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Zusammenfassung Hintergrund Die COVID-19 Pandemie stellt die medizinischen Fakultäten vor beispiellose Herausforderungen. Kontaktbeschränkung als wirksamstes Mittel der Infektionsprävention macht den traditionellen Präsenzunterricht nahezu unmöglich. Daher sind neue Lehrmethoden erforderlich, um das Infektionsrisiko einzudämmen und gleichzeitig hochwertigen Unterricht zu gewährleisten. Fragestellung Um den Bedarf an Präsenzunterricht zu reduzieren, wurde unter Anwendung von Open-Source-Software im Rahmen eines Pilotprojekts eine multimediale, virtuelle Lernumgebung für das Fach „Anästhesiologie und Notfallmedizin“ entwickelt und deren Akzeptanz bei Studierenden untersucht. Gleichzeitig beantworten wir die Frage, ob diese Technologie eine taugliche Alternative zum klassischen Präsenzunterricht darstellt. Material und Methoden Wir haben mit dem Lernmanagementsystem „Moodle“ eine multimediale eLearning-Plattform entsprechend dem Lehrplan „Anästhesiologie und Notfallmedizin“ für das 2. klinische Studienjahr geschaffen. Es wurde eine anonymisierte Nachkursbefragung mit Multiple-Choice- und Freitextfragen durchgeführt. Ergebnisse 85,4 % der 157 Teilnehmer bewerteten den Kurs als „sehr gut“, 12,1 % als „gut“ und 1,9 % als „o.k.“. Niedrigere Bewertungen wurden nicht gegeben. 54,8 % bewerteten den Kursinhalt als „sehr relevant“, 43,3 % als „relevant“ und 1,9 % als „neutral“. 94,3 % waren der Ansicht, dass „mehr vergleichbare Online-Kurse angeboten werden sollten“. Die Freitextantworten zeigten, dass Barrierefreiheit und multimediales, selbstgesteuertes Lernen sehr geschätzt wurden. Es wurde jedoch auch angemerkt, dass die praktische Ausbildung nicht durch eLearning ersetzt werden kann. Diskussion „Technology enhanced learning“ wurde von unseren Studierenden sehr gut angenommen und als gute Alternative zum Präsenzunterricht bewertet. Für das Erlernen praktischer Fertigkeiten bleibt der Präsenzunterricht jedoch unverzichtbar.

Highlights • Deletion of fibronectin in cancer cells prolongs survival • Pharmacologic inhibition of fibronectin deposition slows down cancer progression in two models • Decreasing fibronectin in the matrix diminishes proliferation in tumors and can serve as an adjuvant therapy, Understanding how the extracellular matrix affects cancer development constitutes an emerging research field. Fibronectin and collagen are two intriguing matrix components found in cancer. Large concentrations of fibronectin or collagen type I have been implicated in poor prognosis in patients. In a mouse model, we had shown that genetically decreasing circulating fibronectin resulted in smaller tumors. We therefore aimed to manipulate fibronectin pharmacologically and determine how cancer development is affected. Deletion of fibronectin in human breast cancer cells (MDA-MB-231) using shRNA (knockdown: Kd) improved survival and diminished tumor burden in a model of metastatic lesions and in a model of local growth. Based on these findings, it seemed reasonable to attempt to prevent fibronectin accumulation using a bacterial derived peptide called pUR4. Treatment with this peptide for 10 days in the breast cancer local growth model or for 5 days in a melanoma skin cancer model (B16) was associated with a significant suppression of cancer growth. Treatment aimed at inhibiting collagen type I accumulation without interfering with fibronectin could not affect any changes in vivo. In the absence of fibronectin, diminished cancer progression was due to inhibition of proliferation, even though changes in blood vessels were also detected. Decreased proliferation could be attributed to decreased ERK phosphorylation and diminished YAP expression. In summary, manipulating fibronectin diminishes cancer progression, mostly by suppressing cell proliferation. This suggests that matrix modulation could be used as an adjuvant to conventional therapy as long as a decrease in fibronectin is obtained., Graphical abstract Image, graphical abstract

Wahrend bis vor wenigen Jahren nur eine begrenzte Auswahl an digitalen Moglichkeiten zur genetischen Diagnostik zur Verfugung stand, kann heute zur Diagnosestellung auf eine Vielzahl von digitalen Datenbanken und genetischen Testsystemen zuruckgegriffen werden. Damit stieg auch die Zahl der genetischen Zuordnungen – abgesehen von einer immer groser werdenden Zahl von Genen, die mit Krankheitsbildern in Verbindung gebracht werden. Im Folgenden werden anhand eines komplexen neuropadiatrischen Krankheitsbildes die schrittweise Stufendiagnostik vorgestellt, die zur Diagnosestellung fuhrte, sowie weitere digitale Systeme, die aktuell fur verschiedene Fragestellungen nutzbar sind.

Purpose In the ACOSOG Z0011 trial, completing axillary lymph node dissection (cALND) did not benefit patients with T1–T2 cN0 early breast cancer and 1–2 positive sentinel lymph nodes (SLN) undergoing breast-conserving surgery (BCT). This paper reports cALND rates in the clinical routine for patients who had higher (T3–T4) tumor stages and/or underwent mastectomy but otherwise met the ACOSOG Z0011 eligibility criteria. Aim of this study is to determine cALND time trends and non-sentinel axillary metastases (NSAM) rates to estimate occult axillary tumor burden. Methods Data were included from patients treated in 179 German breast cancer centers between 2008 and 2015. Time-trend rates were analyzed for cALND of patients with T3–T4 tumors separated for BCT and mastectomy and regarding presence of axillary macrometastases or micrometastases. Results Data were available for 188,909 patients, of whom 19,009 were identified with 1–2 positive SLN. Those 19,009 patients were separated into 4 cohorts: (1) Patients with T1–T2 tumors receiving BCT (ACOSOG Z0011 eligible; n = 13,741), (2) T1–T2 with mastectomy (n = 4093), (3) T3–T4 with BCT (n = 269), (4) T3–T4 with mastectomy (n = 906). Among patients with T3–T4 tumors, cALND rates declined from 2008 to 2015: from 88.2 to 62.6% for patients receiving mastectomy and from 96.6 to 58.1% in patients receiving BCT. Overall rates for any NSAM after cALND for cohorts 1–4 were 33.4%, 42.3%, 46.9%, 58.8%, respectively. Conclusions The cALND rates have decreased substantially in routine care in patients with ‘extended’ ACOSOG Z0011 eligibility criteria. Axillary tumor burden is higher in these patients than in the ACOSOG Z0011 trial.

