Publications by authors named "Manfred Wischnewsky"

46 Publications

BRENDA-Score, a Highly Significant, Internally and Externally Validated Prognostic Marker for Metastatic Recurrence: Analysis of 10,449 Primary Breast Cancer Patients.

Cancers (Basel) 2021 Jun 22;13(13). Epub 2021 Jun 22.

Frauenklinik Universität Ulm, Prittwitzstr. 43, 89075 Ulm, Germany.

Background Current research in breast cancer focuses on individualization of local and systemic therapies with adequate escalation or de-escalation strategies. As a result, about two-thirds of breast cancer patients can be cured, but up to one-third eventually develop metastatic disease, which is considered incurable with currently available treatment options. This underscores the importance to develop a metastatic recurrence score to escalate or de-escalate treatment strategies. Patients and methods Data from 10,499 patients were available from 17 clinical cancer registries (BRENDA-project []. In total, 8566 were used to develop the BRENDA-Index. This index was calculated from the regression coefficients of a Cox regression model for metastasis-free survival (MFS). Based on this index, patients were categorized into very high, high, intermediate, low, and very low risk groups forming the BRENDA-Score. Bootstrapping was used for internal validation and an independent dataset of 1883 patients for external validation. The predictive accuracy was checked by Harrell's c-index. In addition, the BRENDA-Score was analyzed as a marker for overall survival (OS) and compared to the Nottingham prognostic score (NPS). Results Intrinsic subtypes, tumour size, grading, and nodal status were identified as statistically significant prognostic factors in the multivariate analysis. The five prognostic groups of the BRENDA-Score showed highly significant ( < 0.001) differences regarding MFS:low risk: hazard ratio (HR) = 2.4, 95%CI (1.7-3.3); intermediate risk: HR = 5.0, 95%CI.(3.6-6.9); high risk: HR = 10.3, 95%CI (7.4-14.3) and very high risk: HR = 18.1, 95%CI (13.2-24.9). The external validation showed congruent results. A multivariate Cox regression model for OS with BRENDA-Score and NPS as covariates showed that of these two scores only the BRENDA-Score is significant (BRENDA-Score < 0.001; NPS = 0.447). Therefore, the BRENDA-Score is also a good prognostic marker for OS. Conclusion: The BRENDA-Score is an internally and externally validated robust predictive tool for metastatic recurrence in breast cancer patients. It is based on routine parameters easily accessible in daily clinical care. In addition, the BRENDA-Score is a good prognostic marker for overall survival. Highlights: The BRENDA-Score is a highly significant predictive tool for metastatic recurrence of breast cancer patients. The BRENDA-Score is stable for at least the first five years after primary diagnosis, i.e., the sensitivities and specificities of this predicting system is rather similar to the NPI with AUCs between 0.76 and 0.81 the BRENDA-Score is a good prognostic marker for overall survival.
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http://dx.doi.org/10.3390/cancers13133121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8268855PMC
June 2021

Ethnic comparison in takotsubo syndrome: novel insights from the International Takotsubo Registry.

Clin Res Cardiol 2021 May 19. Epub 2021 May 19.

Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany.

Background: Ethnic disparities have been reported in cardiovascular disease. However, ethnic disparities in takotsubo syndrome (TTS) remain elusive. This study assessed differences in clinical characteristics between Japanese and European TTS patients and determined the impact of ethnicity on in-hospital outcomes.

Methods: TTS patients in Japan were enrolled from 10 hospitals and TTS patients in Europe were enrolled from 32 hospitals participating in the International Takotsubo Registry. Clinical characteristics and in-hospital outcomes were compared between Japanese and European patients.

Results: A total of 503 Japanese and 1670 European patients were included. Japanese patients were older (72.6 ± 11.4 years vs. 68.0 ± 12.0 years; p < 0.001) and more likely to be male (18.5 vs. 8.4%; p < 0.001) than European TTS patients. Physical triggering factors were more common (45.5 vs. 32.0%; p < 0.001), and emotional triggers less common (17.5 vs. 31.5%; p < 0.001), in Japanese patients than in European patients. Japanese patients were more likely to experience cardiogenic shock during the acute phase (15.5 vs. 9.0%; p < 0.001) and had a higher in-hospital mortality (8.2 vs. 3.2%; p < 0.001). However, ethnicity itself did not appear to have an impact on in-hospital mortality. Machine learning approach revealed that the presence of physical stressors was the most important prognostic factor in both Japanese and European TTS patients.

Conclusion: Differences in clinical characteristics and in-hospital outcomes between Japanese and European TTS patients exist. Ethnicity does not impact the outcome in TTS patients. The worse in-hospital outcome in Japanese patients, is mainly driven by the higher prevalence of physical triggers.

Trial Registration: URL: https://www.clinicaltrials.gov ; Unique Identifier: NCT01947621.
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http://dx.doi.org/10.1007/s00392-021-01857-4DOI Listing
May 2021

Prognostic impact of acute pulmonary triggers in patients with takotsubo syndrome: new insights from the International Takotsubo Registry.

ESC Heart Fail 2021 06 13;8(3):1924-1932. Epub 2021 Mar 13.

Department of Cardiology, Charité, Campus Rudolf Virchow, Berlin, Germany.

Aims: Acute pulmonary disorders are known physical triggers of takotsubo syndrome (TTS). This study aimed to investigate prevalence of acute pulmonary triggers in patients with TTS and their impact on outcomes.

Methods And Results: Patients with TTS were enrolled from the International Takotsubo Registry and screened for triggering factors and comorbidities. Patients were categorized into three groups (acute pulmonary trigger, chronic lung disease, and no lung disease) to compare clinical characteristics and outcomes. Of the 1670 included patients with TTS, 123 (7%) were identified with an acute pulmonary trigger, and 194 (12%) had a known history of chronic lung disease. The incidence of cardiogenic shock was highest in patients with an acute pulmonary trigger compared with those with chronic lung disease or without lung disease (17% vs. 10% vs. 9%, P = 0.017). In-hospital mortality was also higher in patients with an acute pulmonary trigger than in the other two groups, although not significantly (5.7% vs. 1.5% vs. 4.2%, P = 0.13). Survival analysis demonstrated that patients with an acute pulmonary trigger had the worst long-term outcome (P = 0.002). The presence of an acute pulmonary trigger was independently associated with worse long-term mortality (hazard ratio 2.12, 95% confidence interval 1.33-3.38; P = 0.002).

