No abstract

One hundred and twenty-eight patients with a first cadaveric kidney allograft participated in a prospective, randomized, clinical trial comparing triple treatment, consisting of initial low-dose cyclosporine (CsA), azathioprine (Aza) and methylprednisolone (MP), with all possible combinations of two immunosuppressive drugs. A protocol core biopsy was performed on all patients with a functioning graft two years after transplantation. The histological findings were evaluated blindly and correlated to possible risk factors for renal allograft damage. The most common histological features were diffuse fibrosis in 62% of biopsies, tubular atrophy in 64% and diffuse inflammation in 30%. Two other important findings were glomerulosclerosis (43%) and vascular intimal proliferation (36%). The histological findings were scored mostly mild. A total of 77% (69 of 89) of patients had normal or only slightly increased serum creatinine. Decreased graft function was related to increased interstitial fibrosis, inflammation, glomerulosclerosis, mesangial matrix increase of glomeruli, intimal proliferation of vessels and tubular atrophy. These findings are characteristic, but not pathognomonic, of chronic renal allograft rejection both in experimental models and in humans. Possible risk factors were correlated to graft histology. Donor age correlated strongly with mesangial matrix increase, intimal proliferation, and tubular atrophy; there was no correlation with interstitial changes. The number of acute rejections and cold ischaemia time did not correlate with any one of the histological findings at two years following transplantation. Cyclosporine dose and concentration had a negative correlation to interstitial inflammation. A "chronic allograft damage index" was eventually created for the comparison of the four different treatment groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Although the outgrowth of micrometastases into macrometastases is the rate-limiting step in metastatic progression and the main determinant of cancer fatality, the molecular mechanisms involved have been little studied. Here, we compared the gene expression profiles of melanoma lymph node micro- and macrometastases and unexpectedly found no common up-regulation of any single growth factor/cytokine, except for the cytokine-like SPP1. Importantly, metastatic outgrowth was found to be consistently associated with activation of the transforming growth factor-beta signaling pathway (confirmed by phospho-SMAD2 staining) and concerted up-regulation of POSTN, FN1, COL-I, and VCAN genes-all inducible by transforming growth factor-beta. The encoded extracellular matrix proteins were found to together form intricate fibrillar networks around tumor cell nests in melanoma and breast cancer metastases from various organs. Functional analyses suggested that these newly synthesized protein networks regulate adhesion, migration, and growth of tumor cells, fibroblasts, and endothelial cells. POSTN acted as an anti-adhesive molecule counteracting the adhesive functions of FN1 and COL-I. Further, cellular FN and POSTN were specifically overexpressed in the newly forming/formed tumor blood vessels. Transforming growth factor-beta receptors and the metastasis-related matrix proteins, POSTN and FN1, in particular, may thus provide attractive targets for development of new therapies against disseminated melanoma, breast cancer, and possibly other tumors, by affecting key processes of metastasis: tumor/stromal cell migration, growth, and angiogenesis.

Objective: The cell block (CB) technique refers to the processing of sediments, blood clots, or grossly visible tissue fragments from cytological specimens into paraffin blocks that can be cut and stained by the same methods used for histopathology. The technique brings additional tissue architectural information. CB can be used for ancillary techniques such as immunocytochemistry and molecular techniques. Study Design: We reviewed the literature on the various preparatory techniques of CBs. Results: There is a wide range of preparatory techniques for CBs and no golden standard for CBs exists: tens of methods are used in various institutions. The majority of the methods are modified in house techniques with a few commercially available kits. The techniques most commonly used are the plasma/thrombin method, the agar method, and commercially available Histogel- and Cellient CB-methods. Dissatisfaction with the cellular yield of the CBs is common. Conclusions: In the CBs, the cytological material is preserved for future use, which is a tremendous advantage in the era of targeted therapy and biobanking. The CB is thus central to the future of cytology: more can be done with less material and with less invasiveness to the patient.