The antitumor and antiangiogenic activity of vascular endothelial growth factor receptor inhibition is potentiated by ErbB1 blockade.

PURPOSE: Receptor tyrosine kinases of the ErbB family play important roles in the control of tumor growth. Vascular endothelial growth factor (VEGF) stimulates endothelial cell proliferation, enhances vascular permeability, and plays an important role in tumor vascularization. We evaluated the effects of selective VEGF receptor (VEGFR; PTK787/ZK222584) and ErbB (PKI166 and ZD1839) inhibitors on tumor growth and angiogenesis and asked whether additional therapeutic benefit was conferred by combination treatment. EXPERIMENTAL DESIGN: The antitumor activity of each inhibitor alone or in combination was assessed in human cancer models in immunocompromised mice. ErbB receptor expression and activation of downstream signaling pathway was evaluated in both tumor and endothelial cells. RESULTS: Both ErbB inhibitors significantly enhanced the antitumor activity of PTK787/ZK222584. In vitro, ErbB1 inhibition blocked VEGF release by tumor cells and proliferation of both tumor and endothelial cells. In an in vitro angiogenesis assay, epidermal growth factor (EGF) stimulated the release of VEGF by smooth muscle cells resulting in increased angiogenesis, a response blocked by administration of PTK787/ZK222584. Under basal condition, both ZD1839 and PTK787/ZK222584 blocked sprouting, likely via inhibition of an autocrine ErbB1 loop and VEGFR signaling, respectively, in endothelial cells. In conditions of limiting VEGF, EGF plays an important role in endothelial cell proliferation, survival, and sprouting. CONCLUSION: We have shown that activation of ErbB1 triggers a plethora of effects, including direct effects on tumor and endothelial cells and indirect effects mediated via induction of VEGF release. Simultaneous blockade of ErbB1 and VEGFR pathways results in a cooperative antitumor effect, indicating that this combination may represent a valid therapeutic strategy.     

IL-2-mediated augmentation of NK-cell activity and activation antigen expression on NK- and T-cell subsets in patients with metastatic melanoma treated with interferon-α and DTIC

Considering that well-defined and comprehensive immunological monitoring is the basis for the evaluation of the obtained immunmodulatory effects, we evaluated NK-cell activity, the number of CD3+CD4+, CD3+CD8+ T cells and CD16+CD56+ NK cells, as well as the expression of activation antigens, CD69, CD38 and HLA-DR on CD56+ NK cells, CD8+ and CD3+ T cells, simultaneously with IL-2 and TNF-α production, during chemoimmunotherapy with dacarbazine (DTIC) and interferon-α (IFN-α) in 39 patients with metastatic melanoma. In the first cycle of therapy, there was a significant rise in NK-cell activity, CD4+ T helper cell number, CD4/CD8 T-cell ratio, and the expression of activation antigens CD69 and CD38, on NK and T cells, respectively. However, in the following cycles there was a significant increase only in activation antigens without an increase in the percent or activity of NK cells. The early, but transient, immunopotentiation, present only in the first cycle of combined DTIC and IFN-α therapy, suggests that, in spite of increased IL-2 level, associated with augmented NK-cell activity, this therapy has a limited effect probably owing to the adverse effect of persistently high level of TNF-α in metastatic disease. This revised version was published online in July 2006 with corrections to the Cover Date.     