Conclusions: The present study demonstrates that TTS is related to acute pulmonary triggers in 7% of all TTS patients, which accounts for 21% of patients with physical triggers. The presence of acute pulmonary trigger is associated with a severe in-hospital course and a worse long-term outcome.
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http://dx.doi.org/10.1002/ehf2.13165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8120351PMC
June 2021

Short-term fasting accompanying chemotherapy as a supportive therapy in gynecological cancer: protocol for a multicenter randomized controlled clinical trial.

Trials 2020 Oct 15;21(1):854. Epub 2020 Oct 15.

Institute of Social Medicine, Epidemiology and Health Economics, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.

Background/objectives: A few preliminary studies have documented the safety and feasibility of repeated short-term fasting in patients undergoing chemotherapy. However, there is a lack of data from larger randomized trials on the effects of short-term fasting on quality of life, reduction of side effects during chemotherapy, and a possible reduction of tumor progression. Moreover, no data is available on the effectiveness of fasting approaches compared to so-called healthy diets. We aim to investigate whether the potentially beneficial effects of short-term fasting can be confirmed in a larger randomized trial and can compare favorably to a plant-based wholefood diet.

Methods: This is a multicenter, randomized, controlled, two-armed interventional study with a parallel group assignment. One hundred fifty patients, including 120 breast cancer patients and 30 patients with ovarian cancer, are to be randomized to one of two nutritional interventions accompanying chemotherapy: (1) repeated short-term fasting with a maximum energy supply of 350-400 kcal on fasting days or (2) repeated short-term normocaloric plant-based diet with restriction of refined carbohydrates. The primary outcome is disease-related quality of life, as assessed by the functional assessment of the chronic illness therapy measurement system. Secondary outcomes include changes in the Hospital Anxiety and Depression Score and as well as frequency and severity of chemotherapy-induced side effects based on the Common Terminology Criteria of Adverse Events. Explorative analysis in a subpopulation will compare histological complete remissions in patients with neoadjuvant treatments.

Discussion/planned Outcomes: Preclinical data and a small number of clinical studies suggest that repeated short-term fasting may reduce the side effects of chemotherapy, enhance quality of life, and eventually slow down tumor progression. Experimental research suggests that the effects of fasting may partly be caused by the restriction of animal protein and refined carbohydrates. This study is the first confirmatory, randomized controlled, clinical study, comparing the effects of short-term fasting to a short-term, plant-based, low-sugar diet during chemotherapy on quality of life and histological tumor remission.

Trial Registration: ClinicalTrials.gov NCT03162289 . Registered on 22 May 2017.
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http://dx.doi.org/10.1186/s13063-020-04700-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7559781PMC
October 2020

Rationale and design of the MULTISTARS AMI Trial: A randomized comparison of immediate versus staged complete revascularization in patients with ST-segment elevation myocardial infarction and multivessel disease.

Am Heart J 2020 10 30;228:98-108. Epub 2020 Jul 30.

Department of Cardiology, University Heart Center, University Hospital Zurich, Zurich, Switzerland. Electronic address:

About half of patients with acute ST-segment elevation myocardial infarction (STEMI) present with multivessel coronary artery disease (MVD). Recent evidence supports complete revascularization in these patients. However, optimal timing of non-culprit lesion revascularization in STEMI patients is unknown because dedicated randomized trials on this topic are lacking. STUDY DESIGN: The MULTISTARS AMI trial is a prospective, international, multicenter, randomized, two-arm, open-label study planning to enroll at least 840 patients. It is designed to investigate whether immediate complete revascularization is non-inferior to staged (within 19-45 days) complete revascularization in patients in stable hemodynamic conditions presenting with STEMI and MVD and undergoing primary percutaneous coronary intervention (PCI). After successful primary PCI of the culprit artery, patients are randomized in a 1:1 ratio to immediate or staged complete revascularization. The primary endpoint is a composite of all-cause death, non-fatal myocardial infarction, ischemia-driven revascularization, hospitalization for heart failure, and stroke at 1 year. CONCLUSIONS: The MULTISTARS AMI trial tests the hypothesis that immediate complete revascularization is non-inferior to staged complete revascularization in stable patients with STEMI and MVD.
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http://dx.doi.org/10.1016/j.ahj.2020.07.016DOI Listing
October 2020

Coexistence and outcome of coronary artery disease in Takotsubo syndrome.

Eur Heart J 2020 09;41(34):3255-3268

Department of Cardiology, Kantonsspital Lucerne, Lucerne, Switzerland.

Aims: Takotsubo syndrome (TTS) is an acute heart failure syndrome, which shares many features with acute coronary syndrome (ACS). Although TTS was initially described with angiographically normal coronary arteries, smaller studies recently indicated a potential coexistence of coronary artery disease (CAD) in TTS patients. This study aimed to determine the coexistence, features, and prognostic role of CAD in a large cohort of patients with TTS.

Methods And Results: Coronary anatomy and CAD were studied in patients diagnosed with TTS. Inclusion criteria were compliance with the International Takotsubo Diagnostic Criteria for TTS, and availability of original coronary angiographies with ventriculography performed during the acute phase. Exclusion criteria were missing views, poor quality of angiography loops, and angiography without ventriculography. A total of 1016 TTS patients were studied. Of those, 23.0% had obstructive CAD, 41.2% had non-obstructive CAD, and 35.7% had angiographically normal coronary arteries. A total of 47 patients (4.6%) underwent percutaneous coronary intervention, and 3 patients had acute and 8 had chronic coronary artery occlusion concomitant with TTS, respectively. The presence of CAD was associated with increased incidence of shock, ventilation, and death from any cause. After adjusting for confounders, the presence of obstructive CAD was associated with mortality at 30 days. Takotsubo syndrome patients with obstructive CAD were at comparable risk for shock and death and nearly at twice the risk for ventilation compared to an age- and sex-matched ACS cohort.

Conclusions: Coronary artery disease frequently coexists in TTS patients, presents with the whole spectrum of coronary pathology including acute coronary occlusion, and is associated with adverse outcome.

