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  • 1
    Abstract: PURPOSE: We elucidated the value of tumor-infiltrating lymphocytes (TIL) as an independent predictor for pathologic complete response (pCR) rate and as a prognostic marker for disease-free survival (DFS) in patients with HER2-positive breast cancer in the neoadjuvant setting. EXPERIMENTAL DESIGN: We evaluated stromal TILs in 498 HER2-positive breast cancer samples of the neoadjuvant GeparQuattro (G4) and GeparQuinto (G5) trials. Levels of TILs were determined as a continuous parameter per 10% increase and as lymphocyte-predominant breast cancer (LPBC; 〉/= 60% TILs), and correlated with pCR rate and DFS. RESULTS: In the complete cohort, HER2-positive LPBC cases had a significantly increased pCR rates compared with non-LPBC types. They were significant predictors for pCR in univariate (10% TILs: OR 1.12, P = 0.002; LPBC: OR 2.02, P = 0.002) and multivariate analyses (10% TILs: OR 1.1, P = 0.014; LPBC: OR 1.87, P = 0.009). This effect was also detectable in the trastuzumab-treated (10% TILs: OR 1.12, P = 0.018; LPBC: OR 2.08, P = 0.013) but not in the lapatinib-treated subgroup. We identified a low-risk (pCR/LPBC) and a high-risk group (no pCR/no LPBC) regarding DFS. In triple-positive breast cancer, TILs are of more prognostic relevance than pCR. CONCLUSIONS: We could demonstrate the predictive and prognostic impact of TILs in HER2-positive breast cancer in the neoadjuvant setting. In combination with pCR rate, TILs may help to stratify prognostic subgroups, thereby guiding future therapy decisions. Clin Cancer Res; 22(23); 5747-54. (c)2016 AACR.
    Type of Publication: Journal article published
    PubMed ID: 27189162
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  • 2
    Abstract: BACKGROUND: The PI3K/AKT pathway and phosphatase and tensin homolog (PTEN) aberrations are common in breast cancer. We investigated the correlation between phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), PTEN, p4EBP1 (phosphorylated E4 binding protein 1), and pathologic complete response (pCR) in patients receiving neoadjuvant therapy. EXPERIMENTAL DESIGN: We retrospectively evaluated PIK3CA, PTEN, and p4EBP1 protein expression in centrally HER2-positive patients (n = 181) who received epirubicin cyclophosphamide/trastuzumab followed by docetaxel/trastuzumab alone or concomitant/followed by capecitabine within the GeparQuattro study. PTEN was assessed using the automated quantitative immunofluorescence analysis and was analyzed as a dichotomic variable. p4EBP1 was assessed by immunohistochemistry and used as a continuous and dichotomic variable. RESULTS: p4EBP1 was available from 137, PTEN from 108, and PIK3CA genotype from 83 patients. Overall, the pCR rate in PTEN-low tumors was 27.6%, and in PTEN-high tumors, it was 57.1% (P = 0.010). pCR rates were not statistically different between PIK3CA wild-type and mutant (35% vs. 22%) or p4EBP1 IRS 〈/= 4 and IRS 〉 4 (39% vs. 33%). pCR rate was 57.1% (8/14) in PTEN-high/PIK3CA wild-type and decreased to 15.4% in PTEN-low/PIK3CA-mutant tumors (P = 0.023). In multivariable analysis adjusted for baseline parameters, PTEN independently predicted pCR in the following cohorts: overall [OR, 7.54; 95% confidence interval (CI), 2.03-28.06; P = 0.003], PIK3CA wild-type (OR, 23.81; 95% CI, 1.75-324.05; P = 0.017), p4EBP1 IRS 〉 4 (OR, 11.53; 95% CI, 1.84-72.24; P = 0.009), and hormone receptor-positive (OR, 40.91; 95% CI, 2.93-570.44; P = 0.006). p4EBP1 was independently predictive for pCR in PIK3CA wild-type tumors (OR, 0.14; 95% CI, 0.03-0.78; P = 0.025). CONCLUSIONS: The study showed the potential role of PIK3CA genotype, PTEN, and p4EBP in predicting pCR after anthracycline-taxane-based chemotherapy and anti-HER2 treatment. Clin Cancer Res; 22(11); 2675-83. (c)2016 AACR.
