HIF Transcription Factor Expression and Induction of Hypoxic Response Genes in a Retroperitoneal Angiosarcoma

Angiosarcoma is a rare and highly aggressive tumor of endothelial origin. The molecular mechanisms driving angiosarcoma growth have not been fully elucidated, although autocrine stimulation by vascular endothelial growth factor (VEGF) secretion may play a role in the pathogenesis of this tumor. We identified a patient with a very rare form of angiosarcoma arising from the retroperitoneum. Immunohistochemical analysis demonstrated widespread up-regulation of the hypoxic response pathway as a mechanism of enhanced VEGF expression. Disordered regulation of the hypoxic response pathway can result in the expression of factors such as VEGF and erythropoietin, which may promote autocrine tumor growth in angiosarcoma

Treatment Choices Based on Onco type

Introduction. This study aimed to evaluate whether OncotypeDx test results predict receipt of adjuvant chemotherapy in breast cancer patients who received an OncotypeDx recurrence score (RS). Materials and Methods. Pathology records were used to identify breast cancer patients who had OncotypeDx testing between December 2004 and January 2009 (n=118). Patient sociodemographic information, tumor characteristics, RS, and treatment-specific data were collected via chart review. RS was classified as follows: low (RS≤17), intermediate (RS = 18–30), or high (RS≥31). Bivariate analyses were conducted to investigate the relationship between adjuvant chemotherapy receipt and each sociodemographic and clinical characteristic; significant sociodemographic and clinical variables were included in a multivariable logistic regression model. Results. In multivariable analysis controlling for tumor size, histologic grade, and nuclear grade, only RS remained significantly associated with chemotherapy uptake. Relative to low RS, an intermediate (adjusted odds ratio [AOR], 21.24; 95% confidence interval [CI], 3.62–237.52) or high (AOR, 15.07; 95% CI, 1.28–288.21) RS was associated with a greater odds of chemotherapy uptake. Discussion. Results indicate that RS was significantly associated with adjuvant chemotherapy uptake, suggesting that OncotypeDx results were used to inform treatment decision making, although it is unclear if and how the information was conveyed to patients

Connexin 43 Is a Potential Prognostic Biomarker for Ewing Sarcoma/Primitive Neuroectodermal Tumor

Connexins (Cxs) are building unit proteins of gap junctions (GJs) that are prognostic markers in carcinomas. To investigate the role of Cx in Ewing sarcoma (EWS)/primitive neuroectodermal tumor (PNET), we examined the expression of Cx43 and Cx26 in 36 EWS/PNETs and found (1) cytoplasmic Cx43 reactivity in 28/36 (78%) cases. (2) Cx43 score was significantly correlated with overall survival (P = .025). The average scores for patients alive and dead at 3 years are 46.08 and 96.98 (P = .004) at 5 years are 46.06 and 96.42 (P = .002). (3) Metastasis had a significant effect on the overall survival (P = .003). (4) Cytoplasmic Cx26 reactivity was detected in 2 of 36 (6%) patients who died with metastasis. Our results suggest a possible oncogenic and prognostic role for Cx43 and Cx26 in EWS/PNET. The lack of membranous immunoreactivity suggests that the effect of Cx in EWS/PNET is via a GJ function-independent mechanism

Loss of Membrane Expression of E-Cadherin in Leukemic Erythroblasts

Abstract Context.—The special societal relationships existing between various cell types in bone marrow suggests that there may be a link between the adhesive characteristics of hematopoietic cells and their maturation. Egress of the developing hematopoietic cells is also a highly regulated process governed by adhesive interactions. In leukemia, immature blasts are not retained within the marrow, suggesting a breakdown of adhesive mechanisms. Recent reports suggest that E-cadherin, an epithelial adhesion molecule, is expressed on erythroid precursors and megakaryocytes, but not on other hematopoietic marrow elements. Objective.—To characterize the expression pattern of E-cadherin in normal and leukemic erythroid precursors by immunohistochemistry in paraffin-embedded tissue and bone marrow aspirate smears. Methods.—Five normal bone marrow specimens from rib resections, 15 trephine bone marrow biopsy specimens, and 6 bone marrow aspirate smears from the iliac crest of patients with no known leukemia were selected. Fourteen bone marrow biopsy specimens from patients with erythroleukemia were also studied. Immunoperoxidase staining of paraffin-embedded tissue and air-dried aspirate smears for E-cadherin (1:200 dilution, HECD-1 clone) was performed using the avidin-biotin peroxidase technique. Results.—In paraffin-embedded bone marrow biopsy and rib specimens and in air-dried bone marrow aspirate smears, strong membrane expression of E-cadherin was seen in the normal erythroid precursors in all cases. In contrast, no membrane expression of E-cadherin was present in any of the bone marrow biopsy specimens from patients with erythroleukemia. Conclusions.—Immunohistochemical detection of membrane expression of E-cadherin may be a useful tool for identification of erythroid precursors. Cells of erythroleukemia lack membrane expression of E-cadherin, in contrast to their normal counterparts. Further studies are needed to define the potential role of E-cadherin in the maturation of erythroid precursors and to ascertain the significance of loss of membrane expression of E-cadherin in erythroleukemia.</jats:p

Recent Advances in Understanding of Vanilloid Receptors: A Therapeutic Target for Treatment of Pain and Inflammation in Skin

C-fiber sensory afferent neurons, which contain neuropeptides such as calcitonin-gene related peptide and substance P, mediate a wide variety of physiologic responses, including chemogenic pain, thermoregulation, and neurogenic inflammation. Capsaicin, the pungent constituent in red pepper, functions to activate and then, at higher doses and longer times, desensitize this class of neurons. This latter response provides the basis for the therapeutic application of capsaicin. A major advance in the field has been the identification of resiniferatoxin, a phorbol-related diterpene, as an analog of capsaicin that is ultrapotent but with differential selectivity. In particular, resiniferatoxin is only similar in potency for induction of pain but is much more effective for desensitization. Structure-activity analysis in whole animal experiments provides further evidence for dissociation of biologic endpoints, strongly arguing for the existence of vanilloid receptor subclasses. Using resiniferatoxin, we have been able to define specific, high-affinity receptors for capsaicin both in animal models such as rats and in man. Of great importance, the pharmacologic characterization in cultured dorsal root ganglion cells of the high-affinity resiniferatoxin-binding site and of the physiologic response believed to be directly coupled to the receptor, viz. calcium uptake, differed in structure-activity and in cooperativity. We conclude that multiple high-affinity vanilloid receptor subclasses mediate vanilloid response; moreover, the resiniferatoxin-selective subclass of vanilloid receptors is not the voltage-independent, cation-nonselective ion channel as previously believed. Optimization of ligands for the individual vanilloid receptor subclasses should revolutionize this therapeutic area. Journal of Investigative Dermatology Symposium Proceedings 2:56–60, 199