COGNITION: a prospective precision oncology trial for patients with early breast cancer at high risk following neoadjuvant chemotherapy.

BACKGROUND: COGNITION (Comprehensive assessment of clinical features, genomics and further molecular markers to identify patients with early breast cancer for enrolment on marker driven trials) is a diagnostic registry trial that employs genomic and transcriptomic profiling to identify biomarkers in patients with early breast cancer with a high risk for relapse after standard neoadjuvant chemotherapy (NACT) to guide genomics-driven targeted post-neoadjuvant therapy. PATIENTS AND METHODS: At National Center for Tumor Diseases Heidelberg patients were biopsied before starting NACT, and for patients with residual tumors after NACT additional biopsy material was collected. Whole-genome/exome and transcriptome sequencing were applied on tumor and corresponding blood samples. RESULTS: In the pilot phase 255 patients were enrolled, among which 213 were assessable: thereof 48.8% were identified to be at a high risk for relapse following NACT; 86.4% of 81 patients discussed in the molecular tumor board were eligible for a targeted therapy within the interventional multiarm phase II trial COGNITION-GUIDE (Genomics-guided targeted post neoadjuvant therapy in patients with early breast cancer) starting enrolment in Q4/2022. An in-depth longitudinal analysis at baseline and in residual tumor tissue of 16 patients revealed some cases with clonal evolution but largely stable genetic alterations, suggesting restricted selective pressure of broad-acting cytotoxic neoadjuvant chemotherapies. CONCLUSIONS: While most precision oncology initiatives focus on metastatic disease, the presented concept offers the opportunity to empower novel therapy options for patients with high-risk early breast cancer in the post-neoadjuvant setting within a biomarker-driven trial and provides the basis to test the value of precision oncology in a curative setting with the overarching goal to increase cure rates.

Preoperative portal vein or portal and hepatic vein embolization: DRAGON collaborative group analysis.

BACKGROUND: The extent of liver resection for tumours is limited by the expected functional reserve of the future liver remnant (FRL), so hypertrophy may be induced by portal vein embolization (PVE), taking 6 weeks or longer for growth. This study assessed the hypothesis that simultaneous embolization of portal and hepatic veins (PVE/HVE) accelerates hypertrophy and improves resectability. METHODS: All centres of the international DRAGON trials study collaborative were asked to provide data on patients who had PVE/HVE or PVE on 2016-2019 (more than 5 PVE/HVE procedures was a requirement). Liver volumetry was performed using OsiriX MD software. Multivariable analysis was performed for the endpoints of resectability rate, FLR hypertrophy and major complications using receiver operating characteristic (ROC) statistics, regression, and Kaplan-Meier analysis. RESULTS: In total, 39 patients had undergone PVE/HVE and 160 had PVE alone. The PVE/HVE group had better hypertrophy than the PVE group (59 versus 48 per cent respectively; P = 0.020) and resectability (90 versus 68 per cent; P = 0.007). Major complications (26 versus 34 per cent; P = 0.550) and 90-day mortality (3 versus 16 per cent respectively, P = 0.065) were comparable. Multivariable analysis confirmed that these effects were independent of confounders. CONCLUSION: PVE/HVE achieved better FLR hypertrophy and resectability than PVE in this collaborative experience.

Eliminating the breast cancer surgery paradigm after neoadjuvant systemic therapy: current evidence and future challenges.

In patients with operable early breast cancer, neoadjuvant systemic treatment (NST) is a standard approach. Indications have expanded from downstaging of locally advanced breast cancer to facilitate breast conservation, to in vivo drug-sensitivity testing. The pattern of response to NST is used to tailor systemic and locoregional treatment, that is, to escalate treatment in nonresponders and de-escalate treatment in responders. Here we discuss four questions that guide our current thinking about 'response-adjusted' surgery of the breast after NST. (i) What critical diagnostic outcome measures should be used when analyzing diagnostic tools to identify patients with pathologic complete response (pCR) after NST? (ii) How can we assess response with the least morbidity and best accuracy possible? (iii) What oncological consequences may ensue if we rely on a nonsurgical-generated diagnosis of, for example, minimally invasive biopsy proven pCR, knowing that we may miss minimal residual disease in some cases? (iv) How should we design clinical trials on de-escalation of surgical treatment after NST?

