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Background . Localized (solitary) fibrous tumors (LFTPs) of the pleura are rare, slow-growing neoplasms thought to originate from submesothelial connective issue. The aim of this article is to present 55 new cases of LFTP, and to discuss the treatment of choice and the clinical behavior of such neoplasms. Methods . From July 1990 to November 1999, 55 patients (32 male, 23 female) with an LFTP were surgically treated at our Institution. Neoplasms were considered to be malignant if one or more of the following histologic features were present: high cellularity with crowding and overlapping of nuclei; high mitotic activity; or mild, moderate, or marked pleomorphism. Results . No operative mortality was reported. Forty-eight of the cases arose from the visceral pleura and seven arose from the parietal pleura. A local removal of the neoplasm with free surgical margins was accomplished by video-assisted thoracic surgery in 39 patients and by standard thoracotomy in 10 patients. Four patients underwent formal lung resections, 1 had thymectomy, and 1 had en bloc chest wall resection. Four malignant variants were identified. One patient developed local recurrence and underwent redo surgery with chest wall resection. One patient died of unrelated disease. The remaining patients are alive and disease free at a median follow-up of 53.2 months. Conclusions . LFTPs show a benign outcome in most of the cases. Video-assisted thoracic surgery, with intraoperative assessment of the surgical margins, represents the treatment of choice.

Background. There is a need to develop a single prognostically significant classification of rhabdomyosarcomas (RMS) and other related tumors of children, adolescents, and young adults which would be a current guide for their diagnosis, allow valid comparison of outcomes between protocols carried out anywhere in the world, and should enhance recognition of prognostic subsets. Method. Sixteen pathologists from eight pathology groups, representing six countries and several cooperative groups, classified by four histopathologic classification schemes 800 representative tumors of the 999 eligible cases treated on Intergroup Rhabdomyosarcoma Study II. Each tumor was classified according to each of the four systems by each of the pathologists. In addition, two independent subsamples of 200 of the 800 patients were reviewed according to the new system, so that 343 distinct patients were reviewed once, and 57 of these twice. Results. A study of the survival rates of all subtypes in the sample of 800 patients led to the formation of a new system. This was tested on two independent subsets of 200 of the original cases and found to be reproducible and predictive of outcome by univariate analysis. A multivariate analysis of the 343 patients classified according to the new system indicated that a survival model including pathologic classification and known prognostic factors of primary site, clinical group, and tumor size was significantly better at predicting survival than a model with only the known prognostic factors. Conclusion. This new classification, termed International Classification of Rhabdomyosarcoma (ICR) by the authors, was reproducible and predictive of outcome among patients with differing histologies treated uniformly on the Intergroup Rhabdomyosarcoma II protocols. We believe it should be utilized by all pathologists and cooperative groups to classify rhabdomyosarcomas in order to provide comparability among and within multi-institutional studies. Cancer 1995;76:1073-85.

Background. An International Pathology study was conducted to measure the agreement demonstrated among and within groups of pathologists involved in the categorization of childhood rhabdomyosarcoma according to four pathology classifications. Data concerning agreement and survival experience according to pathonew subtypes were used as a basis for selection of a proposed new pathologic classification. Methods. A random sample of 800 eligible patients was chosen from the Intergroup Rhabdomyosarcoma Study II (IRS-II) and was reviewed by pathologists representing eight institutions. A 20% sample of the 800 patients was then rereviewed by the pathologists to determine the level of agreement with their original classification. In each instance the patients were classified according to four pathology systems: the conventional system, the International Society for Pediatric Oncology system (SIOP), the National Cancer Institute (NCI) system, and the cytohistologic system. Results. Among the groups of pathologists, the highest measure of agreement was a Kappa value of K = 0,451 for the conventional system, followed by K = 0,406 for the SIOP system, K = 0,384 for the NCI system, and K = 0,328 for the cytohistologic system. For reproducibility within the groups of pathologists, the highest measure of agreement was K = 0.605 for the conventional system, followed by K = 0.579 for the NCI system, K = 0.573 for the SIOP system, and K = 0.508 for the cytohistologic system. Conclusions. There was a general similarity between the agreement reached within the modified conventional, SIOP, and NCI systems, with the modified conventional system having the highest Kappa values, and thus the highest measure of agreement, both among and within the groups of pathologists. Also, the subtypes of the conventional system demonstrated a highly significant relationship to survival time. Hence, based on criteria of reproducibility and prognostic significance, the proposed classification will essentially be a modification of the conventional system with elements of the SIOP and NCI systems.

Insulin-like growth factor II (IGF-II) is a mitogen for many cell types and an important modulator of muscle growth and differentiation. IGF-II gene is prevalently expressed during prenatal development and its gene activity is regulated by genomic imprinting, in that the allele inherited from the father is active and the allele inherited from the mother is inactive in most normal tissues. IGF-II expression is activated in several types of human neoplasms and an alteration of IGF-II imprinting has been described in Beckwith-Wiedemann syndrome and Wilms' tumour. Here we show that monoallelic expression of IGF-II gene is conserved in normal adult muscle tissue whereas two or more copies of active IGF-II alleles, arising by either relaxation of imprinting or duplication of the active allele, are found in 9 out of 11 (82%) rhabdomyo-sarcomas retaining heterozygosity at 11p15, regardless of the histological subtype. Since IGF-II has been indicated as an autocrine growth factor for rhabdomyosarcoma cells, these findings strongly suggest that acquisition of a double dosage of active IGF-II gene is an important step for the initiation or progression of rhabdomyosarcoma tumorigenesis. Among different types of muscle tumors, relaxation of imprinting seems to arise prevalently in rhabdomyosarcomas, since we have detected only one case of partial reactivation of the maternal IGF-II allele out of 7 lelomyosarcomas tested. © 1994 Oxford University Press.

