Associations of stress, anxiety, and partner satisfaction with maternal-fetal attachment in women pregnant during the COVID-19 pandemic: an online study.

BACKGROUND: The COVID-19 pandemic has led to exceptional stress in pregnant women. The aim of the present study was to investigate associations of maternal stress (pandemic-related and -unrelated), anxiety, and relationship satisfaction experienced during the COVID-19 pandemic with prenatal mother-infant attachment. METHODS: An online study was conducted evaluating pandemic-related stress, pregnancy-specific stress (unrelated to the pandemic), anxiety, partnership satisfaction, and maternal-fetal attachment in German-speaking women during the second COVID-19 lockdown between January and March 2021. In total, 431 pregnant women (349 lived in Germany and 82 in Switzerland) filled in the questionnaires and gave information on demographic and pregnancy-related variables (i.e. age, gestational age, parity). Bivariate correlations were calculated in order to investigate associations between the different variables and additionally, a hierarchical regression model was conducted in order to evaluate the influence of the independent variables on prenatal attachment. RESULTS: The hierarchical regression analysis revealed that after controlling for age, gestational age, and parity higher pandemic-related stress, namely stress associated with feeling unprepared for birth, higher partnership satisfaction as well as higher positive appraisal (considered as a way of coping with pandemic-related stress) was associated with stronger maternal-fetal attachment, whereas associations of anxiety and other forms of stress were non-significant. CONCLUSIONS: The study highlights interesting associations between maternal pandemic-related preparedness stress and positive appraisal of the pregnancy as well as partnership satisfaction and prenatal attachment in women pregnant during the COVID-19 pandemic.

The influence of being pregnant during the COVID-19 pandemic on birth expectations and antenatal bonding.

PURPOSE: The aim of the present study was to compare birth expectations and antenatal bonding of women pregnant prior to and during the COVID-19 pandemic. MATERIALS AND METHODS: In total, 74 pregnant women (mean age: 33.9 ± 4.1 years, gestational age: 36 ± 2 weeks) participated in the study, who were pregnant either during the the COVID-19 pandemic (corona group, N = 35, April-July 2020) or before the pandemic (control group, N = 39, October 2017-January 2019). Birth expectations were measured using the Wijma Delivery Expectancy Questionnaire (WDEQ) and Salmon's Item List (SIL) and antenatal bonding with the Maternal Antenatal Attachment Scale (MAAS). Additionally, the corona group indicated their level of worry regarding different pandemic-related aspects using visual analogue scales. RESULTS: The corona group displayed significantly elevated fear of childbirth measured by the WDEQ and lower antenatal bonding quality compared to the control group. The additional items regarding COVID-19 burdens highlighted that the aspects that the partner may not be present during labour and that no visitors will be allowed in hospital were associated with the highest worries. CONCLUSIONS: Midwives and gynaecologists should be aware of the negative impact of the COVID-19 pandemic on fear of childbirth and antenatal bonding .

Pregnant and breastfeeding women's attitudes and fears regarding the COVID-19 vaccination.

PURPOSE: The COVID-19 vaccination is probably the most important source to fight the COVID-19 pandemic. However, recommendations and possibilities for vaccination for pregnant and breastfeeding women are inconsistent and dynamically changing. METHODS: An anonymous, online, cross-sectional survey was conducted among pregnant and breastfeeding women in Germany between 30th March and 19th April 2021 addressing COVID-19 vaccination attitudes including the underlying reasons for their decision. Additionally, anxiety regarding a SARS-CoV-2 infection and a symptomatic course of the infection were evaluated. RESULTS: In total, 2339 women (n = 1043 pregnant and n = 1296 breastfeeding) completed the survey. During pregnancy the majority (57.4%) are not in favour of receiving the vaccine, 28.8% are unsure and only 13.8% would get vaccinated at the time of the survey. In contrast, 47.2% would be in favour to receive the vaccine, if more scientific evidence on the safety of the vaccination during pregnancy would be available. Breastfeeding women show higher vaccination willingness (39.5% are in favour, 28.1% are unsure and 32.5% not in favour). The willingness to be vaccinated is significantly related to the women's anxiety levels of getting infected and to develop disease symptoms. Main reasons for vaccination hesitancy are the women's perception of limited vaccination-specific information, limited scientific evidence on vaccination safety and the fear to harm the fetus or infant. CONCLUSIONS: The results provide important implications for obstetrical care during the pandemic as well as for official recommendations und information strategies regarding the COVID-19 vaccination.