    Type of Publication: Journal article published
    PubMed ID: 26758558
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  • 3
    Keywords: CELLS ; LIGAND ; PREOPERATIVE CHEMOTHERAPY ; TUMORIGENESIS ; bone metastasis ; NEOADJUVANT CHEMOTHERAPY ; OSTEOCLAST ; III RANDOMIZED GEPARTRIO ; RANKL/RANK/OPG ; DENOSUMAB
    Abstract: RANK ligand (RANKL) is crucial for the development of mouse mammary glands during pregnancy. RANKL functions as a major paracrine effector of the mitogenic action of progesterone in mammary epithelium via its receptor RANK and has a role in expansion and regenerative potential of mammary stem cells. Pharmacologic inhibition of RANKL attenuates the development of mammary carcinoma and inhibits metastatic progression in multiple mouse models. Primary breast carcinoma samples from the neoadjuvant GeparTrio study were analyzed to correlate the expression of human RANK and RANKL with pathological complete response (pCR), disease-free (DFS), and overall (OS) survival. Pre-treatment FFPE core biopsies (n = 601) were analyzed for percentage and intensity of immunohistochemical RANK and RANKL expression. Antibodies against human RANK (N-1H8; Amgen) and human RANKL (M366; Amgen) were used. RANK protein was expressed in 160 (27 %) patients. Increased RANK expression was observed in 14.5 % of patients and correlated with high tumor grade (p 〈 0.023) and negative hormone receptor (HR) status (p 〈 0.001). Patients with high RANK expression showed a higher pCR rate (23.0 % vs. 12.6 %, p = 0.010), shorter DFS (p = 0.038), and OS (p = 0.011). However, prognostic and predictive information was not an independent parameter. Only 6 % of samples expressed RANKL, which was not correlated with any clinical features. Higher RANK expression in the primary tumor is associated with a higher sensitivity to chemotherapy, but also a higher risk of relapse and death. Our study provides a basis for further exploration of the antitumor activity of clinical antibodies against RANKL.
    Type of Publication: Journal article published
    PubMed ID: 24737168
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  • 4
    Abstract: Importance: The GeparSixto trial provided evidence that the addition of neoadjuvant carboplatin to a regimen consisting of anthracycline, taxane, and bevacizumab increases pathological complete response (pCR) rates in patients with triple-negative breast cancer (TNBC). Whether BRCA1 and BRCA2 germline mutation status affects treatment outcome remains elusive. Objective: To determine whether BRCA1 and BRCA2 germline mutation status affects therapy response in patients with TNBC. Design, Setting, and Participants: This secondary analysis of a randomized clinical trial used archived DNA samples and cancer family history of 315 patients with TNBC enrolled between August 1, 2011, and December 31, 2012, in the GeparSixto trial. In all, 291 participants (92.4%) were included in this multicenter prospective investigation. DNA samples were analyzed for germline mutations in BRCA1, BRCA2, and 16 other cancer predisposition genes. The pCR rates between the carboplatin and noncarboplatin arms were compared. Genetic analyses were performed at the Center for Familial Breast and Ovarian Cancer in Cologne, Germany; data analysis, November 1 through December 31, 2015. Main Outcomes and Measures: Proportion of patients who achieved pCR and disease-free survival after neoadjuvant treatment according to BRCA1 and BRCA2 germline mutation status. For pCR rates, the ypT0/is ypN0 definition was used as a primary end point. Results: Of the 291 patients with TNBC, all were women; the mean (SD) age was 48 (11) years. The pCR rate in the carboplatin group was 56.8% (83 of 146) and 41.4% (60 of 145) in the noncarboplatin group (odds ratio [OR], 1.87; 95% CI, 1.17-2.97; P = .009). Pathogenic BRCA1 and BRCA2 germline mutations were present in 50 of the 291 patients (17.2%). In the noncarboplatin arm, the pCR rate was 66.7% (16 of 24) for patients with BRCA1 and BRCA2 mutations and 36.4% (44 of 121) for patients without (OR, 3.50; 95% CI, 1.39-8.84; P = .008). The high pCR rate observed in BRCA1 and BRCA2 mutation carriers (16 of 24 [66.7%]) was not increased further by adding carboplatin (17 of 26 [65.4%]). In contrast, carboplatin increased response rates in patients without BRCA1 and BRCA2 mutations: 66 of the 120 patients (55%) without BRCA1 and BRCA2 mutations achieved pCR in the carboplatin arm vs 44 of the 121 patients (36.4%) in the noncarboplatin arm (OR, 2.14; 95% CI, 1.28-3.58; P = .004). Patients without pathogenic BRCA1 and BRCA2 alterations showed elevated disease-free survival rates when carboplatin was added (without carboplatin, 73.5%; 95% CI, 64.1%-80.8% vs with carboplatin, 85.3%; 95% CI, 77.0%-90.8%; hazard ratio, 0.53; 95% CI, 0.29-0.96; P = .04). Conclusions and Relevance: Under the nonstandard GeparSixto polychemotherapy regimen, patients without BRCA1 and BRCA2 germline mutations benefited from the addition of carboplatin and those with BRCA1 and BRCA2 mutations showed superior response rates without additive effects observed for carboplatin. Trial Registration: clinicaltrials.gov Identifier: NCT01426880.
