Preliminary Experience with a New Sclerosing Foam in the Treatment of Varicose Veins

BACKGROUND: Recently a new method of using a foam sclerosing agent for the treatment of leg veins has been described. We present a pilot study of a new technique for producing the sclerosing foam (Tessari's method) (SFT) and its use in sclerotherapy of major and minor varicosities. OBJECTIVE: A preliminary multicenter experience of sclerotherapy performed by means of this new kind of sclerosing foam made of purified sodium tetradecylsulfate is described. The authors evaluated the safety and efficacy of different doses and concentrations of the drug as well as different methods of preparing the foam in addition, the results of this technique were evaluated. METHODS: Over a 6-week period the three authors performed sclerotherapy or duplex-guided sclerotherapy using SFT, treating 77 patients. The SFT was formed using a three-way stopcock and two syringes, mixing air with liquid sodium tetradecylsulfate to create a foam. Each author used different concentrations (0.1-3%) and doses (2-8 ml) of SFT according to the size and number of the veins. Alternate methods of preparing the foam were examined as well. Seventy percent of the sclerotherapy sessions were performed on either the long or short saphenous veins, recurrent varices, or collaterals. Thirty percent of the treatments were for reticular varices and telangiectases. RESULTS: At 1-month follow-up, the vast majority of treated larger veins were either obliterated or showed a normal state of cephalad blood flow. Results for minor varicosities were good, but with related complications of hyperpigmentation and small areas of cutaneous necrosis. Two patients experienced transient scotomas and one patient developed segmental phlebitis of a collateral vein. The best foam was obtained by mixing one part liquid sodium tetradecylsulfate and four to five parts air, but the duration of the foam product was also related to several other factors. CONCLUSION: This preliminary pilot study demonstrates that the technique of producing sclerosing foam according to Tessari's method (three-way stopcock device) is very promising, especially for larger veins. No serious complications were reported, and further standardization of the method may improve the results and feasibility of this technique. Further studies are needed to validate this new technique.     

Activation of the cAMP/PKA/DARPP-32 signaling pathway is required for morphine psychomotor stimulation but not for morphine reward.

Activation of the cAMP/PKA pathway in the dopaminoceptive neurons of the striatum has been proposed to mediate the actions of various classes of drugs of abuse. Here, we show that, in the mouse nucleus accumbens and dorsal striatum, acute administration of morphine resulted in an increase in the state of phosphorylation of the dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) at Thr34, without affecting phosphorylation at Thr75. The ability of morphine to stimulate Thr34 phosphorylation was prevented by blockade of dopamine D1 receptors. DARPP-32 knockout mice and T34A DARPP-32 mutant mice displayed a lower hyperlocomotor response to a single injection of morphine than wild-type controls. In contrast, in T75A DARPP-32 mutant mice, morphine-induced psychomotor activation was indistinguishable from that of wild-type littermates. In spite of their reduced response to the acute hyperlocomotor effect of morphine, DARPP-32 knockout mice and T34A DARPP-32 mutant mice were able to develop behavioral sensitization to morphine comparable to that of wild-type controls and to display morphine conditioned place preference. These results demonstrate that dopamine D1 receptor-mediated activation of the cAMP/DARPP-32 cascade in striatal medium spiny neurons is involved in the psychomotor action, but not in the rewarding properties, of morphine.     

NGF topical application in patients with corneal ulcer does not generate circulating NGF antibodies.

Nerve growth factor (NGF) is the prototype of the neurotrophin family and promotes the survival of specific populations of neurons, stimulates their morphological differentiation and regulates neuronal gene expression. Since its discovery, NGF attracted clinicians for its potential application in the treatment of neurological disorders. Recent studies demonstrated murine NGF eye drops may be successfully used to treat neurotrophic keratopathy. Neurotrophic keratopathy is a degenerative corneal disease caused by an impairment of the trigeminal nerve, which leads to corneal epithelial defect, ulcer, and perforation. NGF topical application induced complete ulcer healing and a recovery of the corneal sensitivity. The intent of this study is to address the question if murine NGF topical treatment stimulates the production of circulating anti-NGF antibodies. We evaluated patients with neurotrophic keratopathy who underwent topical therapy with NGF eye drops for possible ocular or systemic adverse effects in the course of 16-72 months follow up. None of the patients suffered any adverse reaction, except for mild and transient conjunctival hyperaemia and photophobia. Moreover, none of the treated patients developed circulating antibodies to NGF.     

The retinoblastoma family member pRb2/p130 is an independent predictor of survival in human soft tissue sarcomas

PURPOSE: pRb2/p130, a member of the Retinoblastoma gene family, has been shown to be a powerful prognostic factor in several malignancies. We sought to evaluate pRb2/p130 protein expression and its clinical effect in patients affected with soft tissue sarcomas (STS). EXPERIMENTAL DESIGN: Expression of pRb2/p130 was evaluated by immunohistochemistry on formalin-fixed, paraffin-embedded sections in 41 STSs. Results obtained were correlated with clinicopathologic variables and disease-free and overall survival (OS) in univariate and multivariate analysis. RESULTS: Expression of pRb2/p130 was diminished in 25 (61%) tumors, whereas the remaining ones (39%) were classified as high expressors. No correlation between pRb2/p130 expression and clinicopathologic variables was observed. However, a direct relationship between pRb2/p130 expression and clinical outcome of the patients was found in the subgroup of nonmetastatic tumors (n = 31). In univariate analysis, reduced pRb2/p130 expression was a negative prognostic factor and correlated with shorter disease-free survival (P = 0.021) and OS (P = 0.017) survival. In multivariate analysis, reduced pRb2/p130 expression was confirmed to be an independent predictor of shorter OS when considered together with tumor stage and grading (risk ratio, 7.893; confidence interval, 1.618-38.509; P = 0.011). CONCLUSIONS: This study shows for the first time the potential prognostic value of pRb2/130 expression evaluated on formalin-fixed, paraffin-embedded sections in STSs patients. pRb2/p130 immunoreactivity can be used to predict OS in patients with nonmetastatic STSs and, therefore, may represent a new prognostic marker.     