The influence of maternal singing on well-being, postpartum depression and bonding - a randomised, controlled trial.

BACKGROUND: Postpartum depression is fairly common in new mothers and moreover associated with impaired bonding and poor maternal well-being. The aim of the present study was to investigate the impact of a mother-infant singing intervention within the first three months after birth on maternal well-being, depressive symptoms and bonding. METHODS: 120 women who were recruited at the maternity ward at the University Clinic in Düsseldorf took part in this prospective, randomised-controlled study. Beside the baseline measurement 1-3 days after childbirth, depressive symptoms, maternal well-being and mother-infant bonding were evaluated with questionnaires before (two weeks after birth) and after (twelve weeks after birth) the intervention took place. The experimental group (n = 59) participated in several singing intervention sessions while the control group (n = 61) did not. In the intervention group, salivary cortisol as well as attachment and mood were assessed immediately before and after the singing sessions. RESULTS: The participants of the intervention group showed a significant reduction of cortisol (p = .023) and an improvement of attachment and mood from start to end of the intervention session (all p ≤ .008). However, no prolonged effects were revealed beyond the intervention sessions as the two groups did not differ regarding the alterations of the primary outcomes postpartum depression (interaction effect p = .187) and postpartum bonding (interaction effect p = .188) in the 10-week period from two up to twelve weeks after childbirth (all p > .05). Additional analyses of singing habits at home in both groups, revealed that only in the singing group more frequent singing was associated with less anxiety and more well-being of the mother. CONCLUSION: Singing towards the infant seems to have positive immediate effects on the well-being of new mothers (on subjective variables as well as physiological measurements). However, the intervention did not lead to more long lasting positive effects although several limitations should be considered. TRIAL REGISTRATION: DRKS00015178 (registered at the German Clinical Trial Registry), date of registration: 09.11.2018.

The effects of a music intervention during port catheter placement on anxiety and stress.

Studies have shown that perioperative music interventions can reduce patients' anxiety levels. However, in small operations like port catheter surgery evidence is sparse. The present single-blinded, randomised controlled two-armed study included 84 female patients undergoing port catheter placement who were randomly assigned to either listening to music during surgery vs. no music intervention. The medical staff was blind to group allocation. On the day of the surgery anxiety and stress levels were evaluated using subjective (STAI questionnaire, visual analogue scales) and objective (vital parameters, salivary cortisol) parameters at different time points (before the surgery, at the end of the surgery and 1 h post-surgery). The music group showed significant reductions of systolic blood pressure (from 136.5 mmHg ± 26.1 to 123.3 mmHg ± 22.0, p = .002) and heart rate (from 75.6 bpm ± 12.3 to 73.1 bpm ± 12.2, p = .035) from beginning of the surgery to skin suture, whereas the control group did not. No significant effects of the music intervention on subjective anxiety measures or salivary cortisol were revealed. In sum, the study demonstrates that a music intervention during port catheter placement positively influences physiological anxiety levels, whereas no effects were revealed for subjective anxiety and salivary cortisol. Thus, music can be considered as a low cost addition in clinical routine in order to reduce patients' heart rate and blood pressure. Future studies are encouraged to further explore the differential effects of intraoperative music interventions on physiological, endocrinological and subjective anxiety levels.

Use of music during vaginal birth and caesarean section: an interprofessional survey.