ZusammenfassungNur wenigen Erwachsenen gelingt es, den gesundheitsförderlichen Bewegungs-Mindestempfehlungen der Weltgesundheitsorganisation zu entsprechen. Menschen mit psychischen Erkrankungen, wie beispielsweise Menschen mit einer Abhängigkeitserkrankung, fällt es oft noch schwerer, ausreichend körperlich aktiv zu sein [1]. Während Patient*innen in stationärer Versorgung die Mindestempfehlung körperlich-sportlicher Aktivität erreichen, ist es eine große Herausforderung, diese positiven Adaptionen über die stationäre Rehabilitation hinaus langfristig aufrechtzuerhalten [2]. Das Anliegen dieses Beitrags ist es, die theoriegeleitete Kurzintervention MoVo-EvA zur Steigerung der poststationären körperlichen Aktivität im Rahmen einer medizinischen Entwöhnungsbehandlung von abhängigkeitserkrankten Menschen vorzustellen. Weiterhin werden auf Grundlage von Erkenntnissen aus einem Pilotprojekt allgemeine, personelle, organisatorische und strukturelle Umsetzungshinweise für die Implementierung der MoVo-EvA-Intervention in Rehabilitationskliniken dargestellt.

Triple-negative breast cancer constitutes ~ 15% of all breast cancer subtypes. Because of the negative hormone receptor and human epidermal growth factor receptor 2 status, therapy is mainly based on chemotherapy with a poor median overall survival in the metastatic setting of ~ 18 months. Compared to other breast cancer subtypes, triple-negative breast cancer is characterized by a higher mutational load, which renders the tumor immunogenic and amenable to immunotherapeutic intervention. Based on the promising results of immunotherapy in other cancer entities, including melanoma or non-small cell lung cancer, a vast number of studies are currently assessing immunotherapeutic approaches in patients with triple-negative breast cancer. While monotherapies with antibodies against programmed death-1 and programmed death ligand-1 have shown little efficacy in patients with heavily pretreated metastatic triple-negative breast cancer, treatment efficacy likely depends on the therapeutic setting, the treatment line, and the combination of immunotherapies with other anticancer drugs. Several studies are currently evaluating the safety and efficacy of immune checkpoint inhibition in combination with chemotherapy, angiogenesis inhibitors, poly(ADP-ribose) polymerase inhibitors, as well as radiotherapy in the metastatic and (neo-)adjuvant settings. The US Food and Drug Administration approval of nab-paclitaxel in combination with atezolizumab in 2019 presented a landmark therapeutic development for patients with triple-negative breast cancer, given the limited treatment options available for this highly aggressive disease. In this review, we provide an overview on important ongoing and completed immunotherapeutic studies in triple-negative breast cancer and their possible implications for clinical practice.

Locoregional control is a prerequisite to cure primary breast cancer but the prediction of locoregional recurrence to guide further local therapy following neoadjuvant chemotherapy remains a challenge. The CPS + EG score was designed to predict distant recurrences. Here we examine its ability to predict both not only distant but also locoregional recurrences with respect to accuracy and clinical applicability. Clinical data from 432 patients with primary breast cancer treated with neoadjuvant chemotherapy between 2003 and 2011 were prospectively collected. Using the Kaplan–Meier method we analyzed the risk of local and distant recurrences according to individual CPS + EG scores, stratified by type of surgery. Possible confounding of the relationship between recurrence risk and CPS + EG score by established risk factors was accounted for in multiple survival regression models. Additionally, we analyzed the performance of the CPS + EG score to predict isolated locoregional recurrence by censoring patients with prior or simultaneous distant metastases. 5-year locoregional recurrence-free survival was 90%, and 5-year distant metastases-free survival was 82%. The CPS + EG score stratified patients into six prognostic groups with distinct 5-year locoregional recurrence-free survival, ranging from 100 to 41% (p = 0.02) and 5-year distant metastases-free survival, ranging from 96 to 35% (p

Purpose: Presence of disseminated tumour cells (DTCs) in the bone marrow (BM) has been described as a surrogate of residual disease in patients with early breast cancer (EBC). PADDY (Pooled Analysis of DTC Detection in Early Breast Cancer) is a large international analysis of pooled data that aimed to assess the prognostic impact of DTCs in patients with EBC. Experimental design: Individual patient data were collected from 11 centres. Patients with EBC and available follow-up data in whom BM sampling was performed at the time of primary diagnosis before receiving any anticancer treatment were eligible. DTCs were identified by antibody staining against epithelial cytokeratins. Multivariate Cox regression was used to compare the survival of DTC-positive versus DTC-negative patients. Results: In total, 10,307 patients were included. Of these, 2814 (27.3%) were DTC-positive. DTC detection was associated with higher tumour grade, larger tumour size, nodal positivity, oestrogen receptor and progesterone receptor negativity, and HER2 positivity (all p < 0.001). Multivariate analyses showed that DTC detection was an independent prognostic marker for overall survival, disease-free survival and distant disease-free survival with hazard ratios (HR) and 95% confidence intervals (CI) of 1.23 (95% CI: 1.06-1.43, p = 0.006), 1.30 (95% CI: 1.12 e1.52, p < 0.001) and 1.30 (95% CI: 1.08-1.56, p = 0.006), respectively. There was no association between locoregional relapse-free survival and DTC detection (HR 1.21; 95% CI 0.68-2.16; p = 0.512). Conclusions: DTCs in the BM represent an independent prognostic marker in patients with EBC. The heterogeneous metastasis-initiating potential of DTCs is consistent with the concept of cancer dormancy. (C) 2021 Elsevier Ltd. All rights reserved.