Trial Registration: ClinicalTrials.gov number: NCT01947621.
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http://dx.doi.org/10.1093/eurheartj/ehaa210DOI Listing
September 2020

Effect of adjuvant radiotherapy in elderly patients with breast cancer.

PLoS One 2020 20;15(5):e0229518. Epub 2020 May 20.

Department of Mathematics and Computer Science, University of Bremen, Bremen, Germany.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0229518PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7239665PMC
July 2020

Age-Related Variations in Takotsubo Syndrome.

J Am Coll Cardiol 2020 04;75(16):1869-1877

Krankenhaus "Maria Hilf" Medizinische Klinik, Stadtlohn, Germany.

Background: Takotsubo syndrome (TTS) occurs predominantly in post-menopausal women but is also found in younger patients.

Objectives: This study aimed to investigate age-related differences in TTS.

Methods: Patients diagnosed with TTS and enrolled in the International Takotsubo Registry between January 2011 and February 2017 were included in this analysis and were stratified by age (younger: ≤50 years, middle-age: 51 to 74 years, elderly: ≥75 years). Baseline characteristics, hospital course, as well as short- and long-term mortality were compared among groups.

Results: Of 2,098 TTS patients, 242 (11.5%) patients were ≤50 years of age, 1,194 (56.9%) were 51 to 74 years of age, and 662 (31.6%) were ≥75 years of age. Younger patients were more often men (12.4% vs. 10.9% vs. 6.3%; p = 0.002) and had an increased prevalence of acute neurological (16.3% vs. 8.4% vs. 8.8%; p = 0.001) or psychiatric disorders (14.1% vs. 10.3% vs. 5.6%; p < 0.001) compared with middle-aged and elderly TTS patients. Furthermore, younger patients had more often cardiogenic shock (15.3% vs. 9.1% vs. 8.1%; p = 0.004) and had a numerically higher in-hospital mortality (6.6% vs. 3.6% vs. 5.1%; p = 0.07). At multivariable analysis, younger (odds ratio: 1.60; 95% confidence interval: 0.86 to 3.01; p = 0.14) and older age (odds ratio: 1.09; 95% confidence interval: 0.66 to 1.80; p = 0.75) were not independently associated with in-hospital mortality using the middle-aged group as a reference. There were no differences in 60-day mortality rates among groups.

Conclusions: A substantial proportion of TTS patients are younger than 50 years of age. TTS is associated with severe complications requiring intensive care, particularly in younger patients.
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http://dx.doi.org/10.1016/j.jacc.2020.02.057DOI Listing
April 2020

Deceleration of Disease Progress Through Ayurvedic Treatment in Nondialysis Stages IV-V Patients with Chronic Renal Failure: A Quasi-Experimental Clinical Pilot Study with One Group Pre- and Postdesign and Two Premeasurements.

J Altern Complement Med 2020 May 30;26(5):384-391. Epub 2020 Mar 30.

Department of Kayachikitsa, J. S. Ayurveda College & P. D. Patel Ayurveda Hospital, Nadiad, India.

The aim of this study was to evaluate the effects of Ayurvedic treatment on deceleration of the disease progress of nondialysis patients with stage IV or V chronic renal failure (CRF). A complex oral and proctocolonic Ayurvedic multiherbal medication was administered daily for 1 month to inpatients. Thereafter, patients were treated as outpatients with oral medication for additional 5 months. Four renal function tests (RFTs) were evaluated at various time points (TPs): (1) 6 months before baseline (TP -6), (2) at baseline (TP 0), and (3) after completion of 6 months of treatment (TP +6). Repeated-measures analysis of variance (ANOVA) with Greenhouse-Geisser correction and Friedman's ANOVA by ranks were used to analyze the RFTs. For tests, the Bonferroni correction was applied. Bias-corrected effect sizes (Hedges) for the treatment were calculated. Sixty-four nondialysis CRF patients with laboratory investigations of the preceding 6 months were included; 12 patients discontinued the treatment. Fifty-two patients with stage IV or V at baseline completed the study. Mean concentrations of estimated glomerular filtration rate (eGFR), serum creatinine, and hemoglobin differed significantly between TPs (eGFR:  = 15.3,  < 0.001; serum creatinine:  = 29.3,  < 0.001; blood urea:  = 2.0,  = 0.159; hemoglobin:  = 53.9,  < 0.001). Pairwise comparisons of the mean differences between TPs are significant for eGFR, creatinine, and hemoglobin. For blood urea, a significant decrease was observed for the treatment period [15.9(↓) mg/dL, standard error 4.0;  = 52], but a nonsignificant increase was observed for the pretreatment period [16.2(↑) mg/dL, standard error 9.8] due to insufficient data for TP -6 ( = 26). The effect sizes for eGFR, creatinine, blood urea, and hemoglobin were medium (0.45, 0.53, 0.44, and 0.30). After 6 months of treatment, statistically and clinically significant improvements of eGFR, creatinine, blood urea, and hemoglobin and a significant shift to better CRF stages were observed. Several cardinal symptoms were also significantly reduced. Randomized controlled trials are warranted to evaluate the effects in comparison to usual care.
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http://dx.doi.org/10.1089/acm.2019.0419DOI Listing
May 2020

Intraventricular Thrombus Formation and Embolism in Takotsubo Syndrome: Insights From the International Takotsubo Registry.

Arterioscler Thromb Vasc Biol 2020 01 26;40(1):279-287. Epub 2019 Nov 26.

Service de cardiologie, Hôpitaux Universitaires de Genève, Switzerland (P. Meyer, J.D.A.).

Objective: Takotsubo syndrome (TTS) is characterized by acute left ventricular dysfunction, which can contribute to intraventricular thrombus and embolism. Still, prevalence and clinical impact of thrombus formation and embolic events on outcome of TTS patients remain unclear. This study aimed to investigate clinical features and outcomes of patients with and without intraventricular thrombus or embolism. Additionally, factors associated with thrombus formation or embolism, as well as predictors for mortality, were identified. Approach and Results: TTS patients enrolled in the International Takotsubo Registry at 28 centers in Australia, Europe, and the United States were dichotomized according to the occurrence/absence of intraventricular thrombus or embolism. Patients with intraventricular thrombus or embolism were defined as the ThrombEmb group. Of 1676 TTS patients, 56 (3.3%) patients developed intraventricular thrombus and/or embolism following TTS diagnosis (median time interval, 2.0 days [range, 0-38 days]). Patients in the ThrombEmb group had a different clinical profile including lower left ventricular ejection fraction, higher prevalence of the apical type, elevated levels of troponin and inflammatory markers, and higher prevalence of vascular disease. In a Firth bias-reduced penalized-likelihood logistic regression model apical type, left ventricular ejection fraction ≤30%, previous vascular disease, and a white blood cell count on admission >10×10 cells/μL emerged as independent predictors for thrombus formation or embolism.

