Combined Expression of HGFR with Her2/neu, EGFR, IGF1R, Mucin-1 and Integrin α2ß1 Is Associated with Aggressive Epithelial Ovarian Cancer.

Hepatocyte growth factor receptor (HGFR), also known as c-mesenchymal-epithelial transition factor (c-MET), plays a crucial role in the carcinogenesis of epithelial ovarian cancer (EOC). In contrast, the mechanisms contributing to aberrant expression of HGFR in EOC are not fully understood. In the present study, the expression of HGFR with its prognostic and predictive role was evaluated immunohistochemically in a cohort of 42 primary ovarian cancer patients. Furthermore, we analyzed the dual expression of HGFR and other druggable biomarkers. In the multivariate Cox regression analysis, high HGFR expression was identified as an independent prognostic factor for a shorter progression-free survival (PFS) (hazard ratio (HR) 2.99, 95% confidence interval (CI95%) 1.01-8.91, p = 0.049) and overall survival (OS) (HR 5.77, CI95% 1.56-21.34, p = 0.009). In addition, the combined expression of HGFR, human epidermal growth factor receptor 2 (Her2/neu), epithelial growth factor receptor (EGFR), insulin-like growth factor 1 (IGF1R), Mucin-1 and Integrin α2ß1 further significantly impaired PFS, platinum-free interval (PFI) and OS. Protein co-expression analyses were confirmed by transcriptomic data in a large, independent cohort of patients. In conclusion, new biomarker-directed treatment targets were identified to fight poor prognosis of primary EOC.

Late Presentation at Primary Diagnosis of Breast Cancer: Patients' Personality Characteristics and Attitudes.

INTRODUCTION: Breast cancer (BC) is the most common cancer in women worldwide. Despite screening and information efforts, about 10% of patients present with tumor size T3 or T4 at primary diagnosis. Late presentation is associated with more advanced tumor stage and consecutively with worse survival rates. OBJECTIVE: This study aimed to evaluate whether patients with a late presentation at primary BC diagnosis differ in their personality from those with early diagnosis. METHODS: In this bicentric, observational study, personality traits, positive and negative affectivity, anxiety, spirituality, illness beliefs, and sociodemographic characteristics were assessed in BC patients who presented with T-stages 3 or 4 (late presenters) and T-stages 1 or 2 (controls) at initial diagnosis. RESULTS: Forty patients (20 controls, 20 late presenters) were interviewed. "Late presenters" perceived their disease as long lasting and had significantly more "positive affectivity" in the current trait. Although no significant associations were found, there was a trend for late presenters to have higher education levels, less spiritual longing, less accurate explanation of their illness, less anxiety in the trait scale, and more conscientiousness than the controls. CONCLUSION: As patients with late presentation for BC differ in specific psychological and sociodemographic characteristics from patients with early BC, the findings of this pilot project warrant additional investigations to identify further specific characteristics and motivations. Identifying patients at risk for late presentation and encouraging them to accept an earlier diagnosis could help to improve their therapy and, finally, their outcome.

Post-Neoadjuvant Gemcitabine and Cisplatin with Regional Hyperthermia for Patients with Triple-Negative Breast Cancer and Non-pCR after Neoadjuvant Chemotherapy: A Single-Institute Experience.