Introduction and hypothesis Urinary incontinence (UI) has a potentially devastating effect on women’s quality of life (QoL). Conservative treatment by means of pelvic floor muscle training is the first-choice treatment modality. Nowadays, this can be supported by digital apps like pelvina©—a digital health companion pelvic floor course. Methods Using pelvina©, UI symptoms and QoL are regularly examined through the questionnaires QUID and SF-6D. Subsequently, we analyzed the incidence and degree of UI and its impact on QoL in 293 users in a real-world environment. Results The 293 patients included in this study had a median age of 36 years and a median of two children. Patients were slightly to moderately affected by UI with a QUID of 6 (2–11, maximum 24). Age and number of children were independently associated with the incidence of UI with an adjusted odds ratio (aOR) of 1.06 (95% CI 1.01–1.12) and aOR of 1.86 (95% CI 1.12–3.08). The severity of UI strongly correlated with impairment of QoL (ρ = 0.866, P Conclusions The use of real-world data generated by digital health solutions offers the opportunity to gain insight into the reality of patients’ lives. In this article, we corroborate the known associations between number of children and UI as well as the great influence UI has on QoL. This study shows that, in the future, the use of digital apps can make an important contribution to scientific data acquisition and, for example, therapy monitoring.

Objective The FUSION-X-US-II prototype was developed to combine 3D automated breast ultrasound (ABUS) and digital breast tomosynthesis in a single device. We evaluated the performance of ABUS and tomosynthesis in a single examination in a clinical setting. Methods In this prospective feasibility study, digital breast tomosynthesis and ABUS were performed using the FUSION-X-US-II prototype without any change of the breast position in patients referred for clarification of breast lesions with an indication for tomosynthesis. The tomosynthesis and ABUS images of the prototype were interpreted independently from the clinical standard by a breast diagnostics specialist. Any detected lesion was classified using BI-RADS® scores, and results of the standard clinical routine workup (gold standard) were compared to the result of the separate evaluation of the prototype images. Image quality was rated subjectively and coverage of the breast was measured. Results One hundred one patients received both ABUS and tomosynthesis using the prototype. The duration of the additional ABUS acquisition was 40 to 60 s. Breast coverage by ABUS was approximately 80.0%. ABUS image quality was rated as diagnostically useful in 86 of 101 cases (85.1%). Thirty-three of 34 malignant breast lesions (97.1%) were identified using the prototype. Conclusion The FUSION-X-US-II prototype allows a fast ABUS scan in combination with digital breast tomosynthesis in a single device integrated in the clinical workflow. Malignant breast lesions can be localized accurately with direct correlation of ABUS and tomosynthesis images. The FUSION system shows the potential to improve breast cancer screening in the future after further technical improvements. Key Points • The FUSION-X-US-II prototype allows the combination of automated breast ultrasound and digital breast tomosynthesis in a single device without decompression of the breast. • Image quality and coverage of ABUS are sufficient to accurately detect malignant breast lesions. • If tomosynthesis and ABUS should become part of breast cancer screening, the combination of both techniques in one device could offer practical and logistic advantages. To evaluate a potential benefit of a combination of ABUS and tomosynthesis in screening-like settings, further studies are needed.

Brustkrebs in der Schwangerschaft ist selten. Die Tendenz ist steigend, was sicher auch dem hoheren Alter der Frauen bei Eintreten der Schwangerschaft geschuldet ist. Aufgrund erschwerter und konsekutiv verzogerter Diagnostik zeigen sich vermehrt fortgeschrittene Tumorstadien mit ungunstiger Tumorbiologie, sodass eine multimodale Therapie erforderlich ist. Oft herrscht grose Unsicherheit uber die bestmogliche Behandlung fur Mutter und Kind. Der folgende Artikel gibt einen Uberblick uber diagnostische, lokale und systemische Therapieoptionen des schwangerschaftsassoziierten Mammakarzinoms. Insgesamt konnte gezeigt werden, dass nach Abschluss des 1. Trimenons sichere medikamentose und operative Therapiekonzepte existieren, welche die Prognose der Mutter trotz bestehender Schwangerschaft nicht verschlechtern und die Entwicklung des Feten nicht gefahrden. Schwangerschaftsassoziierter Brustkrebs stellt keine zwingende, medizinische Indikation fur einen Schwangerschaftsabbruch dar.

Das Zervixkarzinom stellt in der Schwangerschaft das am haufigsten diagnostizierte gynakologische Malignom dar. Da eine leitliniengerechte Therapie analog der Behandlung nichtschwangerer Patientinnen in den meisten Fallen nicht mit dem Erhalt einer Schwangerschaft vereinbar ware, ist nach interdisziplinarer Diskussion des Falls die Erstellung eines individuellen Therapiekonzepts unter Berucksichtigung des Patientenwunsches von zentraler Bedeutung. Prinzipiell wird die Therapie neben dem FIGO-Stadium (FIGO International Federation of Gynecology and Obstetrics) der Erkrankung und dem Nodalstatus masgeblich von zwei weiteren Faktoren bestimmt: dem Schwangerschaftsalter bei Erstdiagnose sowie dem Wunsch eines Schwangerschafts- bzw. Fertilitatserhalts seitens der Patientin. Wahrend bei klinischem Verdacht auf eine zervikale Neoplasie diagnostische Masnahmen wie die Kolposkopie und Biopsie auch in der Schwangerschaft jederzeit moglich sind, sollten operative Masnahmen erst nach Abschluss des 1. Trimenons erfolgen. Zur moglichst prazisen Risikoeinschatzung ist ab Stadium FIGO IB1 eine laparoskopische pelvine Lymphonodektomie empfohlen. Bei hohergradigen FIGO-Stadien kann die Durchfuhrung einer neoadjuvanten Chemotherapie mit einem Cisplatin-haltigen Regime das Fortfuhren der Schwangerschaft bis zum Erreichen der fetalen Reife ermoglichen. Trotz der insgesamt sparlichen Datenlage scheint ein Schwangerschaftserhalt in den meisten Fallen moglich zu sein, ohne signifikant die Prognose der Patientin zu verschlechtern.