Conclusions: Intraventricular thrombus or embolism occur in 3.3% of patients in the acute phase of TTS. A simple risk score including clinical parameters associated with intraventricular thrombus formation or embolism identifies patients at increased risk.

Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01947621.
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http://dx.doi.org/10.1161/ATVBAHA.119.313491DOI Listing
January 2020

Does chemotherapy improve survival in patients with nodal positive luminal A breast cancer? A retrospective Multicenter Study.

PLoS One 2019 8;14(7):e0218434. Epub 2019 Jul 8.

Department of Obstetrics and Gynaecology, Würzburg University Medical Centre, Würzburg, Germany.

Background: In this study based on the BRENDA data, we investigated the impact of endocrine ± chemotherapy for luminal A, nodal positive breast cancer on recurrence free (RFS) and overall survival (OS). In addition, we analysed if tumor size of luminal A breast cancer influences survival in patients with the same number of positive lymph nodes.

Methods: In this retrospective multi-centre cohort study data of 1376 nodal-positive patients with primary diagnosis of luminal A breast cancer during 2001-2008 were analysed. The results were stratified by therapy and adjusted by age, tumor size and number of affected lymph nodes.

Results: In our study population, patients had a good to excellent prognosis (5-year RFS: 91% and tumorspecific 5-year OS 96.5%). There was no significant difference in RFS stratified by patients with only endocrine therapy and with endocrine plus chemo-therapy. Patients with 1-3 affected lymph nodes had no significant differences in OS treated only with endocrine therapy or with endocrine plus chemotherapy, independent of tumor size. Patients with large tumors and more than 3 affected lymph nodes had a significant worse survival as compared to the small tumors. However, despite the worse prognosis of those, adjuvant chemotherapy failed in order to improve RFS.

Conclusions: According to our data, nodal positive patients with luminal A breast cancer have, if any, a limited benefit of adjuvant chemotherapy. Tumor size and nodal status seem to be of prognostic value in terms of survival, however both tumor size as well as nodal status were not predictive for a benefit of adjuvant chemotherapy.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0218434PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6613686PMC
February 2020

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

Clin Breast Cancer 2019 10 3;19(5):333-339. Epub 2019 May 3.

Department for Obstetrics and Gynecology, University of Würzburg Medical School, Würzburg, Germany.

Background: The B Prognostic Score (BPS) is a clinical decision-making tool in metastatic breast cancer (MBC) that provides risk classification based on routine parameters. This study validates the BPS 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 BPS. Overall survival (OS) curves for the various BPS groups were compared with Kaplan-Meier method.

Results: According to the BPS 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 BPS 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 BPS risk groups varied significantly within the intrinsic subtypes. For each intrinsic subtype, BPS gives an additional risk classification.

Conclusions: This study demonstrates the reproducibility of the BPS 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.
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http://dx.doi.org/10.1016/j.clbc.2019.04.015DOI Listing
October 2019

Cardiac arrest in takotsubo syndrome: results from the InterTAK Registry.

Eur Heart J 2019 07;40(26):2142-2151

Department of Internal Medicine/Cardiology, University of Leipzig-Heart Center, Leipzig, Germany.

Aims: We aimed to evaluate the frequency, clinical features, and prognostic implications of cardiac arrest (CA) in takotsubo syndrome (TTS).

Methods And Results: We reviewed the records of patients with CA and known heart rhythm from the International Takotsubo Registry. The main outcomes were 60-day and 5-year mortality. In addition, predictors of mortality and predictors of CA during the acute TTS phase were assessed. Of 2098 patients, 103 patients with CA and known heart rhythm during CA were included. Compared with patients without CA, CA patients were more likely to be younger, male, and have apical TTS, atrial fibrillation (AF), neurologic comorbidities, physical triggers, and longer corrected QT-interval and lower left ventricular ejection fraction on admission. In all, 57.1% of patients with CA at admission had ventricular fibrillation/tachycardia, while 73.7% of patients with CA in the acute phase had asystole/pulseless electrical activity. Patients with CA showed higher 60-day (40.3% vs. 4.0%, P < 0.001) and 5-year mortality (68.9% vs. 16.7%, P < 0.001) than patients without CA. T-wave inversion and intracranial haemorrhage were independently associated with higher 60-day mortality after CA, whereas female gender was associated with lower 60-day mortality. In the acute phase, CA occurred less frequently in females and more frequently in patients with AF, ST-segment elevation, and higher C-reactive protein on admission.

Conclusions: Cardiac arrest is relatively frequent in TTS and is associated with higher short- and long-term mortality. Clinical and electrocardiographic parameters independently predicted mortality after CA.
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http://dx.doi.org/10.1093/eurheartj/ehz170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6612368PMC
July 2019

Does the number of removed axillary lymphnodes in high risk breast cancer patients influence the survival?

BMC Cancer 2019 Jan 18;19(1):90. Epub 2019 Jan 18.

Department of Mathematics and Computer Science, University Bremen, Germany, Universitätsallee, 28359, Bremen, Germany.

Background: The decision making process for axillary dissection has changed in recent years for patients with early breast cancer and positive sentinel lymph nodes (LN). The question now arises, what is the optimal surgical treatment for patients with positive axillary LN (pN+). This article tries to answer the following questions: (1) Is there a survival benefit for breast cancer patients with 3 or more positive LN (pN3+) and with more than 10 removed LN? (2) Is there a survival benefit for high risk breast cancer patients (triple negative or Her2 + breast cancer) and with 3 or more positive LN (pN3+) with more than 10 removed LN? (3) In pN + patients is the prognostic value of the lymph node ratio (LNR) of pN+/pN removed impaired if 10 or less LN are removed?

