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Biomedical subjects

Lee M Ellis

Publications and source records attributed to Lee M Ellis.

At least 55 records · Page 3Linked to original sources
PubMed2004

Oral capecitabine for the treatment of hepatocellular carcinoma, cholangiocarcinoma, and gallbladder carcinoma.

BACKGROUND: The goal of the current study was to evaluate the efficacy and toxicity of capecitabine in patients with nonresectable hepatobiliary carcinoma. METHODS: The authors performed a retrospective analysis of all patients with hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), or gallbladder carcinoma (GBC) who were ever treated with oral capecitabine. The medical records of 116 patients with hepatobiliary carcinoma who were treated at The University of Texas M. D. Anderson Cancer Center (Houston, TX) between July 1998 and March 1999 were reviewed. RESULTS: A total of 63 patients were treated with capecitabine (37 with HCC, 18 with CCA, 8 with GBC). Capecitabine 1000 mg/m(2) was administered twice daily for 14 days. Treatment was repeated every 21 days. Each patient received 1-15 treatment cycles. Nine patients (14%)-11% of patients with HCC, 6% of patients with CCA, and 50% of patients with GBC-had either a complete response (CR) or a partial response. A CR was radiologically confirmed in one patient with HCC and in two patients with GBC. The median survival times were 10.1 months (95% confidence interval [CI], 4.5-15.7 months) for patients with HCC, 8.1 months (95% CI, 7.4-8.9 months) for patients with CCA, and 9.9 months (95% CI, 4.4-15.4 months) for patients with GBC. The most common toxicity was hand-foot syndrome (37%). Grade 3 thrombocytopenia occurred in 8% of patients with HCC. No other significant toxicities were observed. For all patients, response to treatment was positively correlated with survival and decline in tumor markers. CONCLUSIONS: Capecitabine was found to be safe for patients with hepatobiliary carcinoma, including those with cirrhosis. The antitumor activity of single-agent capecitabine was most pronounced in patients with GBC, was modest in patients with HCC, and was poor in patients with CCA.

Administration, Oral↗
PubMed2004

Role of hypoxia-inducible factor 1alpha in gastric cancer cell growth, angiogenesis, and vessel maturation.

BACKGROUND: Hypoxia-inducible factor 1 (HIF-1), a heterodimer comprising the oxygen-regulated subunit, HIF-1alpha, and HIF-1beta, mediates transcription of the gene for vascular endothelial growth factor (VEGF). Overexpression of HIF-1alpha is associated with tumor angiogenesis and tumor cell proliferation and invasion. We examined the effects of inhibiting HIF-1alpha activity on angiogenesis and human gastric cancer growth in vivo. METHODS: Human gastric cancer TMK-1 cells were stably transfected with pHIF-1alphaDN, an expression plasmid encoding a dominant-negative form of HIF-1alpha that dimerizes with endogenous HIF-1beta to produce HIF-1 complexes that cannot activate transcription, or with the empty expression vector (pCEP4). Two clones of pHIF-1alphaDN-transfected cells, DN2 and DN3, were tested in all experiments. We used an enzyme-linked immunosorbent assay to measure VEGF secretion by transfected cells cultured in hypoxic (1% O2) or nonhypoxic (20% O2) conditions. We used subcutaneous and orthotopic mouse tumor models to examine the growth of tumors derived from injected pHIF-1alphaDN-or pCEP4-transfected cells. Tumor cell proliferation, vessel area (a measure of functional vascular volume), and tumor endothelial cell association with pericyte-like cells (a measure of vessel maturation) were analyzed by immunohistochemical or immunofluorescent staining. All statistical tests were two-sided. RESULTS: DN2 cells and DN3 cells secreted less VEGF than pCEP4-transfected TMK-1 cells when cultured in nonhypoxic or hypoxic conditions (e.g., DN2 versus pCEP4 in nonhypoxic conditions: 645 pg of VEGF/10(6) cells versus 1591 pg of VEGF/10(6) cells, difference = 946 pg of VEGF/10(6) cells [95% confidence interval [CI] = 640 to 1251 pg of VEGF/10(6) cells; P =.006]; DN2 versus pCEP4 in hypoxic conditions: 785 pg of VEGF/10(6) cells versus 2807 pg of VEGF/10(6) cells, difference = 2022 pg of VEGF/10(6) cells [95% CI = 1871 to 2152 pg of VEGF/10(6) cells; P<.001]). In the subcutaneous tumor model, tumors derived from DN2 or DN3 cells had lower final volumes, weights, and vessel areas, less tumor endothelial cell association with desmin-positive cells, and fewer proliferating tumor cells than tumors derived from pCEP4-transfected cells. In the orthotopic tumor model, tumors derived from DN2 cells had smaller volumes and less vessel area and maturation than tumors derived from pCEP4-transfected cells. CONCLUSIONS: Inhibition of HIF-1alpha activity impairs gastric tumor growth, angiogenesis, and vessel maturation.