BACKGROUND: Patients with triple-negative primary breast cancer (TNBC) who have residual invasive carcinoma after neoadjuvant chemotherapy have poor prognosis. Proven adjuvant approaches to reduce the risk of recurrence and improve outcome in patients with non-pathological complete response (non-pCR) are limited. METHODS: From our institutional registry, a consecutive case series of patients with operable, unilateral, primary invasive noninflammatory early TNBC of stage I-IIIB and pathologically verified residual cancer cells (no pathological complete response) after neoadjuvant chemotherapy underwent adjuvant treatment with gemcitabine plus cisplatin combined with regional hyperthermia. For quality assurance, we analyzed feasibility, efficacy, and toxicity of all treated patients. Outcome was evaluated for the entire group of patients as well as for the subgroups of patients with or without lymph node involvement at baseline (cN0/ cN+). RESULTS: From August 2012 to January 2019, we offered this treatment to 53 patients at our center as part of routine care. The median follow-up was 38 months. The majority of patients (64.2%) had cT2 tumors at baseline. Twenty-four patients (45%) were clinically node positive as evaluated by sonography. Thirty-nine patients (74%) had grade 3, and 14 patients (26%) had grade 2 tumors. Forty-one patients (76%) showed a regression grade 1 according to Sinn. Patients received a median of six treatment cycles of gemcitabine and cisplatin (range 1-6) combined with 12 applications of regional hyperthermia (median 12, range 2-12). Disease-free survival (DFS) at 3 years was 57.5%. In patients with no lymph node involvement at baseline (cN0), DFS at 3 years was significantly higher than in initially node-positive (cN+) patients (80 vs. 31%; p = 0.001). Overall survival (OS) at 3 years was 81.6%. In patients with no lymph node involvement at baseline (cN0), OS at 3 years was significantly higher than in node-positive (cN+) patients (93 vs. 70.4%; p = 0.02). Overall, grade 3/4 toxicities were leukopenia (38%), thrombocytopenia (4%), and anemia (4%). CONCLUSION: After standard neoadjuvant chemotherapy containing anthracycline plus cyclophosphamide followed by taxanes, addition of adjuvant gemcitabine plus cisplatin in combination with regional hyperthermia was safe and effective in TNBC patients with non-pCR.

Growth restricted placentas show severely reduced volume of villous components with perivascular myofibroblasts.

INTRODUCTION: The restricted placental growth in IUGR is associated with a simultaneous weight and volume restriction for the placental villous tree. It is unknown whether the whole villous tree or only specific parts of it are growth restricted in IUGR. In the case of uniform growth restriction of the villous tree, IUGR placentas could be interpreted as symmetrically smaller versions of normal placentas. Otherwise, IUGR placentas would be morphologically, developmentally and, therefore, functionally different from normal placentas. METHODS: We investigated ten normal and eleven IUGR placentas with quantitative microscopic techniques. Using immunohistochemical detection of placental myofibroblasts (γ-sm-actin) and foetoplacental endothelium (CD34), we distinguished between more centrally located villi showing the presence of myofibroblasts (contractile villi; C-villi) and more peripherally located villi showing the absence of myofibroblasts (noncontractile villi; NC-villi). RESULTS: Compared to normal placentas, IUGR placentas showed significantly reduced mean volume of C-villi, but not of NC-villi. The volume of vessels in both, C-villi and NC-villi, was significantly reduced in IUGR. Additional stereologic estimates confirmed the known alterations in the morphology of NC-villi in IUGR. DISCUSSION: Our results suggest that IUGR placentas are not just smaller but morphologically (and therefore functionally) different from normal placentas. We propose that the reduced volume of C-villi and vessels in C-villi reflects a developmental disturbance in the formation of C-villi, which are mostly composed of stem villi. As such, key pathological villous alterations in IUGR placentas could begin before the formation of intermediate and terminal villi, possibly already in the late first trimester of pregnancy.

Immune Heterogeneity Between Primary Tumors and Corresponding Metastatic Lesions and Response to Platinum Therapy in Primary Ovarian Cancer.

CD3+ and CD8+ lymphocytes are well known prognostic markers in primary ovarian cancer. In contrast, the predictive value of the immune infiltrate concerning treatment response and the involvement of immune heterogeneity between primary and metastatic lesions are poorly understood. In this study, the immune infiltrate of 49 primary tumors and 38 corresponding lesions in the omentum (n = 23) and the peritoneum (n = 15) was immunohistochemically analyzed and correlated with clinicopathological factors and platinum-sensitivity. Immune heterogeneity was observed between paired primary and metastatic lesions for all immune cell phenotypes. The stromal immune infiltrate was higher in the omental lesions than in the primary tumors, which was reflected by CD45 (p=0.007), CD3 (p=0.005), CD8 (p=0.012), and PD-1 (programmed cell-death protein 1) (p=0.013). A higher stromal infiltrate of both CD45+ and CD3+ cells in the omental lesions was associated with the detection of lymph node metastasis (CD45, p=0.018; CD3, p=0.037). Platinum-sensitive ovarian cancers revealed a higher intratumoral CD8+ infiltrate in the peritoneal lesions compared to the primary tumors (p=0.045). In contrast, higher counts of stromal PD-1+ cells in the peritoneal lesions have been associated with reduced platinum-sensitivity (p=0.045). Immune heterogeneity was associated with platinum response and might represent a selection marker for personalized therapy.