Methods: A retrospective database analysis of the multi center cohort database BRENDA (breast cancer under evidence based guidelines) with data from 9625 patients from 17 breast centers was carried out. Guideline adherence was defined by the 2008 German National consensus guidelines.

Results: 2992 out of 9625 patients had histological confirmed positive lymph nodes. The most important factors for survival were intrinsic sub types, tumor size and guideline adherent chemo- and hormonal treatment (and age at diagnosis for overall survival (OAS)). Uni-and multivariable analyses for recurrence free survival (RFS) and OAS showed no significant survival benefit when removing more than 10 lymph nodes even for high-risk patients. The mean and median of LNR were significantly higher in the pN+ patients with ≤10 excised LN compared to patients with > 10 excised LN. LNR was in both, uni-and multivariable, analysis a highly significant prognostic factor for RFS and OAS in both subgroups of pN + patients with less respective more than 10 excised LN. Multivariable COX regression analysis was adjusted by age, tumor size, intrinsic sub types and guideline adherent adjuvant systemic therapy.

Conclusion: The removal of more than 10 LN did not result in a significant survival benefit even in high risk pN + breast cancer patients.
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http://dx.doi.org/10.1186/s12885-019-5292-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6339270PMC
January 2019

Reliability of Ayurvedic Diagnosis for Knee Osteoarthritis Patients: A Nested Diagnostic Study Within a Randomized Controlled Trial.

J Altern Complement Med 2019 Sep 17;25(9):910-919. Epub 2019 Jan 17.

Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute for Social Medicine, Epidemiology and Health Economics, Berlin, Germany.

Ayurveda is a traditional Indian system of medicine. The customized Ayurvedic approach consists of a combination of several diagnostic procedures and subsequent individualized therapeutic interventions. Evaluation of inter-rater reliability (IRR) of Ayurvedic diagnoses has rarely been performed. The aim of this study was to evaluate IRR of Ayurvedic diagnosis for patients with knee osteoarthritis. A diagnostic reliability study of 30 patients and 4 Ayurvedic experts was nested in a randomized controlled trial. Patients were diagnosed in a sequential order by all experts utilizing a semistructured patient history form. A nominal group technique as consensus procedure was performed to reach agreement on the items to be diagnosed. An IRR analysis using Fleiss' and Cohen's kappa statistics was performed to determine a chance-corrected measure of agreement among raters. One hundred and twenty different ratings and 30 consensus ratings were performed and analyzed. While high percentages of agreement for main diagnostic entities and the final Ayurveda diagnosis (95% consensus agreement on main diagnosis) could be observed, this was not reflected in the corresponding kappa values, which largely yielded fair-to-poor inter-rater agreement kappas for central diagnostic aspects such as and κ values between 0 and 0.4). Notably, agreement on disease-related entities was better than that on constitutional entities. This is the first diagnostic study embedded in a clinical trial on patients with knee osteoarthritis utilizing a multimodality whole systems approach. Results showed a contrast between the high agreement of the consented final diagnosis and disagreement on certain diagnostic details. Future diagnostic studies should have larger sample sizes and a methodology more tailored to the specificities of traditional whole systems of medicine. Equal emphasis will need to be placed on all core diagnostic components of Ayurveda, both constitutional and disease specific, using detailed structured history taking forms.
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http://dx.doi.org/10.1089/acm.2018.0273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6748397PMC
September 2019

Gender and age differences in outcomes of patients with acute coronary syndromes referred for coronary angiography.

Catheter Cardiovasc Interv 2019 01 5;93(1):16-24. Epub 2018 Oct 5.

Department of Cardiology, University Heart Center, University Hospital Zurich and University of Zurich, Zurich, Switzerland.

Objectives: The number of elderly patients undergoing coronary revascularization is steadily increasing, and data on the impact of gender on outcomes are scarce. This study sought to assess gender-related differences in outcomes in elderly patients with acute coronary syndromes (ACS).

Methods: We investigated outcomes in elderly ACS patients referred for coronary angiography and prospectively enrolled in the Swiss ACS Cohort between December 2009 and October 2012. Adjudicated major adverse cardiovascular and cerebrovascular events (MACCE) included all-cause death, non-fatal myocardial infarction, clinically indicated repeat coronary revascularization, definite stent thrombosis, and transient ischemic attack/stroke.

Results: Among 2,168 patients recruited, 481 (22%) patients were >75 years of age (37% women). In patients >75 years, 1-year MACCE rates were 15% and 23% in women and men (OR 0.59, 95% CI 0.36-0.97, P = 0.04), respectively, and differences remained significant after adjustments for baseline variables (adjusted OR 0.48, 95% CI 0.26-0.90, P = 0.02). Women >75 years had a lower cardiovascular mortality (6% versus 12%, adjusted OR 0.31, 95% CI 0.12-0.81, P = 0.02). In patients ≤75 years, 1-year MACCE rates did not differ between gender (10% and 8% for women and men, adjusted OR 1.28, 95% CI 0.77-2.14, P = 0.34). Rates of TIMI major bleeding for women and men were 4% and 4% in patients >75 years (P = 0.96), and 5% and 3% in those ≤75 years (P = 0.11).

Conclusions: The low rates of MACCE observed in elderly women in this patient cohort suggest that with current interventional strategies the gender gap in ACS management has been attenuated.
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http://dx.doi.org/10.1002/ccd.27712DOI Listing
January 2019

Long-Term Prognosis of Patients With Takotsubo Syndrome.

J Am Coll Cardiol 2018 08;72(8):874-882

Deutsches Herzzentrum München, Technische Universität München, Munich, Germany; DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany.

Background: Prognosis of Takotsubo syndrome (TTS) remains controversial due to scarcity of available data. Additionally, the effect of the triggering factors remains elusive.

Objectives: This study compared prognosis between TTS and acute coronary syndrome (ACS) patients and investigated short- and long-term outcomes in TTS based on different triggers.

Methods: Patients with TTS were enrolled from the International Takotsubo Registry. Long-term mortality of patients with TTS was compared to an age- and sex-matched cohort of patients with ACS. In addition, short- and long-term outcomes were compared between different groups according to triggering conditions.

