P = 0.56]. Patients with RAD51-low tumors benefited from PMCb (pCR 66% versus 33%, OR 3.96, 1.56-10.05, P = 0.004; interaction test P = 0.02). This benefit maintained statistical significance in the multivariate analysis. Carboplatin addition showed similar disease-free survival in the RAD51-high [hazard ratio (HR) 0.40, log-rank P = 0.11] and RAD51-low (0.45, P = 0.11) groups. CONCLUSIONS: The RAD51 test identifies tumors with functional HRD and is highly concordant with tBRCA mutation and genomic HRD. RAD51 independently predicts clinical benefit from adding Cb to NACT in TNBC. Our results support further development to incorporate RAD51 testing in clinical decision-making.

Reconstructing tumor history in breast cancer: signatures of mutational processes and response to neoadjuvant chemotherapy⋆.

BACKGROUND: Different endogenous and exogenous mutational processes act over the evolutionary history of a malignant tumor, driven by abnormal DNA editing, mutagens or age-related DNA alterations, among others, to generate the specific mutational landscape of each individual tumor. The signatures of these mutational processes can be identified in large genomic datasets. We investigated the hypothesis that genomic patterns of mutational signatures are associated with the clinical behavior of breast cancer, in particular chemotherapy response and survival, with a particular focus on therapy-resistant disease. PATIENTS AND METHODS: Whole exome sequencing was carried out in 405 pretherapeutic samples from the prospective neoadjuvant multicenter GeparSepto study. We analyzed 11 mutational signatures including biological processes such as APOBEC-mutagenesis, homologous recombination deficiency (HRD), mismatch repair deficiency and also age-related or tobacco-induced alterations. RESULTS: Different subgroups of breast carcinomas were defined mainly by differences in HRD-related and APOBEC-related mutational signatures and significant differences between hormone-receptor (HR)-negative and HR-positive tumors as well as correlations with age, Ki-67 and immunological parameters were observed. We could identify mutational processes that were linked to increased pathological complete response rates to neoadjuvant chemotherapy with high significance. In univariate analyses for HR-positive tumors signatures, S3 (HRD, P < 0.001) and S13 (APOBEC, P = 0.001) as well as exonic mutation rate (P = 0.002) were significantly correlated with increased pathological complete response rates. The signatures S3 (HRD, P = 0.006) and S4 (tobacco, P = 0.011) were prognostic for reduced disease-free survival of patients with chemotherapy-resistant tumors. CONCLUSION: The results of this investigation suggest that the clinical behavior of a tumor, in particular, response to neoadjuvant chemotherapy and disease-free survival of therapy-resistant tumors, could be predicted by the composition of mutational signatures as an indicator of the individual genomic history of a tumor. After additional validations, mutational signatures might be used to identify tumors with an increased response rate to neoadjuvant chemotherapy and to define therapy-resistant subgroups for future therapeutic interventions.

Tumor mutational burden and immune infiltration as independent predictors of response to neoadjuvant immune checkpoint inhibition in early TNBC in GeparNuevo.

BACKGROUND: The predictive value of tumor mutational burden (TMB), alone or in combination with an immune gene expression profile (GEP), for response to neoadjuvant therapy in early triple negative breast cancer (TNBC) is currently not known, either for immune checkpoint blockade (ICB) or conventional chemotherapy. PATIENTS AND METHODS: We obtained both whole exome sequencing and RNA-Seq data from pretreatment samples of 149 TNBC of the recent neoadjuvant ICB trial, GeparNuevo. In a predefined analysis, we assessed the predictive value of TMB and a previously developed immune GEP for pathological complete remission (pCR). RESULTS: Median TMB was 1.52 mut/Mb (range 0.02-7.65) and was significantly higher in patients with pCR (median 1.87 versus 1.39; P = 0.005). In multivariate analysis, odds ratios for pCR per mut/Mb were 2.06 [95% confidence intervals (CI) 1.33-3.20, P = 0.001] among all patients, 1.77 (95% CI 1.00-3.13, P = 0.049) in the durvalumab treatment arm, and 2.82 (95% CI 1.21-6.54, P = 0.016) in the placebo treatment arm, respectively. We also found that both continuous TMB and immune GEP (or tumor infiltrating lymphocytes) independently predicted pCR. When we stratified patients in groups based on the upper tertile of TMB and median GEP, we observed a pCR rate of 82% (95% CI 60% to 95%) in the group with both high TMB and GEP in contrast to only 28% (95% CI 16% to 43%) in the group with both low TMB and GEP. CONCLUSIONS: TMB and immune GEP add independent value for pCR prediction. Our results recommend further analysis of TMB in combination with immune parameters to individually tailor therapies in breast cancer.

