Air contrast of the intervillous space enables non-disruptive Micro-CT analysis of paraffin-embedded archival placental tissue.

The morphometric parameters of the villous tree are a strong indicator of deviant placentas. Methods have been established to digitally reconstruct small peripheral branches by tracing with 3D Microscopy at subcellular resolution. Micro-CT can help scale up the scanning of villous trees with resolution in the range of a few micrometers. As placental tissue samples are routinely conserved and archived by fixation and paraffin embedding, the villous structures are inaccessible to Micro-CT imaging due to poor contrast between paraffin and paraffinized tissue. We present a novel procedure for contrast enhancement by selectively replacing wax by air in the intervillous space.

The volume of villi with γ-sm-actin positive perivascular cells correlates with placental weight and thickness.

INTRODUCTION: The classification of histologically stained villous cross sections in villous types (terminal, intermediate and stem villi) by stromal peculiarities is known to be observer predicated. Therefore, quantitative histology of villous trees has not become a routine endpoint of studies on the role of the placenta in prenatal programming, as opposed to the gross placental parameters weight and thickness. The classification of villous cross sections in central (stem) and peripheral (terminal) parts based on the presence or absence, respectively, of immunohistochemical detection of myofibroblasts in perivascular position is less observer dependent. We hypothesized that it will, possibly, identify microscopic correlates of placental weight and thickness within the villous tree. METHODS: 50 placentas from clinically normal pregnancies were processed for the present study. Thin villous cross sections, obtained in a systematic random manner, were stained immunohistochemically to detect γ-smooth muscle (sm) actin and to classify them subsequently as part of central or peripheral villous tree. The volume fractions of histological structures visible in villous cross sections (stroma, lumen, endothelium and syncytium) were estimated by design-based stereology. RESULTS: The present study reveals a significant correlation of placental weight and thickness with the volume estimate of stroma that have myofibroblasts in perivascular position. DISCUSSION: The positive linear correlation between the volume of central parts of villous trees and the placental weight and thickness is new. Surprisingly, the volume of more peripheral parts of villous trees, which is the main site of materno-fetal exchange does not correlate with placental weight and thickness.

Lymph node dissection in endometrial cancer and clinical outcome: A population-based study in 5546 patients.

BACKGROUND: According to current treatment guidelines, comprehensive surgical staging procedures in endometrial cancer confined to the uterus depend on uterine risk factors: a systematic lymph node dissection (LND) is recommended in high risk patients and should be omitted in low risk patients. Its role in intermediate and high intermediate risk patients is inconclusive. The aim of this analysis was to review the implementation of this risk-adopted strategy. MATERIALS AND METHODS: Data were provided by the population-based Munich Cancer Registry. Patients with endometrial cancer diagnosed between 1998 and 2016 were included. RESULTS: Of 5446 eligible patients, 58.5%, 30.1% and 11.4% belonged to the low risk, intermediate/high-intermediate and high risk group, respectively. Lymph node dissection was performed in 20.2%, 53.0% and 63.7% within these groups. Lymph node involvement was diagnosed in 1.7%, 9.6% and 19.3%, respectively. Within these risk groups, there was no significant difference in the time to local recurrence, lymph node recurrence or distant metastases between patients with and without LND. After adjusting for age and comorbidity-status, no significant difference in overall survival was found. CONCLUSIONS: The application of a risk-adopted management of LND in early endometrial cancer in real-life is associated with a high rate of surgical under- and overtreatment. Corresponding survival data do not show a significant benefit of a systematic lymph node dissection. In order to improve the management and outcome of early endometrial cancer in the future, prospective trials, new surgical concepts and prognostic markers will be primary and necessary.

Syncytial nuclei accumulate at the villous surface in IUGR while proliferation is unchanged.

