FGFR3 expression in primary invasive bladder cancers and matched lymph node metastases

PURPOSE FGFR3 is considered a good therapeutic target for bladder cancer. However, to our knowledge it is unknown whether the FGFR3 status of primary tumors is a surrogate for related metastases, which must be targeted by FGFR targeted systemic therapies. We assessed FGFR3 protein expression in primary bladder tumors and matched nodal metastases. MATERIALS AND METHODS We examined matched primary tumor and nodal metastases from 150 patients with bladder cancer clinically staged as N0M0. Four samples per patient were incorporated into a tissue microarray and FGFR3 expression was assessed by immunohistochemistry. FGFR3 expression was tested for an association with categorical clinical data using the Fisher exact test, and with overall and recurrence-free survival by Kaplan-Meier analysis. RESULTS Duplicate spots from primary tumors and lymph node metastases were highly concordant (OR 8.6 and 16.7, respectively, each p <0.001). Overall FGFR protein expression levels did not differ between primary and metastatic lesions (p = 0.78). Up-regulated expression was recorded in 53 of 106 evaluable primary tumor spots and 56 matched metastases. Concordance of FGFR3 expression levels in 79 matched primary tumor and metastasis specimens was high (OR 8.45, p <0.001). In 15 and 12 patients expression was up-regulated in only metastasis and in only the primary tumor, respectively. Overall and recurrence-free survival was not related to FGFR3 expression. CONCLUSIONS FGFR3 expression in matched primary and metastasized bladder cancer specimens showed good but not absolute concordance. Thus, in most patients primary tumor FGFR3 status can guide the selection of FGFR targeted therapy.

Bacillus Calmette-Guérin strain differences have an impact on clinical outcome in bladder cancer immunotherapy

BACKGROUND Whether the commonly used bacillus Calmette-Guérin (BCG) strains Connaught and Tice confer different treatment responses in non-muscle-invasive bladder cancer (NMIBC) is unknown. OBJECTIVES To compare clinical efficacy, immunogenicity, and genetics of BCG Connaught and Tice. DESIGN, SETTING, AND PARTICIPANTS A prospective randomized single-institution trial with treatment of 142 high-risk NMIBC patients with BCG Connaught or Tice. INTERVENTION Patients were randomized to receive six instillations of BCG Connaught or Tice. For experimental studies, BCG strains were compared in C57Bl/6 mice. Bladders and lymphoid tissues were analyzed by cytometry and the latter cultivated to detect live BCG. BCG genomic DNA was sequenced and compared with reference genomes. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Recurrence-free survival was the primary end point of the clinical study. The Kaplan-Meier estimator was used for estimating survival and time-to-event end points. Nonparametric tests served for the analysis of the in vivo results. RESULTS AND LIMITATIONS Treatment with BCG Connaught conferred significantly greater 5-yr recurrence-free survival compared with treatment with BCG Tice (p=0.0108). Comparable numbers of patients experienced BCG therapy-related side effects in each treatment group (p=0.09). In mice, BCG Connaught induced stronger T-helper cell 1-biased responses, greater priming of BCG-specific CD8(+) T cells, and more robust T-cell recruitment to the bladder than BCG Tice. Genome sequencing of the BCG strains revealed candidate genes potentially involved in the differential clinical responses. CONCLUSIONS BCG strain may have an impact on treatment outcome in NMIBC immunotherapy. PATIENT SUMMARY We compared the efficacy of two commonly used bacillus Calmette-Guérin (BCG) strains for the treatment of NMIBC and found that treatment with BCG Connaught prevented recurrences more efficiently than BCG Tice. Comparison of the immunogenicity of the two strains in mice indicated superior immunogenicity of BCG Connaught. We also identified genetic differences that may explain the differential efficacy of the Connaught and Tice BCG strains. TRIAL REGISTRATION NCT00003779.

