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// 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.

Glucose transporter-1 (GLUT-1) is one of the major isoforms of the family of glucose transporter proteins that facilitates the import of glucose in human cells to fuel anaerobic metabolism. The present study was meant to determine the extent of the anaerobic/hypoxic state of the intratumoral microenvironment by staining for GLUT-1 in intracranial non-embolized typical (WHO grade I; n = 40), brain invasive and atypical (each WHO grade II; n = 38) and anaplastic meningiomas (WHO grade III, n = 6). In addition, GLUT-1 staining levels were compared with the various histological criteria used for diagnosing WHO grade II and III meningiomas, namely, brain invasion, increased mitotic activity and atypical cytoarchitectural change, defined by the presence of at least three out of hypercellularity, sheet-like growth, prominent nucleoli, small cell change and “spontaneous” necrosis. The level of tumor hypoxia was assessed by converting the extent and intensity of the stainings by multiplication in an immunoreactive score (IRS) and statistically evaluated. The results were as follows. (1) While GLUT-1 expression was found to be mainly weak in WHO grade I meningiomas (IRS = 1–4) and to be consistently strong in WHO grade III meningiomas (IRS = 6–12), in WHO grade II meningiomas GLUT-1 expression was variable (IRS = 1–9). (2) Histologically typical, but brain invasive meningiomas (WHO grade II) showed no or similarly low levels of GLUT-1 expression as observed in WHO grade I meningiomas (IRS = 0–4). (3) GLUT-1 expression was observed in the form of a patchy, multifocal staining reaction in 76% of stained WHO grade I-III meningiomas, while diffuse staining (in 11%) and combined multifocal and areas of diffuse staining (in 13%) were only detected in WHO grades II and III meningiomas, except for uniform staining in angiomatous WHO grade I meningioma. (4) “Spontaneous” necrosis and small cell change typically occurred away from the intratumoral capillary network embedded within the pattern of GLUT-1 staining. Taken together, GLUT-1 staining cannot be applied as a substitute for histologic grading in order to predict tumor behavior. However, assessment of tumor hypoxia in association with “spontaneous” necrosis and foci of small cell change may substantially contribute to the neuropathologic diagnosis of WHO grades II and III meningioma.

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.

In den letzten Jahren wurde durch Grundlagenforschung und translationale Forschung in der Onkologie eine Reihe von Biomarkern identifiziert, die fur Diagnostik, Staging, Prognoseabschatzung und als Ansatzpunkte fur individualisierte Therapien potentiellen klinischen Wert haben. Einige dieser Marker sind bereits in die klinische Praxis eingefuhrt, andere werden derzeit im Rahmen wissenschaftlicher Programme an Comprehensive Cancer Centers und innerhalb von Studiengruppen in ihrer Anwendung erprobt. Dieser Beitrag gibt einen Uberblick uber bereits klinisch etablierte Biomarker bei soliden Krebserkrankungen und einen Ausblick auf Kandidaten, die an der Schwelle zur breiten klinischen Anwendung stehen.

Hintergrund und Fragestellung Trotz aller Erfolge in der Transplantationsmedizin sterben in Deutschland jahrlich etwa 1000 Patienten wahrend der Wartezeit auf ein geeignetes Organ. Der chronische Mangel an Spenderorganen konnte durch eine Erhohung der Bereitschaft zur Organspende verbessert werden. Da die Mitarbeiter der Universitatskliniken unmittelbar an der Transplantationsmedizin beteiligt sind, ist ihre Meinung von besonderem Interesse bei der Analyse der Organspendebereitschaft.

We study the influence of shape mixing on the Gamow–Teller β decay of the nucleus 74Kr using the complex EXCITED VAMPIR variational approach for the description of the ground state of 74Kr and the 1 + states appearing within the β + -decay window in the daughter nucleus 74Br. The Gamow–Teller strength is obtained describing consistently the shape mixing in both parent and daughter nucleus. The theoretical results for the Gamow–Teller strength distribution as well as accumulated strength are compared with the available experimental data.

The complex Excited Vampir approach was applied to the description of the recently identified magnetic cascade of negative-parity states in the odd-odd 82Rb nucleus. Strong M1, ΔI = 1 transitions as well as rather weak crossover B(E2) strengths are obtained in agreement with the available data. The decrease of the B(M1) strengths with increasing spin is revealed by the calculations. A strong mixing of differently deformed states at the highest calculated spins is responsible for the trend of the B(M1;ΔI = 1) and B(E2;ΔI = 2) strengths.