Chronic hepatitis B and C infections in the Netherlands: estimated prevalence in risk groups and the general population.

Chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are usually asymptomatic for decades, thus targeted screening can prevent liver disease by timely diagnosis and linkage to care. More robust estimates of chronic HBV and HCV infections in the general population and risk groups are needed. Using a modified workbook method, the total number of ever chronically infected individuals in the Netherlands in 2016 was determined using population size and prevalence estimates from studies in the general and high-risk population. The estimated 2016 chronic HBV infection prevalence is 0.34% (low 0.22%, high 0.47%), corresponding to approximately 49 000 (low 31 000, high 66 000) HBV-infected individuals aged 15 years and older. The estimated ever-chronic HCV infection prevalence is 0.16% (low 0.06%, high 0.27%), corresponding to approximately 23 000 (low 8000, high 38 000) ever-chronic HCV-infected individuals. The prevalence of chronic HBV and HCV infections in the Netherlands is low. First-generation migrants account for most infections with 81% and 60% of chronic HBV and HCV infections, respectively. However, about one-fifth of HCV infections is found in the general population at low risk. This method can serve as an example for countries in need of more accurate prevalence estimates, to help the design and evaluation of prevention and control policies.

Changes of breast and axillary surgery patterns in patients with primary breast cancer during the past decade.

PURPOSE: Breast-conserving therapy (BCT) is the standard procedure for most patients with primary breast cancer (BC). By contrast, axillary management is still under transition to find the right balance between avoiding of morbidity, maintaining oncological safety, and performing a staging procedure. The rising rate of primary systemic therapy creates further challenges for surgical management. METHODS: Patients with primary, non-metastatic BC treated between 01.01.2003 and 31.12.2016 under guideline-adherent conditions were included in this study. For this prospectively followed cohort, breast and axillary surgery patterns are presented in a time-trend analysis as annual rate data (%) for several subgroups. RESULTS: Overall, 6700 patients were included in the analysis. While BCT rates remained high (mean 2003-2016: 70.4%), the proportion of axillary lymph node dissection has declined considerably from 80.1% in 2003 to 16.0% in 2016, while the proportion for sentinel lymph node biopsy (SLND) has increased correspondingly from 10.3 to 76.4%. Among patients with cT1-2, cN0 breast cancer receiving BCT with positive SLND, the rate of axillary completion has decreased from 100% in 2008 to 24.4% in 2016. CONCLUSIONS: In the past decade, SLNB has been established as the standard procedure for axillary staging of clinically node-negative patients. Surgical morbidity has been further reduced by the rapid implementation of new evidence from the ACOSOG Z0011 trial into clinical routine. The results reflect the transition towards more individually tailored, less invasive treatment for selected patient subgroups, especially in regards to axillary lymph node management.

Time trends (2006-2015) of quality indicators in EUSOMA-certified breast centres.

AIM OF THE STUDY: The European Society of Breast Cancer Specialists (EUSOMA) has fostered a voluntary certification process for breast centres to establish minimum standards and ensure specialist multidisciplinary care. Prospectively collected anonymous information on primary breast cancer cases diagnosed and treated in the units is transferred annually to a central EUSOMA data warehouse for continuous monitoring of quality indicators (QIs) to improve quality of care. Units have to comply with the EUSOMA Breast Centre guidelines and are audited by peers. The database was started in 2006 and includes over 110,000 cancers from breast centres located in Germany, Switzerland, Belgium, Austria, The Netherlands, Spain, Portugal and Italy. The aim of the present study is assessing time trends of QIs in EUSOMA-certified breast centres over the decade 2006-2015. MATERIALS AND METHODS: Previously defined QIs were calculated for 22 EUSOMA-certified breast centres (46122 patients) during 2006-2015. RESULTS: On the average of all units, the minimum standard of care was achieved in 8 of 13 main EUSOMA QIs in 2006 and in all in 2015. All QIs, except removal of at least 10 lymph nodes at axillary clearance and oestrogen receptor-negative tumours (T > 1 cm or N+) receiving adjuvant chemotherapy, improved significantly in this period. The desirable target was reached for two QIs in 2006 and for 7 of 13 QIs in 2015. CONCLUSION: The EUSOMA model of audit and monitoring QIs functions well in different European health systems and results in better performance of QIs over the last decade. QIs should be evaluated and adapted on a regular basis, as guidelines change over time.