Sportmotorische Leistungsfähigkeit und schulische Leistung – Zum mediierenden Effekt der exekutiven Funktionen

Introduction: Die sportmotorische Leistungsfähigkeit (SMLF) hängt nicht nur positiv mit der körperlichen Gesundheit zusammen, sondern gilt auch als Prädiktor für die schulische Leistung (SL) (van der Niet, Hartmann, Smith, & Visscher, 2014). Um die Frage zu beantworten, wie denn zwei auf den ersten Blick so distale Merkmale zusammenhängen sollen, werden unterschiedliche erklärende Variablen diskutiert, wobei die kognitive Stimulationshypothese die exekutiven Funktionen (EF) als mediierende Variable im Zusammenhang zwischen SMLF und SL postuliert. Die Annahme hierbei ist, dass die mit komplexen motorischen Kontrollprozessen einhergehende kognitive Beanspruchung bei einem wiederholten Ausführen von nicht-automatisierten sportbezogenen Handlungen zu einer Aktivierung und somit Förderung der EF führt (Best, 2010). EF, verstanden als höhere kognitive Prozesse, die ein zielorientiertes und situationsangepasstes Handeln erlauben, sind für den schulischen Erfolg von zentraler Bedeutung und gleichzeitig wichtige Prädiktoren der SL (Diamond, 2013). Obwohl diese Mediation seit einigen Jahren in der Literatur diskutiert wird, wurde sie bis heute noch nicht mit Hilfe längsschnittlicher Daten geprüft. Daher wird im Folgenden der mediierende Effekt der EF im Zusammenhang zwischen SMLF und SL getestet. Methods: Im Rahmen der Studie Sport und Kognition 5.0 wurden insgesamt 237 Primarschulkinder (52.3% ♀; 11.31 ± 0.62 Jahre) zu drei Messzeitpunkten in ihrer SMLF (T1) und ihren EF (T2) getestet. Zusätzlich wurde die SL (T3) mittels objektiver Schulleistungstests (Mathematik und Deutsch) erhoben. Um die Hauptfragestellung zu prüfen, ob die SL vorwiegend mediiert über die EF durch die SMLF vorhergesagt werden kann, wurde eine bootstrapping-basierte Mediationsanalyse in AMOS 22 durchgeführt. Results: Das theoretisch abgeleitete Strukturgleichungsmodell (2 (22, N = 237) = 30.357, p = .110; CFI = .978) weist eine zufriedenstellende Anpassungsgüte auf. Erwartungsgemäss zerfällt der Zusammenhang innerhalb des Mediationsmodells zwischen der SMLF und der SL, alsbald die EF ins Modell aufgenommen werden (β = .16, p = .634). Sowohl der Zusammenhang zwischen der SMLF und den EF (β = .38, p = .039), als auch der Zusammenhang zwischen den EF und der SL fallen signifikant aus (β = .91, p = .001) und ergeben dabei eine volle Mediation über den indirekten (p = .021) und totalen Effekt (p = .001). Discussion/Conclusion: Die erstmals vorliegenden längsschnittlichen Daten bestätigen den Zusammenhang zwischen SMLF und SL bei einer Mediation über die EF und decken sich mit den, aus einem querschnittlichen Design stammenden, Befunden von van der Niet et al. (2014). Zur Steigerung der schulischen Leistung sollten zukünftige Schulsportinterventionen die SMLF von Kindern erhöhen und dabei die EF bei der Auswahl von sportlichen Aufgaben mitberücksichtigen. References: Best, J. R. (2010). Effects of physical activity on children’s executive function: Contributions of experimental research on aerobic exercise. Developmental Review, 30, 331-351. Diamond, A. (2013). Executive functions. Annual Review of Psychology, 64, 135-168. van der Niet, A. G., Hartmann, E., Smith, J. & Visscher, C. (2014). Modeling relationships between physical fitness, executive functioning, and academic achievement in primary school children. Psychology of Sport & Exercise, 15(4), 319-325.

Metastases in normal-sized pelvic lymph nodes: detection with diffusion-weighted MR imaging