Separation among Species of Mycobacterium terrae Complex by Lipid Analyses: Comparison with Biochemical Tests and 16S rRNA Sequencing

Fatty acids, alcohols, and mycolic acid cleavage products were determined for 13 ATCC strains and 24 clinical isolates, which were initially identified by biochemical and growth characteristics as the Mycobacterium terrae complex. The clinical isolates were also analyzed by partial sequencing of the 16S rRNA gene, which divided them into five genetic entities, M. triviale (three strains), M. terrae (four strains), M. nonchromogenicum sensu stricto (seven strains), Mycobacterium sp. strain MCRO 6 (seven strains), and Mycobacterium sp. strain 31958 (one strain). After acidic methanolysis, secondary alcohols were a characteristic feature in all members of the M. terrae complex but M. triviale. In addition to the prominent secondary alcohols, 2-octadecanol and 2-eicosanol, two previously unidentified alcohols, 2-(8,15-dimethyl)docosenol and 2-(8,17-dimethyl)tetracosenol, were detected in M. nonchromogenicum, Mycobacterium sp. strain MCRO 6, and Mycobacterium sp. strain 31958. Only 2-(8,17-dimethyl)tetracosenol was detected in trace amounts in M. terrae. Genetic differences were associated with differences in phenotypic characteristics, including growth at 42°C and pyrazinamidase production. Based on fatty acid and alcohol composition and biochemical and genetic characteristics, M. nonchromogenicum and Mycobacterium sp. strains MCRO 6 and 31958 were found to be a closely related group, named the M. nonchromogenicum complex. Detected genetic variations associated with phenotypic characteristics may indicate further species separation of this complex. In conclusion, the results of gas-liquid chromatography fatty acid analysis, combined with those of a Tween 80 test, enable identification of the species of the M. terrae complex and their separation from other nonpigmented slowly growing mycobacteria.     

The prognostic influence of lymphatic endothelium–specific hyaluronan receptor 1 in cancer: A systematic review

Lymphangiogenesis is a key process in cancer development and metastasis. Lymphatic vessel endothelial hyaluronan receptor 1 (LYVE‐1) is a widely used marker for lymphatic endothelial cells (LEC), which also mediates immune and cancer cell migration. Recently, LYVE‐1–positive tumor cells were shown to acquire LEC‐like phenotype and exploit this receptor for lymphatic dissemination. Furthermore, selective targeting of LYVE‐1 impaired the growth of cancer‐related vasculature and reduced metastasis in vivo, signifying its role in therapeutic and prognostic applications. Although numerous studies have investigated the role of LYVE‐1 in cancer, a unifying detailed review of its prognostic utility is lacking to date. Thus, we compiled and critically appraised evidence from clinical studies comprising a total of 2352 patients diagnosed with different types of cancer and using a variety of experimental approaches. Collectively, most studies revealed a significant association between LYVE‐1 overexpression and dismal outcome of at least one survival estimate. Furthermore, the importance of vasculature location, intra‐ or peritumoral, and the influence of various lymphangiogenesis‐related parameters, such as lymphatic vessel density and invasion, were discussed. However, the specificity of LYVE‐1 staining is challenged by its expression in non‐LEC cells, implying the need for double labelling to better estimate its prognostic significance. In conclusion, this is to our knowledge the first comprehensive systematic review on the prognostic value of LYVE‐1 in cancer. More well‐designed studies across different populations and the development of standardized protocols would be paramount for the consistency of LYVE‐1 findings and for its potential transferability to clinical practice in future.     

A novel MYH7 mutation occurring independently in French and Norwegian Laing distal myopathy families and de novo in one Finnish patient

Laing early-onset distal myopathy is a rare autosomal dominant myopathy and caused by mutations in the MYH7 gene, encoding the slow beta myosin heavy chain. We report the first molecularly verified Laing distal myopathy in a French family caused by a novel p.Glu1508del mutation in the MYH7 gene. Interestingly, we identified the identical mutation in an unrelated Norwegian family and, as a de novo mutation, in one sporadic Finnish patient. Described in detail are the clinical and electrophysiological characteristics of 5 patients from the French family. The phenotype in the Finnish patient and the Norwegian patients is largely similar. This mutation causes a benign myopathy within the range of previously reported Laing myopathy phenotype variations. Onset of weakness in the tibialis anterior (TA) muscles occurred in early childhood in all patients. Finger extensor and neck flexor weakness together with Achilles tendon retractions were other frequent findings. The independent recurrence of the identical mutation without any founder background may reflect a mutational susceptibility of this residue, in accordance with some other MYH7 mutations previously reported. De novo mutations seem to be frequent in Laing distal myopathy. This is of clinical importance since a dominant family history is missing, which may confuse differential diagnostic efforts.     

