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Background: Routine use of multigene RT-PCR based assays as Recurrence Score (RS) vs. single markers (grade, uPA/PAI-1, HR, HER2, Ki-67) is controversially discussed in early BC. Several definitions of luminal A/B subtypes have been proposed by St. Gallen guidelines and individual researchers (grade 1/2 vs. 3, Ki-67 cut-offs 14 or 20%). Recently, integration of PR>20% was proposed as an immunhistochemical luminal A subtype definition (Ki-67 Methods: planB trial (04/09 to 11/11: n=2,449 randomized for 6xTC vs. 4xEC-4xDOC in locally HER2− BC; n=3197 registered; n=3072 available for central tumor bank). RS was used as selection criterion for chemotherapy (CTx) omission in HR+ BC (if RS Results: RS distribution in 2569 HR+ tumors: 0–11 (18%), 12–25 (60%), >25 (22%) (RS1853%/34%/13%). Luminal A subtype based on Ki-67 cut-off of 20% was included in the luminal A/Ki-67 Luminal A/B based on local/central grade: 79%/21%; 67.9%/32.1%. In 354 pN0-1 patients, CTx was omitted based on low RS (88% compliance). In this group, 62% were high-risk by clinical-pathological criteria. Allocation to luminal A/B subtypes based on local/central grade varied substantially: overall concordance was 72%, but 40% of locally luminal B (HR+/G3) were luminal A (HR+/G1/2) by central and 60% of centrally luminal B were luminal A locally. Moderate correlations were found between RS and central grade (Spearman correlation rs=0.317; p < 0.001), local grade (0.321; p < 0.001) and Ki-67 (rs = 0.374; p < 0.001), particularly due to poor correlations in the RS group Inclusion of PR>20% moderately improved the correlation between luminal subtypes and RS to rs=0.34; p < 0.001. Data on allocation to luminal subtypes by local/central Ki-67 will be presented at the meeting. Conclusions: Our results represent the first prospective correlation of different luminal A/B definitions vs. a guideline mentioned gene signature (RS). High RS usually implies high grade and luminal B classification, the converse is not true. There is substantial heterogeneity in risk assessment by luminal A/B classification and grade in low/intermediate RS groups. Concordance for central/local assessment of grade and luminal A/B status was limited. There is strong need for standardization of molecular subtype's immunhistochemical/clinical definition prior to implementation into daily routine. Clinical significance of these findings will be addressed by further follow up of the WSG-planB trial. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-10-08.

Die Gruppe der sogenannten spaten Fruhgeborenen („Late preterm“- Kinder mit einem Gestationsalter von 340/7–366/7 Schwangerschaftswochen (SSW)) wird hinsichtlich ihres neonatologischen Outcomes unterschatzt. Bei vor der 29. SSW geborenen Kindern zeigte sich ein fur Madchen vorteilhafter geschlechtsspezifischer Unterschied bezuglich der Morbiditat. Ziel dieser Studie ist es, zu prufen ob diese Ergebnisse auf die Late preterm-Gruppe ubertragbar sind. Untersucht wurde das neonatale Outcome bei 528 konsekutiven intensivpflichtigen Einlingen des Gestationsalters 340/7–366/7 Wochen. Neonatologische Komplikationen wurden auf Geschlechtsspezifitat gepruft. Jungen (n=292) wiesen signifikant haufiger eine Sepsis (3,8 vs. 0,9%; p=0,0314, x 2-Test), Madchen signifikant langere Aufenthalte auf der neonatologischen Intensivstation auf (Median 12 (Q1:8; Q3:17) vs. 11 (6;16) Tage; p=0,0149, t-Test). Im multiplen logistischen Regressionsmodell zeigte sich eine grenzwertige Signifikanz fur das mannliche Geschlecht und fur vorzeitigen Blasensprung bezuglich des Auftretens einer Sepsis – ein 4,4-faches Risiko fur Jungen (OR=0,228 [95% CI: 0,050–1,041]; p=0,0564) und ein 3,5-faches Risiko fur vorzeitigen Blasensprung (OR=3,462 [0,938–12,779]; p=0,0623). Als starke Einflussgrosen fur die Aufenthaltsdauer auf der Intensivstation zeigten sich nach Adjustierung Geburtsgewicht, Gestationsalter und vorzeitiger Blasensprung. Der Einfluss des fetalen Geschlechtes auf das neonatologische Outcome hat sich in der Late preterm-Gruppe (340/7–366/7 SSW) relativiert.