Results: Overall, TTS patients had a comparable long-term mortality risk with ACS patients. Of 1,613 TTS patients, an emotional trigger was detected in 485 patients (30%). Of 630 patients (39%) related to physical triggers, 98 patients (6%) had acute neurologic disorders, while in the other 532 patients (33%), physical activities, medical conditions, or procedures were the triggering conditions. The remaining 498 patients (31%) had no identifiable trigger. TTS patients related to physical stress showed higher mortality rates than ACS patients during long-term follow-up, whereas patients related to emotional stress had better outcomes compared with ACS patients.

Conclusions: Overall, TTS patients had long-term outcomes comparable to age- and sex-matched ACS patients. Also, we demonstrated that TTS can either be benign or a life-threating condition depending on the inciting stress factor. We propose a new classification based on triggers, which can serve as a clinical tool to predict short- and long-term outcomes of TTS. (International Takotsubo Registry [InterTAK Registry]; NCT01947621).
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http://dx.doi.org/10.1016/j.jacc.2018.06.016DOI Listing
August 2018

Predictive value of the age, creatinine, and ejection fraction (ACEF) score in patients with acute coronary syndromes.

Int J Cardiol 2018 Nov 1;270:7-13. Epub 2018 Jun 1.

Department of Cardiology, University Heart Center, University Hospital Zurich and University of Zurich, Zurich, Switzerland.

Background: This study sought to investigate the predictive value of the age, creatinine, and ejection fraction (ACEF) score in patients with acute coronary syndromes (ACS). The ACEF score (age/left ventricular ejection fraction +1 [if creatinine > 176 μmol/L]) has been established in patients evaluated for coronary artery bypass surgery. Data on its predictive value in all-comer ACS patients undergoing percutaneous coronary intervention are scarce.

Methods: A total of 1901 patients prospectively enrolled in the Swiss ACS Cohort were included in the analysis. Optimal ACEF score cut-off values were calculated by decision tree analysis, and patients divided into low-risk (≤1.45), intermediate-risk (>1.45 and ≤2.0), and high-risk groups (>2.0). The primary endpoint was all-cause mortality. Major adverse cardiac and cerebrovascular events (MACCE) included all-cause death, non-fatal myocardial infarction, clinically indicated repeat coronary revascularization, definite stent thrombosis, and transient ischemic attack/stroke.

Results: One-year rates of all-cause death increased across ACEF score groups (1.6% versus 5.6% versus 23.0%, p < 0.001). In multivariate analysis, the ACEF score was related with an increased risk of all-cause mortality (adjusted HR 3.53, 95% CI 2.90-4.31, p < 0.001), MACCE (adjusted HR 2.23, 95% CI 1.88-2.65, p < 0.001), and transient ischemic attack/stroke (adjusted HR 2.58, 95% CI 1.71-3.89, p < 0.001) at 1 year. Rates of Thrombolysis in Myocardial Infarction (TIMI) major and Global use of Strategies to Open Occluded Coronary Arteries (GUSTO) severe bleeding paralleled the increased ischemic risk across the groups (p < 0.001).

Conclusions: The ACEF score is a simple and useful risk stratification tool in patients with ACS referred for coronary revascularization.
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http://dx.doi.org/10.1016/j.ijcard.2018.05.134DOI Listing
November 2018

The effects of short-term fasting on quality of life and tolerance to chemotherapy in patients with breast and ovarian cancer: a randomized cross-over pilot study.

BMC Cancer 2018 04 27;18(1):476. Epub 2018 Apr 27.

Institute of Social Medicine, Epidemiology and Health Economics, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.

Background: This pilot trial aimed to study the feasibility and effects on quality of life (QOL) and well-being of short-term fasting (STF) during chemotherapy in patients with gynecological cancer.

Methods: In an individually-randomized cross-over trial patients with gynecological cancer, 4 to 6 planned chemotherapy cycles were included. Thirty-four patients were randomized to STF in the first half of chemotherapies followed by normocaloric diet (group A;n = 18) or vice versa (group B;n = 16). Fasting started 36 h before and ended 24 h after chemotherapy (60 h-fasting period). QOL was assessed by the FACIT-measurement system.

Results: The chemotherapy-induced reduction of QOL was less than the Minimally Important Difference (MID; FACT-G = 5) with STF but greater than the MID for non-fasted periods. The mean chemotherapy-induced deterioration of total FACIT-F was 10.4 ± 5.3 for fasted and 27.0 ± 6.3 for non-fasted cycles in group A and 14.1 ± 5.6 for non-fasted and 11.0 ± 5.6 for fasted cycles in group B. There were no serious adverse effects.

Conclusion: STF during chemotherapy is well tolerated and appears to improve QOL and fatigue during chemotherapy. Larger studies should prove the effect of STF as an adjunct to chemotherapy.

Trial Registration: This trial was registered at clinicaltrials.gov: NCT01954836 .
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http://dx.doi.org/10.1186/s12885-018-4353-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5921787PMC
April 2018

Highly significant improvement in guideline adherence, relapse-free and overall survival in breast cancer patients when treated at certified breast cancer centres: An evaluation of 8323 patients.

Breast 2018 Aug 23;40:54-59. Epub 2018 Apr 23.

Faculty of Mathematics and Computer Science, University of Bremen, Bibliothekstr. 1 MZH, 28359 Bremen, Germany.

Objectives: Certified multi-disciplinary breast cancer centres (CBCs) have been established worldwide. Development of CBCs, guideline-adherent systemic therapy and surgical management should now show an impact on outcomes. This analysis aimed to investigate whether guideline adherence (GA) rates, relapse-free survival (RFS) and overall survival (OS) have significantly improved at CBCs compared to the pre-certification period.

Materials And Methods: 8323 patients with primary breast cancer were treated in 17 German CBCs, which had been certified between 2003 and 2007 [2003 (n = 1), 2004 (n = 6), 2005 (n = 3), 2006 (n = 6) and 2007 (n = 1)]. 3544 patients (42.6%) were treated before certification and 4779 patients (57.4%) after certification.