[Intramedullary injection with tethered cord : Case report of a rare complication during spinal anesthesia]. / Intramedulläre Injektion bei "tethered cord" : Fallbericht einer seltenen Komplikation bei Spinalanästhesie.

Although very rare, severe neurological complications can occur when undergoing spinal anesthesia. This report describes and analyses a case of spinal injury due to an undiagnosed tethered cord (TC) during spinal anesthesia for a cesarean section of a 31-year-old woman expecting twins. As a consequence of spinal dysraphism during embryogenesis, an atypically low conus level can occur and increase the risk of injury during neuraxial anesthesia, especially in the absence of symptoms. Injuries can be caused by mechanical trauma from direct needle injury, hematoma or neurotoxicity from local anesthetics. Special attention should therefore be paid to frequent symptoms, such as a hairy nevus on the back, deformities of the feet or bladder and bowels, voiding and micturition dysfunction in order to reduce the risk of complications.

Higher rate of severe toxicities in obese patients receiving dose-dense (dd) chemotherapy according to unadjusted body surface area: results of the prospectively randomized GAIN study.

BACKGROUND: In routine clinical practice, chemotherapy doses are frequently capped at a body surface area (BSA) of 2.0 m2 or adjusted to an ideal weight for obese patients due to safety reasons. MATERIALS AND METHODS: Between August 2004 and July 2008, a total of 3023 patients were enrolled in the GAIN study, a randomized phase III adjuvant trial, comparing two types of dose-dense (dd) regimen [epirubicin, docetaxel and cyclophosphamide (iddETC) versus epirubicin and cyclophosphamide (EC) followed by docetaxel (T) plus capecitabine (X)]. We retrospectively evaluated a total of 555 patients with a BMI of ≥30 for safety and outcome. RESULTS: Eighteen percent of all patients were obese: 31% of those received chemotherapy according to an unadjusted BSA. For the remaining patients, BSA was adjusted to ideal weight or was capped at 2.0 m2. A total of 15% of obese patients receiving full (unadjusted) dose of chemotherapy versus 6% of obese patients with an adjusted BSA experienced febrile neutropenia (P = 0.003) and 9% versus 3% high-grade thrombopenia (P = 0.002). Overall, 17% versus 10% had a thromboembolic event (P = 0.017), which was high grade in 13% versus 6%, respectively (P = 0.019), and 3% versus 0.3% high-grade hot flushes (P = 0.013). Dizziness (5% versus 11%; P = 0.016), diarrhea (19% versus 27%; P = 0.033) and an increase in serum creatinine (7% versus 14%; P = 0.019) were higher in the adjusted group. However, no differences in disease-free survival (DFS) and overall survival (OS) were observed between non-obese patients, obese patients receiving full-dose chemotherapy or according to an adjusted BSA [5-year DFS 81% (confidence interval 79% to 83%) versus 82% (75% to 87%) versus 81% (76% to 84%); P = 0.761; 5-year OS 90% (88% to 91%) versus 86% (80% to 91%) versus 88% (84% to 91%); P = 0.143]. CONCLUSION: Obese patients receiving dd chemotherapy according to their real BSA have a higher risk of developing severe toxicities without influencing survival. Therefore, a dose adjustment of intense dd chemotherapy should be carried out to avoid life-threatening complications.

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.

[Case Report on Treatment of Metastatic Breast Cancer with Trastuzumab during Pregnancy]. / Fallbericht einer Trastuzumab-Therapie während der Schwangerschaft bei metastasiertem Mammakarzinom.