Using ultrasound and palpation for predicting axillary lymph node status following neoadjuvant chemotherapy - Results from the multi-center SENTINA trial.

BACKGROUND: With the growing importance of neoadjuvant systemic therapy (NST) the assessment of post neoadjuvant axillary status is of increasing importance especially in patients who presented initially with suspicious nodes (cN1). This study aims to investigate the predictive value of palpation and axillary ultrasound of formerly cN1 patients following NST. PATIENTS AND METHODS: The SENTINA trial (SENTinel NeoAdjuvant) is a 4-arm prospective multicenter study designed to evaluate the role of sentinel node biopsy (SLNB) in the context of neoadjuvant systemic treatment (NST) of breast cancer patients. RESULTS: 1240 patients from 103 institutions entered the trial. 715 (arm C n = 592; arm D n = 123) patients, who presented initially cN1 underwent clinical evaluation of lymph node status following NST. Palpation alone demonstrated a sensitivity of 8.3%, specifity of 94.8% and a negative predictive value (NPV) of 46.6%. Ultrasound alone revealed a sensitivity of 23.9%, specificity 91.7%, and a NPV of 50.3%.The investigators combined classification (palpation and ultrasound) resulted in a sensitivity of 24.4%, specificity 91.4%, and a NPV of 50.3%. Investigators classified the axilla nodes as being unsuspicious (cN0) following NST in 592/715 patients; of them 298 (50.3%) were pN0, 151 (25.5%) had 1-2 histologically involved nodes and 143 (24.2%) had >2 histologically involved nodes. CONCLUSION: The diagnostic accuracy of ultrasound and palpation following NST is unacceptably low and additional tools for evaluation of the axillary lymph node status following NST are urgently needed.

Changes in chemotherapy usage and outcome of early breast cancer patients in the last decade.

BACKGROUND: During the last decade, neoadjuvant chemotherapy (NACT) of early breast cancer (EBC) evolved from a therapy intended to enable operability to a standard treatment option aiming for increasing cure rates equivalent to adjuvant chemotherapy (ACT). In parallel, improvements in the quality control of breast cancer care have been established in specialized breast care units. PATIENTS AND METHODS: This study analyzed chemotherapy usage in patients with EBC treated at the Heidelberg University Breast Unit between January 2003 and December 2014. RESULTS: Overall, 5703 patients were included in the analysis of whom 2222 (39 %) received chemotherapy, 817 (37 %) as NACT, and 1405 (63 %) as ACT. The chemotherapy usage declined from 48 % in 2003 to 34 % in 2014 of the cohort. Further, the proportion of NACT raised from 42 to 65 % irrespective of tumor subtype. In addition, frequency of pathologic complete response (pCR) defined as no tumor residues in breast and axilla (ypT0 ypN0) at surgery following NACT increased from 12 % in 2003 to 35 % in 2014. The greatest effect was observed in HER2+ breast cancer with an increase in patients achieving pCR from 24 to 68 %. CONCLUSIONS: The results mirror the refined indication for chemotherapy in EBC and its preferred usage as NACT in Germany. The increase in pCR rate over time suggests improvement in outcome accomplished by a multidisciplinary decision-making process and stringent measures for quality control.

The effect of EUSOMA certification on quality of breast cancer care.

