Prognostic Significance of Erythropoietin in Pancreatic Adenocarcinoma

BACKGROUND: Erythropoietin (Epo) administration has been reported to have tumor-promoting effects in anemic cancer patients. We investigated the prognostic impact of endogenous Epo in patients with pancreatic ductal adenocarcinoma (PDAC). METHODOLOGY: The clinico-pathological relevance of hemoglobin (Hb, n = 150), serum Epo (sEpo, n = 87) and tissue expression of Epo/Epo receptor (EpoR, n = 104) was analyzed in patients with PDAC. Epo/EpoR expression, signaling, growth, invasion and chemoresistance were studied in Epo-exposed PDAC cell lines. RESULTS: Compared to donors, median preoperative Hb levels were reduced by 15% in both chronic pancreatitis (CP, p<0.05) and PDAC (p<0.001), reaching anemic grade in one third of patients. While inversely correlating to Hb (r = -0.46), 95% of sEPO values lay within the normal range. The individual levels of compensation were adequate in CP (observed to predicted ratio, O/P = 0.99) but not in PDAC (O/P = 0.85). Strikingly, lower sEPO values yielding inadequate Epo responses were prominent in non-metastatic M0-patients, whereas these parameters were restored in metastatic M1-group (8 vs. 13 mU/mL; O/P = 0.82 vs. 0.96; p<0.01)--although Hb levels and the prevalence of anemia were comparable. Higher sEpo values (upper quartile ≥ 16 mU/ml) were not significantly different in M0 (20%) and M1 (30%) groups, but were an independent prognostic factor for shorter survival (HR 2.20, 10 vs. 17 months, p<0.05). The pattern of Epo expression in pancreas and liver suggested ectopic release of Epo by capillaries/vasa vasorum and hepatocytes, regulated by but not emanating from tumor cells. Epo could initiate PI3K/Akt signaling via EpoR in PDAC cells but failed to alter their functions, probably due to co-expression of the soluble EpoR isoform, known to antagonize Epo. CONCLUSION/SIGNIFICANCE: Higher sEPO levels counteract anemia but worsen outcome in PDAC patients. Further trials are required to clarify how overcoming a sEPO threshold ≥16 mU/ml by endogenous or exogenous means may predispose to or promote metastatic progression

The global geology of Rhea: preliminary implications from the Cassini ISS data

With a mean diameter of 1528 km, Rhea is the second-largest satellite of Saturn. The low average density of 1.233 g cm-3 and water ice absorption bands imply that Rhea's interior and its surface are dominated by water ice. Rhea was imaged by the cameras aboard the Cassini Orbiter at spatial resolutions up 10 m/pxl. Rhea's surface is charaterized by densely cratered plains dating back to a period of at least 4.2 billion years ago. Oldest features in the cratered plains are impact basins several 100 km in diameter. Cassini ISS has revealed tectonic features indicative of extensional, compressional and shear stresses which possibly were active prior to 3 billion years ago. One of the youngest features found on Rhea is a bright crater, about 48 km in diameter, with an extended system of bright rays. The butterfly wing pattern of these ejecta suggest an oblique impact from the east

Geomorphology of Saturn's satellite Rhea: preliminary implications from the Cassini ISS data

With a mean diameter of 1528 km, Rhea is Saturn's second-largest satellite. The cameras aboard the Cassini Orbiter have imaged Rhea at resolutions up to 10 m/pxl. At regional image scale (e.g. 350 m/pxl), the densely cratered plains show little variation in terms of albedo and morphology. Large craters and impact stuctures (basins) are abundant. The cratered plains date back to a time of about 4.2 billion years. Ring structures have only one or two rings. Tectonic features provide evidence of extensional, compressive and shear stresses which also appear to have been active at earliest times, possibly at least 3 billion years ago or more

Tectonic features on Saturn's satellites Dione and Rhea: Morphology and stratigraphy derived from Cassini ISS images

Cassini ISS images were used to derive a stratigraphic sequence of tectonic features on the two mid-sized Saturnian satellites Dione and Rhe

Ectopic sources of Epo in tissues of patients with pancreatic diseases.

<p>(A) Remnants of Epo-producing islets in degrading CP-parenchyma. (B) Epo-negativity of tumor cells in primary pancreatic lesion, except for sporadic focal staining observed in intracellular vacuoles of tumor cells (C, arrows and inset). Peripheral capillaries (C, arrowheads) and <i>vasa vasorum</i> (D, arrowheads) of bigger vessels frequently demonstrated Epo positivity in PDAC and CP. (E, F) In liver, cytoplasmic staining of hepatocytes was strong in areas directly bordering Epo-negative metastatic tumor cells and inflammatory infiltrates, but faded away distally, thus pointing to the spatially regulated <i>de novo</i> synthesis and creation of multiple Epo-rich niches. Insets in A, D and E depict negative (isotype IgG) controls; insets in C and F show high-magnification (×630) images of staining patterns in intracellular vacuoles of tumor cells and cytoplasm in hepatocytes.</p

Detection of EpoR-positive tumor cells in PDAC pancreata.

<p>(A) Staining of erythroid precursor cells in human bone marrow with anti-EpoR 3D10 antibody (inset, ×400) and (B) loss of staining if the anti-EpoR antibody has been pre-incubated with soluble EpoR (sol-EpoR). (C, E) Varying intensity and focal character of EpoR-immunopositivity of tumor cells in PDAC tissues (arrows) and (D) blocking of EpoR signal with sol-EpoR. (F) Sporadic EpoR-immunopositivity of non-malignant structures within a PDAC sample and blocking of EpoR signal with sol-EpoR (inset).</p