The increasing number of pregnant breast cancer patients calls for a therapy that is as efficient as possible. After 10 years of collecting data on pregnant breast cancer patients in the German Breast Group (GBG), proposals for diagnostic measures and therapy regarding this special situation have been developed on the basis of 500 observed cases. Chemotherapy is regarded as safe from the 14(th) week of gestation on, but it is strongly advised not to use trastuzumab. Adverse outcomes for the newborn were predominantly observed in cases of early preterms. In our department, a 29-year-old second gravida with metastatic breast cancer first diagnosed 7 years ago continued to receive trastuzumab treatment at her express request after detailed information and advice. Trastuzumab treatment had been started 1.5 years before the pregnancy after surgical removal of a lymph node metastasis. After 7 intravenous administrations at intervals of 3 weeks, an oligohydramnios occurred in the 24(th) week of pregnancy. For this reason, trastuzumab treatment was interrupted for 7 weeks, during which time the quantity of amniotic fluid returned to a normal level. As the 8(th) administration of trastuzumab led to a renewed oligohydramnios, the trastuzumab treatment was suspended until birth. The quantity of amniotic fluid having recovered to normal, labour was induced after 36 weeks of pregnancy, followed by a Caesarian section because of prolonged labour. The newborn boy showed no sign of respiratory or renal dysfunction and has developed normally, having at present reached the age of 3 years. From the few reported cases of pregnancies with trastuzumab therapy, it seems that an occurring oligohydramnios is the typical complication with the problem of life-threatening RDS after birth. Probably the reduction of amniotic fluid can be reversed by interrupting the trastuzumab therapy, as we observed in our case.

Downregulation of MTSS1 expression is an independent prognosticator in squamous cell carcinoma of the lung.

BACKGROUND: The metastasis suppressor 1 (MTSS1) is a newly discovered protein putatively involved in tumour progression and metastasis. MATERIAL AND METHODS: Immunohistochemical expression of MTSS1 was analysed in 264 non-small-cell lung carcinomas (NSCLCs). RESULTS: The metastasis suppressor 1 was significantly overexpressed in NSCLC compared with normal lung (P=0.01). Within NSCLC, MTSS1 expression was inversely correlated with pT-stage (P=0.019) and histological grading (P<0.001). NSCLC with MTSS1 downregulation (<20%) showed a significantly worse outcome (P=0.007). This proved to be an independent prognostic factor in squamous cell carcinomas (SCCs; P=0.041), especially in early cancer stages (P=0.006). CONCLUSION: The metastasis suppressor 1 downregulation could thus serve as a stratifying marker for adjuvant therapy in early-stage SCC of the lung.

Cancer cell invasion and EMT marker expression: a three-dimensional study of the human cancer-host interface.

Cancer cell invasion takes place at the cancer-host interface and is a prerequisite for distant metastasis. The relationships between current biological and clinical concepts such as cell migration modes, tumour budding and epithelial-mesenchymal transition (EMT) remains unclear in several aspects, especially for the 'real' situation in human cancer. We developed a novel method that provides exact three-dimensional (3D) information on both microscopic morphology and gene expression, over a virtually unlimited spatial range, by reconstruction from serial immunostained tissue slices. Quantitative 3D assessment of tumour budding at the cancer-host interface in human pancreatic, colorectal, lung and breast adenocarcinoma suggests collective cell migration as the mechanism of cancer cell invasion, while single cancer cell migration seems to be virtually absent. Budding tumour cells display a shift towards spindle-like as well as a rounded morphology. This is associated with decreased E-cadherin staining intensity and a shift from membranous to cytoplasmic staining, as well as increased nuclear ZEB1 expression.

Long-term outcomes of a randomized, open-label, phase II study comparing cabazitaxel versus paclitaxel as neoadjuvant treatment in patients with triple-negative or luminal B/HER2-negative breast cancer (GENEVIEVE).

