Search

// Fabian Dominik Mairinger 1 , Claudia Vollbrecht 2, 3, 4 , Elena Flom 1 , Daniel Christian Christoph 5 , Kurt-Werner Schmid 1 , Jens Kollmeier 6 , Helmut Hans Popper 7 , Thomas Mairinger 8 and Robert Fred Henry Walter 1, 9 1 Institute of Pathology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany 2 Institute of Pathology, Division of Molecular Pathology, Charite, Berlin, Germany 3 German Cancer Consortium (DKTK), Germany 4 German Cancer Research Center (DKFZ), Heidelberg, Germany 5 Department of Medical Oncology, West German Cancer Centre, University Hospital Essen, University of Duisburg-Essen, Essen, Germany 6 Department of Pneumology, Helios Klinikum Emil von Behring, Berlin, Germany 7 Department of Pathology, Division of Molecular Lung- and Pleurapathology, Medical University of Graz, Graz, Austria 8 Department of Pathology, Helios Klinikum Emil von Behring, Berlin, Germany 9 Ruhrlandklinik, West German Lung Centre, University Hospital Essen, University of Duisburg-Essen, Essen, Germany Correspondence to: Fabian Dominik Mairinger, email: fabian.mairinger@uk-essen.de Keywords: pleural mesothelioma, pemetrexed, thymidylate synthethase, folylpolyglutamate synthase, personalized therapy Received: October 12, 2016 Accepted: March 01, 2017 Published: March 21, 2017 ABSTRACT Background: Malignant pleural mesothelioma (MPM) is a rare tumor linked to a dismal prognosis. Even the most effective chemotherapeutical regime of pemetrexed combined with cisplatin leads to a remission-rate of only about 40%. The reasons for the rather poor efficacy remain largely unknown. Results: Phenotypes were significantly associated with progression (p=0.0279) and remission (p=0.0262). Cox-regression revealed significant associations between SLC19A1 / TYMS -ratio (p=0.0076) as well as FPGS / TYMS -ratio (p=0.0026) and OS. For differentiation by risk-groups, COXPH identified a strong correlation (p=0.0008). Methods: 56 MPM specimens from patients treated with pemetrexed were used for qPCR analysis. Phenotypes and risk groups were defined by their expression levels of members of the folic acid metabolism and correlated to survival and objective response. Conclusion: Our results indicate that the balance between folic acid uptake, activation and metabolism plays a crucial role in response to pemetrexed-based chemotherapy and the prognosis of MPM patients. Implementing this marker profile in MPM stratification may help to individualize MPM-therapy more efficiently.

Objectives Pulmonary adenocarcinomas (ADC) can be sub-grouped based on dominant oncogenic drivers. EGFR mutations define an entity of metastatic ADC with favorable prognosis and high susceptibility to EGFR tyrosine kinase inhibition. In contrast, the clinical impact of additional ERBB family members in ADC is less defined. To this end we prospectively studied HER2 expression, gene amplification, and mutation in relation to outcome of patients with advanced or metastatic ADC. Materials and methods Diagnostic tumor biopsies from 193 sequential patients with stage III/IV ADC were prospectively studied for HER2 expression by immunohistochemistry (IHC). Cases with IHC scores 2+ or 3+ were analyzed by HER2 chromogenic in situ hybridization (CISH), and sequencing of HER2 exons 20 and 23. Additional prospectively determined biomarkers included PTEN, cMET, pAKT, and pERK expression, KRAS , EGFR , BRAF and PIK3CA mutations, and ALK fluorescence ISH (FISH) . Results and conclusion HER2–IHC was feasible in 176 (91.2%) cases. Of 53 (30%) cases with IHC scores 2+/3+, 45 (85%) could be studied by CISH and 34 (64%) by sequencing. The lower number of HER2 -mutational analyses resulted from exhaustion of tumor tissue and DNA following mutational analysis of KRAS , EGFR , BRAF and PIK3CA . HER2 amplification was detected in 4 cases (2.3%), while no mutation was found. HER2 expression correlated with expression of pAKT and cMET. Expression of HER2 and pAKT was associated with favorable overall survival in stage IV disease. HER2-expressing ADC more frequently harbored KRAS mutations, while HER2 expression was absent in all 4 cases with BRAF mutation. HER2–IHC was not predictive of HER2 gene amplification or mutation, which both were rare events in prospectively studied patients with advanced or metastatic ADC. Expression of HER2 and pAKT define a population of patients with stage IV ADC with a distinct disease course, who could benefit from specifically tailored pharmacotherapies.