    Type of Publication: Journal article published
    PubMed ID: 28715532
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  • 5
    Abstract: Human epidermal growth factor receptor 2 (HER2) is a central predictive biomarker in breast cancer. Inaccurate HER2 results in different laboratories could be as high as 20%. However, this statement is based on data generated more than 13 years ago and may not reflect the standards of modern diagnostic pathology. We compared central and local HER2 testing in a total of 1581 HER2-positive tumors from five clinical trials. We evaluated the clinical relevance for pathological complete response (pCR) and disease-free survival in a subgroup of 677 tumors, which received an anti-HER2 therapy. Over the period of 12 years, the discordance rate for HER2 decreased from 52.4 (GeparTrio) to 8.4% (GeparSepto). Discordance rates were significantly higher in hormone receptor (HR)-positive tumors (26.6%), compared to HR-negative tumors (16.3%, P〈0.0001), which could be explained by a different distribution of HER2 mRNA levels in HR-positive and HR-negative tumors. pCR rates were significantly lower in discordant tumors (13.7%) compared to concordant tumors (32.2%, GeparQuattro and GeparQuinto, P〈0.001). In survival analysis, tumors with discordant HER2 testing had a reduced overall survival (OS) in the HR-negative group (P=0.019) and a trend for improved OS in the HR-positive group (P=0.125). The performance of local HER2 testing was considerably improved over time and has reached a 92% concordance, which shows that quality initiatives in diagnostic pathology are working. Tumors with discordant HER2 testing had a reduced therapy response and different survival rates.
    Type of Publication: Journal article published
    PubMed ID: 29271415
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  • 6
    ISSN: 1432-119X
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Description / Table of Contents: Zusammenfassung In einem teilungssynchronen Zellsystem wird die DNS-Synthese mit biochemischen, quantitativ histochemischen und autoradiographischen Methoden studiert. Die DNS-Synthese dient dabei der Kontrolle der Synchronisation. Mehr als 95% der Zellen werden vom synchronisierenden Prinzip erfaßt; ca. 80% der Zellen beginnen innerhalb von 3 Std mit der DNS-Replikation. Mit den ergänzenden quantitativ-morphologischen Methoden konnte ein zweistufiger Ablauf der DNS-Synthese wahrscheinlich gemacht werden.
    Notes: Summary DNA-synthesis as determined by biochemical, cytochemical and autoradiographic methods served as an indicator for the degree of synchrony in a mechanically synchronized monolayer culture of L-cells. Within about 3 hours 80% of the cells enter S-phase. From experiments with asynchronously growing cells a two step kinetic of DNA-synthesis has been made probable.
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1432-119X
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Description / Table of Contents: Zusammenfassung Die aufeinanderfolgende Anwendung der simultanen Feulgen-Naphtholgelbfärbung und der Fastgreenfärbung bei pH 8,2 zur Bestimmung von DNS, Gesamtprotein und Histonprotein wird geprüft. Im Vergleich zu Kontrollen ergaben sich identische Meßergebnisse. Die Formalinfixierung ist am besten geeignet.
    Notes: Summary A sequential cytophotometric determination of DNA, total protein and histone protein using simultaneous Feulgen-Naphthol yellow staining followed by Fastgreenstaining, was examined and there was no difference between successive stained cells and controls. Formalinfixation is to prefer.
