Polyclonal antibodies to xenogeneic endothelial cells induce apoptosis and block support of tumor growth in mice

In this study, we demonstrate that vaccination of rabbits with murine endothelial cells yields polyclonal immunoglobulin (IgG) with potent antiangiogenic activity. The mechanism of this response appears to be through apoptosis of endothelial cells in vitro. Induction of polyclonal IgG in a xenogeneic host may be useful in passive immunotherapy of a variety of cancers. In fact, the antibody showed antitumor activity in three mouse tumor models (murine B16F10 melanoma, murine SVR angiosarcoma, and human DLD-1 colorectal adenocarcinoma). The polyclonal antibody generated here demonstrated utility in radioimaging of tumors in vivo, using positron emission tomography (PET) imaging, and suggested an antitumor effect in vivo. The results suggest that the antitumor effect in vivo may be related to antiangiogenic effects. Furthermore, anti-endothelial cell antibodies such as these could be useful reagents in isolating specific targets that comprise and induce the antiangiogenic effect.     

32P-postlabeling analysis of binding of the cyclophosphamide metabolite, acrolein, to DNA

The cyclophosphamide metabolite, acrolein, was reacted with 2'-deoxyguanosine-3'-monophosphate, and two adducts were detected by high performance liquid chromatography and 32P-postlabeling assay. These adducts were resistant to dephosphorylation by nuclease P1 and could be isolated and detected from calf thymus DNA that had been reacted in vitro with acrolein. A combination of HPLC purification and enzymatic digestion of normal nucleotides by nuclease P1 allowed for the detection of these adducts in hepatic DNA from mice treated with cyclophosphamide. The level of the two adducts in the hepatic DNA, as determined by 32P-postlabeling, was one adduct per 2.7-4.1 x 10(7) normal nucleotides.     

Platelet-activating factor in bronchoalveolar lavage from patients with sarcoidosis.

Platelet-activating factor (PAF), a lipid mediator of inflammation and anaphylaxis, may play a role in several physiopathologic alterations of the lung. A lipid compound with physicochemical and biologic characteristics similar to synthetic PAF was extracted and purified from bronchoalveolar lavage (BAL) fluid of 15 of 34 patients with sarcoidosis. PAF was quantitated by a bioassay on washed rabbit platelets. The specificity of platelet aggregation was assessed by using two different PAF receptor antagonists. The incidence of detectable amounts of PAF in BAL fluid of sarcoid patients was statistically significant (chi 2 = 4.064, p = 0.044) when compared with the 14 normal control subjects. The results demonstrated an increased production of PAF in the lower respiratory tract of patients with sarcoidosis. The presence of PAF in BAL fluid, however, did not correlate with radiologic stage, intensity of alveolitis, gallium scanning positivity, angiotensin-converting enzyme serum level, or lung function tests. Therefore, a direct relationship between presence of PAF in BAL fluid and activity of lung disease in patients with sarcoidosis was not directly established.     

Tracheal stenosis. A study of 100 cases

A series of 100 cases of tracheal stenoses, 66 non-neoplastic and 34 neoplastic, are reviewed; tracheal resection was performed in 28 inflammatory stenoses and in five tumours. A T-tube stent was used in 12 patients. Results were good in 81% of resections for non-neoplastic stenoses; two out of three resections for adenoid cystic carcinoma are alive after ten years and the third died after two years with metastases; two patients who received a tracheal resection for epidermoid carcinomas died after three and four years with metastases. Inflammatory tracheal stenoses treated using T-tube achieved good results only in one third of cases. Pre-operative preparation is the most important factor to obtain good results: end-to-end anastomosis requires a healthy mucosa without infection or ulcers.     

Phase 2 trial of linifanib (ABT-869) in patients with advanced renal cell cancer after sunitinib failure

Purpose

This study assessed the efficacy and safety of linifanib in patients with advanced renal cell carcinoma (RCC) who were previously treated with sunitinib.

Materials and methods

This open-label, multicentre, phase 2 trial of oral linifanib 0.25 mg/kg/day enrolled patients who had prior nephrectomy and adequate organ function. The primary end-point was objective response rate (ORR) per response evaluation criteria in solid tumors (RECIST) by central imaging. Secondary end-points were progression-free survival (PFS), overall survival (OS) and time to progression (TTP). Safety was also assessed.

Results

Fifty-three patients, median age 61 years (range 40-80) were enrolled (August 2007 to October 2008) across 12 North-American centres. Median number of prior therapies was 2 (range 1-4); 43 patients (81%) had clear-cell histology. ORR was 13.2%, median PFS was 5.4 months (95% Confidence Interval (CI): 3.6, 6.0) and TTP was the same; median OS was 14.5 months (95% CI: 10.8, 24.1). The most common treatment-related adverse events (AEs) were diarrhoea (74%), fatigue (74%) and hypertension (66%), and the most common treatment-related Grade 3/4 AE was hypertension (40%).

Conclusions

Linifanib demonstrated clinically meaningful activity in patients with advanced RCC after sunitinib failure. At 0.25 mg/kg/day, significant dose modifications were required. An alternative, fixed-dosing strategy is being evaluated in other trials.     

Surgical wound healing complications in metastatic colorectal cancer patients treated with bevacizumab

BACKGROUND: Bevacizumab (Avastin; rhuMab VEGF), a humanized monoclonal antibody against vascular endothelial growth factor (VEGF), significantly prolongs survival when added to intravenous 5-fluorouracil-based chemotherapy in first-line metastatic colorectal cancer (CRC) treatment. Because antiangiogenic agents might inhibit wound healing, we assessed postoperative wound healing complications in two randomized trials of 5 mg/kg bevacizumab in CRC treatment. METHODS: We assessed the wound healing complications in patients who: (1) underwent cancer surgery 28-60 days before study treatment and (2) underwent major surgery during study treatment. Cases were reviewed for wound healing complications occurring < or = 60 days after surgery. RESULTS: With cancer surgery 28-60 days before study treatment, wound healing complications occurred in 3/230 (1.3%) bevacizumab-treated patients and 1/194 (0.5%) control patients. With major surgery during study treatment, 10/75 bevacizumab-treated patients (13%) and 1/29 control patients (3.4%) had wound healing complications. Bevacizumab-treated patients experienced complications with surgery < or = 30 and 31-60 days after the last dose. CONCLUSIONS: Bevacizumab administered in combination with 5-fluorouracil/leucovorin-based chemotherapy 28-60 days after primary cancer surgery caused no increased risk of wound healing complications compared with chemotherapy alone. While wound healing complications were increased in patients who had major surgery during bevacizumab therapy, the majority of bevacizumab-treated patients experienced no complications.