Eine Magenschleimhautheterotopie ist im Rektum ein auserst seltener Befund. Es existieren 3 atiopathogenetische Hypothesen, wobei man heute von einer Fehldifferenzierung entodermaler Stammzellen ausgeht. Klinisch imponieren durch Salzsaurebildung zumeist peranale Blutabgange. Therapeutisch steht neben konservativ-medikamentosen Methoden die (endoskopische) Resektion im Vordergrund. Aus pathologischer Sicht erfordern Biopsien und Resektate solcher Lasionen auch aufgrund der grundsatzlich moglichen dysplastischen bzw. malignen Transformation eine sorgfaltige Begutachtung.

In conjunctival melanoma, little is known about the tumour biology and protein-expression patterns. In this study, the authors analysed the expression of the antiapoptotic oncoprotein B cell leukaemia/lymphoma-2 protein (Bcl-2), the tumour-suppressor phosphatase and tensin homologue deleted on chromosome ten (PTEN), and the heat-shock-protein HSP-90 in conjunctival melanoma (CoM) and conjunctival nevi (CoN) by immunohistochemistry (IHC).IHC was performed on 70 samples of CoM and 12 samples of CoN. Expression patterns between the diagnosis groups were compared. A receiver operating characteristic analysis was performed to determine the diagnostic value of the antigens.HSP-90 (p0.0001) and PTEN (p=0.001) showed the potential to differentiate between CoM and CoN. Bcl-2 expression was higher in CoM than in CoN (p=0.04). The loss of nuclear PTEN expression was more pronounced in the malignant melanomas than in CoN (p=0.02). Tumours located at unfavourable sites (fornix, palpebral conjunctiva, caruncle) that had developed recurrences expressed almost twice as much HSP-90 than recurrence-free tumours.Conjunctival melanocytes differentially express Bcl-2, HSP-90 and PTEN, depending on their entity. HSP-90- and PTEN expression may add relevant information for the differentiation between conjunctival melanoma and nevi.

Results are presented on shape coexistence effects in the nucleus 78Kr obtained within the complex version of the EXCITED VAMPIR variational approach. Oblate–prolate coexistence and mixing is found to be responsible for the characteristic features identified at low excitation energy for low and intermediate as well as high spins. At the highest investigated spins, the high density of configurations having different deformations results in the fragmentation of B(E2) strengths explaining the experimentally identified forking of the spectrum. The present investigation indicates the essential role played by particular neutron–proton matrix elements of the effective interaction on the oblate–prolate coexistence and mixing in the 78Kr nucleus.

The levels in have been studied employing the pn) reaction with the Bucharest tandem and the p) reaction at 95 MeV with the HHIRF tandem to enhance high spin states. New high spin states have been observed beginning at 1179.5 keV and they include a cascade up to 6092.2 keV, tentatively assigned . These results are compared with the theoretical calculations based on the VAMPIR models which also include neutron - proton mixing.

A systematic numerical investigation of a recently developed nuclear structure approach is presented which diagonalizes the Hamiltonian in the space of the symmetry-projected Hartree-Fock-Bogoliubov (HFB) vacuum and symmetry-projected quasiparticle excitations with respect to it. The underlying HFB transformation, which is assumed to be time-reversal and axially symmetric, is determined by variation after the projection. The model allows the use of large basis systems. It has been applied to the calculation of energy spectra of several even-even, odd-odd and odd mass nuclei in the sd shell with mass numbers reaching from A=20 to 30. The Chung-Wildenthal interaction has been used. Good agreement with the exact shell model diagonalization and a considerable improvement on a previous approach, where the HFB transformation was significantly more restricted, is obtained., Comment: 21 pages LaTeX file, 2 LaTeX tables, 7 Postscript figures