Animals↗
PubMed2004

Interleukin-1beta regulates angiopoietin-1 expression in human endothelial cells.

Angiopoietin (Ang)-1 is an important regulator of endothelial cell (EC) survival and stabilization. Ang-1 exerts its biological effects by binding to the EC-specific tyrosine kinase receptor Tie-2, and initiates intracellular signaling in ECs. However, regulatory mechanisms for endothelial Ang-1 expression have not been completely elucidated. In this study, we investigated the effects of angiogenic cytokines and growth factors on Ang-1 expression in human umbilical vein ECs (HUVECs). Northern blot analysis was performed after HUVECs were exposed to interleukin-1beta (IL-1beta), tumor necrosis factor-alpha, platelet-derived growth factor-BB, insulin-like growth factor-1, or vascular endothelial growth factor (VEGF). Both IL-1beta and tumor necrosis factor-alpha caused marked down-regulation of Ang-1 mRNA levels at 4 h with a further decrease observed at 24 h. Using signaling inhibitors, we identified the P38 pathway as the pathway that mediates IL-1beta down-regulation of Ang-1. Furthermore, treatment of cells with IL-1beta indirectly (via down-regulation of Ang-1) led to a decrease in Tie-2 autophosphorylation levels in HUVECs. We previously demonstrated that IL-1beta regulates VEGF expression in tumor cells. This observation was confirmed in ECs in the present study. Because pericytes play a role in regulating EC function, we also determined whether IL-1beta would also down-regulate Ang-1 in human vascular smooth muscle cells. Similar to our findings in HUVECs, we found that IL-1beta decreased Ang-1 expression in human vascular smooth muscle cells. Direct effects of IL-1beta on angiogenesis were investigated by use of an in vivo Gelfoam angiogenesis assay in which IL-1beta produced a significant increase in vessel counts (P = 0.0189). These results suggest that IL-1beta indirectly regulates angiogenesis by modulating the expression of Ang-1. IL-1beta may trigger a proangiogenic response by decreasing Ang-1 levels in ECs and pericytes and up-regulating VEGF in ECs and tumor cells.

Angiopoietin-1↗
PubMed2004

Epidermal growth factor receptor in tumor angiogenesis.

This article focuses on the preclinical evidence for activation of the epidermal growth factor receptor (EGFR) in promoting angiogenesis and the efficacy of anti-EGFR agents in inhibiting angiogenesis and tumor growth.

ErbB Receptors↗
PubMed2004

The vascular endothelial growth factor family and its receptors.

This article focuses on describing the biology of vascular endothelial growth factor (VEGF) and its receptors as well as the regulation of their expression. A thorough understanding of the VEGF system is paramount in optimizing antiangiogenic therapies as a component of antineoplastic regimens.