Background: Anthracycline-taxane based adjuvant chemotherapy (cht) is considered standard in node-positive and high-risk node-negative BC. However, retrospective analyses suggest that in HER2−BC, benefit from anthracyclines may not outweigh acute and long term toxicities. Recurrence Score (RS) identifies patients who are not candidates for cht based on their low relapse risk, as well as minimal, if any, benefit of cht. The WSG Plan B trial investigates anthracycline-free cht in HER2− BC and is the first trial in Europe prospectively incorporating RS for decision making regarding adjuvant cht in both N0 and N+ BC. Methods: Plan B trial randomizes HER2− BC patients with high-risk N0 (at least one risk factor: ≥pT2; negative HR status; G2-3; age ≤35 years old; high uPA/PAI-1) or N+ disease to 6xTC (Docetaxel 75Cyclophosphomide600) vs. 4xEC (Epirubicin90Cyclophosphomide600)-4xDocetaxel100 G-CSF prophylaxis is recommended according to current ASCO guidelines. The statistical design previews n=2.448 randomized to cht; patients with HR+ BC, N0-3 and a RS ≤11 receive endocrine therapy only. Results: From April 2009 to June 2011, 3037 patients have been recruited and 2296 randomized (TC/EC-Doc: 1146/1150; age The most frequent SAEs were: leucopenia, febrile neutropenia (TC/EC-Doc:37 (3.3%)/31 (2.7%), n.s.), infections and heart/vascular events (TC/EC-Doc 29/40, n.s.). In patients ≥65 years old, there is a trend towards more febrile neutropenia (13 vs. 5; p=0.06) in the TC, and more severe mucositis/diarrhea/nausea (3 vs. 15; p=0.007) and heart/vascular events (5 vs. 14; p=0.06) in the EC-Doc arm. There were 5 therapy related deaths (TC 5 (0.4%)/EC-Doc 0, p=0.03); 3 in patients Detailed data on relationship between the protocol specified, RS-guided treatment assignment and toxicity, and use of G-CSF support will be updated for the meeting. Conclusions: The Plan-B trial is one of the largest randomized phase III trials currently evaluating anthracycline-free adjuvant cht in HER2− BC. The cht administered within the study was generally well tolerated, but higher number of treatment-related deaths has been observed within the TC arm. The short term toxicity profile seems be different between both study arms, particularly in patients >65 years old. On the basis of prognosis as determined by RS, cht has been spared after a shared decision process in a substantial group of patients. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-18-03.

Background The objective of this study was to compare the effect of dose-intensified neoadjuvant chemotherapy with that of standard epirubicin plus cyclophosphamide followed by paclitaxel in combination with or without darbepoetin on survival in primary breast cancer. Patients and methods A total of 733 patients received either four cycles of neoadjuvant epirubicin 90 mg/m2 plus cyclophosphamide 600 mg/m2 every 3 weeks followed by four cycles of paclitaxel 175 mg/m2 every 3 weeks (EC→T), or three cycles of epirubicin 150 mg/m2 every 2 weeks followed by three cycles of paclitaxel 225 mg/m2 every 2 weeks followed by three cycles of combination chemotherapy with cyclophosphamide, methotrexate, and fluorouracil (Edd→Tdd→CMF). The patients were randomly assigned to receive darbepoetin or none. The primary objective was to demonstrate a superior disease-free survival (DFS) of Edd→Tdd→CMF compared with EC→T. Results Estimated 3-year DFS was 75.8% with EC→T versus 78.8% with Edd→Tdd→CMF [hazard ratio (HR) 1.14; P = 0.37] and overall survival (OS) 88.4% versus 91.5% (HR 1.26; P = 0.237). Three-year DFS was 74.3% with darbepoetin versus 80.0% without (HR 1.31; P = 0.061) and OS 88.0% versus 91.8% (HR 1.33; P = 0.139). Patients with a pathologically documented complete response [pathological complete response (pCR)] had a significantly better DFS compared with those without achieving a pCR (estimated 3-year DFS: 89.2% versus 74.9%; HR 2.27; P = 0.001). Conclusion Neoadjuvant dose-intensified chemotherapy compared with standard chemotherapy did not improve DFS, whereas the addition of darbepoetin might have detrimental effects on DFS.