The Density of Cell Nuclei at the Materno-Fetal Exchange Barrier is Sexually Dimorphic in Normal Placentas, but not in IUGR.

Placental sexual dimorphism is of special interest in prenatal programming. Various postnatal diseases with gender dependent incidence, especially neuropsychiatric disorders like schizophrenia and autism spectrum disorders, have prenatal risk factors established. However, the functional relevance of placental microarchitecture in prenatal programming is poorly investigated, mainly due to a lack of statistically efficient methods. We hypothesized that the recently established 3D microscopic analysis of villous trees would be able to identify microscopic structural correlates of human placental sexual dimorphism. We analyzed the density of cell nuclei of villous trophoblast, i.e. the materno-fetal exchange barrier, in placentas from term pregnancies. The cell nuclei were grouped into proliferative and non-proliferative nuclei by detection of a proliferation marker (PCNA). Normal female placentas showed a higher density of non-proliferating nuclei (PCNA-negative) in villous trophoblast than normal male placentas. The density of PCNA-negative cell nuclei was higher in placentas of pregnancies with intrauterine growth retardation (IUGR) than in control placentas. The data of the present study shows that the density of non-proliferative cell nuclei in the syncytial layer of villous trophoblast is influenced by fetal sex and by IUGR, while proliferation remains unchanged. A novel concept of post-fusion regulation of syncytial structure and function is proposed.

Chemotherapy and Post-traumatic Stress in the Causation of Cognitive Dysfunction in Breast Cancer Patients.

Background: Cancer-related cognitive dysfunction has mostly been attributed to chemotherapy; this explanation, however, fails to account for cognitive dysfunction observed in chemotherapy-naïve patients. In a controlled, longitudinal, multisite study, we tested the hypothesis that cognitive function in breast cancer patients is affected by cancer-related post-traumatic stress. Methods: Newly diagnosed breast cancer patients and healthy control subjects, age 65 or younger, underwent three assessments within one year, including paper-and-pencil and computerized neuropsychological tests, clinical diagnostics of post-traumatic stress disorder (PTSD), and self-reported cognitive function. Analysis of variance was used to compare three groups of participants-patients who did or did not receive chemotherapy and healthy control subjects-on age- and education-corrected cognitive performance and cognitive change. Differences that were statistically significant after correction for false discovery rate were investigated with linear mixed-effects models and mediation models. All statistical tests were two-sided. Results: Of 226 participants (166 patients and 60 control subjects), 206 completed all assessment sessions (attrition: 8.8%). Patients demonstrated overall cognitive decline (group*time effect on composite z -score: -0.13, P = .04) and scored consistently worse on Go/Nogo errors. The latter effect was mediated by PTSD symptoms (mediation effect: B = 0.15, 95% confidence interval = 0.02 to 0.38). Only chemotherapy patients showed declined reaction time on a computerized alertness test. Overall cognitive performance correlated with self-reported cognitive problems at one year ( T = -0.11, P = .02). Conclusions: Largely irrespective of chemotherapy, breast cancer patients may encounter very subtle cognitive dysfunction, part of which is mediated by cancer-related post-traumatic stress. Further factors other than treatment side effects remain to be investigated.

Increased trace amine-associated receptor 1 (TAAR1) expression is associated with a positive survival rate in patients with breast cancer.

