Analytic model of a laser-controlled thermally deformable mirror.

We report on an analytic model of a laser-controlled thermally deformable mirror. The model shows the spatial low pass behavior of such a mirror system regarding the intensity distribution that controls the temperature distribution and the optical phase difference distribution of the deformable mirror. The model is validated using the data of measurements described by Schmid and Mahnke [J. Opt. Soc. Am. B35, 2661 (2018)JOBPDE0740-322410.1364/JOSAB.35.002661].

Hepatocyte Growth Factor Receptor overexpression predicts reduced survival but its targeting is not effective in unselected HNSCC patients.

BACKGROUND: MET has emerged as target in head and neck squamous cell carcinoma (HNSCC). However, clinical data on MET inhibition in HNSCC are limited. METHODS: HNSCC biopsies and cell lines were tested for MET activity. The response of cell lines to BAY-853474 was tested in proliferation assays. The prognostic value of MET expression was also analyzed. RESULTS: HNSCC cell lines do not respond to MET inhibition. MET-dependent gastric cancer cell lines have much higher levels of MET expression and phosphorylation than HNSCC cell lines. Clinical samples of HNSCC contain much less MET than responsive models. CONCLUSIONS: No clinical response to MET inhibitors in monotherapy may be expected in unselected cases of HNSCC. Only selected patients with MET amplifications should be treated with MET inhibitors. Patients with increased MET immunoreactivity have shorter overall survival. MET might be useful as marker for the detection of patients with more aggressive types of HNSCC.

EGFR overexpression is not common in patients with head and neck cancer. Cell lines are not representative for the clinical situation in this indication.

BACKGROUND: Based on expression data, Epidermal Growth Factor Receptor (EGFR) emerged as therapeutic target in Head and Neck Cancer but clinical efficacy of EGFR inhibitors was very limited. We reinvestigated the EGFR expression and activation status necessary for response in cell lines and compared that to clinical samples. METHODS: Clinical samples of head and neck squamous cell carcinoma (HNSCC, n=63), mostly from late stage (IV) and poorly or undifferentiated character and cultured cell lines (n=14) were tested by immunohistochemistry (IHC) (n=55) and sandwich immunoassays (n=63) for expression and phosphorylation of EGFR (Tyrosine-1173). Response of 14 different HNSCC cell lines to Erlotinib was tested in proliferation assays. RESULTS: Most HNSCC cell lines respond to Erlotinib. EGFR is phosphorylated in these cell lines. Resistant cell lines display very low level EGFR expression and phosphorylation. EGFR activity in clinical samples is significantly below that observed in cell lines. In clinical samples, EGFR is not overexpressed on the single cellular level. We show similar levels of EGFR expression in growing keratinocytes and tumor cells. CONCLUSIONS: Cell lines are not representative of the clinical situation in HNSCC. Larger studies should investigate whether patient subgroups with activating EGFR mutations or overexpression can be identified.

Heterogeneous PSMA expression on circulating tumor cells: a potential basis for stratification and monitoring of PSMA-directed therapies in prostate cancer.

The prostate specific membrane antigen (PSMA) is the only clinically validated marker for therapeutic decisions in prostate cancer (PC). Characterization of circulating tumor cells (CTCs) obtained from the peripheral blood of PC patients might provide an alternative to tissue biopsies called "liquid biopsy". The aim of this study was to develop a reliable assay for the determination of PSMA on CTCs. PSMA expression was analyzed on tissue samples (cohort one, n = 75) and CTCs from metastatic PC patients (cohort two, n = 29). Specific signals for the expression of PSMA could be seen for different prostate cancer cell line cells (PC3, LaPC4, 22Rv1, and LNCaP) by Western blot, immunohistochemistry (IHC), immunocytochemistry (ICC), and FACS. PSMA expression was found to be significantly increased in patients with higher Gleason grade (p = 0.0011) and metastases in lymph nodes (p = 0.0000085) or bone (p = 0.0020) (cohort one). In cohort two, CTCs were detectable in 20 out of 29 samples (69 %, range from 1 - 1000 cells). Twelve out of 20 CTC-positive patients showed PSMA-positive CTCs (67 %, score 1+ to 3+). We found intra-patient heterogeneity regarding the PSMA status between CTCs and the corresponding primary tumors. The results of our study could help to address the question whether treatment decisions based on CTC PSMA profiling will lead to a measurable benefit in clinical outcome for prostate cancer patients in the near future.