Results And Conclusion: A highly significant (p < 0.001) difference in 100%-GA was found between the various hospitals before certification (min 25.0%; max 54.6%). In 2008, when all participating hospitals were certified, the GA rate was 61.8% (min 39.5%, max 74.4%) and 69.2% (min 45.9%, max 86.4%) for patients <75 y (n = 6675). The difference between pre-certification 100%-GA (46.9%) and post-certification (57.2%) was highly significant (p < 0.001). RFS and OS were both significantly better after certification compared to the pre-certification period (RFS: HR = 0.79; 95% CI: 0.68-0.92; p = 0.003; OS: HR = 0.75; 95% CI: 0.65-0.85; p < 0.001). 5-year RFS (OS) of patients <75 y was 89.6% (85.4%) pre-certification and 91.4% (89.5%) post-certification. Since improvement in GA and outcomes correlated as well, GA remains a highly significant prognostic factor for RFS and OS regardless of NPI, intrinsic subtype and adjuvant systemic therapy. This suggests that the certification process is strongly associated with improvements in outcome.
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http://dx.doi.org/10.1016/j.breast.2018.04.002DOI Listing
August 2018

Personalized axillary dissection: the number of excised lymph nodes of nodal-positive breast cancer patients has no significant impact on relapse-free and overall survival.

J Cancer Res Clin Oncol 2017 Sep 24;143(9):1823-1831. Epub 2017 Apr 24.

Department of Mathematics and Computer Science, University of Bremen, Universitätsallee, 28359, Bremen, Germany.

Purpose: Sentinel lymph node (SLN) biopsy has replaced axillary lymph node dissection (ALND) for the staging of clinically node-negative breast cancer patients (BCP), demonstrating equivalent survival to ALND while resulting in reduced morbidity. ALND has remained the standard of care for the majority of BCP with clinical axillary metastases or metastases found on SLN biopsy. More recently, it is debated whether ALND could be avoided not only in SLN-negative BCP but also in selected SLN-positive disease or even in all patients. This analysis of pN+ BCP shows the impact of the number of excised lymph nodes on RFS and OAS adjusted by age, tumor size, intrinsic subtypes and adjuvant systemic therapy.

Methods: In this retrospective, multicenter cohort study, we investigated data from 2992 pN+ primary BCP recruited from 17 participating certified breast cancer centers in Germany between 2001 and 2008 within the BRENDA study group.

Results: The median number of excised lymph nodes was 17. The number of excised lymph nodes was neither significant for RFS (p = 0.085) nor for OAS (p = 0.285). Adjustments were made for age, tumor size and intrinsic subtypes. The most important significant parameters for RFS were intrinsic subtypes (p < 0.001) and tumor size (p < 0.001) and for OAS age (p < 0.001) and intrinsic subtypes (p < 0.001). There were no significant differences in RFS and OAS in any subgroup stratified by the number of excised lymph nodes. Only for T3/T4 tumors, there is a very small significant advantage of ALND for RFS but not for OAS. After adjusting in addition by guideline adherence of adjuvant systemic therapy (AST), intrinsic subtypes and guideline-adherent AST are the most important significant (p < 0.001) parameters for RFS and OAS.

Conclusions: The number of excised lymph nodes of pN+ BCP neither correlates with RFS nor with OAS. Survival of pN+ BCP is primarily determined by the biology and the guideline-adherent AST based on the corresponding intrinsic subtypes. These results support the omission of a radical ALND at least for pN+ patients scheduled for breast-conserving surgery (not mastectomy), provided they receive whole breast irradiation and guideline-adherent AST.
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http://dx.doi.org/10.1007/s00432-017-2425-3DOI Listing
September 2017

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

Oncology 2017 24;92(6):317-324. Epub 2017 Mar 24.

Department for Obstetrics and Gynecology, University of Würzburg Medical School, Würzburg, Germany.

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.
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http://dx.doi.org/10.1159/000455050DOI Listing
August 2017

Do Patients with Luminal A Breast Cancer Profit from Adjuvant Systemic Therapy? A Retrospective Multicenter Study.

PLoS One 2016 19;11(12):e0168730. Epub 2016 Dec 19.

Department for Obstetrics and Gynecology, University of Würzburg Medical School, Würzburg, Germany.

Background: Luminal A breast cancers respond well to anti-hormonal therapy (HT), are associated with a generally favorable prognosis and constitute the majority of breast cancer subtypes. HT is the mainstay of treatment of these patients, accompanied by an acceptable profile of side effects, whereas the added benefit of chemotherapy (CHT), including anthracycline and taxane-based programs, is less clear-cut and has undergone a process of critical revision.

Methods: In the framework of the BRENDA collective, we analyzed the benefits of CHT compared to HT in 4570 luminal A patients (pts) with primary diagnosis between 2001 and 2008. The results were adjusted by nodal status, age, tumor size and grading.

Results: There has been a progressive reduction in the use of CHT in luminal A patients during the last decade. Neither univariate nor multivariate analyses showed any statistically significant differences in relapse free survival (RFS) with the addition of CHT to adjuvant HT, independent of the nodal status, age, tumor size or grading. Even for patients with more than 3 affected lymph nodes, there was no significant difference (univariate: p = 0.865; HR 0.94; 95% CI: 0.46-1.93; multivariate: p = 0.812; HR 0.92; 95% CI: 0.45-1.88).

Conclusions: The addition of CHT to HT provides minimal or no clinical benefit at all to patients with luminal A breast cancer, independent of the RFS-risk. Consequently, risk estimation cannot be the initial step in the decisional process. These findings-that are in line with several publications-should encourage the critical evaluation of applying adjuvant CHT to patients with luminal A breast cancer.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0168730PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5167411PMC
June 2017

Pattern of metastatic spread and subcategories of breast cancer.

Arch Gynecol Obstet 2017 Jan 10;295(1):211-223. Epub 2016 Nov 10.

Department for Obstetrics and Gynecology, University Hospital of Würzburg, Josef-Schneider-Str. 4, 97080, Würzburg, Germany.

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 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.
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http://dx.doi.org/10.1007/s00404-016-4225-4DOI Listing
January 2017

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

Breast 2017 Feb 2;31:66-75. Epub 2016 Nov 2.

Faculty of Mathematics and Computer Science, University of Bremen, Universitätsallee, GW1, 28359 Bremen, Germany.

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.
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http://dx.doi.org/10.1016/j.breast.2016.10.016DOI Listing
February 2017

The impact of breast cancer biological subtyping on tumor size assessment by ultrasound and mammography - a retrospective multicenter cohort study of 6543 primary breast cancer patients.