PURPOSE: A correlation between breast cancer and thyroid disorders has been described in previous studies. Degraded thyroid hormones are referred to as trace amines. These endogenous amines have the ability to bind to the G-protein-coupled receptor TAAR1 (trace amine-associated receptor) and thereby activate it. TAAR1 is able to modulate the serotonergic and dopaminergic system in the brain and has so far been studied in the neurological field. The following study represents the first investigation of the regulation of TAAR1 in primary breast cancer (no metastases, M0). METHODS: Immunohistochemical analyses were carried out to detect TAAR1 expression in formalin fixed paraffin embedded breast cancer samples. Survival times of primary breast cancer patients (M0) with and without TAAR1 expression in their tumours were compared by Kaplan-Meier curves, and correlations between ordinal variables were determined with Spearman's rank correlation coefficient. RESULTS: The investigation showed a correlation between TAAR1 expression and tumour differentiation grade. A well differentiated tumour grade (G1) was associated with higher TAAR1 expression and HER2 and HER4 positivity predicted higher TAAR1 expression. A TAAR1 overexpression (IRS ≥ 6) was associated with significantly longer overall survival (OS) (p = 0.02) than that of reduced TAAR1 expression (IRS < 6) during a maximum follow-up of 14 years, demonstrating that TAAR1 has a favourable effect on OS of early breast cancer patients. CONCLUSIONS: We conclude that TAAR1 seems to be an independent predictor for breast cancer survival. Modulation of TAAR1 may represent a novel targeting strategy for breast cancer prevention and therapy.

Clinically assessed posttraumatic stress in patients with breast cancer during the first year after diagnosis in the prospective, longitudinal, controlled COGNICARES study.

OBJECTIVE: There is ongoing debate whether cancer qualifies as traumatic stressor. We investigated prevalence and course of posttraumatic stress in patients with early breast cancer (BC) during their first year after diagnosis and determined effects of mastectomy and chemotherapy. METHODS: Patients with stage 0-III BC aged ≤65 years were evaluated with the Structured Clinical Interview for DSM-IV modules for acute and posttraumatic stress disorder (ASD and PTSD, respectively) before treatment, after chemotherapy, and 1 year after diagnosis. Matched controls were assessed at matched intervals. Effects of time, mastectomy, and chemotherapy on BC-related PTSD symptom severity were tested with linear mixed model analysis. RESULTS: Stress disorder (ASD or PTSD) related to BC was diagnosed in 6 (3.6%) of 166 patients before treatment and in 3 patients (2.0%) 1 year later. The rate of patients who experienced PTSD symptoms related to BC decreased from 82.5 to 57.3% (p < 0.001), and the mean of BC-related PTSD symptoms diminished from 3.1 to 1.7 (p < 0.001). Only university education significantly predicted the course of BC-related PTSD symptom severity (p = 0.009). In 60 controls, no diagnosis of stress disorder, a rate of 18% women experiencing PTSD symptoms, and a mean of 0.4 PTSD symptoms (p vs. patients <0.001) were found. CONCLUSIONS: Most newly diagnosed patients with BC experience PTSD symptoms, whereas full diagnoses of DSM-IV stress disorder are rare. Symptoms diminish somewhat within 1 year furthered by university education but independently from mastectomy and chemotherapy. Throughout the year after diagnosis, having BC entails markedly increased PTSD symptom burden. Copyright © 2016 John Wiley & Sons, Ltd.

Novel 3D light microscopic analysis of IUGR placentas points to a morphological correlate of compensated ischemic placental disease in humans.

The villous tree of the human placenta is a complex three-dimensional (3D) structure with branches and nodes at the feto-maternal border in the key area of gas and nutrient exchange. Recently we introduced a novel, computer-assisted 3D light microscopic method that enables 3D topological analysis of branching patterns of the human placental villous tree. In the present study we applied this novel method to the 3D architecture of peripheral villous trees of placentas from patients with intrauterine growth retardation (IUGR placentas), a severe obstetric syndrome. We found that the mean branching angle of branches in terminal positions of the villous trees was significantly different statistically between IUGR placentas and clinically normal placentas. Furthermore, the mean tortuosity of branches of villous trees in directly preterminal positions was significantly different statistically between IUGR placentas and clinically normal placentas. We show that these differences can be interpreted as consequences of morphological adaptation of villous trees between IUGR placentas and clinically normal placentas, and may have important consequences for the understanding of the morphological correlates of the efficiency of the placental villous tree and their influence on fetal development.