Introduction As early breast cancer might relapse even after complete removal of breast and lymphnodes, the disease must persist in secondary sites. The detection of disseminated tumor cells (DTC) in the bone marrow (BM) has been described as a surrogate of residual disease. Various trials showed an impaired prognosis of DTC positive early breast cancer (EBC) patients. The PADDY (Pooled Analysis of DTC Detection in Early Breast Cancer) study is a large international pooled analysis that aimed to assess the prognostic impact of DTC detection in patients with EBC. Methods A pre-specified protocol was followed, and centers known to practice BM sampling for DTC detection were contacted for individual patient data. Patients with EBC, with available follow-up data and BM sampling before any anti-cancer treatment were eligible. BM aspirates were collected at the time of primary surgery. DTC were identified by antibody (A45-B/B3, AE1/AE3, 2E11 and E29) staining against cytokeratin. The DTC status was compared to other prognostic factors using the chi-squared test. Univariate log-rank test and multivariate cox regression were used to compare survival of DTC positive versus DTC negative patients. Results Individual data from 10,320 patients (11 centers from Europe and USA) were included with a median follow-up of 91 months. Of all patients, 2,823 (27.4 %) were DTC positive. DTC detection was associated with higher tumor grade, higher T stage, nodal positivity, ER and PR negativity, and HER2 positivity (all p Conclusions Detection of DTC in the bone marrow is an independent prognostic marker in patients with non-metastatic breast cancer. Further studies should investigate the impact of DTC on metastatic cancer progression and their role for clinical decision making. Citation Format: Hartkopf AD, Brucker SY, Taran F-A, Harbeck N, von Au A, Naume B, Pierga J-Y, Hoffmann O, Beckmann MW, Rydén L, Fehm T, Aft R, Montserrat S, Walter V, Rack B, Schuetz F, Borgen E, Ta M-H, Bittner A-K, Fasching P, Fernö M, Krawczyk N, Weilbaecher K, Margelí M, Hahn M, Jueckstock J, Domschke C, Bidard F-C, Kasimir-Bauer S, Schoenfisch B, Kurt AG, Wallwiener M, Gebauer G, Wallwiener D, Janni W, Pantel K. International pooled analysis of the prognostic impact of disseminated tumor cells from the bone marrow in early breast cancer: Results from the PADDY study [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr GS5-07.

The Breast Cancer Treatment Outcome Scale (BCTOS) is a questionnaire to evaluate the aesthetic and functional outcome after breast conserving surgery (BCS). The original BCTOS with its 22 items on three subscales was refined to a shorter, improved, and easier to administer patient-reported outcome measure, the BCTOS-12. The BCTOS-12 consists of 12 items on two distinct subscales, the Functional Status and the Aesthetic Status. The aim of this study was to validate the BCTOS-12 in a prospective cohort. For this study, 239 breast cancer patients were included preoperatively, and 204 patients completed the BCTOS-12 and EORTC QLQ C30 BR23 shortly after their BCS, corresponding to a follow-up rate of 85%. The item-factor structure was examined by confirmatory factor analysis. The reliability was calculated by McDonald’s Omega for estimating internal consistency. The convergent validity was assessed by Spearman’s rank correlation coefficients between the related scales of the questionnaires. The BCTOS-12 showed a robust item-factor structure and a good internal consistency with McDonald’s Omega of 0.89 for the Aesthetic Status and 0.90 for the Functional Status. A high convergent and divergent validity was indicated by correlations between the subscales of the EORTC QLQ C30 BR23 and the BCTOS-12. Overall, the results demonstrate a successful psychometric validation of the BCTOS-12. The BCTOS-12 is a refined, improved, and now validated, instrument. It can be used in clinical studies and routine management for the evaluation of the aesthetic and functional outcome after BCS.

Patients with cholestatic liver disease experience increased fracture risk. Higher circulating levels of a fibronectin isoform called oncofetal fibronectin (oFN) were detected in a subset of such patients. Administering this isoform to mice suppresses osteoblast differentiation and diminishes bone mineral density in vivo, suggesting it is responsible for bone loss in cholestatic liver disease. The aim of this study was to define the mechanism by which oFN affects osteoblast function and evaluate possible modifiers in experimental hepatic osteodystrophy. The fibronectin isoform oFN is characterized by the presence of various glycosylations. In line with this, adding oFN that underwent enzymatic O-deglycosylation to osteoblasts normalized nodule formation in vitro. Of three possible O-glycosylation sites in oFN, only a mutation at AA 33 of the variable region or binding of this glycosylated site with an antibody normalized osteoblast differentiation. Because the responsible site is located in the variable region of fibronectin, which binds to α4β1 or α4β7 integrins, these integrins were evaluated. We show that integrin α4β1 mediates the inhibitory effect of oFN both in vitro as well as in vivo. In a hepatic osteodystrophy mouse model, we demonstrate that liver fibrosis is associated with increased circulating oFN and diminished BMD. In addition, trabecular bone loss induced by oFN injection or fibrosis induction could be prevented by either administering an antibody that binds to α4 integrin (PS/2) or the CS1 peptide, which contains a binding site for α4β1 integrin. In summary, oFN inhibits osteoblast activity. This is because of an O-glycosylation in the variable region that results in decreased integrin-mediated signaling. This deleterious effect can be thwarted by binding α4β1 integrin. Thus, we have characterized the defect and the receptor mediating bone loss in patients with hepatic osteodystrophy and evaluated possible therapeutic interventions in a murine model. © 2016 American Society for Bone and Mineral Research.

