Expression Patterns of TNFα, MAdCAM1, and STAT3 in Intestinal and Skin Manifestations of Inflammatory Bowel Disease.

Pathogenesis of cutaneous extraintestinal manifestations [EIM] in inflammatory bowel disease [IBD] remains elusive. Efficacy of anti-TNF agents suggests TNF-dependent mechanisms. The role of other biologics, such as anti-integrins or JAK-inhibitors, is not yet clear. We performed immunohistochemistry for TNFα, NFκB, STAT1/STAT3, MAdCAM1, CD20/68, caspase 3/9, IFNγ, and Hsp-27/70 on 240 intestinal [55 controls, 185 IBD] and 64 skin biopsies [11 controls, 18 erythema nodosum [EN], 13 pyoderma gangenosum [PG], 22 psoriasis]. A semiquantitative score [0-100%] was used for evaluation. TNFα was upregulated in intestinal biopsies from active Crohn`s disease [CD] vs controls [36.2 vs 12.1, p < 0.001], but not ulcerative colitis [UC: 17.9]. NFκB, however, was upregulated in intestinal biopsies from both active CD and UC [43.2 and 34.5 vs 21.8, p < 0.001 and p = 0.017, respectively]. TNFα and NFκB were overexpressed in skin biopsies from EN, PG, and psoriasis. No MAdCAM1 overexpression was seen in skin tissues, whereas it was upregulated in active UC vs controls [57.5 vs 35.4, p = 0.003]. STAT3 was overexpressed in the intestinal mucosa of active and non-active IBD, and a similar upregulation was seen in skin biopsies from EN [84.7 vs 22.3, p < 0.001] and PG [60.5 vs 22.3, p = 0.011], but not in psoriasis. Caspase 3 and CD68 overexpression in skin biopsies distinguished EN/PG from psoriasis and controls. Upregulation of TNFα/NFκB in EN and PG is compatible with the efficacy of anti-TNF in EIM management. Data on overexpressed STAT3, but not MAdCAM1, support a rationale for JAK-inhibitors in EN and PG, while questioning the role of vedolizumab

Periostin is up-regulated in high grade and high stage prostate cancer

BACKGROUND: Expression of periostin is an indicator of epithelial-mesenchymal transition in cancer but a detailed analysis of periostin expression in prostate cancer has not been conducted so far. METHODS: Here, we evaluated periostin expression in prostate cancer cells and peritumoural stroma immunohistochemically in two independent prostate cancer cohorts, including a training cohort (n = 93) and a test cohort (n = 325). Metastatic prostate cancers (n = 20), hormone refractory prostate cancers (n = 19) and benign prostatic tissues (n = 38) were also analyzed. RESULTS: In total, strong epithelial periostin expression was detectable in 142 of 418 (34.0%) of prostate carcinomas and in 11 of 38 benign prostate glands (28.9%). Increased periostin expression in carcinoma cells was significantly associated with high Gleason score (p < 0.01) and advanced tumour stage (p < 0.05) in the test cohort. Whereas periostin expression was weak or absent in the stroma around normal prostate glands, strong periostin expression in tumour stroma was found in most primary and metastatic prostate cancers. High stromal periostin expression was associated with higher Gleason scores (p < 0.001). There was a relationship between stromal periostin expression and shortened PSA relapse free survival times in the training cohort (p < 0.05). CONCLUSIONS: Our data indicate that periostin up-regulation is related to increased tumour aggressiveness in prostate cancer and might be a promising target for therapeutical interventions in primary and metastatic prostate cancer

Prognostic Impacts of Angiopoietins in NSCLC Tumor Cells and Stroma: VEGF-A Impact Is Strongly Associated with Ang-2