PURPOSE To prospectively assess the diagnostic performance of diffusion-weighted (DW) magnetic resonance (MR) imaging in the detection of pelvic lymph node metastases in patients with prostate and/or bladder cancer staged as N0 with preoperative cross-sectional imaging. MATERIALS AND METHODS This study was approved by an independent ethics committee. Written informed consent was obtained from all patients. Patients with no enlarged lymph nodes on preoperative cross-sectional images who were scheduled for radical resection of the primary tumor and extended pelvic lymph node dissection were enrolled. All patients were examined with a 3-T MR unit, and examinations included conventional and DW MR imaging of the entire pelvis. Image analysis was performed by three independent readers blinded to any clinical information. Metastases were diagnosed on the basis of high signal intensity on high b value DW MR images and morphologic features (shape, border). Histopathologic examination served as the standard of reference. Sensitivity and specificity were calculated, and bias-corrected 95% confidence intervals (CIs) were obtained with the bootstrap method. The Fleiss and Cohen κ and median test were applied for statistical analyses. RESULTS A total of 4846 lymph nodes were resected in 120 patients. Eighty-eight lymph node metastases were found in 33 of 120 patients (27.5%). Short-axis diameter of these metastases was less than or equal to 3 mm in 68, more than 3 mm to 5 mm in 13, more than 5 mm to 8 mm in five; and more than 8 mm in two. On a per-patient level, the three readers correctly detected metastases in 26 (79%; 95% CI: 64%, 91%), 21 (64%; 95% CI: 45%, 79%), and 25 (76%; 95% CI: 60%, 90%) of the 33 patients with metastases, with respective specificities of 85% (95% CI: 78%, 92%), 79% (95% CI: 70%, 88%), and 84% (95% CI: 76%, 92%). Analyzed according to hemipelvis, lymph node metastases were detected with histopathologic examination in 44 of 240 pelvic sides (18%); the three readers correctly detected these on DW MR images in 26 (59%; 95% CI: 45%, 73%), 19 (43%; 95% CI: 27%, 57%), and 28 (64%; 95% CI: 47%, 78%) of the 44 cases. CONCLUSION DW MR imaging enables noninvasive detection of small lymph node metastases in normal-sized nodes in a substantial percentage of patients with prostate and bladder cancer diagnosed as N0 with conventional cross-sectional imaging techniques.

Diffusion-weighted magnetic resonance imaging detects significant prostate cancer with high probability

PURPOSE We prospectively assessed the diagnostic accuracy of diffusion-weighted magnetic resonance imaging for detecting significant prostate cancer. MATERIALS AND METHODS We performed a prospective study of 111 consecutive men with prostate and/or bladder cancer who underwent 3 Tesla diffusion-weighted magnetic resonance imaging of the pelvis without an endorectal coil before radical prostatectomy (78) or cystoprostatectomy (33). Three independent readers blinded to clinical and pathological data assigned a prostate cancer suspicion grade based on qualitative imaging analysis. Final pathology results of prostates with and without cancer served as the reference standard. Primary outcomes were the sensitivity and specificity of diffusion-weighted magnetic resonance imaging for detecting significant prostate cancer with significance defined as a largest diameter of the index lesion of 1 cm or greater, extraprostatic extension, or Gleason score 7 or greater on final pathology assessment. Secondary outcomes were interreader agreement assessed by the Fleiss κ coefficient and image reading time. RESULTS Of the 111 patients 93 had prostate cancer, which was significant in 80 and insignificant in 13, and 18 had no prostate cancer on final pathology results. The sensitivity and specificity of diffusion-weighted magnetic resonance imaging for detecting significant PCa was 89% to 91% and 77% to 81%, respectively, for the 3 readers. Interreader agreement was good (Fleiss κ 0.65 to 0.74). Median reading time was between 13 and 18 minutes. CONCLUSIONS Diffusion-weighted magnetic resonance imaging (3 Tesla) is a noninvasive technique that allows for the detection of significant prostate cancer with high probability without contrast medium or an endorectal coil, and with good interreader agreement and a short reading time. This technique should be further evaluated as a tool to stratify patients with prostate cancer for individualized treatment options.

Apoptotic enteropathy caused by antimetabolites and TNF-α antagonists.

AIMS To investigate whether drugs others than mycophenolic acid and ipilimumab might cause graft-versus-host-like apoptotic enteropathy, the clinicopathological findings in four patients were examined who had developed watery diarrhoea and apoptotic enteropathy (three cases from colon and one case from ileal pouch) after intake of antimetabolites (methotrexate and capecitabine) and/or tumour necrosis factor-α inhibitors (etanercept and infliximab). METHODS The clinical charts, endoscopy reports and intestinal biopsies from all endoscopies were reviewed for all patients. Biopsies were evaluated semiquantitatively for apoptosis of basal crypts, dilated damaged crypts, defined as cystically dilated crypts with flattened degenerated epithelium containing apoptotic debris and few neutrophils, and mucosal architecture. Further, the presence of intraepithelial lymphocytes, chronic inflammatory cells in the lamina propria and mucosal ulcerations was recorded and immunohistochemical analysis for human cytomegalovirus and herpes simplex virus was performed. RESULTS Endoscopic examination revealed normal mucosa in two patients, whereas the other two showed focal ulcerations. Histological changes included increased apoptosis of basal crypts, the presence of dilated damaged crypts and architecture distortion. In all cases, a temporal association between drug intake and/or dose increase, and onset of diarrhoea, was observed, and no convincing evidence of other potentially underlying causes of colitis/enteritis was found, including infections. CONCLUSIONS Pathologists should be aware of the expanding spectrum of drugs that can cause apoptotic enteropathy, including antimetabolites and tumour necrosis factor-α inhibitors.