Does 2D-Histologic identification of villous types of human placentas at birth enable sensitive and reliable interpretation of 3D structure?

INTRODUCTION: The villous tree of human placentas is a complex three-dimensional (3D) structure which enables fetomaternal exchange. Current concepts of microscopic analyses are based on the analysis of two-dimensional (2D) histologic sections. For this approach, the assessment of the stromal core of sectioned villi is of key importance. The classification of stromal properties of sectioned villi allows allocation of villous sections to villous types which are named by their expected position in villous trees (terminal, intermediate, and stem villi). METHOD: The present study takes these current concepts of placental histology as hypothesis and validates them against predetermined 3D positions of branches of villous trees. The 3D positions were determined prior to histologic sectioning using a recently introduced 3D-microscopic approach. Individual histologic sections of villi were classified by their stromal structures and inter rater variability of these histologic assessments were determined. RESULTS/DISSCUSSION: Inter rater variability was high and indicates substantial observer influence on the outcome of histologic assessments. Cross-match of villous types with the predetermined positions of villous branches of villous trees revealed substantial mismatch between the outcome of stromal classification and 3D-position of the sectioned villi in the placental villous trees.

Prospective cohort study using the breast cancer spheroid model as a predictor for response to neoadjuvant therapy--the SpheroNEO study.

BACKGROUND: Aim of this prospective study was to predict response to neoadjuvant therapy in breast cancer patients using an in vitro breast cancer spheroid model. METHODS: Three-dimensional spheroids were directly generated from fresh breast tumor biopsies of 78 patients eligible for neoadjuvant therapy. Cell survival was measured after in vitro exposure to the equivalent therapeutic agents in the breast cancer spheroid model. Treatment results in vitro were correlated with pathological complete response (pCR, i.e. ypT0 ypN0) determined at surgery. RESULTS: A mean cell survival of 21.8 % was found in the breast cancer spheroid model for 22 patients with pCR versus 63.8 % in 56 patients without pCR (P = .001). The area under the receiver operator characteristic curve to predict pCR was 0.86 (95 % CI: 0.77 to 0.96) for cell survival in vitro compared to 0.80 (95 % CI: 0.70 to 0.90) for a combined model of conventional factors (hormone- and HER2 receptor, and age). A cutoff at 35 % cell survival for the spheroid model was proposed. Out of the 32 patients with values below this threshold, 21 patients (65.6 %) and one patient (2.2 %) with a cell survival greater than 35 % achieved pCR respectively; (sensitivity 95.5 % (95 % CI: 0.86 to 1.00); specificity 80.4 % (95 % CI: 0.70 to 0.91)). Extent of residual disease positively correlated with increased cell survival (P = .021). CONCLUSION: The breast cancer spheroid model proved to be a highly sensitive and specific predictor for pCR after neoadjuvant chemotherapy in breast cancer patients.

Elucidating pretreatment cognitive impairment in breast cancer patients: the impact of cancer-related post-traumatic stress.

