Angiogenesis has been associated with the growth, dissemination, and metastasis of solid tumors. The aims of this study were to evaluate the vascularity and the levels of angiogenic factors in patients with acute and chronic leukemias and myelodysplastic syndromes (MDS). The numbers of blood vessels were measured in 145 bone marrow biopsies and the levels of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), tumor necrosis growth factor-α (TNF-α), tumor growth factor-α (TGF-α), and hepatocyte growth factor (HGF) were determined in 417 plasma samples. Except for chronic lymphocytic leukemia (CLL), vascularity was significantly higher in all leukemias and MDS compared with control bone marrows. The highest number of blood vessels and largest vascular area were found in chronic myeloid leukemia (CML). VEGF, bFGF, and HGF plasma levels were significantly increased in acute myeloid leukemia (AML), CML, CLL, chronic myelomonocytic leukemia (CMML), and MDS. HGF, TNF-α, and bFGF but not VEGF were significantly increased in acute lymphoblastic leukemia (ALL). TNF-α levels were significantly increased in all diseases except for AML and MDS. No significant increase was found in TGF-α in any leukemia or MDS. The highest plasma levels of VEGF were in CML, and the highest plasma levels of bFGF were in CLL. The levels of HGF were highest in CMML. These data suggest that vascularity and angiogenic factors are increased in leukemias and MDS and may play a role in the leukemogenic process.

Bone marrow microenvironment plays a crucial role inthe leukemogenic process. New studies suggest that the bone marrow vascularity changes significantly in the leukemic process and that angiogenic factors play a major role in leukemia and myelodysplasia. However, hematologic malignancies appear to be particularly vulnerable to the effects of angiogenic factors because most of these factors appear to be secreted by hematopoietic cells, and they may have autocrine and paracrine regulatory effects on the hematopoietic system. The use of angiogenesis inhibitors for the treatment of hematologic malignancies is particularly attractive because it may target not only the environment but also the malignant cells.

Vascular endothelial growth factor (VEGF) is a potent mitogen for vascular endothelial cells. It has been associated with angiogenesis, growth, dissemination, metastasis, and poor outcome in solid tumors. To assess cellular VEGF levels and their prognostic significance in newly diagnosed acute myeloid leukemia (AML), we used a radioimmunoassay (RIA) to quantify VEGF levels in stored samples obtained before treatment from 99 patients with newly diagnosed AML treated at the MD Anderson Cancer Center from 1996 to 1998. Outcome in the 99 patients was representative of that observed in all patients seen at this institution with this diagnosis during these years, but the 99 patients had higher white blood cell (WBC) and blast counts than the other patients. Results of the RIA were confirmed by Western blot. There was a relationship between increasing VEGF levels and shorter survival (P = .01), as well as shorter disease-free survival, both from start of treatment and from complete response (CR) date. In contrast, there was no relationship between VEGF level and WBC or blast count, or between VEGF level and such established prognostic factors as age, cytogenetics, performance status, or presence of an antecedent hematologic disorder, and multivariate analysis indicated that VEGF was still prognostic for the above outcomes after accounting for these factors, as well as treatment. Our results suggest that at least in AML patients with higher WBC and blast counts, cellular VEGF level is an independent predictor of outcome.

BACKGROUNDThe goal of the current study was to evaluate the efficacy and toxicity of capecitabine in patients with nonresectable hepatobiliary carcinoma.METHODSThe 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.RESULTSA total of 63 patients were treated with capecitabine (37 with HCC, 18 with CCA, 8 with GBC). Capecitabine 1000 mg/m2 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.CONCLUSIONSCapecitabine 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. Cancer 2004. © 2004 American Cancer Society.

Access to polycyclic polyethers is facilitated by a synthetic strategy involving two‐step B‐alkyl Suzuki coupling reactions for the stereoselective construction of the polyether skeleton. Thus, a convergent synthetic route to the heptacyclic GHIJKLM ring system 1 of ciguatoxin, a marine algal toxin implicated in ciguatera fish poisoning, was developed. Bn=benzyl.