Changes in Psychotropic Drug Concentrations Across the Menstrual Cycle: A Pilot Study.

BACKGROUND: The escalating prescription of psychopharmacological medications to women of reproductive age underscores the growing significance of sex-specific variations in pharmacotherapy. Despite this, clinical trials have largely overlooked these differences. Preliminary data indicate sex-specific variations in the neurobiology of affective disorders and in the metabolism, pharmacodynamics, and kinetics of therapeutic drugs. This underscores the imperative for a more nuanced exploration of menstrual cycle-dependent fluctuations in psychotropic drugs. This pilot study aimed to investigate drug and hormone fluctuations in female patients with affective disorders, aiming to enhance comprehension of the interplay between cycle-related hormone fluctuations and pharmacokinetics. The ultimate goal is to facilitate more effective and safer pharmacological therapy in the future. METHODS: Blood samples were collected from 27 patients and 27 age-matched control participants at 3 distinct time points (early follicular phase, ovulation, and late luteal phase) during each menstrual cycle. Depressive and manic symptoms were assessed, and hormone concentrations were measured in the entire sample, while drug concentrations were assessed solely in the affective disorder sample using mass spectrometry. RESULTS: Significant variations in drug concentration were observed throughout the menstrual cycle for bupropion, with a trend toward altered concentration for venlafaxine. Moreover, notable differences in hormone concentrations were identified between patients and controls, even after accounting for the impact of contraceptive use, diagnoses, and medication. CONCLUSIONS: This pilot study reinforces previously reported data, underscoring the significance of sex-specific pharmacological therapy approaches. It provides further evidence supporting the interaction among sex hormones, drugs, and symptoms of affective disorders.

Ovarian cancer cells regulate their mitochondrial content and high mitochondrial content is associated with a poor prognosis.

Most cancer patients ultimately die from the consequences of distant metastases. As metastasis formation consumes energy mitochondria play an important role during this process as they are the most important cellular organelle to synthesise the energy rich substrate ATP, which provides the necessary energy to enable distant metastasis formation. However, mitochondria are also important for the execution of apoptosis, a process which limits metastasis formation. We therefore wanted to investigate the mitochondrial content in ovarian cancer cells and link its presence to the patient's prognosis in order to analyse which of the two opposing functions of mitochondria dominates during the malignant progression of ovarian cancer. Monoclonal antibodies directed against different mitochondrial specific proteins, namely heat shock proteins 60 (HSP60), fumarase and succinic dehydrogenase, were used in immunohistochemistry in preliminary experiments to identify the antibody most suited to detect mitochondria in ovarian cancer cells in clinical tissue samples. The clearest staining pattern, which even delineated individual mitochondria, was seen with the anti-HSP60 antibody, which was used for the subsequent clinical study staining primary ovarian cancers (n = 155), borderline tumours (n = 24) and recurrent ovarian cancers (n = 26). The staining results were semi-quantitatively scored into three groups according to their mitochondrial content: low (n = 26), intermediate (n = 50) and high (n = 84). Survival analysis showed that high mitochondrial content correlated with a statistically significant overall reduced survival rate In addition to the clinical tissue samples, mitochondrial content was analysed in ovarian cancer cells grown in vitro (cell lines: OVCAR8, SKOV3, OVCAR3 and COV644) and in vivo in severe combined immunodeficiency (SCID) mice.In in vivo grown SKOV3 and OVCAR8 cells, the number of mitochondria positive cells was markedly down-regulated compared to the in vitro grown cells indicating that mitochondrial number is subject to regulatory processes. As high mitochondrial content is associated with a poor prognosis, the provision of high energy substrates by the mitochondria seems to be more important for metastasis formation than the inhibition of apoptotic cell death, which is also mediated by mitochondria. In vivo and in vitro grown human ovarian cancer cells showed that the mitochondrial content is highly adaptable to the growth condition of the cancer cells.

Breastfeeding Behavior Within the Covid-19 Related Obstetric and Neonatal Outcome Study (CRONOS).