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1432-0584
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Zusammenfassung Es wird über eine Patientin mit einer akuten myeloischen Leukämie berichtet, die im Knochenmark überwiegend atypische Myeloblasten aufwies. Im Gegensatz dazu fanden sich im peripheren Blut eine große Anzahl ebenfalls atypischer “Neutrophiler” sowie eine beträchtliche Zahl monozytenähnlicher Zellen, die wirals Zwischenformen zwischen den atypischen Myeloblasten und den pathologischen Neutrophilen auffassen. Die pathologischen “Neutrophilen” zeigen ein ungewöhnliches zytochemisches Muster, in dem der größte Teil dieser Zellen keine Sudanschwarz-B-positiven Lipide sowie kaum Peroxydase-Naphthol-AS-D-Cloroacetat-Esterase-Aktivität aufweist. Diese drei zytochemischen Reaktionen geben normalerweise eine starke positive Reaktion in den neutrophilen Granulozyten. Außerdem wurde eine atypische Werteinteilung sowohl der alkalischen Phosphatase als auch der Naphthylamidase festgestellt. Die monozytenähnlichen Zwischenformen unterscheiden sich deutlich in ihrem zytochemischen Muster von normalen Monozyten und gleichen den atypischen neutrophilen Zellen. Diese zytochemischen Befunde stützen die Ansicht, daß es bei der Patientin zu einer Ausreifung der Myeloblasten über ein monozytenähnliches Zwischenstadium zu atypischen “neutrophilen” Granulozyten gekommen ist. Trotz der hohen Zahl “neutrophiler” Granulozyten im peripheren Blut (10 350/mm3) wurden in den blutbildenden Organen nur wenig typische neutrophile Vorstufen mit einem normalen Enzymmuster festgestellt.
    Notes: Summary A case of a patient is presented, who suffered from acute leukemia, showing predominantly atypical myeloblasts in the bone marrow. In contrast, a high amount of atypical “neutrophils” were present in the peripheral blood, as well as there was a conspicuous number of monocyte-like intermediate forms between the myeloblasts and the atypical segmented “neutrophils.” The cytochemical pattern of the “Neutrophils” was highly atypical, the main part being devoid of sudanblack B-positive lipids, as well as of peroxidase and chloroacylesterase activity, which characteristically are present in large amounts in the neutrophil granulocytes. Moreover, atypical distribution of alkaline phosphatase and naphthylamidase activities were encountered in these cells. The intermediate or transitional cells exhibited a cytochemical pattern different from that of normal blood monocytes, but corresponding to that of the atypical neutrophils. Thus, the assumption of a direct maturation way from myeloblasts to “paraneutrophils” with mononuclear, monocyte-like intermediate stages was supported by the results of cytochemical investigations. In contrast to the elevated number of neutrophils in the peripheral blood (10 350/mm3) very rare normal neutrophil precursors with typical cytochemical pattern were encountered in the haematopoietic organs.
    Type of Medium: Electronic Resource
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  • 9
    ISSN: 0014-4827
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Biology , Medicine
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 1432-1335
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Zusammenfassung Mit immunfluoreszenzmikroskopischen Methoden wurde die Verteilung von α 1-Fetoprotein, α 1-Glykoprotein, Magenschleimhautantigen sowie Gastrin und β-Galactosidase im Magencarcinom, bei Ulcus ventriculi, sowie in der näheren und weiteren Umgebung des Carcinoms und in der Ulcusnachbarschaft untersucht. Dabei findet sich kein signifikanter Unterschied zwischen Carcinom und nicht neoplastisch erkranktem Magen, mit Ausnahme des sauren α 1-Glycoproteins. Dies scheint darauf hinzudeuten, daß der Nachweis dieser Substanz in hohem Ausmaß für neoplastisches Wachstum im Magen typisch ist.
    Notes: Summary The distributions of acid alpha1-glycoprotein, alpha1-fetoprotein, beta-galactosidase and gastrin in gastric carcinoma and gastric ulcer as well as in the neighbourhood of these lesions were studied by means of immunohistochemical methods on imprint preparation. We could not find significant differences between gastric carcinoma and the nonneoplastic lesions, except for the acid alpha1-glycoprotein. The results of this first study indicate that the immunochemical and immunohistological assay of acid alpha1-glycoprotein might be of practical value in diagnosing malignant changes of gastric mucosa.
    Type of Medium: Electronic Resource
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