To analyse the expression of melanoma chondroitin sulfate proteoglycan (MCSP) and the preferentially expressed antigen of melanoma (PRAME) in conjunctival melanoma (CoM), lymph node (LN) metastases of cutaneous melanoma (CM) and conjunctival nevi (CoN) by immunohistology.Immunohistology was performed in 70 samples of CoM, 25 of LN metastases of CM and 12 of CoN, and assessed by an immunoreactive score (0-12 points). Statistical analysis was performed to disclose relevant differences in the expression pattern. The diagnostic value of the markers was tested by receiver operating characteristics (ROC) analysis.MCSP and PRAME were expressed at significantly higher levels in CoM and LN metastases of CM than in CoN (p0.0001). Within CoM, an MCSP expression9.0 points meant higher risk for recurrences (Cox HR=3.1) and a shorter recurrence-free survival (p=0.002) than an MCSP expression9.0 points. ROC analysis showed an area under the curve of 91.3% for MCSP (p=0.0002) and 93.8% for PRAME (p0.0001).MCSP and PRAME are differentially expressed in conjunctival melanomas and nevi. MCSP might have an impact on the risk for recurrence in being inversely correlated to the event. Both markers have high potential to discriminate CoM from CoN. The results indicate that immunohistological characteristics gain relevance in the assessment of CoM.

Aquaporin1 (AQP1) is a water channel protein which facilitates water flux across cell membranes. AQP1 is found in epithelial and endothelial cells in various tissues. There is increasing evidence that AQP1 is expressed in malignant tumours and that it may play a role in tumour angiogenesis, cell migration and metastasis. We studied the immunohistochemical expression of AQP1 in a cohort of 203 invasive breast carcinomas with long-term follow up. AQP1 expression was detected in 11 cases (5.4%), and showed a significant correlation with high tumour grade, medullary-like histology, "triple- negativity", as well ascytokeratin 14 and actin expression. In univariate analysis, AQP1 was associated with a significantly poorer prognosis. Multivariate analysis showed that AQP1 expression has an independent predictive value for outcome if stratified by age, tumour size, lymph node status, histological grade and ER status. AQP1 expression in invasive breast carcinomas is associated with a basal-like phenotype and poor prognosis. © 2008 Springer Medizin Verlag.

The convergence of the expansion for the effective interaction is studied considering as examples the shell model for the nuclei 18 O and 18 F. In this work the effective interaction is computed through third order in the Brueckner G matrix using both a harmonic-oscillator (HO) basis and a Brueckner-Hartree-Fock (BHF) basis. We report significant differences in the convergence behavior of the effective interaction in these two cases. Our results indicate that the choice of the BHF single-particle potential seems to facilitate the convergence of the effective interaction in low orders of the expansion, whereas the HO results exhibit a non-convergent behavior. The implications for the HO approach are discussed. All calculations have been performed considering a modern version of the Bonn one-boson-exchange potential for the nucleon-nucleon interaction.

We apply a variational method devised for the nuclear many-body problem to the one-dimensional Hubbard model with nearest neighbor hopping and periodic boundary conditions. The test wave function consist for each state out of a single Hartree--Fock determinant mixing all the sites (or momenta) as well as the spin projections of the electrons. Total spin and linear momentum are restored by projection methods before the variation. It is demonstrated that this approach reproduces the results of exact diagonalizations for half-filled $N=12$ and $N=14$ lattices not only for the energies and occupation numbers of the ground but also of the lowest excited states rather well. Furthermore, a system of ten electrons in an $N=12$ lattice is investigated and, finally, an $N=30$ lattice is studied. In addition to energies and occupation numbers we present the spectral functions computed with the help of the symmetry-projected wave functions as well.