BACKGROUND: The SARS-CoV-2 pandemic and its influence on peripartum processes worldwide led to issues in breastfeeding support. RESEARCH AIM: The aim of this study was to describe breastfeeding behavior and peripartum in-hospital management during the pandemic in Germany and Austria. METHODS: This study was a descriptive study using a combination of secondary longitudinal data and a cross-sectional online survey. Registry data from the prospective multicenter COVID-19 Related Obstetric and Neonatal Outcome Study (CRONOS) cohort study (longitudinal, medical records of 1,815 parent-neonate pairs with confirmed SARS-CoV-2 infection during pregnancy) and a cross-sectional online survey of CRONOS hospitals' physicians (N = 67) were used for a descriptive comparison of feeding outcomes and postpartum management. RESULTS: In 93.7% (n = 1700) of the cases in which information on the neonate's diet was provided, feeding was with the mother's own milk. Among neonates not receiving their mother's own milk, 24.3% (n = 26) reported SARS-CoV-2 infection as the reason. Peripartum maternal SARS-CoV-2 infection, severe maternal COVID-19 including the need for intensive care unit (ICU) treatment or invasive ventilation, preterm birth, mandatory delivery due to COVID-19, and neonatal ICU admission were associated with lower rates of breastfeeding. Rooming-in positively influenced breastfeeding without affecting neonatal SARS-CoV-2 frequency (4.2% vs. 5.6%). CRONOS hospitals reported that feeding an infant their mother's own milk continued to be supported during the pandemic. In cases of severe COVID-19, four of five hospitals encouraged breastfeeding. CONCLUSION: Maintaining rooming-in and breastfeeding support services in the CRONOS hospitals during the pandemic resulted in high breastfeeding rates.

Psycho-Oncological Care Provision in Highly Distressed Breast Cancer Patients.

Objective To evaluate the proportion of breast cancer (BC) patients with distress or psychological comorbidity as well as offer and use of psychological support in subgroups of BC patients with different extents of distress. Methods 456 patients with BC were evaluated at baseline (t1) and until 5 years after diagnosis (t4) at the BRENDA certified BC centers. Logistic regression was used to analyze if patients with distress at t1 received offers and actual psychological support more often than patients without distress at t1. Regression analyses were used to examine if acute, emerging or chronic disease was associated with higher rates of offer and use of psychotherapy as well as intake of psychotropic drugs. Results In 45% of BC patients psychological affection was detected at t4. The majority of patients with moderate or severe distress at t1 (77%) received the offer for psychological service, while 71% of those received the offer for support at t4. Patients, who were psychologically affected at t1, have not been offered psychological services more often than those without, but they significantly more often used services if offered. Especially patients with acute comorbidity received significantly more often an offer for psychotherapy compared to unimpaired patients, while those patients with emerging or chronic disease did not. 14% of BC patients took psychopharmaceuticals. This mainly concerns patients with chronic comorbidity. Conclusion Psychological services were offered to and used by a fair amount of BC patients. All subgroups of BC patients should be addressed, in order to improve the comprehensive supply with psychological services.

[Traumatic childbirth and trauma-sensitive obstetric support]. / Traumatische Geburt und traumasensible Geburtsbegleitung.

Childbirth can be a very happy and empowering experience for women but also one of suffering and despair. Biographical traumatic experiences, especially sexual, physical and emotional violence, are risk factors for a traumatic childbirth experience with the danger of subsequent trauma sequelae and impaired mother-child bonding; however, obstetrically indicated interventions or poor communication in the delivery room can also primarily be experienced as traumatic.In recent years, policies affecting traumatic childbirth experience have been controversially and sometimes emotionally discussed. In the clinical obstetric routine there is often a fine line between medically necessary rapid interventions and emotionally supportive trauma-sensitive and preventive obstetric care. The following article addresses the causes and prevention strategies of traumatic childbirth experiences from obstetric, midwifery and psychotherapeutic perspectives.

Evaluation of different imaging modalities for axillary lymph node staging in breast cancer patients to provide a personalized and optimized therapy algorithm.