INTRODUCTION: Angiopoietins and their receptor Tie-2 are, in concert with VEGF-A, key mediators in angiogenesis. This study evaluates the prognostic impact of all known human angiopoietins (Ang-1, Ang-2 and Ang-4) and their receptor Tie-2, as well as their relation to the prognostic expression of VEGF-A. METHODS: 335 unselected stage I-IIIA NSCLC-patients were included and tissue samples of respective tumor cells and stroma were collected in tissue microarrays (TMAs). Immunohistochemistry (IHC) was used to semiquantitatively evaluate the expression of markers in duplicate tumor and stroma cores. PRINCIPAL FINDINGS: In univariate analyses, low tumor cell expression of Ang-4 (P = 0.046) and low stromal expressions of Ang-4 (P = 0.009) and Ang-2 (P = 0.017) were individually associated with a poor survival. In the multivariate analysis, low stromal Ang-2 (HR 1.88; CI 95% 1.15-3.08) and Ang-4 (HR 1.47, CI 95% 1.02-2.11, P = 0.04) expressions were independently associated with a poor prognosis. In patients with high tumor cell expression of Ang-2, a concomitantly high tumor VEGF-A expression mediated a dramatic survival reduction (P<0.001). In the multivariate analysis of patients with high Ang-2 expression, high tumor VEGF-A expression appeared an independent poor prognosticator (HR 6.43; CI 95% 2.46-16.8; P<0.001). CONCLUSIONS: In tumor cells, only Ang-4 expression has prognostic impact in NSCLC. In tumor stroma, Ang-4 and Ang-2 are independently associated with survival. The prognostic impact of tumor cell VEGF-A in NSCLC appears strongly associated with a concomitantly high tumor cell expression of Ang-2

Down regulation of E-Cadherin (ECAD) - a predictor for occult metastatic disease in sentinel node biopsy of early squamous cell carcinomas of the oral cavity and oropharynx

<p>Abstract</p> <p>Background</p> <p>Prognostic factors in predicting occult lymph node metastasis in patients with head and neck squamous-cell carcinoma (HNSCC) are necessary to improve the results of the sentinel lymph node procedure in this tumour type. The E-Cadherin glycoprotein is an intercellular adhesion molecule in epithelial cells, which plays an important role in establishing and maintaining intercellular connections.</p> <p>Objectives</p> <p>To determine the value of the molecular marker E-Cadherin in predicting regional metastatic disease.</p> <p>Methods</p> <p>E-Cadherin expression in tumour tissue of 120 patients with HNSCC of the oral cavity and oropharynx were evaluated using the tissue microarray technique. 110 tumours were located in the oral cavity (91.7%; mostly tongue), 10 tumours in the oropharynx (8.3%). Intensity of E-Cadherin expression was quantified by the Intensity Reactivity Score (IRS). These results were correlated with the lymph node status of biopsied sentinel lymph nodes. Univariate and multivariate analysis was used to determine statistical significance.</p> <p>Results</p> <p>pT-stage, gender, tumour side and location did not correlate with lymph node metastasis. Differentiation grade (<it>p </it>= 0.018) and down regulation of E-Cadherin expression significantly correlate with positive lymph node status (<it>p </it>= 0.005) in univariate and multivariate analysis.</p> <p>Conclusion</p> <p>These data suggest that loss of E-cadherin expression is associated with increased lymhogeneous metastasis of HNSCC. E-cadherin immunohistochemistry may be used as a predictor for lymph node metastasis in squamous cell carcinoma of the oral cavity and oropharynx.</p> <p><b>Level of evidence: 2b</b></p

Association between Helicobacter pylori genotypes and severity of chronic gastritis, peptic ulcer disease and gastric mucosal interleukin-8 levels: evidence from a study in the Middle East

Background: The varied clinical presentations of Helicobacter pylori (H. pylori) infection are most likely due to differences in the virulence of individual strains, which determines its ability to induce production of interleukin-8 (IL-8) in the gastric mucosa. The aim of this study was to examine association between cagA, vacA-s1 and vacA-s2 genotypes of H. pylori and severity of chronic gastritis and presence of peptic ulcer disease (PUD), and to correlate these with IL-8 levels in the gastric mucosa. Methods: Gastric mucosal biopsies were obtained from patients during esophagogastroduodenoscopy. The severity of chronic gastritis was documented using the updated Sydney system. H. pylori cagA and vacA genotypes were detected by PCR. The IL-8 levels in the gastric mucosa were measured by ELISA. Results: H. pylori cagA and/or vacA genotypes were detected in 99 patients (mean age 38.4±12.9; 72 males), of whom 52.5% were positive for cagA, 44.4% for vacA-s1 and 39.4% for vacA-s2; and 70.7% patients had PUD. The severity of inflammation in gastric mucosa was increased with vacA-s1 (p=0.017) and decreased with vacA-s2 (p=0.025), while cagA had no association. The degree of neutrophil activity was not associated with either cagA or vacA-s1, while vacA-s2 was significantly associated with decreased neutrophil activity (p=0.027). PUD was significantly increased in patients with cagA (p=0.002) and vacA-s1 (p=0.031), and decreased in those with vacA-s2 (p=0.011). The level of IL-8 was significantly increased in patients with cagA (p=0.011) and vacA-s1 (p=0.024), and lower with vacA-s2 (p=0.004). Higher levels of IL-8 were also found in patients with a more severe chronic inflammation (p=0.001), neutrophil activity (p=0.007) and those with PUD (p=0.001). Conclusions: Presence of vacA-s1 genotype of H. pylori is associated with more severe chronic inflammation and higher levels of IL-8 in the gastric mucosa, as well as higher frequency of PUD. Patients with vacA-s2 have less severe gastritis, lower levels of IL-8, and lower rates of PUD. The presence of cagA genotype is not associated with the severity of gastritis or IL-8 induction in the gastric mucosa. The association of cagA with PUD may be a reflection of its presence with vacA-s1 genotype