Background: Preoperative chemotherapy is a recommended treatment of both primary operable and locally advanced breast cancer. Strategies to improve efficacy include the use of anthracyclines, taxanes, and intensified dose with bone marrow support. Patients and methods: Patients received neoadjuvant epirubicin 90 mg/m 2 plus cyclophosphamide 600 mg/m 2 followed by paclitaxel 175 mg/m 2 (EC/T), each 3-weekly for four cycles (n = 370), or epirubicin 150 mg/m 2 followed by paclitaxel 225 mg/m 2 with pegfilgrastim followed by CMF (cyclophosphamide 500 mg/m 2 , methotrexate 40 mg/m 2 , fluorouracil 600 mg/m 2 ) on days 1 and 8 (Edd/Tdd/CMF), each 2-weekly and for three cycles (n = 363). Patients were randomly allocated to either simultaneous darbepoetin alfa (DA) (n = 356) or none (n = 377). Results: Pathological complete response (pCR) rate (breast) was higher with Edd/Tdd/CMF, 18.7% versus 13.2% with EC/T; P = 0.043, ypT0/Tis; ypN0 was reported in 20.9% versus 14.3% respectively; P = 0.019. Patients with grade 3 tumors and negative hormone receptor status had a significantly higher pCR rate. Mean hemoglobin values maintained higher with DA (13.6 versus 12.6 g/dl). Edd/Tdd/CMF regimen showed more grade 3–4 mucositis, sensory neuropathy, and neurological complaints. Thromboembolic events were more frequent on DA (3% versus 6%; P = 0.055). Conclusion: Dose-dense and -intensified neoadjuvant chemotherapy with Edd/Tdd/CMF was potentially superior to EC/T in terms of pCR. Primary use of DA did not affect pCR.

Background: Despite progress in adjuvant breast cancer (BC) treatment, overtreatment due to decisions based on conventional prognostic factors (lymph nodes (LN), grade, tumor size) alone remains an important clinical problem. Recurrence Score®, RS is validated using pre-specified analyses, genes, cutt-offs in several randomized patient collectives as a potent prognostic and predictive marker in HR positive BC. Here, we present the first WSG-Plan B trial preplanned correlation analysis of central grade, nodal status, RS, and luminal A/B subtypes. Material and Methods: The West German Study Group (WSG) Plan B trial (planned n=2,448) is a randomized Phase-III-trial evaluating anthracyline-free adjuvant chemotherapy (Cht) (6x TC) vs. standard 4xEC-4xDOC in high-risk N0 and N+ HER2-negative BC. In HR+ BC with 0-3 LN, RS is the decision criterion for (>11) or against (≥11) Cht randomization. Tumor blocks are prospectively evaluated by a central pathologist for grade, histology and Ki-67. In HR+ disease, molecular subtypes (luminal A vs. B) are grouped using a Ki-67 cut-off of 13.25% (Cheang et al, JNCI 2009) and 20% (Penault-Llorca et al JCO 2009). Exploratory analysis with Elston-Ellis central grade and Ki-67 based (mitosis measured by Ki-67) grade will be performed. Results: As of June 2010, 1375 patients in 96 centers have been registered and 1067 randomized into Plan B. In 298 patients, RS results and clinical-pathological characteristics were available. In 266 patients complete information on all factors was available (132 N0, 134 N+). RS groups using the pre-specified trial cut-offs of 0-11, 12-25 and 30) were 48%, 38%, 14%. Central grade 1, 2, or 3 was observed in 4%, 50%, and 46% of cases. We observed a modest (Spearman) correlation between central grade and RS (e.g 83.8% of G3 tumors with RS >25, rs=0.331, P25), and guideline-recommended 30 (see table 1).Discussion: For the first time, we demonstrate a modest but significant correlation between centrally assed tumor grade, molecular classes by IHC Ki-67 cutt offs, and RS, particularly in the high RS group. However, our data also indicate that there is substantial discordance between the methods and thus an urgent need for optimzing risk-stratification classifiers. Table 1. Association of RS and molecular subtypes Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-10-12.