PURPOSE: The reliable detection of tumor-infiltrated axillary lymph nodes for breast cancer [BC] patients plays a decisive role in further therapy. We aimed to find out whether cross-sectional imaging techniques could improve sensitivity for pretherapeutic axillary staging in nodal-positive BC patients compared to conventional imaging such as mammography and sonography. METHODS: Data for breast cancer patients with tumor-infiltrated axillary lymph nodes having received surgery between 2014 and 2020 were included in this study. All examinations (sonography, mammography, computed tomography [CT] and magnetic resonance imaging [MRI]) were interpreted by board-certified specialists in radiology. The sensitivity of different imaging modalities was calculated, and binary logistic regression analyses were performed to detect variables influencing the detection of positive lymph nodes. RESULTS: All included 382 breast cancer patients had received conventional imaging, while 52.61% of the patients had received cross-sectional imaging. The sensitivity of the combination of all imaging modalities was 68.89%. The combination of MRI and CT showed 63.83% and the combination of sonography and mammography showed 36.11% sensitivity. CONCLUSION: We could demonstrate that cross-sectional imaging can improve the sensitivity of the detection of tumor-infiltrated axillary lymph nodes in breast cancer patients. Only the safe detection of these lymph nodes at the time of diagnosis enables the evaluation of the response to neoadjuvant therapy, thereby allowing access to prognosis and improving new post-neoadjuvant therapies.

Optimized process quality in certified breast centers through adherence to stringent diagnostic and therapeutic algorithms effects of structural as well as socio-demographic factors on start of therapy.

PURPOSE: An increasing incidence of breast cancer can be observed worldwide. Since a delay of therapy can have a negative impact on prognosis, timely cancer care is an important quality indicator. By receiving treatment at a certified breast cancer center, the patient has the best chance of treatment in accordance with guidelines and the best prognosis. The identification of risk factors for a delay of therapy is of central importance and should be the basis for a continuous optimization of treatment at breast cancer centers. METHODS: This retrospective study included women with breast cancer (primary diagnosis, relapse, or secondary malignancy) at the University Hospital Würzburg in 2019 and 2020. Data were retrieved from patients' records. Correlations and regression analyses were performed to detect potential risk factors for treatment delay. RESULTS: Patients who received the histological confirmation of breast cancer at an external institution experienced a later therapy start than those patients who received the histological confirmation at the University Hospital Würzburg itself. (35.7 vs. 32.2 days). The interval between histological confirmation and the first consultation at the University Hospital Würzburg correlated statistically significant with age, distress and distance to the hospital. CONCLUSION: Patients with an in-house diagnosis of breast cancer are treated more quickly than those whose diagnosis was confirmed in an external institution. We identified factors such as increased age, greater distance to the hospital as well as increased distress to prolong the time until start of oncological treatment. Intensified patient care should be offered to these subgroups.

Ovarian Cancer-Cell Pericellular Hyaluronan Deposition Negatively Impacts Prognosis of Ovarian Cancer Patients.

BACKGROUND: Hyaluronan (HA), a component of the extracellular matrix, is frequently increased under pathological conditions including cancer. Not only stroma cells but also cancer cells themselves synthesize HA, and the interaction of HA with its cognate receptors promotes malignant progression and metastasis. METHODS: In the present study, HA deposition in tissue sections was analyzed by hyaluronan-binding protein (HABP) ligand histochemistry in 17 borderline tumors and 102 primary and 20 recurrent ovarian cancer samples. The intensity and, particularly, localization of the HA deposition were recorded: for the localization, the pericellular deposition around the ovarian cancer cells was distinguished from the deposition within the stromal compartment. These histochemical data were correlated with clinical and pathological parameters. Additionally, within a reduced subgroup of ovarian cancer samples (n = 70), the RNA levels of several HA-associated genes were correlated with the HA localization and intensity. RESULTS: Both stroma-localized and pericellular tumor-cell-associated HA deposition were observed. Cancer-cell pericellular HA deposition, irrespective of its staining intensity, was significantly associated with malignancy, and in the primary ovarian cancer cohort, it represents an independent unfavorable prognostic marker for overall survival. Furthermore, a significant association between high CD44, HAS2 and HAS3 mRNA levels and a cancer-cell pericellular HA-deposition pattern was noted. In contrast, stromal hyaluronan deposition had no impact on ovarian cancer prognosis. CONCLUSIONS: In conclusion, the site of HA deposition is of prognostic value, but the amount deposited is not. The significant association of only peritumoral cancer-cell HA deposition with high CD44 mRNA expression levels suggests a pivotal role of the CD44-HA signaling axis for malignant progression in ovarian cancer.