Animals↗
PubMed2004

Regulation of vascular endothelial growth factor expression in human gastric cancer cells by interleukin-1beta.

BACKGROUND: Vascular endothelial growth factor (VEGF), a dominant angiogenic factor in gastric cancer, is upregulated by cytokines in the tumor microenvironment. Interleukin-1beta (IL-1beta), a proinflammatory cytokine, has been shown to be proangiogenic in vivo, despite its not demonstrating angiogenic activity in vitro. We hypothesized that IL-1beta regulates VEGF expression in human gastric cancer cells and investigated the mechanism by which this occurs. METHODS: We treated the TMK-1 human gastric cancer cell line with IL-1beta for 1 to 24 hours, and then analyzed VEGF mRNA expression by Northern blotting and signaling intermediates by Western blotting. Signaling inhibitors were used to identify the dominant pathways involved in IL-1beta induction of VEGF. VEGF promoter-luciferase constructs and transcription blockers were used to investigate the transcriptional regulation of VEGF by IL-1beta. RESULTS: Treating TMK-1 cells with IL-1beta increased VEGF mRNA levels and activated extracellular signal-regulated kinases 1 and 2 (Erk 1/2) and p38, but not Akt. Inhibitors of the Erk and p38 pathways blocked IL-1beta induction of VEGF mRNA. Treating TMK-1 cells with IL-1beta also increased VEGF promoter activity. VEGF transcriptional activity was found to depend on a 120-bp region just proximal to the transcription start site. CONCLUSIONS: In human gastric cancer cells, IL-1beta induced VEGF through Erk- and p38-dependent pathways; this induction of VEGF was transcriptionally regulated.

Cell Line, Tumor↗
PubMed2004

Neuropilin-1 in human colon cancer: expression, regulation, and role in induction of angiogenesis.

Neuropilin-1 (NRP-1), a recently identified co-receptor for vascular endothelial growth factor, is expressed by several nongastrointestinal tumor types and enhances prostate cancer angiogenesis and growth in preclinical models. We investigated the expression and regulation of NRP-1 and the effect of NRP-1 overexpression on angiogenesis and growth of human colon adenocarcinoma by immunohistochemistry and in situ hybridization. NRP-1 was expressed in 20 of 20 human colon adenocarcinoma specimens but not in the adjacent nonmalignant colonic mucosa. By reverse transcriptase-polymerase chain reaction analysis, NRP-1 mRNA was expressed in seven of seven colon adenocarcinoma cell lines. Subcutaneous xenografts of stably transfected KM12SM/LM2 human colon cancer cells overexpressing NRP-1 led to increased tumor growth and angiogenesis in nude mice. In in vitro assays, conditioned medium from NRP-1-transfected cell lines led to an increase in endothelial cell migration, but did not affect endothelial cell growth. Epidermal growth factor (EGF) led to induction of NRP-1 in human colon adenocarcinoma cells and selective blockade of the epidermal growth factor receptor (EGFR) decreased constitutive and EGF-induced NRP-1 expression. Blockade of the Erk 1/2 and P38 mitogen-activated protein kinase signaling pathways also led to a decrease in constitutive and EGF-induced NRP-1 expression. These findings demonstrate the ubiquitous expression of NRP-1 in human colon cancer and suggest that NRP-1 may contribute to colon cancer angiogenesis and growth. This study also suggests that EGF and mitogen-activated protein kinase signaling pathways play an important role in NRP-1 regulation in colon cancer cells.

Adenocarcinoma↗
PubMed2004

Angiogenesis and its role in colorectal tumor and metastasis formation.