The hole--spectral functions and from these the spectroscopic factors have been calculated in an Galilei--invariant way for the ground state wave functions resulting from spherical Hartree--Fock calculations with projection onto zero total linear momentum before the variation for the nuclei 4He, 12C, 16O, 28Si, 32S and 40Ca. The results are compared to those of the conventional approach which uses the ground states resulting from usual spherical Hartree--Fock calculations subtracting the kinetic energy of the center of mass motion before the variation and to the results obtained analytically with oscillator occupations., Comment: 16 pages, 22 postscript figures

Spherical Hartree--Fock calculations with projection onto zero total linear momentum before the variation are performed for the nuclei 4He, 12C, 16O, 28Si, 32S and 40Ca using a density--independent effective nucleon--nucleon interaction. The results are compared to those of usual spherical Hartree--Fock calculations subtracting the kinetic energy of the center of mass motion either before or after the variation and to the results obtained analytically with oscillator occupations. Total energies, hole--energies, elastic charge form factors and charge densities and the mathematical Coulomb sum rules are discussed., Comment: 16 pages, 13 postscript figures

Background The reversible EGFR tyrosine kinase inhibitors E and G are effective treatments for advanced NSCLC, but most pts acquire resistance. Currently, the benefit from sustained EGFR blockade during subsequent salvage therapy is unclear. LUX-Lung 5 is an international, multicenter phase III trial studying the efficacy of BIBW2992 (Afatinib®, A), an irreversible erbB family blocker, in NSCLC pts progressing after treatment with ctx and E or G irrespective of their EGFR mutation status. Here we report the outcome of NSCLC pts treated within LUX-Lung 5 at a single center in relation to EGFR and KRAS mutation status. Methods Pts with stage IV (UICC 7) NSCLC progressing after ctx and E or G were enrolled into LUX-Lung 5. In part A of the study pts received A (starting dose 50 mg/d) until progression. In part B pts with clinical benefit ≥12 wks were randomized between A plus weekly paclitaxel vs investigator's choice mono ctx. Following microdissection, tumor DNA was extracted and analyzed by PCR and Sanger sequencing. Results Between May 2010 and February 2011 39 pts (20 f, 19 m; median age 61 y, 38-83 y) were enrolled at the West German Cancer Center. Median number of pretreatments was 3 (1-8) including E or G. So far, tumor biopsies were retrieved from 25 pts (64%). Somatic EGFR mutations were detected in 11 pts (44% of analyzed tumors, 28% of entire cohort), whereas 14 pts (56%/36%) exhibited EGFR wild type (wt) sequences. EGFR mutation status remains unknown in 14 pts (36%). KRAS mutation analysis was performed in 20 pts (51% of entire cohort) and 4 mutations were observed (20%/10%), 3 in EGFR wt and one in an EGFR mutant tumor. Median survival time from initiation of A was 432 d in EGFR mutant pts, 189 d in EGFR wt pts, and 255 d in KRAS mutant pts. Median survival time of pts with unknown EGFR mutation status was 191 d. Safety of A was manageable. Conclusions A can achieve disease control in heavily pretreated NSCLC pts. Pts with EGFR mutant tumors experience prolonged survival as compared to EGFR wt tumors (HR 0.29; 95% CI 0.07–0.64; p = 0.0058). This argues for sustained tumor dependency on EGFR signaling despite progression after E or G. Disclosure J. Kohler: J. Kohler received financial support from Boehringer Ingelheim for writing a review article. T.C. Gauler: T.C. Gauler is principle investigator of the BI1200.43 trial testing Afatinib in HNSCC. D. Theegarten: D. Theegarten is member of the Lilly Advisory Board. W. Eberhardt: W. Eberhardt received honoraries for advisory board functions from Boehringer Ingelheim, Astra Zeneca, Roche, OSi Pharmaceuticals, Pfizer and honoraries for lectures from Boehringer Ingelheim, Astra Zeneca, Roche and Pfizer. M. Schuler: M. Schuler received research funding from Boehringer Ingelheim and travel support from Lilly. All other authors have declared no conflicts of interest.