BACKGROUND: Pretreatment cognitive impairment in cancer patients is well established but unexplained. Similar cognitive compromise has been observed in post-traumatic stress disorder (PTSD) patients, and PTSD symptoms are a frequent concomitant of cancer diagnosis. We tested the hypothesis that pretreatment cognitive impairment is attributable to cancer-related post-traumatic stress. METHODS: Women aged 65 years or younger who were diagnosed with breast cancer (case patients) or had undergone negative routine breast imaging (control patients) at one of six participating breast centers underwent traditional and computerized neuropsychological testing, clinician-administered diagnostic assessment of stress disorders, and self-report assessments of cognitive function and depression. To minimize confounding, case patients were evaluated prior to any local or systemic treatment. Cognitive indices of case patients, control patients, and normative samples were compared. The patients' risk of overall cognitive impairment was determined. Linear regression and a mediation model were used to test the study hypothesis. All statistical tests were two-sided. RESULTS: The 166 case patients and 60 well-matched control patients showed near-identical deviations from population norms. Case patients scored worse than control patients on two of 20 cognitive indices (Go/Nogo commission errors, Go/Nogo omission errors). Self-reported cognitive problems were associated with Go/Nogo omission errors and more pronounced in case patients. Only PTSD symptoms (Beta = 0.27, P = .004) and age (Beta = 0.22, P = .04) statistically significantly predicted Go/Nogo errors. The effect of having cancer on Go/Nogo errors was mediated by PTSD symptoms. Case patients did not have an increased risk of overall cognitive impairment. CONCLUSION: Prior to any treatment, breast cancer patients may show limited cognitive impairment that is apparently largely caused by cancer-related post-traumatic stress.

Interinstitutional variations in mode of birth after a previous caesarean section: a cross-sectional study in six German hospitals.

AIMS: Regional and interinstitutional variations have been recognized in the increasing incidence of caesarean section. Modes of birth after previous caesarean section vary widely, ranging from elective repeat caesarean section (ERCS) and unplanned repeat caesarean section (URCS) after trial of labour to vaginal birth after caesarean section (VBAC). This study describes interinstitutional variations in mode of birth after previous caesarean section in relation to regional indicators in Germany. MATERIAL AND METHODS: A cross-sectional study using the birth registers of six maternity units (n=12,060) in five different German states (n=370,209). Indicators were tested by χ2 and relative deviations from regional values were expressed as relative risks and 95% confidence intervals. RESULTS: The percentages of women in the six units with previous caesarean section ranged from 11.9% to 15.9% (P=0.002). VBAC was planned for 36.0% to 49.8% (P=0.003) of these women, but actually completed in only 26.2% to 32.8% (P=0.66). Depending on the indicator, the units studied deviated from the regional data by up to 32% [relative risk 0.68 (0.47-0.97)] in respect of completed VBAC among all initiated VBAC. CONCLUSIONS: There is substantial interinstitutional variation in mode of birth following previous caesarean section. This variation is in addition to regional patterns.

Novel 3D microscopic analysis of human placental villous trees reveals unexpected significance of branching angles.

The villous trees of human placentas delineate the fetomaternal border and are complex three-dimensional (3D) structures. Thus far, they have primarily been analyzed as thin, two-dimensional (2D) histological sections. However, 2D sections cannot provide access to key aspects such as branching nodes and branch order. Using samples taken from 50 normal human placentas at birth, in the present study we show that analysis procedures for 3D reconstruction of neuronal dendritic trees can also be used for analyzing trees of human placentas. Nodes and their branches (e.g., branching hierarchy, branching angles, diameters, and lengths of branches) can be efficiently measured in whole-mount preparations of isolated villous trees using high-end light microscopy. Such data differ qualitatively from the data obtainable from histological sections and go substantially beyond the morphological horizon of such histological data. Unexpectedly, branching angles of terminal branches of villous trees varied inversely with the fetoplacental weight ratio, a widely used clinical parameter. Since branching angles have never before been determined in the human placenta, this result requires further detailed studies in order to fully understand its impact.

CEA-, Her2/neu-, BCRP- and Hsp27-positive microparticles in breast cancer patients.