Advances in our comprehension of cancer biology and metastasis formation have led to the development of new therapeutic approaches that target tumor biology. The survival and establishment of metastatic lesions depend on a shift in the normal balance of key regulatory factors in favor of angiogenesis. Although a number of these factors have been identified, the most potent regulator of angiogenesis is vascular endothelial growth factor (VEGF). In phase I trials, targeting VEGF with single-agent therapy did not produce clinical benefit for patients, despite promise in preclinical trials. However, the recent data showing that anti-VEGF therapy can enhance the effects of chemotherapy demonstrate the utility in targeting angiogenic factors as a component of antineoplastic regimens. A better understanding of the functions of VEGF allows the development of new hypotheses with regard to its mechanism of action. This article will highlight what is known about colorectal cancer angiogenesis, and will discuss how therapy targeting VEGF may enhance the effects of chemotherapy (and radiation therapy).

Angiogenesis Inducing Agents↗
PubMed2004

Early and late complications after radiofrequency ablation of malignant liver tumors in 608 patients.

BACKGROUND: Radiofrequency ablation (RFA) has become a common treatment of patients with unresectable primary and secondary hepatic malignancies. We performed this prospective analysis to determine early (within 30 days) and late (more than 30 days after) complication rates associated with hepatic tumor RFA. METHODS: All patients treated between January 1, 1996 and June 30, 2002 with RFA for hepatic malignancies were entered into a prospective database. Patients were evaluated during RFA treatment, throughout the immediate post RFA course, and then every 3 months after RFA to assess for the development of treatment-related complications. RESULTS: A total of 608 patients, 345 men (56.7%) and 263 women (43.3%), with a median age of 58 years (range 18-85 years) underwent RFA of 1225 malignant liver tumors. Open intraoperative RFA was performed in 382 patients (62.8%), while percutaneous RFA was performed in 226 (37.2%). The treatment-related mortality rate was 0.5%. Early complications developed in 43 patients (7.1%). Early complications were more likely to occur in patients treated with open RFA (33 [8.6%] of 382 patients) compared with percutaneous RFA (10 [4.4%] 226 patients, P < 0.01), and in patients with cirrhosis (25 [12.9%] complications in 194 patients) compared with noncirrhotic patients (31 [7.5%] complications in 414 patients, P < 0.05). Late complications arose in 15 patients (2.4%) with no difference in incidence between open and percutaneous RFA treatment. The combined overall early and late complication rate was 9.5%. CONCLUSIONS: Hepatic tumor RFA can be performed with low mortality and morbidity rates. Though relatively rare, late complications can develop and physicians performing hepatic RFA must be cognizant of these delayed treatment-related problems.

Adolescent↗
PubMed2004

Is extended hepatectomy for hepatobiliary malignancy justified?

BACKGROUND: Extended hepatectomy may be required to provide the best chance for cure of hepatobiliary malignancies. However, the procedure may be associated with significant morbidity and mortality. METHODS: We analyzed the outcome of 127 consecutive patients who underwent extended hepatectomy (resection of > or = 5 liver segments) for hepatobiliary malignancies. RESULTS: The patients underwent extended hepatectomy for colorectal metastases (n = 86; 67.7%), hepatocellular carcinoma (n =12; 9.4%), cholangiocarcinoma (n =14; 11.0%), and other malignant diseases (n =15; 11.5%). Thirty-two left and ninety-five right extended hepatectomies were performed. Eight patients also underwent caudate lobe resection, and 40 patients underwent a synchronous intraabdominal procedure. Twenty patients underwent radiofrequency ablation, and 31 underwent preoperative portal vein embolization. The median blood loss was 300 mL for right hepatectomy and 600 mL for left hepatectomy (P = 0.02). Thirty-six patients (28.3%) received a blood transfusion. The overall complication rate was 30.7% (n = 39), and the operative mortality rate was 0.8% (n = 1). Significant liver insufficiency (total bilirubin level > 10 mg/dL or international normalized ratio > 2) occurred in 6 patients (4.7%). Multivariate analysis showed that a synchronous intraabdominal procedure was the only factor associated with an increased risk of morbidity (hazard ratio [HR], 4.9; P = 0.02). The median survival was 41.9 months. The overall 5-year survival rate was 25.5%. CONCLUSIONS: Extended hepatectomy can be performed with a near-zero operative mortality rate and is associated with long-term survival in a subset of patients with malignant hepatobiliary disease. Combining extended hepatectomy with another intraabdominal procedure increases the risk of postoperative morbidity.