PURPOSE: Evidence abounds about the beneficial effects of music on patients and healthcare professionals for many medical indications. This study aimed to evaluate the dissemination and use of music in the obstetrical setting. METHODS: Invitations to an online survey were sent to physicians and midwives of all obstetrics departments in Germany. The survey gathered descriptive data as well as information about the personal relation to music and the use of it during vaginal birth (VB) and caesarean section (CS) and whether data about positive or negative effects of music were known to the participant. RESULTS: In total, there were 293 respondents. The 47% that had the means to play music during CS stated that music was played in 15% of the cases. Most respondents have the means to play music during VB (97%). Music is played in 38% of VB. Regardless of the mode of delivery, music was estimated to be positive for team communication and patient communication. It was also deemed calming and mood lifting on the respondents. Regarding the patient, music during CS and VB was rated as being positive on all scales. Listening to music was recommended more often during VB (66%) than CS (38%). CONCLUSIONS: Although healthcare professionals are mostly aware of the beneficial effects of music in obstetrics, our study shows that music plays a more important role during VB than during CS in Germanys obstetrical wards. There is a lack of equipment to play music in operation theatres where CS take place.

The effects of a music and singing intervention during pregnancy on maternal well-being and mother-infant bonding: a randomised, controlled study.

PURPOSE: Stress and impaired mother-infant bonding during pregnancy can lead to adverse effects for the expectant mother and the unborn child. The present study investigates whether a prenatal music and singing intervention can improve maternal well-being as well as mother-infant bonding. METHODS: A total of 172 pregnant women took part in this prospective, randomised, three-armed (music, singing or control group) study. Depressive symptoms, self-efficacy, maternal well-being and mother-infant bonding were assessed with visual analogue scales and questionnaires before the intervention phase (30th week of gestation) and afterwards (36th week of gestation). Additionally, immediate changes regarding experienced stress and mood from before until after the music and singing interventions were explored with questionnaires as well as saliva samples (for cortisol, alpha-amylase and oxytocin determination). RESULTS: Regarding immediate effects, both interventions showed positive effects on the emotional state, stress (cortisol) and bonding (oxytocin). Additionally, the singing group showed a larger reduction in cortisol and a larger improvement in valence than the music group. Looking at more prolonged effects, significant effects on general self-efficacy and perceived closeness to the unborn child (measured with a visual analogue scale) were found. No significant effects were revealed for the mother-infant bonding questionnaire and for depressive symptoms. CONCLUSION: In the present study, promising effects of music and in particular singing on maternal well-being and perceived closeness during pregnancy appeared. Prenatal music and singing interventions could be an easy to implement and effective addition to improve mood and well-being of the expectant mother and support mother-infant bonding. TRIAL REGISTRATION NUMBER: DRKS00012822, date of registration: 17.10.2017.

The Influence of Personality and Anxiety Traits on Birth Experience and Epidural Use in Vaginal Deliveries - A Cohort Study.

A positive birth experience for the mother is an important goal in obstetric health care and is influenced by several factors. For this study, 186 women filled in questionnaires between 24 and 72 hours after giving birth vaginally. We evaluated the Big-Five personality traits (extraversion, neuroticism, openness, conscientiousness and agreeableness), trait anxiety, different dimensions of childbirth experience and pain management. Correlation analysis revealed that trait anxiety and neuroticism were negatively associated with several dimensions of the birth experience. Furthermore, conscientiousness and extraversion were positively correlated with the dimension Participation. Regression analysis for the individual dimensions and overall score respectively, confirmed the independent impact of anxiety trait on Perceived Safety, Participation and Professional Support and the overall score as well as of neuroticism on Perceived Safety and conscientiousness on Participation. The significant regression models showed small R2-scores (.084-.154). The birth experience did not differ whether the women received an epidural or not. Women who did not receive an epidural displayed higher scores on the personality trait conscientiousness. The study highlights small but important associations between personality traits and birth experience in vaginal births which should sensitize the medical staff when supporting women during labor.

Rationale and description of a lifestyle intervention programme to achieve moderate weight loss in women with non-metastatic breast cancer: the lifestyle intervention part of the SUCCESS C Study.