BACKGROUND: This is the first prospective case-control study that evaluates the expression of tumour-specific antigens on circulating microparticles (MP) in breast cancer patients and in women with benign breast tumour. MATERIALS AND METHODS: MP were determined by flow cytometry in patients with breast cancer (n=34; T1 (n=19) and T2 (n=15)) and women with benign breast tumour (n=19). RESULTS: Patients with lymph node metastases (N1, n=9) showed significantly higher numbers of annexin V(+) MP (p=0.042), CD66(+) MP (p=0.045), BCRP1(+) MP (breast cancer resistance protein) (p=0.025) and Hsp27(+) MP (p=0.034) than controls. Furthermore, T1 patients had significantly higher levels of annexin V(+) MP (p=0.004), CD66(+) MP (p=0.025), BCRP1(+) MP (p=0.008) and Hsp27(+) MP (p=0.02) than controls. CONCLUSION: Significant differences are present between breast cancer patients with lymph node metastases and controls concerning annexin V-, CD66-, BCRP1- and Hsp27-positive MP. To specify the role of these MP subpopulations in breast cancer progression, further studies enrolling larger patient groups are part of ongoing research.

Thyroid function in breast cancer patients.

BACKGROUND: Recent studies indicate a possible relationship between hypothyroidism and breast cancer in vivo. In addition, oestrogen-like effects of thyroid hormones on breast cancer cell growth are seen in vitro. Therefore, this study evaluated thyroid function in breast cancer patients, women with benign breast tumour and healthy controls. PATIENTS AND METHODS: Breast cancer patients (n=65), women with carcinoma in situ (n=13) or benign breast tumour (n=27), and healthy controls (n=38) were included in the study. Thyroid history was reported. Thyroid hormones (fT4, fT3, TSH) and thyroid antibodies (TPO, TRAK and TG) were determined. Statistical analysis was performed by Mann-Whitney U and Fisher's exact test (p<0.005 significant). RESULTS: fT3 and fT4 levels were highest in breast cancer patients, and differed significantly from controls (fT3 and fT4: p<0.001) as well as from patients with benign breast tumour (fT3: p=0.021; fT4: p=0.017). TSH was highest in the control group without reaching significance. With regard to TRAK antibodies, breast cancer patients showed the highest levels differing significantly from women with benign breast tumours (p=0.048). CONCLUSION: Significant differences in fT3/fT4 as well as TRAK levels were observed among breast cancer patients, women with benign breast tumours and healthy controls. Further studies using larger patient groups are part of ongoing research.

Intensive dose-dense compared with conventionally scheduled preoperative chemotherapy for high-risk primary breast cancer.

PURPOSE: To compare preoperative intense dose-dense (IDD) chemotherapy with conventionally scheduled preoperative chemotherapy in high-risk primary breast cancer (BC). PATIENTS AND METHODS: In this randomized phase III trial a total of 668 eligible primary BC patients stratified for tumors > or = 3 cm (n = 567) or inflammatory BC (n = 101) were randomly assigned to receive concurrent preoperative epirubicin/paclitaxel every 3 weeks or dose-dense and dose-escalated sequential epirubicin followed by paclitaxel every 2 weeks. All patients received three cycles of cyclophosphamide, methotrexate, and fluorouracil chemotherapy after surgery. RESULTS: IDD treatment significantly improved pathologic complete response rate (18% v 10%; odds ratio [OR] 1.89; P = .008), disease-free survival (DFS; hazard ratio [HR], 0.71; P = .011), and overall survival (OS; HR, 0.83; P = .041) compared to epirubicin/paclitaxel. Patients with inflammatory BC had a particularly poor prognosis and did not appear to benefit from IDD therapy in this trial (DFS HR, 1.10; P = .739; OS HR, 1.25; P = .544). In contrast, patients with noninflammatory BC significantly benefited from IDD treatment (DFS HR, 0.65, P = .005; OS HR, 0.77, P = .013). Treatment effects in multivariate analysis were significant for noninflammatory BC (DFS HR, 0.65, P = .015; OS HR, 0.79, P = .034), but not for all patients (DFS HR, 0.76; P = .088; OS HR, 0.82; P = .059). IDD therapy was associated with significantly more nonhematologic toxicities, anemia, and thrombocytopenia, but with similar neutropenia and infection rates. CONCLUSION: Our results support the efficacy and short-term safety of IDD as preoperative chemotherapy. IDD was less well tolerated compared to standard treatment, but improved clinical outcomes in patients with noninflammatory high-risk primary BC.