The impact of the COVID-19 pandemic on stress and other psychological factors in pregnant women giving birth during the first wave of the pandemic.

BACKGROUND: The onset of mental illness such as depression and anxiety disorders in pregnancy and postpartum period is common. The coronavirus induced disease 2019 (COVID-19) pandemic and the resulting public policy responses represent an exceptional situation worldwide and there are hints for adverse psychosocial impact, hence, the study of psychological effects of the pandemic in women during hospitalization for delivery and in the postpartum period is highly relevant. METHODS: Patients who gave birth during the first wave of the COVID-19 pandemic in Germany (March to June 2020) at the Department of Obstetrics and Gynecology, University of Würzburg, Germany, were recruited at hospital admission for delivery. Biosamples were collected for analysis of SARS-CoV-2 infection and various stress hormones and interleukin-6 (IL-6). In addition to sociodemographic and medical obstetric data, survey questionnaires in relation to concerns about and fear of COVID-19, depression, stress, anxiety, loneliness, maternal self-efficacy and the mother-child bonding were administered at T1 (delivery stay) and T2 (3-6 months postpartum). RESULTS: In total, all 94 recruited patients had a moderate concern of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at T1 with a significant rise at T2. This concern correlated with low to low-medium general psychosocial stress levels and stress symptoms, and the women showed a significant increase of active coping from T1 to T2. Anxiety levels were low and the Edinburgh Postnatal Depression Scale showed a medium score of 5 with a significant (T1), but only week correlation with the concerns about SARS-CoV-2. In contrast to the overall good maternal bonding without correlation to SARS-CoV-2 concern, the maternal self-efficiency correlated negatively with the obstetric impairment caused by the COVID-19 pandemic. CONCLUSION: Obstetric patients` concerns regarding SARS-CoV-2 and the accompanying pandemic increased during the course of the pandemic correlating positively with stress and depression. Of note is the increase in active coping over time and the overall good mother-child-bonding. Maternal self-efficacy was affected in part by the restrictions of the pandemic. Clinical trial registration DRKS00022506.

The global pandemic of COVID-19 (coronavirus induced disease 2019) is challenging our society in many ways. Especially pregnant women are facing extraordinary conditions and worries, like uncertain risks for mother and fetus in case of infection, restricted prenatal classes or restricted visitor regulations in hospitals. Particularly it is known that pregnancy and the postnatal period are presenting a more psychologically vulnerable time in a woman's life. Developing the GeZeCO study, we aimed to focus on the pandemic's effects on mental health of pregnant women during this time. Women giving birth in the department of obstetrics of the University Hospital Würzburg were asked to participate in the study. In total, 94 women completed several questionnaires concerning their mental health postpartum and again after 3 to 6 months. Further, we took blood samples of the women during the delivery stay and registered sociodemographic and obstetric data. Our results showed, that the women's concern relating to COVID-19, as well as the level of depression and anxiety raised during the pandemic. In addition, the self-efficacy of the mothers was affected by the restriction measures. Despite this, the women had at large a good mother­child-bonding and their competence of active coping increased during time. In summary, we did find that the mental health of obstetric patients is impaired by the COVID-19 pandemic. This points out the importance of not only attending to physical health but also taking care of psychological stress and mental health problems of obstetric patients during this exceptional time.

[COVID-19 in obstetric anesthesia : Prospective surveillance of peripartum infections with SARS-CoV-2 and peripartum course of disease in affected women]. / COVID-19 in der geburtshilflichen Anästhesie : Prospektive Erfassung von SARS-CoV-2-Infektionen zum Zeitpunkt der Geburt sowie des peripartalen Verlaufs SARS-CoV-2-positiver Schwangerer.