OBJECTIVE: There is growing evidence from observational studies that lifestyle factors such as obesity, an unhealthy diet and lack of physical activity are associated with poor long-term outcome in women with breast cancer. The primary objective of the lifestyle modification part of the Simultaneous Study of Docetaxel Based Anthracycline Free Adjuvant Treatment Evaluation, as well as Life Style Intervention Strategies (SUCCESS C) Trial is to investigate the effect of an individualised lifestyle intervention programme aiming at moderate weight loss on disease-free survival in women with HER2/neu-negative breast cancer. Secondary objectives include the effect of the intervention on body weight, cardiovascular risk and quality of life. METHODS: The SUCCESS C Trial is an open-label, multicentre, randomised controlled phase III study using a 2×2 factorial design in women with newly diagnosed HER2/neu-negative intermediate-risk to high-risk breast cancer. The first randomisation served to compare disease-free survival in patients treated with two different chemotherapy regimens (3642 participants). The second randomisation served to compare disease-free survival in patients with a body mass index of 24-40 kg/m² (2292 participants) receiving either a telephone-based individualised lifestyle intervention programme for moderate weight loss or general recommendations for a healthy lifestyle for 2 years. Outcome analyses will be conducted after 5 years of follow-up. PERSPECTIVE: This study will provide information on the efficacy and safety of a comprehensive lifestyle intervention programme on disease-free survival in a large cohort of women with breast cancer. EU Clinical Trials Identifier: 2008-005453-38.

Comparing birth experience and birth outcome of vaginal births between induced and spontaneous onset of labour: a prospective study.

PURPOSE: In developed countries, around 25% of all births involve labour induction. Studies have indicated that labour induction negatively influences the birth experience as well as the birth process. However, the impact of labour induction when only considering vaginal deliveries has not been studied yet, which was the purpose of the present study. METHODS: 186 women who gave birth vaginally took part in this prospective study. 95 women gave birth after spontaneous onset of labour (SL-group) and 91 women received a labour induction (LI-group). Eight to 72 h after birth, the women filled in the revised version of the standardised Childbirth Experience Questionnaire, which examines the birth experience in four dimensions (Own Capacity, Perceived Safety, Participation and Professional Support). Medical details regarding birth and fetal outcomes were taken from the medical records. RESULTS: Birth outcomes (the number of epidural anaesthesia, the duration of birth, birth risks and childbirth injuries) as well as fetal outcomes (APGAR after 1 and 5 min and arterial cord pH) did not differ between the groups. Regarding the subjective birth experience, the LI-group indicated significantly lower values for Perceived Safety and Participation compared to the SL-group, while there were no differences for the dimensions Own Capacity and Professional Support. DISCUSSION: Successful labour induction resulting in a vaginal birth did not negatively influence birth and fetal outcomes and only partly affected the women's birth experience. The negative impact of labour induction on the dimensions Perceived Safety and Participation should sensitize midwives in order to provide optimal support.

Effects of music intervention during caesarean delivery on anxiety and stress of the mother a controlled, randomised study.

BACKGROUND: Stress and anxiety during pregnancy and childbirth have negative consequences for both mother and child. There are indications that music has a positive effect in this situation. The present study investigates the influence of music during the caesarean on anxiety and stress of the expectant mother. METHODS: The SAMBA study is a single-centre, controlled, randomized study including 304 patients. Women in the intervention group heard music via loudspeakers from one of four self-selected genres. The control group had standard treatment without music. The caesarean was performed in regional Anesthesia. At admission, at skin incision, during skin suture and two hours after completion of surgery, different subjective (State-Trait Anxiety Inventory, visual analogue scale for anxiety) and objective parameters (salivary cortisol/amylase, heart rate, blood pressure) were collected. Mixed-factorial Analysis of variances as well as independent sample t-tests were applied for data analysis. RESULTS: At skin suture, significantly lower anxiety levels were reported in the intervention group regarding State anxiety (31.56 vs. 34.41; p = .004) and visual analogue scale for anxiety (1.27 vs. 1.76; p = .018). Two hours after surgery, the measured visual analogue scale for anxiety score in the intervention group was still significantly lower (0.69 vs. 1.04; p = .018). The objective parameters showed significant differences between the groups in salivary cortisol increase from admission to skin suture (12.29 vs. 16.61 nmol/L; p = .043), as well as systolic blood pressure (130.11 vs. 136.19 mmHg; p = .002) and heart rate (88.40 vs. 92.57/min; p = .049) at skin incision. CONCLUSIONS: Music during caesarean is an easy implementable and effective way of reducing stress and anxiety of the expectant mother. TRIAL REGISTRATION: German registry for clinical trials ( DRKS00007840 ). Registered 16/06/2015. Retrospectively registered.