Cancer-initiating cells (CIC) account for metastatic spread, which may rely mostly on CIC exosomes (TEX) that affect host cells and can transfer CIC features into Non-CIC. The CIC marker CD44 variant isoform v6 (CD44v6) being known for metastasis-promotion, we elaborated in cells its contribution to migration and invasion and in TEX the tranfer of migratory and invasive capacity to Non-CIC, using a CD44v6 knockdown (CD44v6kd) as Non-CIC model. A CD44v6kd in human pancreatic and colorectal cancer (PaCa, CoCa) lines led to loss of CIC characteristics including downregulation of additional CIC markers, particularly Tspan8. This aggravated the loss of CD44v6-promoted motility and invasion. Loss of motility relies on the distorted cooperation of CD44v6 and Tspan8 with associated integrins and loss of invasiveness on reduced protease expression. These deficits, transferred into TEX, severely altered the CD44v6kd-TEX composition. As a consequence, unlike the CIC-TEX, CD44v6kd TEX were not taken up by CD44v6kd cells and CIC. The uptake of CIC-TEX was accompanied by partial correction of CIC marker and protease expression in CD44v6kd cells, which regained migratory, invasive and metastatic competence. CIC-TEX also fostered angiogenesis and expansion of myeloid cells, likely due to a direct impact of CIC-TEX on the host, which could be supported by reprogrammed CD44v6kd cells. Taken together, the striking loss of tumor progression by a CD44v6kd relies on the capacity of CD44v6 to cooperate with associating integrins and proteases and its promotion of additional CIC marker expression. The defects by a CD44v6kd are efficiently corrected upon CIC-TEX uptake.

Alexandra von Au,1 Eva Milloth,1 Ingo Diel,2 Stefan Stefanovic,1 Andre Hennigs,1 Markus Wallwiener,1 Joerg Heil,1 Michael Golatta,1 Joachim Rom,1 Christof Sohn,1 Andreas Schneeweiss,1 Florian Schuetz,1 Christoph Domschke1 1Breast Unit, Department of Gynecology and Obstetrics, Heidelberg University Hospital, Heidelberg, 2CGG Clinic – Centrum für ganzheitliche Gynäkologie Mannheim, Mannheim, Germany Purpose: Patients with metastasized breast cancer often suffer from discomfort caused by metastatic bone disease. Thus, osteoprotection is an important part of therapy in breast cancer metastasized to bone, and bisphosphonates (BPs) are a major therapeutic option. In this study, our objectives were to compare the side effects of oral versus intravenous BP treatment and to assess their clinical effectiveness. Patients and methods: In this prospective randomized, open-label, non-inferiority trial, we enrolled breast cancer patients with at least one bone metastasis and an Eastern Cooperative Oncology Group performance status of 0–2. Patients were randomly assigned to one of the three treatment groups: A, 60mg pamidronate intravenously q3w; B-iv, 900mg clodronate intravenously q3w; and B-o, 2,400mg oral clodronate daily. Assessments were performed at baseline and every 3months thereafter. Results: Between 1995 and 1999, 321 patients with confirmed bone metastases from breast cancer were included in the study. At first follow-up, gastrointestinal (GI) tract side effects were most common, and adverse effects on the GI tract were more frequent in the oral treatment group (P=0.002 and P

Background Locoregional recurrence after neoadjuvant chemotherapy for primary breast cancer is associated with poor prognosis. It is essential to identify patients at high risk of locoregional recurrence who may benefit from extended local therapy. Here, we examined the prediction accuracy and clinical applicability of the MD Anderson Prognostic Index (MDAPI). Methods Prospective clinical data from 456 patients treated between 2003 and 2011 was analyzed. The Kaplan-Meier method was used to examine the probabilities of locoregional recurrence, local recurrence and distant metastases according to individual prognosis score, stratified by type of surgery (breast conserving therapy or mastectomy). The possible confounding of the relationship between recurrence risk and MDAPI by established risk factors was accounted for in multiple survival regression models. To define the clinical utility of the MDAPI we analyzed its performance to predict locoregional recurrence censoring patients with prior or simultaneous distant metastases. Results Mastectomized patients (42% of the patients) presented with more advanced tumor stage, lower tumor grade, hormone-receptor positive disease and consequently lower pathological complete response rates. Only a few patients presented with high-risk scores (2,7% MDAPI≥3). All patients with high-risk MDAPI score (MDAPI ≥3) who developed locoregional recurrence were simultaneously affected by distant metastases. Conclusion Our data do not support a clinical utility of the MDAPI to guide local therapy.

Immunotherapies are set to become part of the therapeutic repertoire for breast cancer in the near future. Active vaccination is a promising strategy, especially in tumors that have a specific tumor-associated antigen. Although cellular immunotherapies have not yet shown efficacy, new technologies are on the way to improve this approach. Given the recent Food and Drug Administration approval of chimeric antigen receptor (CAR) T cells for leukemia, it is only a question of time before solid tumors will follow. However, not all breast cancer patients will respond to cellular or other immunotherapy. Hence, we must define subpopulations of breast cancer patients who benefit from this new approach.

The aim of this study was to identify differences between breast cancer patients with and without migrant background in Germany, especially differences concerning patient characteristics, tumor biology, diagnostics, therapy, and oncological outcome. In 99 breast cancer patients (composed of 50 native, randomly selected Germans and 49 consecutively selected immigrants of Anatolian origin) who were operated due to breast cancer at the Heidelberg University Hospital between the years 2009–2012, relevant information was retrospectively reviewed. Patients with migrant background were significantly younger at the time of receiving the diagnosis of breast cancer than native German patients with an average age difference of nine years (p

We present clinical features and genetic results of 1206 index patients and 124 affected relatives who were referred for genetic testing of Charcot-Marie-Tooth (CMT) neuropathy at the laboratory in Aachen between 2001 and 2012. Genetic detection rates were 56% in demyelinating CMT (71% of autosomal dominant (AD) CMT1/CMTX), and 17% in axonal CMT (24% of AD CMT2/CMTX). Three genetic defects (PMP22 duplication/deletion, GJB1/Cx32 or MPZ/P0 mutation) were responsible for 89.3% of demyelinating CMT index patients in whom a genetic diagnosis was achieved, and the diagnostic yield of the three main genetic defects in axonal CMT (GJB1/Cx32, MFN2, MPZ/P0 mutations) was 84.2%. De novo mutations were detected in 1.3% of PMP22 duplication, 25% of MPZ/P0, and none in GJB1/Cx32. Motor nerve conduction velocity was uniformly 40 m/s in MFN2, and more variable in GJB1/Cx32, MPZ/P0 mutations. Patients with CMT2A showed a broad clinical severity regardless of the type or position of the MFN2 mutation. Out of 75 patients, 8 patients (11%) with PMP22 deletions were categorized as CMT1 or CMT2. Diagnostic algorithms are still useful for cost-efficient mutation detection and for the interpretation of large-scale genetic data made available by next generation sequencing strategies.