INTRODUCTION: Placental syncytiotrophoblast is responsible for feto-maternal nutrient exchange during pregnancy. It is assumed that in IUGR, placental dysfunction is crucially bound to compromised stability and function of syncytiotrophoblast, the latter being related to altered proliferation of villous trophoblast. Cell cycle data obtained on conventional thin sections has produced inconsistent results. In the present study we investigated cell cycle markers found in the villous trophoblast using a novel 3D histological quantification method. METHODS AND FINDINGS: We analyzed 40 placentas from IUGR pregnancies and 42 placentas from clinically normal pregnancies by immunohistochemical detection of the cell cycle marker PCNA. Nuclei immuno-positive for PCNA were quantified using 3D microscopy, and the results were compared to corresponding results obtained on conventional thin histological sections. These data did not show any evidence of altered trophoblast proliferation in IUGR, while the density of post-proliferative (i.e. PCNA-negative) trophoblast nuclei was statistically significantly increased in IUGR. The latter could be revealed by 3D topological microscopy, but not by conventional histology of thin sections. DISCUSSION: The data of the present study indicate a previously unknown type of regulation of syncytial stability and function, independent of proliferation. We hypothesize that in IUGR, post-proliferative trophoblast nuclei accumulate at the villous surface of peripheral villous branches. This could possibly reflect the presence of an unknown mechanism controlling syncytial function and stability by modulation of syncytial passage time rather than by modulation of proliferative supply.

Birth weight correlates with size but not shape of the normal human placenta.

INTRODUCTION: Studies on developmental programming rely on various measures of size and form of the human placenta. Size and form are not independent of each other and covariation patterns were not determined systematically. METHODS: Twenty-two morphologic parameters were determined on 418 placentas from uncomplicated singleton pregnancies. We determined (i) placenta weight and birth weight, (ii) form parameters such as diameters, thickness, roundness, and eccentricity of cord insertion, and (iii) shape variability by geometric morphometry. Geometric morphometry analyzes shape variability independent of size. We define the technical terms form and shape according to the language of geometric morphometry. RESULTS: Placenta weight correlated with birth weight. The form parameters correlated variably with placenta weight and shape. Shape variability did not correlate with birth weight and placenta weight. DISCUSSION AND CONCLUSIONS: The correlation of placenta weight with birth weight stays a cornerstone of prenatal programming. Shape analysis shows that form parameters are hybrids of size and shape. Shape variability can be interpreted as an outcome of adaptation of a placenta to maternal factors and the associated uterine habitat. Correlation analysis of the whole data array provides a rigorous statistical frame to interpret published data and plan new studies.

Dose-dense intensified sequential versus conventionally-dosed anthracycline and taxane-containing neoadjuvant therapy in patients with inflammatory breast cancer.

BACKGROUND: This post-hoc analysis aimed to compare an intense dose-dense sequential chemotherapy (DD-CT) and a conventionally-dosed chemotherapy (CD-CT) in the neoadjuvant AGO-1 study, focusing on the subgroup with inflammatory breast cancer (IBC). PATIENTS AND METHODS: Out of 668 randomised patients, 101 patients presented with IBC. Patients received epirubicin followed by paclitaxel every 2 weeks (DD-CT) or simultaneously every 3 weeks (CD-CT). RESULTS: No differences in pathological complete response rates were observed [odds ratio (OR)=1.27, p=0.33]. Most patients were scheduled for mastectomy before starting therapy; however, in 21.7% breast-conserving surgery was performed. Disease-free survival rates [Hazard Ratio (HR)=0.65; p=0.597] and overall survival rates (HR=1.40; p=0.327) were similar for both treatment arms. Patients with breast-conserving surgery had a significantly better outcome than patients treated with mastectomy (disease-free survival: HR=0.41; p=0.034 and overall survival: HR=0.09; p=0.003). CONCLUSION: Patients with IBC benefited not from DD-CT but from breast-conserving surgery after neoadjuvant chemotherapy.

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.

Management of anaemia in patients with breast cancer: role of epoetin.

Many patients with breast cancer suffer from anaemia, as a consequence of the disease itself or its treatment. Anaemia has a negative impact on treatment outcome and overall survival, and affects the quality of life (QoL) of patients with cancer. Previously, cancer-related anaemia was treated with blood transfusion, but this is inconvenient, offers only temporary improvement in haemoglobin (Hb) level and is associated with several risks. Consequently, blood transfusion is usually reserved for patients with severe anaemia (Hb levels <8 g/dl). Recombinant human erythropoietin (epoetin) is an effective and convenient treatment for cancer-related anaemia without the risks associated with red blood cell transfusion. Epoetin therapy effectively increases Hb levels, thereby reducing the need for emergency blood transfusion and improving the QoL of patients with anaemia and breast cancer. Epoetin beta is also effective for the prevention of anaemia and reduction of transfusion requirements in patients with a high risk of developing anaemia during chemotherapy. With the increased use of dose-intensified chemotherapy in an attempt to improve response rates, administration of epoetin to prevent anaemia could potentially benefit many patients with breast cancer.