Adult↗
PubMed2004

Recurrence and outcomes following hepatic resection, radiofrequency ablation, and combined resection/ablation for colorectal liver metastases.

OBJECTIVE: To examine recurrence and survival rates for patients treated with hepatic resection only, radiofrequency ablation (RFA) plus resection or RFA only for colorectal liver metastases. SUMMARY BACKGROUND DATA: Thermal destruction techniques, particularly RFA, have been rapidly accepted into surgical practice in the last 5 years. Long-term survival data following treatment of colorectal liver metastasis using RFA with or without hepatic resection are lacking. METHODS: Data from 358 consecutive patients with colorectal liver metastases treated for cure with hepatic resection +/- RFA and 70 patients found at laparotomy to have liver-only disease but not to be candidates for potentially curative treatment were compared (1992-2002). RESULTS: Of 418 patients treated, 190 (45%) underwent resection only, 101 RFA + resection (24%), 57 RFA only (14%), and 70 laparotomy with biopsy only or arterial infusion pump placement ("chemotherapy only," 17%). RFA was used in operative candidates who could not undergo complete resection of disease. Overall recurrence was most common after RFA (84% vs. 64% RFA + resection vs. 52% resection only, P < 0.001). Liver-only recurrence after RFA was fourfold the rate after resection (44% vs. 11% of patients, P < 0.001), and true local recurrence was most common after RFA (9% of patients vs. 5% RFA + resection vs. 2% resection only, P = 0.02). Overall survival rate was highest after resection (58% at 5 years); 4-year survival after resection, RFA + resection and RFA only were 65%, 36%, and 22%, respectively (P < 0.0001). Survival for "unresectable" patients treated with RFA + resection or RFA only was greater than chemotherapy only (P = 0.0017). CONCLUSIONS: Hepatic resection is the treatment of choice for colorectal liver metastases. RFA alone or in combination with resection for unresectable patients does not provide survival comparable to resection, and provides survival only slightly superior to nonsurgical treatment.

Adenocarcinoma↗
PubMed2004

Long-term survival after an aggressive surgical approach in patients with breast cancer hepatic metastases.

BACKGROUND: Metastatic breast cancer is generally believed to be associated with a poor prognosis. Therapeutic advances over the past two decades, however, have resulted in improved outcomes for selected patients with limited metastatic disease. METHODS: Between March 1991 and October 2002, 31 patients had hepatic resection for breast cancer metastases limited to the liver. Clinical and pathologic data were collected prospectively from breast and hepatobiliary databases. RESULTS: Median age of patients was 46 years (range, 31 to 70). Liver metastases were solitary in 20 patients and multiple in 11 patients. Median size of the largest liver metastasis was 2.9 cm (range, 1 to 8). Major liver resections (three or more segments resected) were performed in 14 patients, whereas minor resections (fewer than three segments resected) with or without radiofrequency ablation (RFA) were performed in 17 patients. No postoperative mortality occurred. Of the 31 patients, 27 (87%) received either preoperative or postoperative systemic therapy as treatment for metastatic disease. The median survival was 63 months; a single patient died within 12 months of hepatic resection. The overall 2- and 5-year survival rates were 86% and 61%, respectively, whereas the 2- and 5-year disease-free survival rates were 39% and 31%, respectively. No treatment- or patient-specific variables were found to correlate with survival rates. CONCLUSIONS: In selected patients with liver metastases from breast cancer, an aggressive surgical approach is associated with favorable long-term survival. Hepatic resection should be considered a component of multimodality treatment of breast cancer in these patients.

Adult↗
PubMed2004

Preclinical data targeting vascular endothelial growth factor in colorectal cancer.