An asbestos hazard in the reprocessed textile industry

Epidemiologic studies have identified an excess risk of lung cancer and mesothelioma among workers in the reprocessed textile industry in Prato, Italy. These studies suggested that there may have been asbestos hazard in this industry although exposure was not known to exist. An industrial hygiene investigation was conducted to determine whether there was previous or current asbestos exposure in the industry. Walk-through surveys, environmental sampling, process documentation, and management and worker interviews were conducted in 13 textile reprocessing establishments. Polypropylene bags that once contained asbestos were found in 2 of the 13. Asbestos bags were cut open and used to cover bales of rags which were then distributed throughout the world. Workers were exposed to asbestos while handling the bags which were contaminated with chrysotile, amosite, and crocidolite. Additional sources of asbestos exposure that may have existed in the past in the industry are also discussed.     

Biliopancreatic diversion: long-term effects on gonadal function in severely obese men

BACKGROUND: This study investigated hormonal parameters of gonadal function in severely obese men before and 1 year after undergoing biliopancreatic diversion (BPD). METHODS: This observational 1-year postoperative study conducted at medical and surgical clinics at an academic medical center in Italy followed 20 severely obese men age 21 to 63 years, with a mean (+/- standard deviation) body mass index (BMI) of 47.3 +/- 13.1. The following parameters were evaluated: body composition, using body impedance analysis (BIA), and serum levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), total testosterone, estradiol 17beta, and leptin. RESULTS: At a mean 12 +/- 1 months after surgery, the patients showed a significant decrease in weight, from 132.1 +/- 36.9 before surgery to 93.5 +/- 20 kg (P < .0001), and BMI, from 47.3 +/- 13.1 before surgery to 33.5 +/- 7 (P < .0001). LH increased from 2.42 +/- 1.59 to 4.97 +/- 2.6 mIU/ml (P < .0001), FSH increased from 2.85 +/- 1.85 to 4.9 +/- 4.2 mIU/mL (P = .021), and total testosterone increased from subnormal presurgical values to within normal range (2.81 +/- 1.08 to 9.12 +/- 1.37 ng/mL; P < .0001), whereas estradiol 17beta decreased from elevated basal levels of 44.0 +/- 29 to 16.7 +/- 6.9 pg/mL (P < .0001). The basal leptin level dropped from 33.0 +/- 9.23 to 16.6 +/- 5.12 ng/mL (P < .0001), reflecting the decrease in body fat. Subjective improvement in sexual performance was reported by 80% of patients. CONCLUSIONS: Severe obesity is coupled with some significant alterations of the gonadotropin-testicular axis and estradiol 17beta and leptin blood levels. These derangements were substantially corrected by 1 year after BPD.     

Combination chemotherapy with 5-fluorouracil and methyl-CCNU for the treatment of advanced gastrointestinal cancer.

Sixteen patients with advanced gastrointestinal cancer (colorectal 12/16, gastric 4/16) were treated with a combination of 5-fluorouracil (5-FU) plus 1-(2-chlorethyl)-3(4-methyl-cycloexyl)-1-nitrosourea (Me-CCNU). The therapeutic program consisted of orally administered Me-CCNU (140 mg/m2) and intravenous 5-FU (9.5 mg/kg by bolus injection for 5 days). The cycles were repeated at 6-week intervals. At the beginning of the therapy, 11/16 patients were in performance status (PS) 0-1 and 5 patients in PS 2-3. Eight patients developed early progressive disease between the 1st and 2nd course of therapy. Only a minor tumor response was observed in the remaining 50% of the patients. However, the patients with stabilized disease lived longer (11.8 months) than non-responders (3.5 months).