Preclinical evaluation of biomarkers for response monitoring to the MET inhibitor BAY-853474.

CONTEXT: The receptor tyrosine kinase MET contributes to a wide range of biological activities, including survival, proliferation, and metastasis, which play an important role in cancer progression. MET is frequently overexpressed or amplified in a range of malignancies. Therefore, MET is an attractive therapeutic target for treatment of cancer. BAY-853474 is a novel specific MET inhibitor highly effective in preclinical tumor models. OBJECTIVE: For response monitoring in clinical studies, soluble plasma biomarkers are the most convenient and least invasive choice. Therefore, we sought to identify such biomarkers in xenograft models. RESULTS: We show that BAY-853474 reduces the tumor burden in U87MG glioblastoma, NCI-H1993 nonsmall cell lung cancer, and HS746T gastric cancer xenograft models. We demonstrate that the dose dependence is reflected by inhibition of MET phosphorylation and that the soluble plasma biomarkers hepatocyte growth factor, vascular endothelial growth factor, and interleukin-8 as well as the MET-ectodomain can be used to monitor the tumor size and response to treatment. Clinical samples, however, show only moderately elevated levels of these biomarker candidates in cancer patients even with MET amplification. We, therefore, established an immunohistochemistry (IHC) protocol to detect MET phosphorylation that is suitable to monitor the effect of BAY-853474 in tumor biopsies. CONCLUSION: IHC-based analysis of target phosphorylation in tumor biopsies is recommended in addition to testing plasma biomarkers for response monitoring.

Capsule endoscopy versus standard tests in influencing management of obscure digestive bleeding: results from a German multicenter trial.

BACKGROUND: Capsule endoscopy (CE) is a new modality for obscure digestive bleeding (OBD), but little is known about its influence on management and outcome. PATIENTS AND METHODS: Fifty-six patients (male/female 26/30; mean age 63 yr) with ODB, and negative upper and lower gastrointestinal (GI) endoscopy were included in this multicenter study. The diagnostic yield of CE was compared to three other tests (OT: push enteroscopy, enteroclysis, angiography), and patients were followed up for at least 6 months. Parameters were analyzed that led to major management changes such as surgical or endoscopic intervention or specific medical therapy, as well as their correlation to further bleeding. RESULTS: CE had a diagnostic yield higher than OT (68% vs 38%). Major management changes and an improvement in bleeding activity were observed in 21 and 44 patients, respectively. The number and type of positive findings on CE were associated with significant management changes (p < 0.05). The number of positive findings detected by CE as well as by OT correlated with further bleeding episodes (p < 0.05). However, clinical parameters (lowest hemoglobin (Hb) value, number of blood transfusions) were also significantly associated with outcome. Diagnoses of specific diseases (tumor, Crohn, NSAID ulcer) by CE led to a favorable outcome in 64% of cases, whereas negative CE cases were associated with no further bleeding in 80%. CONCLUSION: CE helps with management decisions and can replace other more complex and risky standard tests. Nevertheless, clinical parameters are equally important for predicting further bleeding and should also be used to decide on further management.

Design and synthesis of macrocyclic inhibitors of phosphatase cdc25B.

Based on molecular modeling studies, macrocyclic inhibitors of phosphatase cdc25B were synthetically derived from steroids. A preliminary SAR for this new template was elaborated. A series of compounds shows inhibition of cdc25B in the low micromolar range and good selectivity versus other phosphatases. The compounds did not show a significant antiproliferative effect in MaTu or HaCaT cells.