BACKGROUND: The GENEVIEVE study, comparing neoadjuvant cabazitaxel versus paclitaxel in triple-negative breast cancer (TNBC) and luminal B/human epidermal growth factor receptor 2 (HER2)-negative breast cancer (BC), previously reported significant differences in pathological complete response (pCR) rates. Effects on long-term outcome are unknown. PATIENTS AND METHODS: GENEVIEVE randomized patients with cT2-3, any cN or cT1, cN+/pNSLN+, centrally confirmed TNBC or luminal B/HER2-negative BC (latter defined as estrogen/progesterone receptor-positive and >14% Ki-67-stained cells) to receive either cabazitaxel 25 mg/m2 q3w for four cycles or paclitaxel 80 mg/m2 weekly for 12 weeks. Anthracycline-containing chemotherapy was allowed in case of histologically proven invasive residuals as neoadjuvant treatment or after surgery as adjuvant treatment. Here we report the secondary endpoints invasive disease-free survival (iDFS), distant disease-free survival (DDFS), and overall survival (OS). RESULTS: Of the 333 patients randomized, 74.7% and 83.2% completed treatment in the cabazitaxel and paclitaxel arms, respectively. After a median follow-up of 89.3 months (interquartile range 68.8-97.3 months), 80 iDFS events (43 after cabazitaxel and 37 after paclitaxel) and 47 deaths (23 after cabazitaxel and 24 after paclitaxel) were reported. IDFS rates were not significantly different between the cabazitaxel and paclitaxel arms after a 3-year (83.6% versus 85.0%) and 5-year follow-up (76.2% versus 78.3%) [hazard ratio (HR) = 1.27, 95% confidence interval 0.82-1.96, P = 0.294], respectively. DDFS rates at 3 years (88.6% versus 87.8%) and 5 years (82.1% versus 82.8%) for cabazitaxel and paclitaxel were comparable (HR = 1.15, P = 0.573). Similarly, OS rates at 3 years (91.6% versus 91.8%) and 5 years (89.2% versus 86.8%) showed no significant differences (HR = 1.05, P = 0.872). Subgroup analysis for TNBC and luminal B/HER2-negative BCs indicated no significant variations in 3- or 5-year iDFS, DDFS, or OS. CONCLUSIONS: The significant differences in pCR rates observed in both treatment arms did not significantly impact long-term outcomes for patients treated with cabazitaxel versus paclitaxel in the GENEVIEVE trial.

PREPARE trial: a randomized phase III trial comparing preoperative, dose-dense, dose-intensified chemotherapy with epirubicin, paclitaxel and CMF versus a standard-dosed epirubicin/cyclophosphamide followed by paclitaxel ± darbepoetin alfa in primary breast cancer--results at the time of surgery.

BACKGROUND: Preoperative chemotherapy is a recommended treatment of both primary operable and locally advanced breast cancer. Strategies to improve efficacy include the use of anthracyclines, taxanes, and intensified dose with bone marrow support. PATIENTS AND METHODS: Patients received neoadjuvant epirubicin 90 mg/m(2) plus cyclophosphamide 600 mg/m(2) followed by paclitaxel 175 mg/m(2) (EC→T), each 3-weekly for four cycles (n = 370), or epirubicin 150 mg/m(2) followed by paclitaxel 225 mg/m(2) with pegfilgrastim followed by CMF (cyclophosphamide 500 mg/m(2), methotrexate 40 mg/m(2), fluorouracil 600 mg/m(2)) on days 1 and 8 (E(dd)→T(dd)→CMF), each 2-weekly and for three cycles (n = 363). Patients were randomly allocated to either simultaneous darbepoetin alfa (DA) (n = 356) or none (n = 377). RESULTS: Pathological complete response (pCR) rate (breast) was higher with E(dd)→T(dd)→CMF, 18.7% versus 13.2% with EC→T; P = 0.043, ypT0/Tis; ypN0 was reported in 20.9% versus 14.3% respectively; P = 0.019. Patients with grade 3 tumors and negative hormone receptor status had a significantly higher pCR rate. Mean hemoglobin values maintained higher with DA (13.6 versus 12.6 g/dl). E(dd)→T(dd)→CMF regimen showed more grade 3-4 mucositis, sensory neuropathy, and neurological complaints. Thromboembolic events were more frequent on DA (3% versus 6%; P = 0.055). CONCLUSION: Dose-dense and -intensified neoadjuvant chemotherapy with E(dd)→T(dd)→CMF was potentially superior to EC→T in terms of pCR. Primary use of DA did not affect pCR.

PREPARE trial: a randomized phase III trial comparing preoperative, dose-dense, dose-intensified chemotherapy with epirubicin, paclitaxel, and CMF versus a standard-dosed epirubicin-cyclophosphamide followed by paclitaxel with or without darbepoetin alfa in primary breast cancer--outcome on prognosis.