Einleitung: Bis in die spaten 90er-Jahre haben die meisten Studien beim Mammakarzinom keine Patientinnen jenseits des 65. Lebensjahres eingeschlossen. Daher harren viele Fragen fur diese zunehmend groser werdende Altersgruppe der Beantwortung. Die ICE-Studie widmet sich der Frage nach der Durchfuhrbarkeit und der Wertigkeit der adjuvanten Chemotherapie in dieser Altersgruppe. Design/Methoden: Die Indikationsstellung erfolgt in Extrapolation der St. Gallen Leitlinien. Randomisierbar sind Frauen uber 64 mit einem N+ Mammakarzinom oder einer N0 Hochrisikosituation (Tumordurchmesser >2cm und/oder G II/III und/oder HR negativ). Zum Ausschluss von Patientinnen, deren Lebensspanne fuhrend durch die Komorbidat bestimmt wird, erfolgt die Beurteilung anhand des Charlson Score und des VES 13-Score. Therapie: Alle Patienten erhalten Ibandronat (p.o. oder 6mg i.v.) uber 2 Jahre und bei hormonrezeptorpositiven Tumor sequenziell Anastrozol uber 5 Jahre. Randomisiert werden 6 Zyklen Capecitabine 2000mg/m2p.o. b.i.d Tag 1–14 q3w versus nihil. Primares Studienziel: Vergleich des ereignisfreien Uberlebens. Sekundare Studienziele: Vergleiche des Gesamtuberlebens, der Compliance, Nebenwirkungen, Lebensqualitat, Anzahl osteoporosebedingter Ereignisse, geriatrische Beurteilung und die Bestimmung der Praferenz fur orale oder intravenose Gabe des Biphosphonats. Statistik: Angenommen wird eine Verbesserung des ereignisfreien Uberlebens von 65% auf 71,5% durch die adjuvante Chemotherapie. Bei einem a-Fehler von 5%, einem b-Fehler von 20% betragt die Zielzahl 1394. Ergebnisse: Von 4/04 bis 02/06 wurden insgesamt 517 Patientinnen randomisiert. (257 N-; 260 N+, 408 HR+). 62 SAEs wurden bislang gemeldet (54 Arm A/8 Arm B). Die Haupttoxizitaten beziehen sich auf Diarrhoe, Mukositis und Hand-Fus-Syndrome. Schlussfolgerung: Die bisher monitorierten Toxizitatsdaten und die gemeldeten SAEs sprechen fur die Durchfuhrbarkeit der adjuvanten Capecitabine-Therapie. Ein aktualisierter Statusreport wird vorgestellt.

Mit dem Ziel einer flexiblen und objektangepassten flächenhaften Beleuchtung wurde ein frei programmierbarer LCD-Matrixmodulator entwickelt. Zur Messung von Materialeigenschaften unter thermischer Belastung wurden Systemkomponenten zur präzisen Temperaturregelung im Vakuum sowie zur Kleinsignalverstärkung implementiert.

Ausgehend von Bariumcarbonat-C wurde N-(2-Diathylaminoathy1)-S,S-diphenyl-sulfoximin in 8 Stufen in Position 1 der Seitenkette radioaktiv markiert (IA). Bezogen auf die Ausgangssubstanz betrug die radiochemische Ausbeute 44,6%. Zur Markierung in den Phenylgruppen (IB) wurde Benzol- (U-l4c) verwendet. Uber Diphenylsulfoxid und das entsprechende Sulfoximin wurde IB mit einer Ausbeute von 30,4% erhalten. Starting from barium carbonate-14C N-(2-diethylaminoethyl) - S,S-diphenyl-sulfoximine was labelled in position 1 of the side chain via 8 stages (IA). The overall radiochemical yield based on BaCO3 was 44.6%. For the labelling in the phenyl groups (IB) benzene-(U-14C) was used. Via diphenylsulfoxide and the corresponding sulfoximine IB was obtained with an overall yield of 30.4%.

This report deals with a cryopreservation technique and procedure; clinical data concerning the therapy itself are not presented here. A cryopreservation procedure was developed which proved to be effective for large volumes of lymphocytes and stem cells (CFU-c) obtained exclusively from the peripheral blood of man. Viability criteria used for lymphocytes include determination of the number of living cells, absolute recovery and immunologic assays. Stem cell counts and recovery were determined by the semisolid agar colony assay. A specially designed freezing process and a revitalization method using an atomizing system were applied to cell concentrates of patients with different types of cancer. The results indicate that nearly all cell functions of interest are fully preserved and that very high amounts of MNC and CFU-c are obtained after the freeze-thaw cycle. Up to now, units of cryopreserved autologous cells were retransfused to 40 patients.