Use of Granulocyte-colony Stimulating Factor During Chemotherapy and Its Association With CA27.29 and Circulating Tumor Cells-Results From the SUCCESS A Trial.

BACKGROUND: Little is known about the effect of granulocyte colony-stimulating factor (G-CSF) treatment during adjuvant chemotherapy on prognostic markers. The present study explored the association between G-CSF and changes in cancer antigen (CA)27.29 and circulating tumor cell (CTC) levels during therapy. PATIENTS AND METHODS: A total of 3754 node-positive or high-risk node-negative early-stage breast cancer patients were treated within the SUCCESS-A trial (simultaneous study of gemcitabine-docetaxel combination adjuvant treatment, as well as extended bisphosphonate and surveillance-trial). CA27.29 and CTCs were determined before the start and within 6 weeks after the end of chemotherapy. RESULTS: Overall, 1324 of the 2646 patients (50.0%) available for analysis had ≥ 1 G-CSF applications during chemotherapy. G-CSF application was significantly associated with CA27.29 status before and after chemotherapy (χ2 = 30.6, df = 3; P < .001), because 238 patients (18.0%) with G-CSF treatment but only 146 (11.0%) without G-CSF treatment switched from a negative CA27.29 status before to a positive CA27.29 status after chemotherapy. In addition, patients with G-CSF application showed a significantly greater increase in CA27.29 levels after chemotherapy compared with patients without any G-CSF application during chemotherapy (Mann-Whitney U test; Z = -7.81, P < .001). No significant association was found between G-CSF application and CTC status before or after chemotherapy (χ2 = 1.2, df = 3; P = .75). CONCLUSION: Cautious interpretation is needed regarding elevated levels of MUC-1-derived tumor markers such as CA27.29 shortly after adjuvant chemotherapy when G-CSF has been given, because G-CSF treatment was associated with increased CA27.29 levels after chemotherapy.

Music in Obstetrics: An Intervention Option to Reduce Tension, Pain and Stress.

In recent years, the effect of music interventions and music therapy has experienced increased attention in the literature. It has been shown that music has positive effects on cognitive and physical performance, such as concentration and endurance, as well as on psychological parameters, such as anxiety and relaxation. Studies within the context of medicine in particular are increasingly indicating that music may be used as an intervention for relief against anxiety, stress and pain. Music is therefore seen in actual practice as a supplement to conventional pharmacological and non-pharmacological forms of treatment - and the trend is rising. Studies involving music interventions in the field of obstetrics have shown, amongst other things, that music improves the ability to relax during pregnancy and can reduce anxiety. It was also discovered that during childbirth music interventions resulted in a reduction of pain and stress. Music also has the effect of reducing stress, pain and anxiety in expectant mothers during deliveries by caesarean section. This review intends to provide an overview of the literature on music interventions in the field of obstetrics and to give a resume on the current state of research around the topic of music in relation to pregnancy, spontaneous deliveries and caesarean sections. Furthermore, the relevance of music for everyday obstetrics will be illustrated.

Association of CA27.29 and Circulating Tumor Cells Before and at Different Times After Adjuvant Chemotherapy in Patients with Early-stage Breast Cancer - The SUCCESS Trial.