BACKGROUND: In the current pandemic regarding the infection with the SARS-CoV-2-virus and COVID-19 as the disease, concerns about pregnant women, effects on childbirth and the health of the newborn remain high. Initially, due to the early manifestation of the disease in younger patients, high numbers of COVID-19 patients in women needing peripartum care were expected. OBJECTIVE: This article aims to provide a general overview over the beginning of the pandemic as well as the second wave of infections in Germany and Switzerland, regarding SARS-CoV­2 positive pregnant women hospitalized for childbirth. We therefore launched a registry to gain timely information over the dynamic situation during the SARS-CoV­2 pandemic in Germany. MATERIAL AND METHODS: As part of the COVID-19-related Obstetric Anesthesia Longitudinal Assessment (COALA) registry, centers reported weekly birth rates, numbers of suspected SARS-CoV­2 cases, as well as the numbers of confirmed cases between 16 March and 3 May 2020. Data acquisition was continued from 18 October 2020 till 28 February 2021. The data were analyzed regarding distribution of SARS-CoV­2 positive pregnant women hospitalized for childbirth between centers, calendar weeks and birth rates as well as maternal characteristics, course of disease and outcomes of SARS-CoV­2 positive pregnant women. RESULTS: A total of 9 German centers reported 2270 deliveries over 7 weeks during the first wave of infections including 3 SARS-CoV­2 positive cases and 9 suspected cases. During the second survey period, 6 centers from Germany and Switzerland reported 41 positive cases out of 4897 deliveries. One woman presented with a severe and ultimately fatal course of the disease, while another one needed prolonged ECMO treatment. Of the women 28 presented with asymptomatic infections and 6 neonates were admitted to a neonatal intensive care unit for further treatment. There was one case of neonatal SARS-CoV­2 infection. CONCLUSION: The number of pregnant women infected with SARS-CoV­2 was at a very low level at the time of delivery, with only sporadic suspected or confirmed cases. Due to the lack of comprehensive testing in the first survey period, however, a certain number of asymptomatic cases are to be assumed. Of the cases 68% presented as asymptomatic or as mild courses of disease but the data showed that even in young healthy patients without the presence of typical risk factors, serious progression can occur. These outcomes should raise awareness for anesthesiologists, obstetricians, pediatricians and intensive care physicians to identify severe cases of COVID-19 in pregnant women during childbirth and to take the necessary precautions to ensure the best treatment of mother and neonate. The prospective acquisition of data allowed a timely assessment of the highly dynamic situation and gain knowledge regarding this vulnerable group of patients.

The effects of the COVID-19 pandemic on psychological stress in breast cancer patients.

BACKGROUND: The majority of breast cancer patients are severely psychologically affected by breast cancer diagnosis and subsequent therapeutic procedures. The COVID-19 pandemic and associated restrictions on public life have additionally caused significant psychological distress for much of the population. It is therefore plausible that breast cancer patients might be particularly susceptible to the additional psychological stress caused by the pandemic, increasing suffering. In this study we therefore aimed to assess the level of psychological distress currently experienced by a defined group of breast cancer patients in our breast cancer centre, compared to distress levels pre-COVID-19 pandemic. METHODS: Female breast cancer patients of all ages receiving either adjuvant, neoadjuvant, or palliative therapies were recruited for the study. All patients were screened for current or previous COVID-19 infection. The participants completed a self-designed COVID-19 pandemic questionnaire, the Stress and Coping Inventory (SCI), the National Comprehensive Cancer Network® (NCCN®) Distress Thermometer (DT), the European Organization for Research and Treatment of Cancer (EORTC) QLQ C30, and the BR23. RESULTS: Eighty-two breast cancer patients were included. Therapy status and social demographic factors did not have a significant effect on the distress caused by the COVID-19 pandemic. The results of the DT pre and during COVID-19 pandemic did not differ significantly. Using the self-designed COVID-19 pandemic questionnaire, we detected three distinct subgroups demonstrating different levels of concerns in relation to SARS-CoV-2. The subgroup with the highest levels of concern reported significantly decreased life quality, related parameters and symptoms. CONCLUSIONS: This monocentric study demonstrated that the COVID-19 pandemic significantly affected psychological health in a subpopulation of breast cancer patients. The application of a self-created "COVID-19 pandemic questionnaire" could potentially be used to help identify breast cancer patients who are susceptible to increased psychological distress due to the COVID-19 pandemic, and therefore may need additional intensive psychological support. TRIAL REGISTRATION: DRKS-ID: DRKS00022507 .

