We intended to identify the prognostic factors and the results of interventions on patients with liver metastatic midgut carcinoids. Five institutions that are part of United Kingdom and Ireland neuroendocrine tumour (NET) group took part in this study. Patients were included if they had histology proven NET of midgut origin and liver metastases at the time of the study. Clinical and biochemical data were collected retrospectively from hospital charts, pathology reports, radiology reports and biochemistry records for each patient. Three hundred and sixty patients were included in the study. The median survival from date of diagnosis was 7.69 years (confidence interval (CI) 6.40-8.99) and 5.95 years (CI 5.02-6.88) from date of diagnosis of liver metastases. On univariate analysis, increasing age at diagnosis, increasing urinary hydroxyindole acetic acid levels, increasing plasma chromogranin A levels, high Ki67, high tumour volume and treatment with chemotherapy were identified as factors associated with a significantly poorer outcome. Resection of liver metastases, resection of small bowel primary, treatment with somatostatin analogue therapy and treatment with peptide receptor therapy were associated with improved prognosis. Multivariate analysis revealed that age at diagnosis (PZ0.014), Ki67 level (PZ0.039) and resection of primary (PZ0.015) were independent predictors of survival. This is the largest study to our knowledge looking specifically at the prognosis and clinical course of patients with liver metastatic midgut NETs. For the first time, we have shown that Ki67 and resection of primary are independent predictors of survival for this group of patients.

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We report studies that suggest enzyme replacement therapy will result in a significant reduction in disease progression and tissue pathology in patients with Maroteaux-Lamy syndrome (Mucopolysaccharidosis type VI, MPS VI). A feline model for MPS VI was used to evaluate tissue distribution and clinical efficacy of three forms of recombinant human N -acetylgalactosamine-4-sulfatase (rh4S, EC 3.1.6.1). Intravenously administered rh4S was rapidly cleared from circulation. The majority of rh4S was distributed to liver, but was also detected in most other tissues. Tissue half-life was ‫ف‬ 2-4 d. Three MPS VI cats given regular intravenous infusions of rh4S for up to 20 mo showed variable reduction of storage vacuoles in Kupffer cells and connective tissues, however cartilage chondrocytes remained vacuolated. Vertebral bone mineral volume was improved in two MPS VI cats in which therapy was initiated before skeletal maturity, and increased bone volume appeared to correlate with earlier age of onset of therapy. One cat showed greater mobility in response to therapy. (

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Mucopolysaccharidosis type IIIA (MPS IIIA) is an inherited neurodegenerative lysosomal storage disorder characterized by progressive loss of learned skills, sleep disturbance and behavioural problems. Reduced activity of sulphamidase (N-sulphoglucosamine sulphohydrolase; SGSH; EC 3.10.1.1) results in intracellular accumulation of heparan sulphate (HS), with the brain as the primary site of pathology. We have used a naturally occurring MPS IIIA mouse model to determine the effectiveness of SGSH replacement through the cerebrospinal fluid (CSF) to decrease neuropathology. This is a potential therapeutic option for patients with this disorder. Mice received intra-CSF injections of recombinant human SGSH (30, 50 or 70 mg) fortnightly from 6 to 18 weeks of age, and the cumulative effect on neuropathology was examined and quantified. Anti-SGSH antibodies detected in plasma at euthanasia did not appear to impact upon the health of the mice or the experimental outcome, with significant but regiondependent and dose-dependent reductions in an HSderived oligosaccharide observed in the brain and spinal cord using tandem mass spectrometry. SGSH infusion reduced the number of storage inclusions observed in the brain when visualized using electron microscopy, and this correlated with a significant decrease in the immunohistochemical staining of a lysosomal membrane marker. Reduced numbers of activated isolectin B4-positive microglia and glial fibrillary acidic protein-positive astrocytes were seen in many, but not all, brain regions. Significant reductions in the number of ubiquitin-positive intracellular inclusions were also observed. These outcomes show the effectiveness of this method of enzyme delivery in reducing the spectrum of neuropathological changes in murine MPS IIIA brain.