Oncogenes as regulators of tissue factor expression in cancer: implications for tumor angiogenesis and anti-cancer therapy

Up-regulation of tissue factor (TF) is often observed in cancer. TF is a cell-associated receptor for coagulation factor VII/VIIa, an interaction known to activate the coagulation cascade. At the same time, TF is also known as a mediator of intracellular signaling events that can alter gene expression patterns and cell behavior. Both aspects of TF activity are of possible relevance to tumor growth, metastasis, and angiogenesis, including up-regulation of vascular endothelial growth factor (VEGF). TF up-regulation is often observed on the surfaces of tumor-associated endothelial cells, inflammatory cells, and particularly on cancer cells themselves. In the last case, high TF levels may be associated with poor prognosis and parallel clinical (and genetic) tumor progression. We have proposed elsewhere that TF may be a target of oncogenic events in cancer. Here we discuss our observations suggesting that oncogene-targeting agents may down-regulate TF expression. Such is the effect of treatment with the neutralizing monoclonal antibody (C225) raised against the epidermal growth factor receptor (EGFR) in EGFR-dependent squamous cell carcinoma cells (A431). This two- to threefold TF down-regulation by C225 treatment is paralleled by a decrease in expression of VEGF. It is conceivable that TF participates in signals that regulate VEGF and angiogenesis triggered by activated oncogenic pathways. Therefore, direct targeting of TF in cancer should be considered in combination with other treatment modalities such as oncogene-directed therapies, antiangiogenic agents (e.g., VEGF antagonists), and anti-cancer chemotherapy.     

Advances in preconception genetic counseling

Preconception counseling offers couples contemplating pregnancy the opportunity to identify and reduce potential pregnancy risks, plan care for known risks, and establish early prenatal care. The goal of preconception counseling is to promote physically and emotionally healthy parents in an attempt to ensure optimal prenatal, intrapartum, and postpartum maternal and fetal health. The advantages of addressing these issues prior to conception include the opportunity of giving recurrence or occurrence risk information for informed decision regarding pregnancy, the accessibility of more reproductive options such as preimplantation genetic diagnosis, and the opportunity to make lifestyle, medical, and behavior alterations for optimal maternal and fetal outcome. This article will discuss advances and updates in preconception genetic counseling including risk assessment and potential intervention for concerns identified through evaluation of family history, ethnicity, maternal age, medical and obstetric history, and associated psychosocial and nursing implications. Significant advances have emerged in the areas of cystic fibrosis carrier screening, first trimester screening, preimplantation genetic diagnosis, and detection and treatment of maternal thrombophilia.     

Impact of volume and specialization for cancer surgery

BACKGROUND/AIMS: The so-called volume/outcome relationship postulates that a higher caseload and specialization results in an improved outcome. The existence of such a relationship, however, is still debated in the literature. The objective of this review is to discuss the available data on this relationship in surgical oncology. METHODS: A Medline analysis was performed using the following terms: volume, outcome, cancer, and surgery. The bibliography of each relevant article was screened for further studies. RESULTS: For most malignancies a volume/outcome relationship was demonstrated in recent years. Components of this improved outcome are decreased perioperative morbidity and mortality, higher quality of life after surgery, improved economic outcome, and a better long-term prognosis for patients with cancer. The magnitude of this relationship, however, varies greatly among different malignancies. The exact reason for the volume/outcome relationship is still unknown. CONCLUSION: Concentrating high-risk procedures in high-volume hospitals might prevent thousands of perioperative deaths per year. This concept seems feasible for rare and high-risk diseases; however, it is unclear what threshold should be used for the definition of a high-volume provider. For common and low-risk diagnoses, it seems more realistic to educate the medical community in order to improve the outcome for the patients.     

Development and evaluation of an integrated musculoskeletal disease course for medical students

BACKGROUND: A recent survey of medical and surgical residents in the United States suggested that our current training of physicians may be inadequate to meet the increasing demand for diagnosis and treatment of musculoskeletal disorders. In response, we developed an integrated, multidisciplinary course to teach knowledge and skills related to musculoskeletal disease to second-year medical students. A three-year prospective outcomes study was conducted to evaluate the new course. METHODS: The primary outcomes that were studied during the first year of the new course were the gains in knowledge, changes in levels of confidence, and long-term retention of skills. Secondary outcomes consisted of student and faculty satisfaction. Ten-item pre-tests and post-tests covering core course concepts were administered to students. A matched-pairs t test was used to evaluate the difference between pre-test and post-test scores. Students were also asked to rate, on a 10-point scale, how much confidence they had in their ability to perform the musculoskeletal physical examination before and after the institution of the new curriculum. A general linear model analysis with post hoc pairwise comparisons (F test) was used to evaluate the changes in the confidence levels of the students. Also, a knee examination station was organized to compare students' scores before and after revision of the course. At the conclusion of the course, students rated each aspect of it on a scale of 1 to 5. Instructors were asked to rate the effectiveness of all elements of the course on the same scale. RESULTS: On the basis of student satisfaction and confidence and faculty satisfaction, the most effective changes in the curriculum were the introduction of a physical examination workshop and simulated clinical situations. Students' knowledge increased significantly (p < 0.001), and their level of confidence increased significantly in thirteen specifically targeted areas (p < 0.0001). On the end-of-the-year examination assessing retention of physical examination skills, the scores for the skills emphasized in the revised course increased significantly whereas the scores for a skill not emphasized in the course remained the same. Revisions made in the second and third years after implementation of the course expanded the more successful elements and further improved student ratings. CONCLUSIONS: Integration of the three clinical disciplines related to musculoskeletal disease--orthopaedics, rheumatology, and physical medicine and rehabilitation--resulted in a highly effective introductory course for second-year medical students. The heuristic strategy of introducing core content through lectures and workshops followed by small-group teaching sessions for practice with the new knowledge effectively increased students' knowledge, confidence, and satisfaction.     