Expression of the Peptidase "Fibroblast Activation Protein" on Decidual Stromal Cells Facilitating Tissue Remodeling.

INTRODUCTION: Expression of fibroblast activation protein (FAP) has been detected in activated fibroblasts participating in injury response, fibrotic and inflammatory conditions, and tumorigenesis. Human endometrium is equally characterized by rapid tissue remodeling events due to the reproductive tasks comprising the activity of proteolytic enzymes. OBJECTIVE: We therefore hypothesized that FAP-positive fibroblasts could also be involved in physiological processes requiring tissue remodeling, such as decidualization during early pregnancy. METHODS/RESULTS: The expression of FAP was analyzed by immunohistochemistry in frozen sections of decidual tissue from early pregnancy (gestational weeks: 6-12). All tissue samples clearly displayed a strong expression of FAP on the surface of stromal fibroblasts. Additionally, the percentage of FAP-positive fibroblasts freshly isolated from the decidua of the corresponding gestational weeks was calculated by applying FACS analysis. Decidual fibroblasts of different gestational weeks showed a significant decrease in FAP expression between the 6th and 7th weeks of gestation, which was followed by a steady slow reconstitution. By analyzing the expression of cytokines, chemokines, and growth factors of isolated FAP-positive decidual fibroblasts, we detected high levels of monocyte-attracting chemokines (growth-related oncogene alpha and monocyte chemoattractant protein-1 and -2), granulocyte-attracting chemokines (e.g., IL-8), proinflammatory factors (IL-1α and tumor necrosis factor alpha), and angiogenic substances (e.g., vascular endothelial growth factor and IL-8), which all promote an optimal microenvironment for implantation and growth of the conceptus. CONCLUSIONS: Our data demonstrate that the healthy early pregnancy decidua is characterized by a general occurrence of FAP-positive fibroblasts possibly participating in active tissue remodeling during implantation.

Effect of adjuvant radiotherapy in elderly patients with breast cancer.

BACKGROUND: Radiotherapy (RT) is of critical importance in the locoregional management of early breast cancer. Although RT is routinely used following breast conserving surgery (BCS), patients may occasionally be effectively treated with BCS alone. Currently, the selection of patients undergoing BCS who do not need breast irradiation is under investigation. With the advancement of personalized medicine, there is an increasing interest in reduction of aggressive treatments especially in older women. The primary objective of this study was to identify elderly patients who may forego breast irradiation after BCS without measurable consequences on local tumor growth and survival. METHODS: We analyzed 2384 early breast cancer patients aged 70 and older who were treated in 17 German certified breast cancer centers between 2001 and 2009. We compared RT versus no RT after guideline adherent (GA) BCS. The outcomes studied were breast cancer recurrence (RFS) and breast cancer-specific survival (BCSS). Low-risk patients were defined by luminal A, tumor size T1 or T2 and node-negative whereas higher-risk patients were defined by patients with G3 or T3/T4 or node-positive or other than Luminal A tumors. To test if there is a difference between two or more survival curves, we used the Gp family of tests of Harrington and Fleming. RESULTS: The median age was 77 yrs (mean 77.6±5.6 y) and the median observation time 46 mths (mean 48.9±24.8 mths). 950 (39.8%) patients were low-risk and 1434 (60.2%) were higher-risk. 1298 (54.4%) patients received GA BCS of which 85.0% (1103) received GA-RT and only 15% (195) did not. For low-risk patients with GA-BCS there were no significant differences in RFS (log rank p = 0.651) and in BCSS (p = 0.573) stratified by GA-RT. 5 years RFS in both groups were > 97%. For higher-risk patients with GA-BCS we found a significant difference (p<0.001) in RFS and tumor-associated OS stratified by GA-RT. The results remain the same after adjusting by adjuvant systemic treatment (AST) and comorbidity (ASA and NYHA). CONCLUSIONS: Patients aged 70 years and older suffering from low-risk early breast cancer with GA-BCS can avoid breast irradiation with <3% chance of relapse. In the case of higher-risk, breast irradiation should be used routinely following GA-BCS. As a side effect of these results, removing the entire breast of elderly low risk patients to spare them from breast irradiation seems to be not necessary.