BACKGROUND: Evidence for the prognostic value of circulating tumor cells (CTCs) in early-stage breast cancer is swiftly increasing. An alternative approach for identifying patients at risk for recurrence is based on the detection of the mucin-1 (MUC1)-based tumor marker CA27.29. Here we report the association of these two prognostic markers before and immediately after chemotherapy (CHT), as well as after 2 and 5 years of follow-up. PATIENTS AND METHODS: The SUCCESS trial compared fluorouracil, epirubicin and cyclophosphamide followed by docetaxel vs. FEC followed by docetaxel plus gemcitabine, and 2 vs. 5 years of treatment with zoledronic acid in 3,754 patients with node-positive or high-risk node-negative early-stage breast cancer. CA27.29 was measured with the ST AIA-PACK CA27.29 reagent (Tosoh Bioscience, Belgium). The cutoff for CA27.29 positivity was >31 U/ml. CTCs were assessed with the CellSearch System (Veridex, USA). The cutoff for CTC positivity was ≥1 CTC/15 ml whole blood. The relationship between CTC positivity and CA27.29 positivity was assessed based on Chi-square statistics and Cramer's V, which varies from 0 (no association between the variables) to 1 (complete association). Samples for CA27.29 and CTC determinations during follow-up were only drawn from patients that had no relapse. RESULTS: Both CA27.29 and CTC data were available for 1,981, 1,602, 1,159 and 707 patients before, immediately after and at 2 and 5 years after CHT, respectively. Positivity rates for CTC were 21.3%, 22.8%, 18.6% and 8.5%, respectively. CA27.29 was positive in 7.9%, 21.0%, 2.8%and 7.5%, respectively. Positivity for both CA27.29 and CTC was found in 2.4%, 4.2%, 0.7% and 1.8% of patients, respectively. The association between CA27.29 and CTC was significant but weak before CHT (p=0.0015; Cramer's V=0.063) and 5 years after CHT (p<0.001; Cramer's V=0.164), and not significant immediately after CHT (p=0.162; Cramer's V=0.035) and 2 years after (p=0.349; Cramer's V=0.028). CONCLUSION: We showed that CTC and CA27.29 positivity were significantly, but only weakly associated before CHT and 5 years after CHT, while no significant association was found immediately or 2 years after CHT during the course of early-stage breast cancer. It, therefore, seems reasonable to further evaluate the prognostic value of CTCs and CA27.29 as a combined prognostic test of two potentially independent markers that might provide complementary prognostic information.

Measuring the course of anxiety in women giving birth by caesarean section: a prospective study.

BACKGROUND: Women undergoing elective caesarean section experience anxiety. However, course, extent and duration of anxiety have not been investigated yet. This study aimed to explore anxiety levels during the course of the day of surgery by employing and comparing subjective as well as objective measures. By examining their correlation it is intended to give methodological support for interventional studies. METHODS: This is a monocentric, prospectively planned study in which 47 women with an indication for primary caesarean section took part. Anxiety levels were evaluated using the State-Trait Anxiety Inventory (STAI-trait and STAI-state), the visual analogue scale for anxiety (VASA) as well as saliva cortisol at three time points on the day of the caesarean section (at admission, at skin closure and 2 h post surgery). RESULTS: Peak anxiety levels for the STAI-state and VASA were highest at admission and showed significant decreases to skin closure (p < .001). The subjective measures correlated significantly at all time points (p-values < .001). For cortisol levels the peak level of anxiety was shown at skin closure with a significant increase from admission to skin closure and a significant decrease from skin closure to 2 h post operation (p-values < .001). Additionally women with STAI-trait scores above the median showed significantly higher levels at the peaks of anxiety. CONCLUSION: The study reveals the course of anxiety on the day of the caesarean section. A strong correlation of STAI-state and VASA was demonstrated. Cortisol showed a different course, which fits into its known biological kinetics. Taking into account all measures, anxiety seems to be most bothersome before surgery until skin closure. In a differentiated approach using STAI-trait scores as a discriminator we showed that the group with STAI-trait levels above the median is particularly prone to develop anxiety in the setting of the caesarean section and might therefore mostly be in need of an intervention against anxiety.

Rapid correction of severe hyponatremia after hysteroscopic surgery ­ a case report.