Aim: Mutations and/or amplifications of HER2 can be found in approximately 4% of patients with NSCLC. In patients with NSCLC and amplification of HER2, identified by immunohistochemistry (IHC3+) or positive fluorescence in situ hybridization (FISH), preliminary clinical data suggests efficacy of trastuzumab. AUY922 is an inhibitor of the heat shock protein HSP90. This protein acts as molecular chaperone for processing and transport of various intracellular proteins including HER2. AUY922 has shown single agent activity in patients suffering from HER2 amplified breast cancer. This trial investigates the efficacy of trastuzumab combined with AUY922 in patients with NSCLC. Methods: Patients with metastatic NSCLC and overexpression or amplification of HER2 (IHC DAKO 3+ or positive FISH) or activating mutation after failure of at least one standard treatment are enrolled for combination treatment with trastuzumab and AUY922 in this bicentric phase II study (study centers Cologne and Essen). Treatment starts as monotherapy with trastuzumab, restaging is performed every 6 weeks by CT scan. AUY922 is added at 70mg/m2 once weekly once progression occurs. The primary endpoint is response rate of combination therapy. Results: We screened 3,863 patients with NSCLC within the Network of Genomic Medicine for amplification or mutation of HER2 in Cologne; patients in Essen were screened separately. An amplification was detected in 4% of these patients, mutations occurred in 1.6%. So far, 5 patients have been treated within the ongoing trial. One patient is currently being treated with trastuzumab monotherapy and has shown stable disease in the third restaging after 18 weeks of treatment. The preliminary best response to combination therapy is disease stabilization for 12 weeks until progression, the maximum reduction in tumor volume is -29.3%, six weeks after start of combination therapy. Conclusions: Patients with NSCLC and amplified/mutated HER2 are treated with trastuzumab and AUY922 in this ongoing study. We will present preliminary data of clinical outcome and tolerability of this treatment. Disclosure: L. Nogova: Honoraria by Roche, Travel grant by Novartis; M. Schuler: Advisory Board/Consultant: AstraZeneca, Boehringer Ingelheim, Novartis, Pfizer Research grants: Boehringer Ingelheim, Novartis Honoraries: Alexion, Boehringer Ingelheim, Celgene, GlaxoSmithKline, Lilly, Novartis, Pfizer; J. Wolf: Advisory boards (compensated) and lecture fees: AstraZeneca, BMS, Boehringer-Ingelheim, Clovis, Novartis, Pfizer, Roche Research support: Bayer, Boehringer-Ingelheim, Novartis, Pfizer, Roche. All other authors have declared no conflicts of interest.

Nuclei at or near the N=Z line are of particular interest as micro-laboratory for fundamental effects. The simulation of many astrophysical objects requires the knowledge of properties and decay rates of nuclei near the drip lines. The structure and dynamics of proton-rich A70 nuclei and neutron-rich A100 nuclei are influenced by shape coexistence and mixing. A realistic description of shape coexistence phenomena requires beyond-mean-field approaches. Results concerning the self-consistent description of exotic phenomena including anomalies in mirror energy differences of proton-rich nuclei, triple shape coexistence in neutron-rich N=58 Sr and Zr isotopes as well as Gamow-Teller β-decay strength distributions, half-lives, and β- delayed neutron emission probabilities of neutron-rich nuclei in the A100 mass region obtained in the frame of the complex Excited Vampir model using realistic effective interactions in large model spaces are presented.

The shape transition, shape coexistence, and shape mixing characterizing the netron-rich Zr nuclei in the A100 region are consistently described at low and high spin states in the frame of the complex Excited Vampir variational approach using a realistic effective interaction obtained from Bonn A potential in a large model space. The influence of the shape mixing on the structure and dynamics of the investigated Zr isotopes is discussed and comparison with the available data is presented.

In the present paper a number conserving random phase approximation is derived as a special case of the recently developed random phase approximation in general symmetry projected quasiparticle mean fields. All the occurring integrals induced by the number projection are performed analytically after writing the various overlap and energy matrices in the random phase approximation equation as polynomials in the gauge angle. In the limit of a large number of particles the well-known pairing vibration matrix elements are recovered. We also present a new analytically number projected variational equation for the number conserving pairing problem.