The expression of neurotrophins (NTs) and related high- and low-affinity receptors was studied in surgical samples of histologically diagnosed human tumors of the lower respiratory tract. The experiment was conducted with 30 non-small cell lung cancer specimens and in eight small cell lung cancer specimens by Western blot analysis and immunohistochemistry to assess expression and distribution of NT and NT receptor proteins in tissues examined. Immunoblots of homogenates from human tumors displayed binding of anti-nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and NT-3 antibodies as well as of anti-tyrosine-specific protein kinase (Trk) A, TrkB, and TrkC receptor antibodies, with similar migration characteristics than those displayed by human beta-NGF and proteins from rat brain. A specific immunoreactivity for NTs and NT receptors was demonstrated in vessel walls, stromal fibroblasts, immune cells, and sometimes within neoplastic cell bodies. Approximately 33% of bronchioloalveolar carcinomas exhibited a strong membrane NGF and TrkA immunoreactivity, whereas 46% adenocarcinomas expressed an intense TrkA immunoreactivity but a weak immunostaining for NGF within tumor cells. Moreover, squamous cell carcinomas developed an intense TrkA immunoreactivity only within stroma surrounding neoplastic cells. A faint BDNF and TrkB immunoreactivity was documented in adenocarcinomas, squamous cell carcinomas, and small cell lung cancers. NT-3 and its corresponding TrkC receptor were found in a small number of squamous cell carcinomas within large-size tumor cells. No expression of low-affinity p75 receptor protein was found in tumor cells. The detection of NTs and NT receptor proteins in tumors of the lower respiratory tract suggests that NTs may be involved in controlling growth and differentiation of human lung cancer and/or influencing tumor behavior.

The expression of Insulin-like Growth Factor 2 (IGF-2) and H19, two genes located on human chromosome 11p15 and provided with cell growth modulating activity, is regulated by parental imprinting, in that the activity of their alleles is dependent on the parental origin. Parental bias in the genetic alterations of chromosome 11p15 observed in several pediatric cancers suggests the involvement of imprinted genes in tumor development. We have previously reported that the number of functional IGF-2 alleles is frequently increased in rhabdomyosarcoma (RMS), as a consequence of either relaxation of imprinting (LOI) or gene duplication. Here we show that the expression of the H19 gene is significantly suppressed with respect to normal muscle tissue in 13 out of 15 rhabdomyosarcomas with embryonal histology (ERMS) and in three out of 11 rhabdomyosarcomas classified as alveolar subtype (ARMS). Since a growth-inhibitory activity has been found associated with the H19 gene, the extinction of its expression can contribute to RMS development. Parental imprinting of the H19 gene was found conserved in all informative RMSs, including those whose ICF-2 imprinting was relaxed, indicating that LOI is a gene-specific event. Seven ERMSs and one ARMS displaying low H19 RNA levels showed an underrepresentation of the expressed allele in their genotype. This result is consistent with the paternal imprinting of the H19 gene and with the preferential loss of the maternal 11p15 alleles in these neoplasms. Low H19 expression was also found in four out of eight RMSs retaining the heterozygosity at 11p15, but showing IGF-2 LOI. These findings suggest that the genetic and epigenetic alterations affecting chromosome 11p15 in a high number of RMSs cause deregulation of more than one imprinted gene, possibly affecting tumor growth, including the extinction of H19 expression and an increase in the number of active IGF-2 alleles.

Glycosaminoglycans prevent morphological renal alterations and albuminuria in diabetic rats. Abnormal glycosaminoglycan metabolism is involved in the onset of anatomo-functional derangements in diabetic nephropathy, and determines the loss of glomerular basement membrane anionic charges leading to albuminuria. Glycosaminoglycan administration was shown to increase the negative electrical potential of the vessel wall, inhibit mesangial cell proliferation, which is an anatomical hallmark of diabetic nephropathy, and slow down the progression to uremia in subtotally nephrectomized rats, a model that shares some pathogenetic key events with diabetic nephropathy. Based on these considerations, we verified the effect of exogenous glycosaminoglycans on renal involvement in streptozotocin diabetic rats. Long-term administration of two glycosaminoglycans (low-molecular weight heparin and dermatan sulphate) prevented glomerular basement membrane thickening, glomerular anionic charge reduction, as well as the onset of albuminuria without affecting glomerular filtration rate and metabolic control of the disease. Our data demonstrate that the long-term administration of glycosaminoglycans has a favorable effect on morphological and functional renal abnormalities in diabetic rats.

A continuous tumor cell line (LAP-35) was established from a primitive neuroectodermal tumor of bone from the right tibia of a 12-year-old female. The neural character of the cell line was documented by the spontaneous growth of neurites and by the presence of several neural markers, including neuron-specific enolase (NSE), S-100 protein, neurofilaments, chromogranin A, synaptophysin and positivity to monoclonal antibodies UJ127.11, UJ13A, UJ181.4. Cell-sorter analysis showed a high expression of nerve growth factor receptor (NGFr) and major histocompatibility complex class I-related molecules. A unique cytogenetic profile was observed, including a reciprocal chromosomal translocation (rct) 11:22 (q24;q12), typically associated with Ewing's sarcoma and neuroepithelioma, and deletion of the short arm of chromosome 1 (lp-), otherwise a feature of neuroblastoma. N-myc proto-oncogene was neither amplified nor expressed, whereas the expression of c-myc was documented by northern blot analysis. These features distinguish this new cell line from previously reported neuroectodermal cell lines, identifying LAP-35 as a unique model of a group of neural bone tumors that share characteristics of neuroblastoma as well as neuroepithelioma.