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.

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.

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.