BACKGROUND: The objective of this study was to compare the effect of dose-intensified neoadjuvant chemotherapy with that of standard epirubicin plus cyclophosphamide followed by paclitaxel in combination with or without darbepoetin on survival in primary breast cancer. PATIENTS AND METHODS: A total of 733 patients received either four cycles of neoadjuvant epirubicin 90 mg/m(2) plus cyclophosphamide 600 mg/m(2) every 3 weeks followed by four cycles of paclitaxel 175 mg/m(2) every 3 weeks (EC→T), or three cycles of epirubicin 150 mg/m(2) every 2 weeks followed by three cycles of paclitaxel 225 mg/m(2) every 2 weeks followed by three cycles of combination chemotherapy with cyclophosphamide, methotrexate, and fluorouracil (E(dd)→T(dd)→CMF). The patients were randomly assigned to receive darbepoetin or none. The primary objective was to demonstrate a superior disease-free survival (DFS) of E(dd)→T(dd)→CMF compared with EC→T. RESULTS: Estimated 3-year DFS was 75.8% with EC→T versus 78.8% with E(dd)→T(dd)→CMF [hazard ratio (HR) 1.14; P = 0.37] and overall survival (OS) 88.4% versus 91.5% (HR 1.26; P = 0.237). Three-year DFS was 74.3% with darbepoetin versus 80.0% without (HR 1.31; P = 0.061) and OS 88.0% versus 91.8% (HR 1.33; P = 0.139). Patients with a pathologically documented complete response [pathological complete response (pCR)] had a significantly better DFS compared with those without achieving a pCR (estimated 3-year DFS: 89.2% versus 74.9%; HR 2.27; P = 0.001). CONCLUSION: Neoadjuvant dose-intensified chemotherapy compared with standard chemotherapy did not improve DFS, whereas the addition of darbepoetin might have detrimental effects on DFS.

Video sequence compared to conventional freeze image documentation: a way to improve the sonographic assessment of breast lesions?

PURPOSE: To compare video sequence and conventional freeze image documentation of breast ultrasound findings with respect to lesion assessment and the diagnostic power of established ultrasound characteristics. MATERIALS AND METHODS: Digitally stored freeze images and corresponding video sequences of 50 breast lesions were randomly arranged and interpreted by eight investigators with breast ultrasound training and experience. Established ultrasound criteria were documented on a standardized classification form for every lesion. The investigators were blinded to the clinical and radiological findings, patient characteristics including age, and lesion histology. Statistical analysis compared both groups and correlated the results with the lesion histology. A receiver operating characteristics (ROC) analysis was performed to evaluate the diagnostic performance of ultrasound criteria in lesions documented by video sequences compared to freeze images. RESULTS: Breast lesions were assessed almost identically in video sequences and freeze images. Only the features echogenic halo, orientation, and margin varied among both groups. The dynamic features compressibility and mobility were highly statistically significant correlated with the lesion histology in the video sequence interpretation (p < 0.0001). ROC analysis revealed almost identical diagnostic accuracy in both groups (area under the curve 0.719 for video sequences and 0.762 for freeze images). CONCLUSION: Video sequences are an appropriate tool to document lesions in breast ultrasound. In contrast to our hypothesis, however, this tool did not improve the diagnostic power of established ultrasound characteristics compared to freeze image documentation.

Resistance to activated protein C and impaired TFPI activity in women with previous hormone-induced venous thromboembolism.

INTRODUCTION: Hormonal contraception is a well-known risk factor for venous thromboembolism (VTE). APC resistance and impaired functions of protein S and TFPI are thought to play an important role in the pathogenesis of hormone-related VTE. It is unknown, whether women, who develop VTE during hormonal contraception possess a vulnerability in these pathways, making them susceptible to thrombosis. MATERIALS AND METHODS: Plasma samples were obtained from 57 premenopausal women in average 15.3 years after hormone-associated VTE and from 31 healthy controls. Thrombin generation at high tissue factor (TF) in the absence and in the presence of activated protein C (APC) and at low TF without and with inhibiting anti-protein S- and anti-TFPI-antibodies was measured via calibrated automated thrombography. RESULTS: Women with previous hormone-related thrombosis had higher thrombin generation at low TF, higher APC resistance, protein S- and TFPI ratios, differences: 219.9 nM IIa.min (95%CI:90.4 to 349.3); 1.88 (95%CI:0.71 to 3.05); 0.13 (95%CI:0.01 to 0.26) and 0.19 (95%CI:0.08 to 0.30), respectively. Thrombin generation at high TF without APC did not differ between the groups. Smoking decreased thrombin generation at low TF by -222.6 nM IIa.min (95%CI: -381.1 to -64.1), the APC sensitivity ratio by -2.20 (95%CI: -3.63 to -0.77) and the TFPI ratio by -0.16 (95%CI: -0.29 to -0.03), but did not influence thrombin generation at high TF. DISCUSSION: We demonstrated impairment of the protein S/TFPI system and increased APC resistance in women with previous hormone-induced VTE. Smoking decreased thrombin generation at assay conditions, dependent on the function of the TFPI system.