Intrahepatic cholangiocarcinomas (ICC) are neoplasms that originate from cholangiocytes and can occur at any level of the biliary tree. Surgical resection is the current therapy of choice for this highly aggressive cancer. However, the 5-year survival still is poor, with high recurrence rates. Due to the intrahepatic growth a signifi cant proportion of patients present with advanced disease and are not candidates for curative surgery or transplantation. The existing palliative options are of limited benefit and there is a great necessity for novel therapeutic options. In this article we review the role of the phosphoinositide 3-kinase(PI3K)/ AKT and extracellular regulated kinase (ERK) signaling pathways in ICC and present new data on the prognostic value of these protein kinases. Finally, we discuss future upcoming therapeutic options based on targeting these signaling pathways.

A Hartree-Fock calculation with parity-mixed orbitals is used in an effort to describe the ground state and O+ excited state of 16O. Parity projection and orthogonality between the ground state and the excited state are imposed as constraints in the variational procedure. It is found that there exists a stable ground state with parity-mixed orbitals. However, the only non spurious excited state which orthogonal to the ground state does not contain parity-mixing.

We have calculated the neutrinoless double beta decay rate of 76Ge. We take into account for the first time a relativistic correction to the nuclear current including weak magnetism. Its effect is to cancel a considerable part of the decay amplitude and we obtain less stringent upper limits on the neutrino Majorana mass and the right-handed weak leptonic current compared with previous calculations.

In the first part of the present series of two papers we discussed several nuclear structure models all working in configuration spaces consisting of spin- and number-projected quasiparticle determinants. In the present paper a particular version of the numerically simplest of these models is presented. This model approximates the nuclear wave functions by linear combinations of the angular momentum- and particle number-projected Hartree-Fock-Bogoliubov vacuum and the equally spin- and number-projected two quasiparticle excitations with respect to it. The model allows the use of realistic two body interactions and rather large model spaces. It can hence be applied to a large number of nuclear structure problems in various mass regions. First applications have been performed for the nuclei /sup 20/Ne, /sup 22/Ne, /sup 46/Ti, and /sup 164/Er. In all these cases the results are very encouraging.

The role of two quasiparticle excitations for the backbending phenomenon in rare earth nuclei is studied in terms of a variational procedure and a dynamical mixing in a trial space spanned simultaneously by BCS ground state configurations and two quasiparticle configurations, both projected accurately on good angular momentum and good particle number. It turns out that in 166Yb the backbending may be caused by the (j, m) = ( 13 2 , ± 5 2 ) two quasiparticle excitation, being closest to the Fermi surface, whereas in 168Yb similar excitations are too high in energy and cause therefore no anomaly of the moment of inertia. In both cases a good agreement between theory and experiment is observed without refitting the P + Q force.

A fully microscopic study of the proton radiative capture on 19 F with excitation of the multipole resonances in 20 Ne is presented. The calculation makes use of a version of the Feshbach formalism of nuclear reactions. The bound states are described as linear combinations of angular momentum projected one particle — one hole configurations in a deformed Hartree-Fock basis. The agreement for the 90° yields with the experimental data is excellent. Gross features as well as intermediate structures are nicely reproduced.

Parameter-free, microscopic predictions are presented for the B (M1)↑ strength distributions in some deformed even-even nuclei of the mass A = 130 region. An extensive fragmentation of the M1 strength, being predominantly of isovector character, is obtained. The major strength is typically split into two regions around 4.0 and 5.0 MeV with the largest transitions having B ( M 1)↑ values of about 1.5–3.0 μ 0 2 . The total strenghts vary from 6.0 to 9.0 μ 0 2 , a value obtained usually for a single collective 1 + state of phenomenological models. The predicted B ( M 1)↓ branching from the 1 + states is sensitively state dependent, the branching to other than the 0 1 + and 2 1 + states being anywhere between 10% and 200% of the joined intensity to these two lowest levels.

Band mixing calculations are performed for the nucleus 166 Yb using angular momentum and particle number projected Hartree-Fock-Bogoliubov wave functions. The calculated spectrum for the yrast band is compared with that obtained from a non-selfconsistent Nilsson + BCS prescription.

The Multi Configuration Hartee-Kock (MCHF) theory is applied to the ground state of 28 Si. The single particle basis states are the 0 d 5 2 and 1 s 1 2 orbitals. A comparison is made with the results of a Hartree-Fock calculation performed in the same space.