Metastasis to the liver is a common event in clinicaloncology. Blood-borne tumor cells (TCs) arriving to the coined the term metastasis in 1829 in his treatise ''Reliver sinusoids run into a special vascular bed. The lining cherches du Cancer,'' the metastatic cascade has been of liver sinusoids is shared by Kupffer cells (KCs) and exhaustively studied.1,2 Metastases originate from a seendothelial cells. KCs, liver-fixed macrophages, are re-lective population of cells within the great biological sponsible for detection and removal of ''non-self'' parti-heterogeneity of the tumor.3 They must invade the vascles. To investigate their role in arresting blood-borne cular wall to be dislodged into the circulation and surTCs and controlling tumor growth, we injected a synge-vive in the blood stream until they arrest at the distant neic colon carcinoma cell line into a mesenteric vein of vascular bed of the target organ by adherence or metwo groups of rats; one group was without Kupffer cells chanical trapping. Then, they have to proliferate to iniand the other normal controls. We removed the liver of tiate a metastatic colony. these animals at different time intervals and performedLiver metastasis is a common event in cancer paimmunohistochemical analysis with monoclonal antitients. This is of particular relevance for neoplasias of bodies (MoAbs) against our tumor cell line, three macrophage subpopulations, natural killer cells, and B and T the gastrointestinal tract, because the liver is the first lymphocytes. Additionally, we showed in vitro spontane-vascular bed to be encountered by blood-borne tumor ous cytotoxicity of KCs against our tumor cell line. Re-cells (TCs) through the portal system. 4 The lumen of sults suggest that KCs play a relevant role in arresting liver sinusoids differ from the ordinary capillaries in circulating TCs at the liver sinusoid, although it is lim-that, besides endothelial cells, the stellate cells of von ited to a small number of malignant cells. They also seem Kupffer are lining the sinusoid wall.5 Kupffer cells to play a major role in clearing neoplastic cells from the (KCs) represent one of the largest populations of the liver parenchyma, in controlling tumor growth in the mononuclear phagocyte system in the body. Their privery early stages of metastatic development, and in mod-mary function is to discriminate between ''self'' and ulating the host immune response to cancer cells. (HEPA-''non-self'' particles, playing a prominent role as anti-

Macrophages play a role in the host defence against cancer. Little is known about changes in macrophage populations during early metastatic growth. To evaluate the distribution, number and phenotype of macrophages in the development of hepatic metastases in a rat model (Wag/Rij rats and syngeneic CC531 colon carcinoma cell line), an immunohistochemical study was performed with the monoclonal antibodies ED1 (monocytes, and all macrophages), ED2 (resident tissue macrophages, like Kupffer cells) and ED3 (a subpopulation of macrophages which may play a role in the recruitment of lymphocytes). OX19 and His14 were used to identify lymphocytes. In this study a new monoclonal antibody CC52 is described, which recognizes the CC531 tumour cell line. Liver metastases were induced by injection of CC531 colon carcinoma cells into a mesenteric vein. Rats were killed at various intervals. Results show three major macrophage populations during hepatic tumour growth: (1) on day 3, infiltrates are observed around the micrometastases, which contain mainly newly recruited macrophages (ED1+ and ED2-); (2) after 7 days, ED3-positive (ED3+) macrophages together with T lymphocytes are found in the infiltrates; (3) an increase in the number of ED2-positive (ED2+) Kupffer cells is observed in the liver parenchyma after 14 days. In conclusion, the present results suggest that various populations of macrophages, newly recruited (ED1+) as well as resident Kupffer cells (ED2+), are involved in the immune response against tumour cell deposits in the liver.

Fabry disease (FD) is an X-linked lysosomal storage disease, with multisystemic glycosphingolipids deposits. Neuro-otological involvement leading to hearing loss and vestibular dysfunctions has been described, but there is limited information about the frequency, site of lesion, or the relationship with peripheral neuropathy. The aim was to evaluate the presence of auditory and vestibular symptoms, and assess neurophysiological involvement of the VIII cranial nerve, correlating these findings with clinical and neurophysiological features of peripheral neuropathy. We studied 36 patients with FD with a complete neurological and neuro-otological evaluation including nerve conduction studies, quantitative sensory testing (to evaluate small fiber by warm and cold threshold detection and cold and heat pain), vestibular evoked myogenic potentials, videonistagmography, audiometry and brainstem auditory evoked potentials. Neuro-otologic symptoms included hearing loss (22.2%), vertigo (27.8%) or both (25%). An involvement of either cochlear or vestibular function was identified in most patients (75%). In 70% of our patients the involvement of both cochlear and vestibular function could not be explained by a neural or vascular mechanism. Small fiber neuropathy was identified in 77.7%. There were no significant associations between neuro-otological and QST abnormalities. Neuro-otologic involvement is frequent and most likely under-recognized in patients with FD. It lacks a specific neural or vascular pattern, suggesting multi-systemic, end organ damage. Small fiber neuropathy is an earlier manifestation of FD, but there is no correlation between the development of neuropathy and neuro-otological abnormalities.

Adriamycin (ADR) was formulated in albumin-heparin conjugate microspheres (AHCMS) to improve site-specific delivery and to reduce the toxicity of the drug. The effect of formulating ADR in AHCMS was investigated upon intrahepatic administration to male Wag/Rij rats. After intraveno-portal (i.v.p.) administration of ADR-AHCMS, ADR peak plasma concentrations were reduced 10-fold and ADR tissue levels of non-target tissues were significantly reduced, as compared to i.v.p, administration of the free drug. At an i.v.p, administered drug dose of 7.5 mg/kg, free ADR showed distinct signs of acute toxicity. At the same dose of ADR-AHCMS, signs of toxicity were absent. Cardiac function parameters which were determined using an isolated working heart model did not change as a result of i.v.p, administration of free ADR or ADR-AHCMS at a dose of 7.5 mg/kg. Heart weights of animals in the ADR-AHCMS or the free ADR groups, however, were significantly lower than controls. Dose tolerance studies after intrahepatic-arterial (i.h.a.) administration of free ADR, empty AHCMS and ADR-AHCMS in rats demonstrated that empty AHCMS are tolerated at a dose of 45 mg/kg. Free ADR was tolerated at a dose of 4 mg/kg, whereas ADR-AHCMS were tolerated up to a dose of 10 mg ADR/kg, as indicated by the survival.

No abstract