B2 Prognostic Score: External Validation of a Clinical Decision-making Tool for Metastatic Breast Cancer.

BACKGROUND: The B2 Prognostic Score (B2PS) is a clinical decision-making tool in metastatic breast cancer (MBC) that provides risk classification based on routine parameters. This study validates the B2PS in an independent series of MBC for the whole study group and for each intrinsic subtype. PATIENTS AND METHODS: We analyzed 641 metastasized patients, treated in 17 German certified breast cancer centers between 2001 and 2009. They were classified into low, intermediate, and high-risk groups according to B2PS. Overall survival (OS) curves for the various B2PS groups were compared with Kaplan-Meier method. RESULTS: According to the B2PS formula, 42.3% of patients were classified as low risk, 25.4% as intermediate risk and 32.3% as high risk. Intermediate- and high-risk patients had a statistically significant decreased OS compared with B2PS low-risk patients: (intermediate-risk: hazard ratio, 1.36; 95% confidence interval, 1.04-1.77; P = .023; high-risk: hazard ratio, 2.62; 95% confidence interval, 2.06-3.32; P < .001). The 5-year survival rates of low-, intermediate-, and high-risk patients were 41.3%, 26.9%, and 10.2%, respectively. The distribution of B2PS risk groups varied significantly within the intrinsic subtypes. For each intrinsic subtype, B2PS gives an additional risk classification. CONCLUSIONS: This study demonstrates the reproducibility of the B2PS based on routinely assessable parameters and confirms its prognostic value in an independent entire cohort of MBC as well as in the separate intrinsic subtypes. It therefore can help in counseling and individualizing the therapeutic regimens of those patients.

Beta-hydroxybutyrate (3-OHB) can influence the energetic phenotype of breast cancer cells, but does not impact their proliferation and the response to chemotherapy or radiation.

BACKGROUND: Ketogenic diets (KDs) or short-term fasting are popular trends amongst supportive approaches for cancer patients. Beta-hydroxybutyrate (3-OHB) is the main physiological ketone body, whose concentration can reach plasma levels of 2-6 mM during KDs or fasting. The impact of 3-OHB on the biology of tumor cells described so far is contradictory. Therefore, we investigated the effect of a physiological concentration of 3 mM 3-OHB on metabolism, proliferation, and viability of breast cancer (BC) cells in vitro. METHODS: Seven different human BC cell lines (BT20, BT474, HBL100, MCF-7, MDA-MB 231, MDA-MB 468, and T47D) were cultured in medium with 5 mM glucose in the presence of 3 mM 3-OHB at mild hypoxia (5% oxygen) or normoxia (21% oxygen). Metabolic profiling was performed by quantification of the turnover of glucose, lactate, and 3-OHB and by Seahorse metabolic flux analysis. Expression of key enzymes of ketolysis as well as the main monocarboxylic acid transporter MCT2 and the glucose-transporter GLUT1 was analyzed by RT-qPCR and Western blotting. The effect of 3-OHB on short- and long-term cell proliferation as well as chemo- and radiosensitivity were also analyzed. RESULTS: 3-OHB significantly changed the oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) in BT20 cells resulting in a more oxidative energetic phenotype. MCF-7 and MDA-MB 468 cells had increased ECAR only in response to 3-OHB, while the other three cell types remained uninfluenced. All cells expressed MCT2 and GLUT1, thus being able to uptake the metabolites. The consumption of 3-OHB was not strongly linked to mRNA overexpression of key enzymes of ketolysis and did not correlate with lactate production and glucose consumption. Neither 3-OHB nor acetoacetate did interfere with proliferation. Further, 3-OHB incubation did not modify the response of the tested BC cell lines to chemotherapy or radiation. CONCLUSIONS: We found that a physiological level of 3-OHB can change the energetic profile of some BC cell lines. However, 3-OHB failed to influence different biologic processes in these cells, e.g., cell proliferation and the response to common breast cancer chemotherapy and radiotherapy. Thus, we have no evidence that 3-OHB generally influences the biology of breast cancer cells in vitro.

Are There Breast Cancer Patients with Node-Negative Small Tumours, Who Do Not Benefit from Adjuvant Systemic Therapy?