[Adjuvant treatment of breast cancer in 2004. A review of the 8th consensus conference of St. Gallen and new study results]. / Adjuvante Therapie des Mammakarzinoms 2004. Eine Bewertung der 8. Konsensuskonferenz von St. Gallen und neuer Studienergebnisse.

The emerging evidence gained from randomized controlled trials accelerated the widespread use of adjuvant endocrine and cytotoxic regimens and their combinations for most breast cancer patients. Even for the earliest cancer stages with low-risk tumour profiles, endocrine treatment can be recommended as adjuvant therapy if the tumour is endocrine responsive. The 8th consensus conference on early breast cancer in St. Gallen in 2003 opened a plethora of treatment options to nearly all breast cancer patients. Key issues were the introduction of adjuvant therapy with anastrozole for those postmenopausal patients with contra-indications or intolerability of tamoxifen and the definition of a group of 'more potent' regimens like the FEC- and the taxane-based regimens for high-risk patients. Unfortunately the expert panel did not clearly define any recommendations either for choosing optimal candidates for purely endocrine treatments (which are a valid option for all patients with optimal endocrine responsive disease or arguments against chemotherapy) or for the proper high-risk patients scheduled for more aggressive regimens. In the meantime, new or updated studies have provided additional information helpful for the shared decision-making with our patients. The Canadian MA.17 study revealed a significant benefit from adding a sequential therapy with letrozole after 5 years of tamoxifen compared to tamoxifen alone. Together with the updated evaluation from the ATAC trial and the Italian ITA study, the role of adjuvant treatment with aromatase inhibitors is steadily strengthened. Several studies comparing taxane-based and taxane-free regimens showed significant survival and/or recurrence benefits for the former. These data should be communicated to the patients. In the complex process of decision-making, a profound knowledge of the study results and the early and complete involvement of the woman and her personal beliefs are mandatory.

Dose-dense and sequential strategies in adjuvant breast cancer therapy.

Several attempts have been made to improve the survival rates of breast cancer patients. The benefit of adjuvant chemotherapy was clearly shown, but the absolute difference of 2% to 11% in overall survival, depending on the patient group, is disappointingly small. In particular, high-risk patients, such as those with > or = 10 involved lymph nodes, extracapsular spread, or vascular invasion, still have an excessive risk of recurrence even after standard adjuvant chemotherapy. To increase the survival rates after adjuvant therapy, new chemotherapeutic agents and new strategies of application are currently being evaluated in clinical trials. Chemotherapy with cyclophosphamide (Cytoxan, Neosar), methotrexate, and fluorouracil (CMF) seems to be safe and effective in patients with breast cancer. In addition, in metastatic patients, dose-intensified chemotherapy is being investigated. The introduction of epirubicin (Ellence), an agent less cardiotoxic and equally active compared to doxorubicin, enabled the escalation of anthracyclines in adjuvant therapy without serious cardiotoxic effects. The combination of dose-intensified chemotherapy and sequential application in the treatment of breast cancer is reviewed.

Overview of epirubicin-based adjuvant therapy in breast cancer.

Clinical trial data indicate that epirubicin-based adjuvant treatment of breast cancer is associated with marked improvement in relapse-free and overall survival compared with traditional cyclophosphamide/methotrexate/5-fluorouracil. The outcomes are comparable to those achieved with sequential use of doxorubicin/cyclophosphamide and paclitaxel. Dose intensification of epirubicin is feasible, with tolerable side effects and no increased risk of cardiotoxicity beyond that expected. Clinical trial data coupled with pharmacokinetic evidence provide a strong foundation and rationale for current and future investigation of epirubicin in combination with the taxanes in the adjuvant setting. An ongoing German study is evaluating epirubicin/cyclophosphamide in combination with trastuzumab as first-line therapy of metastatic breast cancer in patients whose tumors overexpress HER2/neu protein. These results, particularly the tolerability of this regimen, will form the basis for future adjuvant and neoadjuvant studies of epirubicin/trastuzumab-based regimens.