To determine the feasibility of a prototype device combining 3D-automated breast ultrasound (ABVS) and digital breast tomosynthesis in a single device to detect and characterize breast lesions.In this prospective feasibility study, the FUSION-X-US prototype was used to perform digital breast tomosynthesis and ABVS in 23 patients with an indication for tomosynthesis based on current guidelines after clinical examination and standard imaging. The ABVS and tomosynthesis images of the prototype were interpreted separately by two blinded experts. The study compares the detection and BI-RADS® scores of breast lesions using only the tomosynthesis and ABVS data from the FUSION-X-US prototype to the results of the complete diagnostic workup.Image acquisition and processing by the prototype was fast and accurate, with some limitations in ultrasound coverage and image quality. In the diagnostic workup, 29 solid lesions (23 benign, including three cases with microcalcifications, and six malignant lesions) were identified. Using the prototype, all malignant lesions were detected and classified as malignant or suspicious by both investigators.Solid breast lesions can be localized accurately and fast by the Fusion-X-US system. Technical improvements of the ultrasound image quality and ultrasound coverage are needed to further study this new device.The prototype combines tomosynthesis and automated 3D-ultrasound (ABVS) in one device. It allows accurate detection of malignant lesions, directly correlating tomosynthesis and ABVS data. The diagnostic evaluation of the prototype-acquired data was interpreter-independent. The prototype provides a time-efficient and technically reliable diagnostic procedure. The combination of tomosynthesis and ABVS is a promising diagnostic approach.

Breast ultrasound could be a valuable tool complementary to mammography in breast cancer screening. Automated 3D breast ultrasound (ABUS) addresses challenges of hand-held ultrasound and could allow double reading analysis of ultrasound images. This trial assesses the inter-rater reliability and double reading analysis of an ABUS system. To assess the reproducibility and diagnostic validity of the ABUS system, SomoV™, a blinded double reading analysis, was performed in 1019 patients (2038 breasts) by two examiners (examiner A/B) and compared to single reading results, as well as to the reference standard regarding its diagnostic validity. Cohen’s kappa coefficients were calculated to measure the inter-rater reliability and agreement of the different diagnostic modalities. Patient comfort and time consumption for image acquisition and reading were analyzed descriptively as secondary objectives. Analysis of inter-rater reliability yielded agreement in 81.6% (κ = 0.37; p

Spinal muscular atrophy is an autosomal-recessive neuromuscular disorder, causing progressive proximal weakness and atrophy of the voluntary muscles. More than 96% of the spinal muscular atrophy patients show a homozygous absence of exons 7 and 8, or exon 7 only, in SMN1, the telomeric copy of the SMN gene. We report a young male patient with neurogenic symptoms and sparse muscle fiber atrophy, suggestive of a mild form of type III spinal muscular atrophy. He was found to be a carrier of intragenic mutations in both copies of the SMN gene, exhibiting a homozygous duplication of exons 7 and 8 in SMN1 and a homozygous deletion of exon 8 as well as a heterozygous deletion of exon 7 in SMN2. However, an intact full-length SMN1 complementary deoxyribonucleic acid was identified, and SMN protein levels in a muscle specimen were identical to that of a healthy control, formally excluding the diagnosis of spinal muscular atrophy III.

Department of Neurology & Neurosurgery, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands Department of Pediatrics, Pediatric Pathology Unit, Hacettepe University, Ankara, Turkey Department of Clinical Neurophysiology, Great Ormond Street Hospital for Sick Children NHS Trust, WC1N 3JH London, United Kingdom Department of Pediatric Neurology, Charite University Medical Center, Augustenburger Platz 1, 13353 Berlin, Germany

Some reproductive factors are well-known general risk factors for breast cancer (BC). On the other hand, BC subtypes also have a high prognostic value. Correlations, however, that link these risk factors to the development of a particular one of the different BC subtypes are still poorly understood. The primary objective of our study was to assess the influence of different reproductive factors (duration of breastfeeding, parity, and age at first childbirth) on pathological BC subtypes. Secondarily, we correlated body mass index (BMI), age at primary diagnosis, and smoking behavior with tumor subclasses. We performed a retrospective chart review of 1082 patients with BC who had been treated for postmenopausal BC at the Heidelberg University Hospital during the period 2009–2014. For statistical analysis, different types of correlation analysis as well as a logistic regression model were used. Relating to the primary objective, we found that patients with luminal-like BC had significantly fewer children than patients with triple-negative or HER2-positive subtype tumors (P = 0.027). Concerning the duration of breastfeeding, patients with a luminal A-like tumor had a significantly lower mean nursing period than patients with other subtypes (P = 0.012). Furthermore, patients who did breastfeed presented with a significantly lower number of hormone receptor-positive tumors (estrogen receptor-positive, P = 0.04; progesterone receptor-positive, P = 0.017) but the highest rate of HER2-overexpressing malignancies (P = 0.011). Moreover, late first childbirth was associated with the occurrence of luminal tumors (OR 0.952; P = 0.041). Regarding our secondary aim, higher BMI (P = 0.031) and higher age at primary diagnosis (P = 0.038) were both found to be significantly associated with luminal-like BC. The results suggest a correlation of the occurrence of luminal-like BC subtypes with low parity and short or no duration of breastfeeding. Prospective investigations are needed for further confirmation and to evaluate the molecular basis of our findings.