BMC Cancer 2016 07 13;16:459. Epub 2016 Jul 13.

Department of Obstetrics and Gynecology, Ulm University Hospital, Ulm, Germany.

Background: Mammography and ultrasound are the gold standard imaging techniques for preoperative assessment and for monitoring the efficacy of neoadjuvant chemotherapy in breast cancer. Maximum accuracy in predicting pathological tumor size non-invasively is critical for individualized therapy and surgical planning. We therefore aimed to assess the accuracy of tumor size measurement by ultrasound and mammography in a multicentered health services research study.

Methods: We retrospectively analyzed data from 6543 patients with unifocal, unilateral primary breast cancer. The maximum tumor diameter was measured by ultrasound and/or mammographic imaging. All measurements were compared to final tumor diameter determined by postoperative histopathological examination. We compared the precision of each imaging method across different patient subgroups as well as the method-specific accuracy in each patient subgroup.

Results: Overall, the correlation with histology was 0.61 for mammography and 0.60 for ultrasound. Both correlations were higher in pT2 cancers than in pT1 and pT3. Ultrasound as well as mammography revealed a significantly higher correlation with histology in invasive ductal compared to lobular cancers (p < 0.01). For invasive lobular cancers, the mammography showed better correlation with histology than ultrasound (p = 0.01), whereas there was no such advantage for invasive ductal cancers. Ultrasound was significantly superior for HR negative cancers (p < 0.001). HER2/neu positive cancers were also more precisely assessed by ultrasound (p < 0.001). The size of HER2/neu negative cancers could be more accurately predicted by mammography (p < 0.001).

Conclusion: This multicentered health services research approach demonstrates that predicting tumor size by mammography and ultrasound provides accurate results. Biological tumor features do, however, affect the diagnostic precision.
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http://dx.doi.org/10.1186/s12885-016-2426-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4943017PMC
July 2016

Evaluation of clinical parameters influencing the development of bone metastasis in breast cancer.

BMC Cancer 2016 05 12;16:307. Epub 2016 May 12.

Department for Obstetrics and Gynecology, University of Würzburg Medical School, Josef-Schneider-Str. 4, 97080, Würzburg, Germany.

Background: The development of metastases is a negative prognostic parameter for the clinical outcome of breast cancer. Bone constitutes the first site of distant metastases for many affected women. The purpose of this retrospective multicentre study was to evaluate if and how different variables such as primary tumour stage, biological and histological subtype, age at primary diagnosis, tumour size, the number of affected lymph nodes as well as grading influence the development of bone-only metastases.

Methods: This retrospective German multicentre study is based on the BRENDA collective and included 9625 patients with primary breast cancer recruited from 1992 to 2008. In this analysis, we investigated a subgroup of 226 patients with bone-only metastases. Association between bone-only relapse and clinico-pathological risk factors was assessed in multivariate models using the tree-building algorithms "exhausted CHAID (Chi-square Automatic Interaction Detectors)" and CART(Classification and Regression Tree), as well as radial basis function networks (RBF-net), feedforward multilayer perceptron networks (MLP) and logistic regression.

Results: Multivariate analysis demonstrated that breast cancer subtypes have the strongest influence on the development of bone-only metastases (χ2 = 28). 29.9 % of patients with luminal A or luminal B (ABC-patients) and 11.4 % with triple negative BC (TNBC) or HER2-overexpressing tumours had bone-only metastases (p < 0.001). Five different mathematical models confirmed this correlation. The second important risk factor is the age at primary diagnosis. Moreover, BC subcategories influence the overall survival from date of metastatic disease of patients with bone-only metastases. Patients with bone-only metastases and TNBC (p < 0.001; HR = 7.47 (95 % CI: 3.52-15.87) or HER2 overexpressing BC (p = 0.007; HR = 3.04 (95 % CI: 1.36-6.80) have the worst outcome compared to patients with luminal A or luminal B tumours and bone-only metastases.

Conclusion: The bottom line of different mathematical models is the prior importance of subcategories of breast cancer and the age at primary diagnosis for the appearance of osseous metastases. The primary tumour stage, histological subtype, tumour size, the number of affected lymph nodes, grading and NPI seem to have only a minor influence on the development of bone-only metastases.
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http://dx.doi.org/10.1186/s12885-016-2345-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4865990PMC
May 2016

Guidelines are advantageous, though not essential for improved survival among breast cancer patients.

Breast Cancer Res Treat 2015 Jul 24;152(2):357-66. Epub 2015 Jun 24.

Faculty of Mathematics and Computer Science, University of Bremen, Universitätsallee GW1, 28359, Bremen, Germany.

The purpose of this retrospective multicenter study was to resolve the pseudo-paradox that the clinical outcome of women affected by breast cancer has improved during the last 20 years irrespective of whether they were treated in accordance with clinical guidelines or not. This retrospective German multicenter study included 9061 patients with primary breast cancer recruited from 1991 to 2009. We formed subgroups for the time intervals 1991-2000 (TI1) and 2001-2009 (TI2). In these subgroups, the risk of recurrence (RFS) and overall survival (OS) were compared between patients whose treatment was either 100% guideline-conforming or, respectively, non-guideline-conforming. The clinical outcome of all patients significantly improved in TI2 compared to TI1 [RFS: p < 0.001, HR = 0.57, 95% CI (0.49-0.67); OS: p < 0.001, HR = 0.76, 95% (CI 0.66-0.87)]. OS and RFS of guideline non-adherent patients also improved in TI2 compared to TI. Comparing risk profiles, determined by Nottingham Prognostic Score reveals a significant (p = 0.001) enhancement in the time cohort TI2. Furthermore, the percentage of guideline-conforming systemic therapy (endocrine therapy and chemotherapy) significantly increased (p < 0.001) in the time cohort TI2 to TI for the non-adherent group. The general improvement of clinical outcome of patients during the last 20 years is also valid in the subgroup of women who received treatments, which deviated from the guidelines. The shift in risk profiles as well as medical advances are major reasons for this improvement. Nevertheless, patients with 100% guideline-conforming therapy always had a better outcome compared to patients with guideline non-adherent therapy.
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http://dx.doi.org/10.1007/s10549-015-3484-2DOI Listing
July 2015