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.

Results are presented concerning shape coexistence and shape transition at low and intermediate spins in the N = Z nuclei 72 Kr, 76 Sr and 80 Zr obtained within the complex version of the Excited Vampir variational approach. The effects of possible contaminations due to the center-of-mass motion are discussed using a rough method to eliminate them at least approximately. The results indicate maximum influence on the observables depending on band mixing. Detailed illustration of the effects on the oblate–prolate mixing and the electromagnetic properties, as well as the alignments and particle occupations of the 0 g 9/2 spherical orbital is presented for the 72 Kr nucleus.

The pair structure and the average pairing gaps of realistic wave functions obtained within the complex Excited Vampir variational approach are investigated in order to evaluate the neutron-proton pairing correlations at low and high spins in medium mass N ∼- Z nuclei. The number of isovector Jπ = 0+ pairs is calculated for the lowest few 0+ states in two chains of nuclei in the A ∼- 70 mass region. The results indicate the dominant role played by the isovector neutron-proton pairing correlations in the structure of odd-odd N = Z nuclei and the reduction of their importance with increasing neutron excess in even-even nuclei. The evolution of particular isovector and isoscalar pairs with increasing angular momentum is analyzed for the odd-odd N = Z nucleus 74Rb and the even-even N = Z nucleus 72Kr. It turns out that in the nucleus 74Rb the neutron-proton correlations play an essential role for the alignment of the yrast positive-parity even-spin band.

Recent investigations of the shape transition and shape coexistence phenomena dominating the structure of the even-even N ≃ Z nuclei in the A ≃ 80 mass region are extended to the odd-odd nucleus 78Rb. Special attention is paid to the structure of some “identical” bands which have been recently identified in 78 Sr and 78Rb. The ground band of78 Sr and the yrast as well as excited negative parity bands in 78Rb are studied within the EXCITED VAMPIR approximation using complex Hartree-Fock-Bogoliubov transformations in a relatively large model space. The results are compared with the available experimental data. The emerging picture reveals the role played by the strong quadrupole deformation on the appearance of identical bands as well as the influence of the shape coexistence on their evolution. Predictions for the electromagnetic and alignment properties of the bands are presented.

The biological behaviour of meningeal haemangiopericytomas was retrospectively studied using immunohistochemical staining with MIB1, a monoclonal antibody against the Ki-67 antigen, a nuclear protein related to cell proliferation. Paraffin-embedded material from 62 tumours from 40 patients were investigated. The proliferating compartment of the tumours was estimated by evaluating the MIB1 staining index, i.e. the percentage of MIB1 positive nuclei in at least 1000 counted tumour cells in representative areas. The staining index ranged from 1.24% to 39.01%. Statistical analysis revealed no significant correlation between the staining index and recurrence-free survival (chi 2 = 0.3922, P = 0.5311). Long-term observation (> 100 months), however, revealed a tendency to longer survival in the group with a staining index less than 5%. According to our results, the MIB1 staining index does not contribute to the accuracy of predicting the clinical outcome of meningeal haemangiopericytomas.

In a previous study immunocytochemically detectable metallothionein (MT) expression in tumor cells of invasive duct carcinoma of the breast was shown to be associated with a more aggressive behavior and these findings have been subsequently confirmed by others. The aim of this study was to examine the prevalence and significance of MT positivity in preinvasive duct carcinoma in situ (DCIS). Fifty-five specimens of pure screen-detected DCIS were stained immunocytochemically for MT using the antibody E9. The intensity and distribution of MT staining were assessed using a semi-quantitative method resulting in intensity distribution (ID) scores allowing duct by duct analysis in relation to architectural and cytological features of the DCIS. In general, myoepithelial cells around benign and malignant structures stained uniformly strongly for MT. Staining in DCIS was analyzed by architecture irrespective of cytology and by nuclear grade irrespective of architecture. The results showed that MT staining was significantly greater in comedo (ducts with necrosis) DCIS (ID = 97) compared with noncomedo (ducts without necrosis) DCIS (ID = 56) ( P = .05 by Mann Whitney U statistic) and that low cytological grade (ID = 50) was associated with less MT staining than was high cytological grade (ID = 92) ( P = .05 by Mann Whitney U statistic). These observations thus are consistent with the previously observed association between MT positivity and more aggressive behavior in invasive duct carcinoma of the breast.