BACKGROUND: One of the most feared complications during hysteroscopic surgery is haemodilution by absorption of distension media. One facet of haemodilution, i.e. hyponatremia, can lead to respiratory distress, pulmonary oedema, as well as cardiovascular collapse. CASE PRESENTATION: Here we report the swift recovery of a 45 year, female, Caucasian patient with acute hyponatremia (74 mEq/L) and pulmonary oedema by the employment of rapid correctional strategies. CONCLUSION: The absorption of irrigation fluids, as presented in this case, is an inevitable side effect of hysteroscopic surgery. Utmost caution should, therefore, be mandatory to reduce and actively monitor fluid intake. If these measures fail, as in the case presented here, it is essential to rapidly eliminate any free water and to normalize the sodium levels. Anecdotal reports of pontine myelinolysis are not in line with literature concerning acute hyponatremia and should, therefore, not obstruct determined action against it.

Circulating tumor cells predict survival in early average-to-high risk breast cancer patients.

BACKGROUND: Circulating tumor cells (CTCs) have been shown to predict reduced survival outcomes in metastatic breast cancer. METHODS: CTCs were analyzed in 2026 patients with early breast cancer before adjuvant chemotherapy and in 1492 patients after chemotherapy using the CellSearch System. After immuno-magnetic enrichment for cells expressing the epithelial-cell adhesion molecule, CTCs were defined as nucleated cells expressing cytokeratin and lacking CD45. The patients were followed for a median of 35 months (range = 0-54). Kaplan-Meier analyses and the log-rank test were used for survival analyses. All statistical tests were two-sided. RESULTS: Before chemotherapy, CTCs were detected in 21.5% of patients (n = 435 of 2026), with 19.6% (n = 136 of 692) of node-negative and 22.4% (n = 299 of 1334) of node-positive patients showing CTCs (P < .001). No association was found with tumor size, grading, or hormone receptor status. After chemotherapy, 22.1% of patients (n = 330 of 1493) were CTC positive. The presence of CTCs was associated with poor disease-free survival (DFS; P < .0001), distant DFS (P < .001), breast cancer-specific survival (P = .008), and overall survival (OS; P = .0002). CTCs were confirmed as independent prognostic markers in multivariable analysis for DFS (hazard ratio [HR] = 2.11; 95% confidence interval [CI] = 1.49 to 2.99; P < .0001) and OS (HR = 2.18; 95% CI = 1.32 to 3.59; P = .002). The prognosis was worst in patients with at least five CTCs per 30 mL blood (DFS: HR = 4.51, 95% CI = 2.59 to 7.86; OS: HR = 3.60, 95% CI = 1.56 to 8.45). The presence of persisting CTCs after chemotherapy showed a negative influence on DFS (HR = 1.12; 95% CI = 1.02 to 1.25; P = .02) and on OS (HR = 1.16; 95% CI = 0.99 to 1.37; P = .06) CONCLUSIONS: These results suggest the independent prognostic relevance of CTCs both before and after adjuvant chemotherapy in a large prospective trial of patients with primary breast cancer.

Diagnostic leukapheresis enables reliable detection of circulating tumor cells of nonmetastatic cancer patients.

Circulating tumor cells (CTCs) are promising biomarkers for diagnosis and therapy in systemic cancer. However, their infrequent and unreliable detection, especially in nonmetastatic cancer, currently impedes the clinical use of CTCs. Because leukapheresis (LA) targets peripheral blood mononuclear cells, which have a similar density to CTCs, and usually involves processing the whole circulating blood, we tested whether LA could substantially increase CTC detection in operable cancer patients. Therefore, we screened LA products generated from up to 25 L of blood per patient in two independent studies, and found that CTCs can be detected in more than 90% of nonmetastatic breast cancer patients. Interestingly, complete white blood cell sampling enabled determining an upper level for total CTC numbers of about 100,000 cells (median, 7,500 CTCs) per patient and identified a correlation of CTC numbers with anatomic disease spread. We further show that diagnostic leukapheresis can be easily combined with the US Food and Drug Administration-approved CellSearch system for standardized enumeration of CTCs. Direct comparison with 7.5 mL of blood revealed a significantly higher CTC frequency in matched LA samples. Finally, genomic single-cell profiling disclosed highly aberrant CTCs as therapy-escaping variants in breast cancer. In conclusion, LA is a clinically safe method that enabled a reliable detection of CTCs at high frequency even in nonmetastatic cancer patients, and might facilitate the routine clinical use of CTCs as in the sense of a liquid biopsy. Combined with technologies for single-cell molecular genetics or cell biology, it may significantly improve prediction of therapy response and monitoring of early systemic cancer.