AIM OF THE STUDY: The European Society of Breast Cancer Specialists (EUSOMA) has fostered a voluntary certification process for breast units to establish minimum standards and ensure specialist multidisciplinary care. In the present study we assess the impact of EUSOMA certification for all breast units for which sufficient information was available before and after certification. MATERIALS AND METHODS: For 22 EUSOMA certified breast units data of 30,444 patients could be extracted from the EUSOMA database on the evolution of QI's before and after certification. RESULTS: On the average of all units, the minimum standard of care was achieved for 12/13 QI's before and after EUSOMA certification (not met for DCIS receiving just one operation). There was a significant improvement of 5 QI's after certification. The proportion of patients with invasive cancer undergoing an axillary clearance containing >9 lymph nodes (91.5% vs 89.4%, p 0.003) and patients with invasive cancer having just 1 operation (83.1% vs 80.4%, p < 0.001) dropped, but remained above the minimum standard. The targeted standard of breast care was reached for the same 4/13 QI's before and after EUSOMA certification. CONCLUSION: Although the absolute effect of EUSOMA certification was modest it further increases standards of care and should be regarded as part of a process aiming for excellence. Dedicated units already provide a high level of care before certification, but continuous monitoring and audit remains of paramount importance as complete adherence to guidelines is difficult to achieve.

Hormone Therapy and its Effect on the Prognosis in Breast Cancer Patients.

Introduction: Use of hormone therapy (HT) has declined dramatically in recent years. Some studies have reported that HT use before a diagnosis of breast cancer (BC) may be a prognostic factor in postmenopausal patients. This study aimed to examine the prognostic relevance of HT use before BC diagnosis. Methods: Four BC cohort studies in Germany were pooled, and 4492 postmenopausal patients with HT use data were identified. Patient data and tumor characteristics were compared between users and nonusers, along with overall survival (OS), distant metastasis-free survival (DMFS), and local recurrence-free survival (LRFS). Cox proportional hazards models were stratified by study center and adjusted for age at diagnosis, tumor stage, grading, nodal status, and hormone receptors. Results: Women with HT use before the diagnosis of BC were more likely to have a lower tumor stage, to be estrogen receptor-negative, and to have a lower grading. With regard to prognosis there were effects seen for OS, DMFS and LRFS, specifically in the subgroup of women with a positive hormone receptor. In these subgroups, BC patients had a better prognosis with previous HT use. Conclusions: HT use before a diagnosis of BC is associated with a more favorable prognosis in women with a positive hormone receptor status. It may be recommended that the prognostic factor HT should be documented and analyzed as a confounder for prognosis in studies of postmenopausal hormone-responsive breast cancers.

[Lobular neoplasms and invasive lobular breast cancer]. / Lobuläre Neoplasie und invasives lobuläres Mammakarzinom.

The term lobular neoplasia (LN) comprises both atypical lobular hyperplasia (ALH), and lobular carcinoma in situ (LCIS) and thus a spectrum of morphologically heterogeneous but clinically and biologically related lesions. LN is regarded as a nonobligatory precursor lesion of invasive breast cancer and at the same time as an indicator lesion for ipsilateral and contralateral breast cancer risk of the patient. Rare pleomorphic or florid variants of LCIS must be differentiated from classical LCIS. The classical type of invasive lobular carcinoma (ILC) can be distinguished from the non-special type of invasive breast cancer (NST) by E-cadherin inactivation, loss of E-cadherin related cell adhesion and the subsequent discohesive growth pattern. Variant forms of ILC may show different molecular features, and solid and pleomorphic differentiation patterns in cases of high grade variants. Important parameters for the prognostic assessment of ILC are tumor grading and the recognition of morphological variants.

Upper Blepharoplasty for Areola Reconstruction.

Blepharoplasty is one of the most common rejuvenating facial plastic surgery procedures. The procedure has been described many times and has very few complications. The tissue removed from the upper eyelid during blepharoplasty can be used as a skin graft for areola reconstruction due to the tissue's similarity to the areola's natural skin. The present study investigated the use of upper blepharoplasty for areola reconstruction. Criteria were patient satisfaction, objective measurements and the assessment of cosmesis by a panel of physicians. All eight patients included in the study were very satisfied with the cosmetic result. Objective measurements and assessment by a panel of physicians using photographs of the reconstructed nipple-areola complex showed very good aesthetic results.

Outcome analysis of patients with primary breast cancer initially treated at a certified academic breast unit.