Wirkung sportlicher Aktivität auf das aktuelle Befinden im höheren Erwachsenenalter - Verlaufsanalysen in Sportprogrammen

Mit zunehmendem Alter nimmt das Sportengagement ab. Wichtig für eine langfristige Sportteilnahme sind positive affektive Reaktionen beim Sporttreiben. Fehlende Studien zur Untersuchung affektiver Reaktionen auf Sportaktivitäten im höheren Erwachsenenalter stellen ein Forschungsdefizit dar. Daher untersucht dieser Beitrag die Wirkung sportlicher Aktivitäten auf die aktuelle Befindlichkeit im Verlauf von Sportprogrammen im höheren Erwachsenenalter. Hierfür wurden 108 Personen (≥ 65 Jahre) in acht Sportprogrammen zu Beginn zu ihren sportbezogenen Zielen schriftlich befragt. Bei einem zweiten Kursbesuch wurde die Befindlichkeit vor, während und nach, die Belastungsintensität während und das Kompetenzerleben nach der Sportaktivität schriftlich erfasst. Die Ergebnisse zeigen eine überwiegend positive Wirkung der Sportaktivitäten auf die aktuelle Befindlichkeit sowohl auf Gruppenebene als auch auf individueller Ebene. Im Einklang mit der Dual Mode Theorie stellt sich das Kompetenzerleben als Prädiktor für das aktuelle Befinden während moderaten Sportaktivitäten heraus. Die sportbezogenen Ziele beeinflussen das Befinden nur, wenn die Belastung differenzierter untersucht wird (niedrig vs. mittel). Die Ergebnisse deuten mehrheitlich darauf hin, dass eine weitere Differenzierung der Dual Mode Theorie in niedrige und mittlere Intensität für Sportaktivitäten im höheren Erwachsenenalter angebracht ist.

Die Effekte einer akuten Bewegungsintervention auf die Konzentrationsleistung von Primarschulkindern

Introduction: Da es sich bei der Konzentrationsleistung um einen zentralen Prädiktor für den Lernerfolg und die akademische Leistung von Schülerinnen und Schülern handelt (Steinmayr, Ziegler, & Träuble, 2010), ist ihre Förderung im Kontext der Schule von hoher Relevanz. Obwohl von Vertretern der „Bewegten Schule“ seit den 90er-Jahren positive Effekte von Bewegungspausen auf die Konzentrationsleistung diskutiert werden, mangelt es bisher an empirischer Evidenz. Die Resultate der wenigen Studien, welche zum Thema durchgeführt wurden, lieferten inkonsistente Befunde. Sie deuten jedoch mehrheitlich darauf hin, dass sich 10 bis 20-minütige Bewegungspausen kurzfristig positiv auf die Konzentrationsleistung von Primarschulkindern auswirken (Janssen, Toussaint, van Mechelen, & Verhagen, 2014). Ob diese Effekte auch durch kürzere und daher im Kontext der Schule praktikablere Interventionen erreicht werden können, ist bisher unklar. Deshalb wird im vorliegenden Beitrag untersucht, ob sich 5-minütige körperliche Aktivität positiv auf die Konzentrationsleistung von Primarschulkindern auswirkt. Methods: Im Rahmen einer randomisierten Kontrollgruppenstudie wurden insgesamt 97 Schülerinnen und Schüler von 5 fünften Klassen (MAlter11.75±.47 Jahre; 44.3% Mädchen) untersucht. Die Experimental-gruppe absolvierte während 5 Minuten eine Bewegungspause, in welcher koordinativ anspruchsvolle bilaterale Ganzkörperübungen durchgeführt wurden. Die Kontrollgruppe hörte sich während dieser Zeit ein Hörbuch an. Vor und nach der Intervention respektive der Kontrollbedingung wurde mit dem Test d2-R (Brickenkamp, Schmidt-Atzert, & Liepmann, 2010) die Aufmerksamkeits- und Konzentrationsleistung erhoben. Results: Zweifaktorielle Varianzanalysen mit Messwiederholung zeigten für die Konzentrationsleistung eine signifikante Interaktion zwischen Gruppe und Testzeitpunkt (F(1, 95) = 3.80, p = .03 (einseitig), Eta2= .04). Da es sich dabei um einen stärkeren Anstieg bei der Experimentalgruppe handelt, weist dieses Resultat auf die positive Wirkung der Bewegungspause hin. Discussion/Conclusion: Die Ergebnisse erweitern den Forschungsstand, indem sie zeigen, dass neben 10 bis 20-minütigen Bewegungspausen auch Bewegungspausen von kürzerer Dauer die Konzentrationsleistung von Primarschulkindern positiv beeinflussen. Es kann deshalb die Empfehlung abgegeben werden, im Kontext der Primarschule regelmässig Bewegungspausen von wenigen Minuten durchzuführen, um die Konzentrationsleistung der Schülerinnen und Schüler kurzfristig wiederherzustellen bzw. zu erhöhen. Ob die Verbesserung der Konzentrationsleistung auf die körperliche Aktivierung, die kognitive Beanspruchung der Bewegungspause oder die Kombination der beiden zurückzuführen ist, muss in weiteren Studien geprüft werden.