Vascular endothelial growth factor (VEGF) is the driving force behind angiogenesis in most solid malignancies. This also holds true for colorectal cancer (CRC), where increased levels of VEGF in primary cancers are associated with increased microvessel density and poor prognosis. These findings have led to preclinical studies evaluating the efficacy of anti-VEGF therapy in inhibiting the growth of CRC in ectopic and orthotopic locations. In preclinical models, numerous approaches to inhibit VEGF activity led to decreased tumor growth and angiogenesis. These studies led to clinical trials in which, unfortunately, single-agent anti-VEGF therapy was relatively ineffective for patients with metastatic CRC. However, combinations of anti-VEGF therapies with chemotherapy have clearly demonstrated clinical benefit. Understanding the mechanisms of the role of VEGF in CRC angiogenesis and the effect of anti-VEGF therapy on the tumor vasculature will allow oncologists to optimize therapeutic regimens targeting VEGF and its receptors.

Angiogenesis Inhibitors↗
PubMed2004

Can inhibition of angiogenic pathways increase the efficacy of intravenous 5-fluorouracil-based regimens?

First-line irinotecan-containing regimens are toxic and may not be tolerated well by all patient subgroups. Trials evaluating less toxic regimens include a randomized, double-blind, multicenter study (AVF2192g) assessing 5-fluorouracil (5-FU)/leucovorin (LV) with bevacizumab. Patients were randomized to 1 of 2 treatment arms. In arm 1, patients received LV intravenously (I.V.) over 2 hours and 5-FU I.V. over 1 hour every week for 6 weeks of an 8-week cycle, and bevacizumab 5 mg/kg was administered I.V. over 30-90 minutes every 2 weeks. In the second arm, patients received LV and 5-FU as in arm 1, and placebo I.V. over 30-90 minutes every 2 weeks. The primary objective was duration of survival. Eligible patients with untreated metastatic colorectal cancer (CRC) were >or= 65 years of age, had an Eastern Cooperative Oncology Group performance status of 1/2, a serum albumin level <or= 3.5 g/dL, or had previous radiation therapy to the pelvis or abdomen. Preliminary results indicated a median survival of 12.9 months versus 16.6 months on the placebo and bevacizumab arms, respectively (P = 0.159). Progression-free survival was 5.5 months in the placebo arm compared to 9.2 months in the bevacizumab arm. The overall response rate was 15% in the placebo arm and 26% in the bevacizumab arm. The percentages of patients experiencing toxicities typically associated with 5-FU/LV were similar in both arms. Toxicities most associated with bevacizuamb included bleeding, thrombolic events, hypertension, and proteinuria. Growing evidence indicates that bevacizumab is an effective agent in CRC when added to several chemotherapy combinations. The current study indicates that subpopulations of patients with advanced age or poor performance status could be treated successfully with 5-FU/LV in combination with bevacizumab without excessive toxicities.

Adult↗
PubMed2004

Monoclonal antibodies: the foundation of therapy for colorectal cancer in the 21st century?

The treatment of colorectal cancer has undergone enormous changes in the past decade. From a disease with a single treatment option (ie, fluorouracil, a modestly effective drug), the treatment options have evolved to include at least five new classes of antineoplastic agents. Among the considerable number of recently approved drugs, two are monoclonal antibodies and are the testing ground for our rapidly emerging knowledge about cancer cell biology. Cetuximab (Erbitux) targets the epidermal growth factor receptor, an important molecule involved with cell cycling, survival, invasion, and metastasis. Bevacizumab (Avastin) neutralizes the vascular endothelial growth factor, blocking its ability to activate its receptor on the endothelial cells. The development of both antibodies resulted from decades of research in molecular and cell biology, as well as preclinical and clinical studies, and signals a new paradigm where the tumor cells' own unique features are exploited in a rational way.

Antibodies, Monoclonal↗