Association of Splenectomy With Postoperative Complications in Patients With Proximal Gastric and Gastroesophageal Junction Cancer

Background: Splenectomy has been associated with increased morbidity after gastrectomy for gastric cancer. Resection of proximal versus distal tumors is associated with a higher morbidity. Because splenectomy is more commonly performed in resection of proximal tumors, these analyses may be biased. The aim of this study was to describe the association of splenectomy with complications in patients undergoing resection of proximal gastric and gastroesophageal junction (GEJ) cancers.Methods: From July 1985 to August 2001, 335 patients underwent resection of proximal gastric or GEJ (type II and III) cancers. Clinical and pathologic factors were retrieved from a prospective database.Results: Overall morbidity was 59% (infectious complications, 41%; noninfectious complications, 36%), and mortality was 4.5%. Splenectomy was associated with a higher rate of infectious complications (57% vs. 33%; P < .01) but not of noninfectious complications (39% vs. 34%; not significant) or mortality (4% vs. 5%; not significant). Splenectomy was also associated with a higher rate of infectious complications on multivariate analysis (hazard ratio, 2.4; P < .01).Conclusions: Morbidity after resection of proximal gastric and GEJ cancer is significant; splenectomy is associated with increased morbidity, but not mortality, in these patients. Because these complications can be managed without an increase in mortality, splenectomy should be performed when indicated by the extent of the tumor.     

Reassessing the level of unintended pregnancy and its correlates in Vietnam

Despite rapidly increasing contraceptive use and rapidly declining fertility, unintended pregnancy and induced abortion remain common in Vietnam. This study reassesses the level of unintended pregnancy in Vietnam and its correlates, drawing on retrospective calendar data gathered for the Vietnam Demographic and Health Survey II. Data from 13,540 "segments" of outcomes and contraceptive practice were analyzed. Based on the calendar data, 40 percent of pregnancies during the 1994-97 period are estimated to have been unintended, a proportion 48 percent higher than the prevailing estimate calculated from the reported intendedness of live births. When concealment of pregnancies ending in induced abortions is taken into account, the unintended pregnancy rate in Vietnam is likely to approach levels found only in developing countries. Unintended pregnancy was found to be associated with age, early marriage, spousal age difference, number of living sons, past unintended pregnancy, geographic region, contraceptive use prior to pregnancy, and the family planning supply environment. The findings suggest that broadening the method mix at the community level, targeting high-risk and underserved groups, and expanding postabortion counseling and services are likely to have a dramatic impact on the unintended pregnancy rate in Vietnam.     

Induction of anti-leukemic cytotoxic T lymphocytes by fusion of patient-derived dendritic cells with autologous myeloblasts

Presentation of AML antigens by dendritic cells (DC) could potentially induce a T cell-mediated anti-leukemic immune response. In the present study, we generated DC from adherent (AD-DC) and non-adherent (NAD-DC) myeloblasts obtained from bone marrows of AML patients. Both cell populations displayed morphological, phenotypic and functional properties of DC. The functions of NAD-DC were compared to AD-DC that had been fused with autologous AML blasts (FC/AML). The FC/AML induced greater T cell proliferation and CTL activity against autologous AML blasts (9/10 cases) as compared to NAD-DC. FC/AML may thus represent a promising strategy for DC-based immunotherapy of patients with AML.     

Imatinib mesylate inhibits platelet-derived growth factor activity and increases chemosensitivity in feline vaccine-associated sarcoma

Feline vaccine-associated sarcoma (VAS) is a biologically aggressive soft-tissue sarcoma that can develop at sites where inactivated feline vaccines have been administered. We showed that platelet-derived growth factor (PDGF) and its receptor (PDGFR) play a role in the growth of VAS cells. The presence of PDGFR- was confirmed in each of five VAS cell lines evaluated, one non-vaccine-associated feline fibrosarcoma (FSA) cell line and a feline fibroblast-derived cell line. The PDGF/PDGFR signaling pathway was inhibited in the VAS cell lines and the FSA cell line using the tyrosine kinase inhibitor imatinib mesylate (formerly called STI-571). Imatinib inhibited PDGF-BB-induced autophosphorylation of PDGFR in VAS cells and feline FSA cells in vitro in a dose-dependent manner. Imatinib also significantly inhibited growth of feline VAS tumors in a murine xenograft model. Imatinib reversed the protective effect of PDGF-BB on growth inhibition by doxorubicin and carboplatin. PDGF-BB protected VAS cells from serum starvation and doxorubicin-induced apoptosis but not carboplatin-induced apoptosis, and imatinib eliminated this protection. These observations suggest that imatinib inhibits PDGFR tyrosine kinase activity in feline soft tissue sarcomas in vitro and inhibits tumor growth in a xenograft model.Abbreviations C/10 Complete minimal essential medium supplemented with 10% FBS - CPT Carboplatin - DOX Doxorubicin - EGF Epidermal growth factor - FBS Fetal bovine serum - FSA Fibrosarcoma - HGF Hepatocyte growth factor - IGF-1 Insulin-like growth factor-1 - MTS 3-(4,5-Dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium - PDGF Platelet-derived growth factor - PDGFR Platelet-derived growth factor receptor - PI Propidium iodide - VAS Vaccine-associated sarcomaThis work was supported in part by the American Veterinary Medical Association Feline Sarcoma Task Force. Imatinib mesylate was provided by Novartis Pharmaceuticals, Inc.