DL-1-(3′-Hydroxyphenyl)-2-aminoathanol-hydrochlorid- (2-14C) wurde ausgehend von Kupfercyanid-14C in einer 2-Stufen-Synthese mit guter Ausbeute dargestellt. Dieser Syntheseweg ist auch zur 14C-Markierung anderer 1-Aryl-2-aminoathanole in Position 2 gut geeignet. DL-1-3-hydroxyphenyl)-2-aminoethanol-hydrochloride-(2-14C) was prepared with good yields by a two-step synthesis starting from copper cyanide-14C. The method described is also suitable for labelling of other 1-aryl-2-amino-ethanols in position 2 with 14C.

We report on 243 patients with sterilisation by the Bleier Clip. 234 patients were operated by coeliotomia posterior. 9 cases were sterilized in combination with Caesarean section. In 4 of 243 women we observed pregnancies during the follow-up period (failure rate = 16%). The mean time of the 4 conceptions after operation was 43 months. This result shows that the primary cause was not the operation technique but the systemic failure of the Bleier Clip. In cases with controls by hysterosalpingography all Fallopian tubes were occluded, 84% together with a sactosalpinx.

Publisher Summary This chapter discusses the biochemical properties of the enigmatic chloroplast cytochrome b -559. The maximum heme content of the cytochrome that has been obtained is 58 nmoles heme/mg protein. In the early preparations, the heme content was much lower. The heme of cytochrome b -559 is more labile than that of cytochrome b 6 and it is difficult to stain the heme on a denaturing gel, even lithium dodecyl sulfate gel run at 0°C. As soon as the denaturing conditions of the gel are sufficient to allow the b -559 to penetrate, the heme is often lost. When the heterogeneity in the N-terminal residues in that preparation is considered, it appears likely that their heme content of one heme per 46,000 polypeptide molecular weight was a result of heme dilution because of heme loss and possibly contamination by other proteins. If high and low potential b -559 are derived from the same molecule, there should be no distinction in the purified cytochrome. However, one cannot eliminate the possibility that 20% of the cytochrome b -559 in the membrane is not extractable and that the unextractable component is phosphorylated.

Nach der derzeit gultigen Lehrmeinung fuhrt die Progesteron-Wirkung in graviditate zu einer Hypotonie der Uretermuskulatur, die Dilatation des Schwangerschaftsureters wird auf hormonale Einflusse zuruckgefuhrt, mechanischen Komponenten wird nur untergeordnete Bedeutung beigemessen.

Jede Uteruskontraktion vermindert passager die Blutzufuhr in die Uterusgefase. Beim Rhesusaffen und auch beim Menschen konnte mit rontgenkinematographischen Untersuchungen nachgewiesen werden, das Wehen den Einstrom von Kontrastmittel in die Kotelydonen der Plazenta verlangsamen oder gar vollig stoppen (Ramsey et al. 1963; Boreil et al. 1964). Moll u. Kunzel (1974) konnten zeigen, das sich der Blutstrom in der A. uterina umgekehrt proportional zum Amniondruck verhalt.

Die O2- Versorgung des Feten ist abhangig von der uteroplazentaren Durchblutung und von der Lage der Sauerstoffbindungskurve im mutterlichen Erythrozyten. So wurde durch Meier (5) eine Rechtsverschiebung der Sauerstoffbindungskurve des mutterlichen Blutes von ca. 2 mmHg nach einer mindestens einwochigen Tokolyse beschrieben. In Zusammenhang damit mussen auch die Untersuchungen von Conradt (1) gesehen werden, die in den ersten 4 Stunden einer intravenosen Gabe von Fenoterol ein Absinken des maternalen 2,3-DPG-Spiegels zeigten. Von Interesse sind auch Untersuchungen von Denis (2) und Humpeier (4), welche gezeigt haben, das das Steroidhormon Progesteron auf den 2,3-DPG-Gehalt und folglich auf den P50 der Erythrozyten einen Einflus hat.