Trastuzumab clears HER2/neu-positive isolated tumor cells from bone marrow in primary breast cancer patients.

PURPOSE: Isolated tumor cells (ITC) in the bone marrow of breast cancer patients increase the risk of recurrence and decrease survival, both at primary diagnosis and during follow-up. We tested the efficacy of trastuzumab in clearing HER2/neu-positive ITC from the marrow of patients completing primary treatment. METHODS: Ten recurrence-free patients with persistent HER2/neu-positive ITC after routine adjuvant treatment received trastuzumab 6 mg/kg q3w for 12 months in a non-randomized pilot phase II interventional study. Bone marrow ITC HER2/neu status was evaluated at baseline, after treatment for 3, 6 and 12 months, and yearly thereafter, in combination with clinical follow-up. Median follow-up was 23 (15-64) months after baseline bone marrow aspiration. RESULTS: Trastuzumab for 12 months eradicated HER2/neu-positive ITC from bone marrow in all patients (P = 0.002) and significantly reduced the number of ITC-positive patients (P = 0.031). However, HER2/neu-negative ITC persisted in three patients immediately after treatment and were detected at yearly bone marrow aspiration in five patients. Two patients with ITC counts ≥5 at yearly follow-up developed metastases and one died. CONCLUSION: This is the first evidence that trastuzumab is effective in clearing HER2/neu-positive cells from bone marrow during recurrence-free follow-up in breast cancer patients. It also suggests, thanks to the antigen shift phenomenon, an important prognostic role for HER2/neu expression on marrow ITC as a real-time biopsy. However, treatment was mainly effective in patients with HER2/neu-positive ITC. Given the heterogeneity of minimal residual disease, these patients might benefit from a combination of targeted treatment approaches.

Toxicity Analysis in the ADEBAR Trial: Sequential Anthracycline-Taxane Therapy Compared with FEC120 for the Adjuvant Treatment of High-Risk Breast Cancer.

BACKGROUND: Data from meta-analyses have shown taxane-containing therapies to be superior to anthracycline-based treatments for high-risk breast cancer. PATIENTS AND METHODS: The ADEBAR trial was a multicenter phase III trial in which patients with lymph node-positive breast cancer were prospectively randomized for either sequential anthracycline-taxane or FEC120 therapy. Patients received 4× epirubicin (90 mg/m(2)) and cyclophosphamide (600 mg/m(2)) every 3 weeks (q3w), followed by 4× docetaxel (100 mg/m(2)) q3w (EC-Doc arm), or 6× epirubicin (60 mg/m(2)) and 5-fluorouracil (500 mg/m(2)) on days 1 and 8 and cyclophosphamide (75 mg/m(2)) on days 1-14, q4w (FEC arm). We compared both arms with respect to toxicity and feasibility. RESULTS: Hematological toxicity was found significantly more often in the FEC arm. Febrile neutropenia was seen in 11.3% of patients in the FEC arm and in 8.4% of patients in the EC-Doc arm (p = 0.027). Non-hematological side effects of grade 3/4 were rarely seen in either arm. Therapy was terminated due to toxicity in 3.7% of the patients in the EC-Doc arm and in 8.0% of the patients in the FEC arm (p = 0.0009). CONCLUSION: The sequential anthracycline-taxane regimen is a well-tolerated and feasible alternative to FEC120 therapy.