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 shape coexistence phenomena dominating the structure of the nucleus 68 Ge are reinvestigated by taking the dominant correlations on top of the symmetry-projected quasiparticle mean-field solutions of the earlier EXCITED VAMPIR description into account. It turns out that in spite of some quantitative changes the main qualitative features of the older description like, e.g., the occurrence of multiple band structures, the coexistence of many differently deformed configurations, the high level density for medium and high spin values, and the corresponding complex feeding pattern do persist. Qualitatively these features are confirmed by recent experimental data. In addition an EXCITED VAMPIR description of the positive-parity states with even angular momenta in the nucleus 70 Se is reported. The results for this nucleus are besides a few peculiarities qualitatively rather similar to those of our earlier calculations for the nucleus 72 Se.

Introduction Monoclonal antibodies and tyrosine kinase inhibitors (TKI) targeting the EGFR are approved or under investigation for the systemic treatment of patients with HNSCC. However, primary and acquired resistance against EGFR-targeted therapies are frequently observed. Mutational activation of the EGFR signaling cascade as well as molecular changes caused by HPV infection are the most abundant oncogenic alterations in HNSCC. Against this background we have used preclinical cancer models to study the impact of activated PI3K/AKT and RAS/RAF/MAPK pathways or HPV16 oncoprotein expression on the response to anti-EGFR therapies. Materia and methods Cetuximab- and erlotinib-sensitive cancer cells were retrovirally transduced to express HPV16 oncoproteins E6 or E7, conditionally active AKT and RAF-1 or a RASG12V mutant. HPV16-positive cancer cells and cells harboring endogenously mutated PIK3CA or RAS were used as alternative models. Cell proliferation, induction of apoptosis, clonogenic survival and tumor growth in immune-compromised mice were analyzed in relation to treatment with anti-EGFR antibodies. In support, tumor samples from cetuximab-treated patients with recurrent or metastatic HNSCC were probed for p16INK4a expression, an established biomarker of HPV infection and retrospectively analyzed concerning the response rates (RR) and progression free survival (PFS) in relation to HPV status. Results Activation of the PI3K/AKT and the RAS/RAF/MAPK pathways strongly protected HNSCC cells against anti-EGFR therapies. Mechanistically, this resistance was mediated by changes in the expression of anti-apoptotic proteins and could be overcome by co-treatment with specific inhibitors of EGFR downstream signaling. In contrast, the endogenous HPV status of HNSCC cells or the expression of HPV oncogenes had no significant impact on cetuximab-mediated suppression of EGFR signaling and proliferation in vitro. In addition, response rates (45.5% versus 45.5%) and median progression-free survival (97 versus 92 days) following cetuximab-based therapy were similar in patients with p16INK4A-positive and p16INK4A-negative tumors. Conclusion Activation of the PI3K/AKT and the RAS/RAF/MAPK pathways functionally interfere with the activity of anti-EGFR therapies. In contrast, HPV status of HNSCC did not influence the response to cetuximab in our retrospective analyses and in our preclinical models. In conclusion, cetuximab treatment should be administered independently of HPV status.

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.

Aims To present wide-ranging clinicopathological data of papillary thyroid cancer in children and adolescents who have no apparent link to previous irradiation or other aetiological cause (genetic predisposition or contact with any well-known canceri-genic agent). Ninety-four consecutive surgically treated patients aged 4–18 years were investigated. Results In the majority of patients the carcinoma had already broken through the organ’s capsule and afflicted lymph nodes of both paratracheal (level VI) and parajugular (level II–IV, in a few cases level V) zones (pT3bN1bM0, n = 27; 28.4%). Median tumour size was 12 (range 1–100) mm. Classical variant of papillary thyroid carcinoma was the most common subtype (43; 45.7%) followed by follicular (20; 21.3%) and tall cell (10; 10.7%) variants. Incidence of lymph node metastases at presentation was 71.3% (N1a 20.2%, N1b 51.1%) and 9.6% of patients had bilateral N1b involvement. Classical architectonic ( p p p p Conclusion Papillary thyroid carcinoma in childhood and adolescence was most commonly diagnosed in patients aged 12–17 years and was usually >10 mm in size (53; 56.4%). Infiltration of soft tissues (36; 38.3%) and intrathyroid lymphatic vessels by tumour complexes and psammoma bodies (59; 62.8%) was common. It is also typical that the tumour undergoes secondary scarring located mostly in central parts (massive fibrosis involves 30–70% of neoplasm volume observed in 25 cases; 26.6%). The tumours spread regionally. Finally, autoimmune thyroiditis appears to play a role in the background pathology (26; 27.6%).

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.

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.