Endocrine stress response in pregnancy and 12 weeks postpartum - Exploring risk factors for postpartum depression.

Pregnancy and the postpartum period are characterized by physiological alterations in cortisol and cortisone levels. In the present study, we sought to explore the risk factors for postpartum depression (PPD) and self-remitting postpartum adjustment disorder (AD) and whether cortisol/cortisone metabolism might have any bearing on them. Hair samples from 196 participants (mean age = 31.44, SD = 4.71) were collected at two time points (1-6 days after childbirth and 12 weeks postpartum) to determine the cumulative hair cortisol (HCC) and hair cortisone (HCNC) exposure in the third trimester and during the 12 weeks postpartum. Compared to the non-depressed group (ND, n = 141), more women in the AD (n = 28) and PPD (n = 27) groups had a personal or family history of depression and more stressful life events. Compared to ND and PPD, more women in the AD group had birth-related complications with their children being more often transferred to a pediatric ward. The factors associated with PPD were found to include being unmarried and having a lower household income, less support at home, more subjectively perceived stress after childbirth and lower maternal sensitivity. The natural decrease in HCC concentration from the third trimester to 12 weeks postpartum was significant only in the ND and AD groups, but not in PPD. In summary, prolonged subjectively perceived postpartum stress associated with living situations may contribute to the development of PPD while birth- and child-related complications are likely to trigger brief episodes of AD. Only in ND and AD, the pregnancy-related physiological changes in glucocorticoid levels return to the pre-pregnancy baseline after 12 weeks. Our observations point to the difference between the ND and PPD groups in glucocorticoid metabolism-related postpartum adjustment, which may be a factor in the development of PPD.

Effect of blood loss during caesarean section on coagulation parameters.

INTRODUCTION: Venous thrombosis is the leading cause of pregnancy-related maternal morbidity and mortality. The thrombosis risk is increased by caesarean section and blood loss, though underlying mechanisms of these prothrombotic changes remain unknown. MATERIALS AND METHODS: This prospective study recruited 50 pregnant women at term undergoing elective caesarean section at University Hospital Magdeburg, Germany. Blood loss during surgery was correlated with the changes in total protein S, full length TFPI (TFPIfl), prothrombin, the endogenous thrombin potential (ETP) and resistance to activated protein C (APCsr) determined via calibrated automated thrombography. RESULTS: Mean blood loss was 506 ml (95%CI: 456 to 557 ml). Total protein S was 0.63 (95%CI: 0.60 to 0.67) U/ml preoperatively, decreased by 14.8% after caesarean section and almost normalised five days later. TFPIfl was 0.47 (95%CI: 0.41 to 0.53) U/ml before, remained unchanged immediately after and increased by 11.5% five days after surgery. Prothormbin was 1.10 (95%CI: 1.03 to 1.16) U/ml preoperatively, reduced by 10.4% immediately after and increased again five days after caesarean section, exceeding the preoperative values by 4.4% (-0.7 to 9.6). The ETP decreased by 3.9%, whereas the APCsr increased by 37.0% immediately after caesarean section. The changes in total protein S, prothrombin, thrombin generation and APC resistance showed a trend to be more pronounced in the subgroups with higher blood loss. DISCUSSION: Moderate blood loss during caesarean section hardly reduces thrombin generation but aggravates pregnancy-induced APC resistance and combined deficiency of TFPI and protein S, which can account for the increased thrombosis risk in early puerperium.