Delayed fracture healing and non-unions of the femoral neck after lag screw osteosynthesis occur particularly in multiply injured young patients, and then surgical revision is often required. Currently no evidence-based treatment guidelines exist and therapeutic options include both hip arthroplasties and femoral head-maintaining operations. Here we report on young patients with delayed fracture healing of the femoral neck. Patients underwent revision surgery by autologous bone cylinder transplantation with mechanical re-stabilisation by cannulated lag screws. We reviewed all patients after femoral neck screw osteosynthesis and identified eight patients at 7.3 [3–24] months after initial osteosynthesis with persisting, or reoccurring postoperative pain. Average patient age was 43 [35–57] years and patient Harris Hip Score (HHS) numbers were low (52 ± 19). Before revision surgery the preoperative CT scans showed a partial bone consolidation (anterior and/or posterior cortices) in the absence of a complete bone consolidation of all cortices. Seven patients were treated by bone cylinder transplantation from the patient’s own iliac crest; one patient underwent an inverse bone cylinder procedure. Seven patients were additionally treated by re-insertion of 1–2 lag screws to increase mechanical stability. After revision surgery the average patient follow-up period was 42 [12–89] months. Five patients achieved favourable clinical and radiographic outcome with both complete bone union and return to work within 7.2 ± 2.75 months. One patient showed fracture healing but developed an aseptic femoral head osteonecrosis. Two patients failed to achieve complete bone consolidation. The postoperative HHS was 92 ± 4 in patients with favourable clinical outcome (n = 5) and 89 ± 2 after second revision surgery (2 hip arthroplasties; 1 valgus osteotomy). Both groups had significantly better HHS numbers compared with before surgical revision (p

Distal spinal muscular atrophy type 1 (DSMA1) is an autosomal recessive disease that is clinically characterized by distal limb weakness and respiratory distress. In this disease, the degeneration of alpha-motoneurons is caused by mutations in the immunoglobulin mu-binding protein 2 (IGHMBP2). This protein has been implicated in DNA replication, pre-mRNA splicing and transcription, but its precise function in all these processes has remained elusive. We have purified catalytically active recombinant IGHMBP2, which has enabled us to assess its enzymatic properties and to identify its cellular targets. Our data reveal that IGHMBP2 is an ATP-dependent 5' --> 3' helicase, which unwinds RNA and DNA duplices in vitro. Importantly, this helicase localizes predominantly to the cytoplasm of neuronal and non-neuronal cells and associates with ribosomes. DSMA1-causing amino acid substitutions in IGHMBP2 do not affect ribosome binding yet severely impair ATPase and helicase activity. We propose that IGHMBP2 is functionally linked to translation, and that mutations in its helicase domain interfere with this function in DSMA1 patients.

In this article, we review the clinical, neuropathological and genetic aspects of distal spinal-muscular atrophy 1 (DSMA1; MIM#604320), formerly designated as autosomal recessive spinal muscular atrophy with respiratory distress type 1 (SMARD1) and also known as distal hereditary-motor neuropathy type 6 (dHMN6 or HMN6).

Distal spinal muscular atrophy type 1 (DSMA1) is caused by mutations in the immunoglobulin mu-binding protein 2 (IGHMBP2) gene. Patients with DSMA1 present between 6 weeks and 6 months of age with progressive muscle weakness and respiratory failure due to diaphragmatic palsy. Contrary to this "classic" infantile disease, we have previously described a DSMA1 patient with juvenile disease onset. In this paper, we present (1) a second juvenile case and (2) the first study of DSMA1 on protein level in patients with infantile (n = 3) as well as juvenile (n = 2) disease onset observing elevated residual steady-state IGHMBP2 protein levels in the patients with late onset DSMA1 as compared to those with classic DSMA1. Mutation screening in IGHMBP2 revealed two patients compound heterozygous for a novel missense mutation (c.1478C-->T; p.T493I) and another previously described mutation. In lymphoblastoid cells of both patients, steady-state IGHMBP2 protein levels were reduced. In comparison to wild-type IGHMBP2, the p.T493I variant protein had an increased tendency to aggregate and spontaneously degrade in vitro. We verified a change in the physicochemical properties of the p.T493I variant which may explain the pathogenicity of this mutation. Our data further suggest that the age of onset of DSMA1 is variable, and we discuss the effect of residual IGHMBP2 protein levels on the clinical course and the severity of the disease.

Autosomal recessive spinal muscular atrophy with respiratory distress (SMARD) is a heterogeneous disorder. Mutations in the immunoglobulin micro-binding protein gene (IGHMBP2) lead to SMARD1, but clinical criteria that delineate SMARD1 from other SMARD syndromes are not well established. Here we present a retrospective clinical and genetic study to determine the criteria that would predict the presence or absence of IGHMBP2 mutations. From 141 patients with respiratory distress and a spinal muscular atrophy phenotype we recorded the clinical features through a questionnaire and sequenced the entire coding region of IGHMBP2. In 47 (33%) patients we identified IGHMBP2 mutations, 14 of which were not described before. Clinical features and combinations thereof associated with the presence of IGHMBP2 mutations were discovered through hierarchical cluster analysis. This method detects common traits not evident at first sight by grouping items according to their similarity. The combination of "manifestation of respiratory failure between 6 weeks and 6 months" AND ("presence of diaphragmatic eventration" OR "preterm birth") predicted the presence of IGHMBP2 mutations with 98% sensitivity and 92% specificity. Non-SMARD1 patients fell into two different symptom clusters, mainly separated by the age at respiratory failure and the presence of multiple congenital contractures. The 14 novel IGHMBP2 mutations comprised missense, frameshift, splice-site, and nonsense mutations. All missense mutations altered conserved residues within or adjacent to the putative DNA helicase domain. The c.1235+3A>G splice-site mutation did not entirely suppress correct splicing and we found a residual wild-type IGHMBP2 mRNA steady-state level of 24.4+/-6.9%, which was, however, not sufficient to avert SMARD1 in this patient.