Computer-Based Intensity Measurement Assists Pathologists in Scoring Phosphatase and Tensin Homolog Immunohistochemistry - Clinical Associations in NSCLC Patients of the European Thoracic Oncology Platform Lungscape Cohort.

Phosphatase and tensin homolog (PTEN) loss is frequently observed in NSCLC and associated with both phosphoinositide 3-kinase activation and tumoral immunosuppression. PTEN immunohistochemistry is a valuable readout, but lacks standardized staining protocol and cutoff value. After an external quality assessment using SP218, 138G6 and 6H2.1 anti-PTEN antibodies, scored on webbook and tissue microarray, the European Thoracic Oncology Platform cohort samples (n = 2245 NSCLC patients, 8980 tissue microarray cores) were stained with SP218. All cores were H-scored by pathologists and by computerized pixel-based intensity measurements calibrated by pathologists. All three antibodies differentiated six PTEN+ versus six PTEN- cases on external quality assessment. For 138G6 and SP218, high sensitivity and specificity was found for all H-score threshold values including prospectively defined 0, calculated 8 (pathologists), and calculated 5 (computer). High concordance among pathologists in setting computer-based intensities and between pathologists and computer in H-scoring was observed. Because of over-integration of the human eye, pixel-based computer H-scores were overall 54% lower. For all cutoff values, PTEN- was associated with smoking history, squamous cell histology, and higher tumor stage (p &lt; 0.001). In adenocarcinomas, PTEN- was associated with poor survival. Calibration of immunoreactivity intensities by pathologists following computerized H-score measurements has the potential to improve reproducibility and homogeneity of biomarker detection regarding epitope validation in multicenter studies

When RON MET TAM in Mesothelioma: All Druggable for One, and One Drug for All?

Malignant pleural mesothelioma (MPM) is an aggressive inflammatory cancer with a poor survival rate. Treatment options are limited at best and drug resistance is common. Thus, there is an urgent need to identify novel therapeutic targets in this disease in order to improve patient outcomes and survival times. MST1R (RON) is a trans-membrane receptor tyrosine kinase (RTK), which is part of the c-MET proto-oncogene family. The only ligand recognized to bind MST1R (RON) is Macrophage Stimulating 1 (MST1), also known as Macrophage Stimulating Protein (MSP) or Hepatocyte Growth Factor-Like Protein (HGFL). In this study, we demonstrate that the MST1-MST1R (RON) signaling axis is active in MPM. Targeting this pathway with a small molecule inhibitor, LCRF-0004, resulted in decreased proliferation with a concomitant increase in apoptosis. Cell cycle progression was also affected. Recombinant MST1 treatment was unable to overcome the effect of LCRF-0004 in terms of either proliferation or apoptosis. Subsequently, the effect of an additional small molecular inhibitor, BMS-777607 (which targets MST1R (RON), MET, Tyro3, and Axl) also resulted in a decreased proliferative capacity of MPM cells. In a cohort of MPM patient samples, high positivity for total MST1R by IHC was an independent predictor of favorable prognosis. Additionally, elevated expression levels of MST1 also correlated with better survival. This study also determined the efficacy of LCRF-0004 and BMS-777607 in xenograft MPM models. Both LCRF-0004 and BMS-777607 demonstrated significant anti-tumor efficacy in vitro, however BMS-777607 was far superior to LCRF-0004. The in vivo and in vitro data generated by this study indicates that a multi-TKI, targeting the MST1R/MET/TAM signaling pathways, may provide a more effective therapeutic strategy for the treatment of MPM as opposed to targeting MST1R alone