PurposeTo improve stratification of risk-adapted treatment for non-metastatic (M0), standard-risk medulloblastoma patients by prospective evaluation of biomarkers of reported biological or prognostic significance, alongside clinico-pathological variables, within the multi-center HIT-SIOP-PNET4 trial.MethodsFormalin-fixed paraffin-embedded tumor tissues were collected from 338 M0 patients (>4.0 years at diagnosis) for pathology review and assessment of the WNT subgroup (MBWNT) and genomic copy-number defects (chromosome 17, MYC/MYCN, 9q22 (PTCH1) and DNA ploidy). Clinical characteristics were reviewed centrally.ResultsThe favorable prognosis of MBWNT was confirmed, however better outcomes were observed for non-MBWNT tumors in this clinical risk-defined cohort compared to previous disease-wide clinical trials. Chromosome 17p/q defects were heterogeneous when assessed at the cellular copy-number level, and predicted poor prognosis when they occurred against a diploid (ch17(im)/diploid(cen)), but not polyploid, genetic background. These factors, together with post-surgical tumor residuum (R+) and radiotherapy delay, were supported as independent prognostic markers in multivariate testing. Notably, MYC and MYCN amplification were not associated with adverse outcome. In cross-validated survival models derived for the clinical standard-risk (M0/R0) disease group, (ch17(im)/diploid(cen); 14% of patients) predicted high disease-risk, while the outcomes of patients without (ch17(im)/diploid(cen)) did not differ significantly from MBWNT, allowing re-classification of 86% as favorable-risk.ConclusionBiomarkers, established previously in disease-wide studies, behave differently in clinically-defined standard-risk disease. Distinct biomarkers are required to assess disease-risk in this group, and define improved risk-stratification models. Routine testing for specific patterns of chromosome 17 imbalance at the cellular level, and MBWNT, provides a strong basis for incorporation into future trials.
Immunohistochemistry and image analysis were used to quantify alterations in the Kupffer cell and 'activated' perisinusoidal cell populations in the different stages of primary biliary cirrhosis. Anti-CD68 macrophage antibodies were used to detect Kupffer cells, and anti-alpha-smooth muscle actin (alpha-SMA), PR 2D3 and anti-desmin antibodies to detect perisinusoidal cells. Liver biopsy material was available from 26 patients with primary biliary cirrhosis and 23 patients with histologically normal liver. Increased Kupffer cell numbers were observed in periportal/periseptal zones of stage 3 primary biliary cirrhosis (n = 9), and in random parenchymal areas of stage 3 and stage 4 cases. Significantly increased 'activated' perisinusoidal cell numbers were seen only in periportal/periseptal zones of stage 3 and stage 4 primary biliary cirrhosis. Neither Kupffer cell nor perisinusoidal cell numbers altered significantly in stage 1 and 2 primary biliary cirrhosis (n = 6). PR 2D3 positivity and increased alpha-SMA immunoreactivity by perisinusoidal cells in primary biliary cirrhosis support myofibroblastic differentiation of these cells. Human perisinusoidal cells, unlike their rodent counterparts, did not express desmin in primary biliary cirrhosis or control liver. Kupffer cells and 'activated' perisinusoidal cell accumulation in periportal/periseptal zones of the precirrhotic and cirrhotic primary biliary cirrhosis liver support the concept of Kupffer cell-mediated stimulation of perisinusoidal cells. Furthermore, these findings indicate that Kupffer cell-perisinusoidal interactions play an important role in the development of liver fibrosis and cirrhosis in primary biliary cirrhosis.
Normal lung development is dependent on epithelial-mesenchymal interactions. This study was undertaken to examine the structure of the interstitium of the developing human fetal lung, concentrating particularly on the first and second trimesters. Lung tissue was obtained at autopsy from nonmalformed, nonmacerated cases of spontaneous abortion (n = 15), stillbirth (n = 9), and very early neonatal death (n = 5) (range of gestations, 10-42 weeks). Paraffin-embedded tissue sections were examined using immunohistochemical methods to determine expression of collagens I, III, IV, V, and VI; the glycoproteins fibronectin and laminin; and the intermediate filaments vimentin, alpha-smooth muscle actin (alphaSMA), and desmin. Collagens III and VI and cells expressing alphaSMA were present consistently at points of airway branching and secondary crest formation, indicating a role for these components in the initiation and stabilization of airway branches in the developing lung. Desmin expression by stromal cells succeeded alphaSMA temporally, and may represent a marker of terminal smooth muscle differentiation within the airway; it was not detected in the vascular tree. Other components were widely expressed throughout the extracellular matrix, including basement membranes, at all gestations. The spatial and temporal patterns of expression of components of the lung interstitium provide clues to the mechanisms underlying normal human lung development and possible insights into the pathogenesis of fetal and neonatal lung disease.
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