Objective: To identify the cause of sensorimotor neuropathy in a cohort of patients with genetically unsolved neuropathies (57 families with a total of 74 members) in whom hitherto known disease genes had been excluded. Methods: We used autozygosity mapping or haplotype analysis to delineate potential disease loci in informative families. For mutation detection, we used either whole-exome sequencing or Sanger sequencing of positional candidates. Subsequently, a larger cohort was specifically screened for IGHMBP2 mutations. The pathogenicity of a splice-site mutation was verified in cultured patient skin fibroblasts on the messenger RNA level and by Western blot. Results: We report on 5 patients with neuropathy from 3 families who carried truncating mutations in IGHMBP2 . Contrary to the “classic” phenotype, they did not manifest with respiratory distress, but with progressive sensorimotor neuropathy. Only one patient required nocturnal mask ventilation, while 4 others maintained normal respiratory function by the age of 14, 18, 22, and 37 years. Three patients were still able to walk independently. All patients had a predominantly axonal sensorimotor neuropathy with subsequent muscle atrophy, but without obvious sensory symptoms. Two patients had signs of autonomic neuropathy. Conclusions: Mutations in IGHMBP2 should be considered in the molecular genetic workup of patients with hereditary sensorimotor neuropathies, even in the absence of respiratory symptoms.

Pain perception has evolved as a warning mechanism to alert organisms to tissue damage and dangerous environments. In humans, however, undesirable, excessive or chronic pain is a common and major societal burden for which available medical treatments are currently suboptimal. New therapeutic options have recently been derived from studies of individuals with congenital insensitivity to pain (CIP). Here we identified 10 different homozygous mutations in PRDM12 (encoding PRDI-BF1 and RIZ homology domain-containing protein 12) in subjects with CIP from 11 families. Prdm proteins are a family of epigenetic regulators that control neural specification and neurogenesis. We determined that Prdm12 is expressed in nociceptors and their progenitors and participates in the development of sensory neurons in Xenopus embryos. Moreover, CIP-associated mutants abrogate the histone-modifying potential associated with wild-type Prdm12. Prdm12 emerges as a key factor in the orchestration of sensory neurogenesis and may hold promise as a target for new pain therapeutics. © 2015 Nature America, Inc. All rights reserved.

Purpose To evaluate clinical outcomes and complications after Descemet membrane endothelial keratoplasty (DMEK) in a child. Methods A 12-year-old boy with Kearns-Sayre syndrome (chronic progressive external ophthalmoplegia, cardiac conduction block, and pigmentary retinal degeneration) and corneal endothelial dysfunction was successfully treated with DMEK. Corneal transparency, central corneal thickness (CCT), endothelial cell density (ECD), visual outcomes, and complication rates were measured during the follow-up of 6 months. Results Best spectacle-corrected visual acuity (BSCVA) improved from counting fingers at 4 feet preoperatively to 20/100, 1 week after surgery. The ECD of the graft was 2595 cells per square millimeter. The CCT diminished from 837 μm preoperatively to 735 μm 1 week after surgery. Six months postoperatively, the BSCVA was still 20/100, and the cornea remained clear and compact. The ECD was 2341 cells per square millimeter and CCT was almost normal with 583 μm. No postoperative complications were observed. Fundus examination showed atypical pigmentary retinal degeneration with arterial narrowing. Electroretinography with full-field flash stimulation showed bilaterally severe retinal dysfunction with absent photopic and scotopic amplitudes explaining the reduced BSCVA. Conclusions Although DMEK has been used in adult populations, we are unaware of previous reports of DMEK in a child. DMEK should be considered as a feasible technique in pediatric patients with endothelial dysfunction.

Fibronectin is ubiquitously expressed in the extracellular matrix, and experimental evidence has shown that it modulates blood vessel formation. The relative contribution of local and circulating fibronectin to blood vessel formation in vivo remains unknown despite evidence for unexpected roles of circulating fibronectin in various diseases. Using transgenic mouse models, we established that circulating fibronectin facilitates the growth of bone metastases by enhancing blood vessel formation and maturation. This effect is more relevant than that of fibronectin produced by endothelial cells and pericytes, which only exert a small additive effect on vessel maturation. Circulating fibronectin enhances its local production in tumors through a positive feedback loop and increases the amount of vascular endothelial growth factor (VEGF) retained in the matrix. Both fibronectin and VEGF then cooperate to stimulate blood vessel formation. Fibronectin content in the tumor correlates with the number of blood vessels and tumor growth in the mouse models. Consistent with these results, examination of three separate arrays from patients with breast and prostate cancers revealed that a high staining intensity for fibronectin in tumors is associated with increased mortality. These results establish that circulating fibronectin modulates blood vessel formation and tumor growth by modifying the amount of and the response to VEGF. Furthermore, determination of the fibronectin content can serve as a prognostic biomarker for breast and prostate cancers and possibly other cancers.

The aim of this study was to evaluate in detail the histopathological characteristics of endarterectomized carotid atherosclerotic lesions in symptomatic versus asymptomatic patients. Twenty carotid lesions, 10 from asymptomatic and 10 from symptomatic patients who underwent carotid endarterectomy were classified according to histomorphological features. Samples were analyzed for intraplaque localization and for the expression of proteins associated with inflammation, such as CD68, interleukin (IL)-1β, tumor necrosis factor-α (TNF-α), pentraxin-3 (PTX-3), nuclear factor-κB (NF-κB), C-reactive protein (CRP) and transforming growth factor-β (TGF-β), as well as for proteins associated with vascular remodelling, such as matrix-metalloproteinase-9 (MMP-9), glycophorin A (GYPA), osteoprotegerin (OPG), vascular cell adhesion molecule-1 (VCAM-1), endothelin-1 (ET-1), vascular endothelial growth factor (VEGF) and vascular smooth muscle cell actin (VSMA). Corresponding expression scores were compared between the symptomatic and asymptomatic patients and evaluated statistically. The expression of all 14 evaluated markers was significantly elevated in the border zone adjacent to the mixed plaque compared with the unaffected control area of the same sample (p

After exposure to tacrolimus and CMV reactivation in utero, a preterm infant had a positive CMV polymerase chain reaction (PCR) in urine on day 2 of life. Naive T-cells were reduced, but stimulation with CMV antigen and a polyclonal T-cell activator in vitro yielded no measurable CD4+ T-cell response. When repeated on day 30, polyclonal activation was in the range of healthy adults, while the immune response to CMV was incomplete with a lack of IFNgamma+ CD4+ T-cells and no anti-CMV IgM. Thus, exposure to tacrolimus in utero caused a transitional T-cell activation defect which did not compromise viral clearance.