N- and K-Ras Oncogenes in Plasma Cell Dyscrasias

N- and K-ras oncogene mutations represent the most frequent molecular lesions in plasma cell dyscrasias. They are not randomly distributed since they are detectable in multiple myeloma (MM) (9-31%) and plasma cell leukemia (PCL) (30%), and not in monoclonal gammopathy of undetermined significance (MGUS) and solitary plasmacytoma (SP). Codons 12, 13 and 61 of N- and K-ras genes have been found mutated. Mutations affecting codon 61 of N-ras gene are the most frequent finding. A heterogeneous pattern of mutations is described with a prevalence of purine-pyrimidine trans versions. Ras gene mutations have been predominantly detected in myelomas characterized by an advanced stage disease, and adverse prognostic parameters. These findings suggest that ras mutations represent a late molecular lesion and may be implicated in tumor progression rather than tumor initiation.     

The LFA-1/ICAM cell adhesion pathway is involved in tumor-cell lysis mediated by bispecific monoclonal-antibody-targeted T lymphocytes

We investigated the role of the LFA-1 /ICAM, VLA-4/VCAM-1 and CD2/LFA-3 adhesion pathways in the cytolysis of tumor cells mediated by an anti-EGF-R/anti-CD3 bispecific monoclonal antibody (biMAb). The biMAb induced efficient lysis of EGF-R+ tumor cells (A431, HT-29, IGROV-1 and MDA-MB468) by cytotoxic T lymphocytes (CTL) cultured in IL-2. Protreatment of effector cells by anti-LFA-1α (CDI 1a) and anti-LFA-1 β (CD 18) MAbs significantly inhibited cytolysis of all types of EGF-R+ tumor cells, while anti-CD2 and anti-VLA-4 MAbs were virtually ineffective. We investigated the expression of adhesion-molecule counter-receptors on tumor target cells by indirect immunofluorescence. HT-29, A431 and MDA-MB 468 tumor cells expressed an ICAM-1+2^?3^?VCAM-1^?LFA-3⁺ phenotype, while IGROV-1 was ICAM-1^?2⁺3^?VCAM-1 ^?LFA-3+. Pre-treatment of A431, HT-29 and MDA-MB468 with anti-ICAM-1 MAb inhibited cytolysis, further supporting the functional involvement of the LFA-1 /ICAM adhesion pathway in biMAb-targeted tumor-cell lysis. In addition, treatment of target cells with TNFα or IFN-γ for 24 hr increased the expression of ICAM-1 in HT-29, A431 and MDA-MB468 (ICAM-2 was induced on IGROV-1) and also enhanced the sensitivity of these target cells to biMAb-targeted cytotoxicity. These data suggest that up-regulation of ICAM-molecule expression by inflammatory cytokines may increase susceptibility of tumor cells to biMAb-targeted lysis. Anti-LFA-1 MAbs did not significantly inhibit the formation of conjugates between biMAb-coated T lymphocytes and tumor cells. Co-aggregation of LFA-1 molecules with biMAb-bound CD3 molecules resulted in a more sustained and prolonged increase in the intracellular concentration of. free Ca⁺⁺ in CD8⁺ cultured CTL lines. These findings indicate that in T cells targeted by anti-CD3/anti-TAA biMAb LFA-1 may act as a co-receptor molecule which enhances signal transduction through the CD3/TCR complex.     

Determination of platinum in plasma of patients affected by inoperable lung carcinoma treated with radiotherapy and concurrent low-dose continuous infusion ofcis-dichlorodiammine platinum(II)

Platinum microquantities were determined in plasma of patients affected by lung carcinoma during treatment with radiotherapy (RT) and concurrent low-dose continuous infusion ofcis-dichlorodiammineplatinum(II) (CDDP). RT was given at 50 Gy in continuous course; CDDP was continuously infused at 4 mg/m² daily for 100h/week for 5 weeks, and the infusions were separated by 68h of rest. The percentage of free drug versus total drug in plasma was about 3%. It did not vary with therapy duration and was not significantly different from that found in 5-day continuous infusions at much higher daily doses. Never-theless, maximal values of free Pt in plasma were very low and agreed with the low level of CDDP toxicity encountered on the present administration schedule.     

Epitope selection and development of peptide based vaccines to treat cancer

Cytotoxic T lymphocytes recognize peptides that associate with class I major histocompatibility complex molecules. Since cytotoxic T cells have the capacity to recognize and destroy tumor cells, identification of epitopes recognized by these cells in tumor-associated antigens would allow the production of compounds for the treatment of cancer. Here we review some of the approaches being explored to identify tumor-associated antigens and to develop peptide-based vaccines that induce cytotoxic T lymphocytes against specific tumors.