INTRODUCTION: Evaluation of oncological outcome and prognostic factors of patients with primary breast cancer treated at a certified academic breast unit. PATIENTS AND METHODS: We prospectively collected data of 3338 patients, diagnosed with primary breast cancer between 01.01.2003 and 31.12.2010 and treated at the Breast Unit Heidelberg, Germany, in order to analyze outcome in clinical practice. We evaluated local control rate (LCR), disease-free survival (DFS), distant disease-free survival (DDFS), observed overall survival (OS) and age-adjusted relative overall survival (ROS). In addition, the impact of known prognostic factors on these outcome variables was examined in univariate and multivariate analyses. RESULTS: Of all patients, 368 (11.0%) had carcinoma in situ (CIS) and 197 (5.9%) had bilateral cancers. For the 2970 patients with invasive cancer, of which 49 patients (1.7%) had metastastic disease at time of diagnosis, DFS, LCR, DDFS, OS and ROS at 5 years were 79.8%, 84.7%, 81.2%, 86.3%, and 89.8%, respectively. In multivariate analysis age, pT category, nodal status, hormone receptor status and grading were identified as independent prognostic factors for OS. CONCLUSION: Compared with recent population-based reports from Germany, more favourable patient characteristics and nominally higher survival was found among this large cohort of patients with primary breast cancer treated at a single certified breast unit.

Do patients with invasive lobular breast cancer benefit in terms of adequate change in surgical therapy from a supplementary preoperative breast MRI?

BACKGROUND: Breast magnetic resonance imaging (MRI) has been introduced in the preoperative management of invasive lobular breast cancer (ILC). We analysed if MRI leads to adequate changes in surgical management. PATIENTS AND METHODS: We carried out a single-centre retrospective confirmatory analysis of 92 patients with ILC and a preoperative breast MRI. By applying a blinded tumour board method, we analysed if surgical procedures were altered due to breast MRI. In case of alteration, we analysed whether the change was adequate according to the postoperative pathology findings. We considered an adequate rate of change>5% to be a clinically relevant benefit. RESULTS: A change in surgical therapy due to the MRI findings occurred in 23 of 92 patients (25%). According to the postoperative pathology findings, this change was adequate for 20 of these patients (22%; 95% confidence interval [CI] 14%-31%, P<0.0001). An overtreatment occurred for three patients (3%; 95% CI 0%-6%) who underwent a mastectomy following the results of breast MRI. Patients with larger tumours did likely benefit more from preoperative breast MRI. CONCLUSIONS: Patients with ILC might benefit from a preoperative breast MRI. Possible harm from overtreatment should be minimised by diligent use of preoperative histological clarification.

Change of aesthetic and functional outcome over time and their relationship to quality of life after breast conserving therapy.

PURPOSE: We analyzed changes in aesthetic and functional outcome over time after breast conserving therapy. Our special interest resides in the question of whether these aspects gain or loose their influence on quality of life (QoL) with temporal progress. PATIENTS AND METHODS: This prospective single centre cohort study included 138 patients, treated with breast conserving surgery and consecutive radiotherapy. Patients completed two questionnaires one week and one year after surgery: the BCTOS (Breast Cancer Treatment Outcome Scale) to measure Functional, Aesthetic, and Breast Sensitivity Status and the EORTC (European Organisation for Research and Treatment of Cancer) C30-BR23 to assess QoL. We applied correlation and multiple regression analysis as statistical methods. RESULTS: Aesthetic and Functional Status did not change significantly over one year, whereas Breast Sensitivity Status and several QoL subscales showed significant improvement (p < 0.0001). Correlations between BCTOS scales and EORTC subscales remain similar over time. Functional and Aesthetic Status kept a strong impact on global health (Spearman's Rho = -0.28 to -0.45 depending on time of assessment). Increasing age and poorer Functional Status shortly after surgery are predictors of a decline in global health over one year (p < 0.001). CONCLUSION: Functional and aesthetic outcome after breast conserving surgery maintain their impact on QoL over a one year follow-up period and are valuable predictors of QoL.

The effectiveness of a fertility awareness based method to avoid pregnancy in relation to a couple's sexual behaviour during the fertile time: a prospective longitudinal study.