Motor ability and self-esteem: The mediating role of physical self-concept and perceived social acceptance

Objectives: One important issue in sport and exercise psychology is to determine to what extent sports and exercise can help to increase self-esteem, and what the underlying mechanism might be. Based on the exercise and self-esteem model (EXSEM) and on findings from the sociometer theory, the mediating effect of physical self-concept and perceived social acceptance on the longitudinal relationship between motor ability and self-esteem was investigated. Design: Longitudinal study with three waves of data collection at intervals of ten weeks each. Method: 428 adolescents (46.3 % girls, mean age = 11.9, SD = .55) participated in the study, in which they performed three motor ability tests and completed paper-and-pencil questionnaires for physical self-concept and perceived social acceptance, as well as for self-esteem, at all three measuring points. Results: Using structural equation modelling procedures, the multiple mediation model revealed both physical self-concept and perceived social acceptance to be mediators between motor ability and self-esteem in the case of boys. In girls, on the other hand, the mediation between motor ability and self-esteem only takes place via physical self-concept. Conclusions: Gender differences in the relationship between motor ability and self-esteem suggest gender-specific interventions aimed at promoting self-concept.

Factor analysis of the North American Spine Society outcome assessment instrument: a study based on a spine registry of patients treated with lumbar and cervical disc arthroplasty.

Background context Studies involving factor analysis (FA) of the items in the North American Spine Society (NASS) outcome assessment instrument have revealed inconsistent factor structures for the individual items. Purpose This study examined whether the factor structure of the NASS varied in relation to the severity of the back/neck problem and differed from that originally recommended by the developers of the questionnaire, by analyzing data before and after surgery in a large series of patients undergoing lumbar or cervical disc arthroplasty. Study design/setting Prospective multicenter observational case series. Patient sample Three hundred ninety-one patients with low back pain and 553 patients with neck pain completed questionnaires preoperatively and again at 3 to 6 and 12 months follow-ups (FUs), in connection with the SWISSspine disc arthroplasty registry. Outcome measures North American Spine Society outcome assessment instrument. Methods First, an exploratory FA without a priori assumptions and subsequently a confirmatory FA were performed on the 17 items of the NASS-lumbar and 19 items of the NASS-cervical collected at each assessment time point. The item-loading invariance was tested in the German version of the questionnaire for baseline and FU. Results Both NASS-lumbar and NASS-cervical factor structures differed between baseline and postoperative data sets. The confirmatory analysis and item-loading invariance showed better fit for a three-factor (3F) structure for NASS-lumbar, containing items on “disability,” “back pain,” and “radiating pain, numbness, and weakness (leg/foot)” and for a 5F structure for NASS-cervical including disability, “neck pain,” “radiating pain and numbness (arm/hand),” “weakness (arm/hand),” and “motor deficit (legs).” Conclusions The best-fitting factor structure at both baseline and FU was selected for both the lumbar- and cervical-NASS questionnaires. It differed from that proposed by the originators of the NASS instruments. Although the NASS questionnaire represents a valid outcome measure for degenerative spine diseases, it is able to distinguish among all major symptom domains (factors) in patients undergoing lumbar and cervical disc arthroplasty; overall, the item structure could be improved. Any potential revision of the NASS should consider its factorial structure; factorial invariance over time should be aimed for, to allow for more precise interpretations of treatment success.