OBJECTIVE: To identify subgroups of patients with pT1 pN0 breast cancer (BC) who might not profit from adjuvant systemic therapy (AST). METHODS: Data of 3,774 pT1 pN0 BC patients from 17 certified BC centres within the BRENDA study group were collected between 1992 and 2008 and retrospectively analysed. Uni- and multivariate analyses were performed using Kaplan-Meier methods and Cox regression models. RESULTS: 279 (7.4%) of the pT1 pN0 BC patients were T1a, 944 (25.0%) were T1b and 2,551 (67.6%) were T1c. There was no significant difference (p > 0.1) in recurrence-free survival (RFS)/overall survival (OAS) between patients with pT1a, pT1b, and T1c. Patients receiving any type of AST had a better outcome compared to women without AST after adjusting for age, tumour size, and intrinsic subtypes (RFS: p < 0.001; OAS: p < 0.001). AST was the most important prognostic parameter for RFS followed by intrinsic subtypes and age. CONCLUSION: Patients with pT1 pN0 BC profit from AST independently of molecular subtypes, tumour size, age or comorbidity, with 5-year RFS of more than 95%. The correct definition of subgroups of patients who do not need AST is still an open question.

Factors influencing the development of visceral metastasis of breast cancer: A retrospective multi-center study.

PURPOSE: Visceral metastasis of breast cancer (BC) is an alarming development and correlates with poor median overall survival. The purpose of this retrospective study is to examine the risk factors for developing visceral metastasis by considering tumor biology and patient characteristics. METHODS: Using the BRENDA database, the risk factors such as histological and intrinsic subtypes of BC, age at primary diagnosis, grading, nodal status, tumor size and year of primary diagnosis were examined in univariate and multivariate analysis. Categorical variables were compared by using χ2 tests. Furthermore, multivariate Cox proportional hazards regression models, Kaplan-Meier product-limit method and log-rank test were applied. The results of two tree-building algorithms, "exhausted CHAID" (Chi-squared Automatic Interaction Detector) and CART (Classification and Regression Trees) were verified with further multivariate analysis, radial basis function networks (RBF-net), feedforward multilayer perceptron networks (MLP) and logistic regression. RESULTS: In a patient collective of 886 metastasized patients, 56.9% had developed visceral metastases and 27.1% visceral-only metastases. The different histological and intrinsic subtypes of BC and the grading correlate significantly with the visceral-only metastasis behavior, whereas the age at primary diagnosis, the nodal status, the tumor size and the year of the primary diagnosis had no influence. Patients with ductal/other BC, LuminalB/HER2, TNBC, HER2 overexpressing subtype and grade 3 had an increased risk for the development of visceral-only metastasis. CONCLUSIONS: Intrinsic and histological subtypes as well as the grading of BC affected significantly the visceral metastasis behavior.

Pattern of metastatic spread and subcategories of breast cancer.

PURPOSE: The development of metastases is the most aggressive attribute of breast cancer. In this retrospective multicenter study, we evaluated if and how the different pathological breast cancer subtypes influence the spreading of tumor cells, the development of metastasis and the survival of breast cancer patients. METHODS: This retrospective German multicenter study is based on the BRENDA collective including 9625 breast cancer patients treated in the adjuvant setting. We used the χ 2 tests for the analysis of the categorical variables between groups of patients with different sites of metastasis. Survival distributions and median survival times were estimated using the Kaplan-Meier product-limit method. The log-rank test was applied to compare survival rates. The Cox proportional hazards model was used to estimate the hazard ratio and confidence intervals. RESULTS: 886 women developed metastases during a time interval of 53 months after primary diagnosis. Luminal A tumor patients were more likely to get bone metastases than lung, liver or CNS metastases. Patients with a triple-negative subtype were, however, the least affected by metastasis in the skeleton. They were most likely to develop visceral metastases. Location, numbers of metastases herein and the subtype influenced the overall survival (OAS). Altogether, the best OAS was found in patients with the luminal A subtype, the worst in patients with the triple-negative subtype. CONCLUSIONS: Knowledge of the typical metastatic pattern of the subtypes of breast cancer will help to personalize therapeutic options and follow-up examinations of cancer patients.