BACKGROUND: The efficacy of fertility awareness based (FAB) methods of family planning is critically reviewed. The objective was to investigate the efficacy and the acceptability of the symptothermal method (STM), an FAB method that uses two indicators of fertility, temperature and cervical secretions observation. This paper will recommend a more suitable approach to measure the efficacy. METHODS: Since 1985, an ongoing prospective observational longitudinal cohort study has been conducted in Germany. Women are asked to submit their menstrual cycle charts that record daily basal body temperature, cervical secretion observations and sexual behaviour. A cohort of 900 women contributed 17,638 cycles that met the inclusion criteria for the effectiveness study. The overall rates of unintended pregnancies and dropout rates have been estimated with survival curves according to the Kaplan-Meier method. In order to estimate the true method effectiveness, the pregnancy rates have been calculated in relation to sexual behaviour using the 'perfect/imperfect-use' model of Trussell and Grummer-Strawn. RESULTS: After 13 cycles, 1.8 per 100 women of the cohort experienced an unintended pregnancy; 9.2 per 100 women dropped out because of dissatisfaction with the method; the pregnancy rate was 0.6 per 100 women and per 13 cycles when there was no unprotected intercourse in the fertile time. CONCLUSIONS: The STM is a highly effective family planning method, provided the appropriate guidelines are consistently adhered to.

Air sac PO2 and oxygen depletion during dives of emperor penguins.

In order to determine the rate and magnitude of respiratory O2 depletion during dives of emperor penguins (Aptenodytes forsteri), air sac O2 partial pressure (PO2) was recorded in 73 dives of four birds at an isolated dive hole. These results were evaluated with respect to hypoxic tolerance, the aerobic dive limit (ADL; dive duration beyond which there is post-dive lactate accumulation) and previously measured field metabolic rates (FMRs). 55% of dives were greater in duration than the previously measured 5.6-min ADL. PO2 and depth profiles revealed compression hyperoxia and gradual O2 depletion during dives. 42% of final PO2s during the dives (recorded during the last 15 s of ascent) were <20 mmHg (<2.7 kPa). Assuming that the measured air sac PO2 is representative of the entire respiratory system, this implies remarkable hypoxic tolerance in emperors. In dives of durations greater than the ADL, the calculated end-of-dive air sac O2 fraction was <4%. The respiratory O2 store depletion rate of an entire dive, based on the change in O2 fraction during a dive and previously measured diving respiratory volume, ranged from 1 to 5 ml O2 kg(-1) min(-1) and decreased exponentially with diving duration. The mean value, 2.1+/-0.8 ml O2 kg(-1) min(-1), was (1) 19-42% of previously measured respiratory O(2) depletion rates during forced submersions and simulated dives, (2) approximately one-third of the predicted total body resting metabolic rate and (3) approximately 10% of the measured FMR. These findings are consistent with a low total body metabolic rate during the dive.

An automated computer system to support ultra high throughput SNP genotyping.

Celera Genomics has constructed an automated computer system to support ultra high-throughput SNP genotyping that satisfies the increasing demand that disease association studies are placing on current genotyping facilities. This system consists of the seamless integration of target SNP selection, automated oligo design, in silico assay quality validation, laboratory management of samples, reagents and plates, automated allele calling, optional manual review of autocalls, regular status reports, and linkage disequilibrium analysis. Celera has proven the system by generating over 2.5 million genotypes from more than 10,000 SNPs, and is approaching the target capacity of over 10,000 genotypes per machine per hour using limited human intervention with state of the art laboratory hardware.

Tubulysins, new cytostatic peptides from myxobacteria acting on microtubuli. Production, isolation, physico-chemical and biological properties.

New cytostatic compounds, tubulysins, were isolated from the culture broth of strains of the myxobacteria Archangium gephyra and Angiococcus disciformis. The compounds are peptides partly consisting of unusual amino acids and are distantly related to the dolastatins. The tubulysins were not active against bacteria and only little against fungi, but showed high cytostatic activity against mammalian cell lines with IC50 values in the picomolar range. An incubation with 50 ng/ml tubulysin A led to a complete disappearance of the microtubuli network of the cells within 24 hours. The more active tubulysin D induced multipolar spindles: At 0.5 ng/ml all mitotic cells showed more than four spindle poles.