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PubMed1994

Sequence and expression pattern of the human MAGE2 gene.

We reported previously identification of the human MAGE1 gene, which encodes an antigen recognized on human melanoma MZ2-MEL by autologous cytolytic T lymphocytes. In addition to MAGE1, melanoma MZ2-MEL expresses several closely related genes, one of which has been named MAGE2. The complete MAGE2 sequence was obtained and it comprises 3 exons homologous to those of MAGE1 and an additional exon homologous to a region of the first MAGE1 intron. Like the open reading frame of MAGE1, that of MAGE2 is entirely encoded by the last exon. The MAGE1 and MAGE2 sequences of this exon show 82% identity and the putative proteins show 67% identity. The MAGE2 gene is expressed in a higher proportion of melanoma tumors than MAGE1. It is also expressed in many small-cell lung carcinomas and other lung tumors, laryngeal tumors, and sarcomas. No MAGE1 and MAGE2 gene expression was found in a large panel of healthy adult tissues, with the exception of testis.

Amino Acid Sequence↗
PubMed2003

Phase I and pharmacokinetic study of anhydrovinblastine every 3 weeks in patients with refractory solid tumors.

PURPOSE: Anhydrovinblastine (AVLB) is a novel semisynthetic vinca alkaloid. We conducted a phase I trial to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLT) and pharmacokinetics of AVLB given as a 1-h intravenous infusion once every 3 weeks in patients with advanced refractory solid tumors. PATIENTS AND METHODS: Entered into the study were 24 patients with normal bone marrow, hepatic and renal function, and of these 21 were evaluable. There were 12 males and 12 females with a median age of 60 years (range 27-75 years). Diagnoses were non-small-cell lung cancer (NSCLC) (11), colorectal cancer (5), soft tissue sarcoma (4), and miscellaneous (4). Patients had had a median of three prior chemotherapy regimens (range one to six). A total of 51 courses were administered at doses of 2.5, 5, 10, 16.5, 21, 25 and 30 mg/m(2) in one, three, one, three, six, six and one patient respectively. RESULTS: Grade 2 infusional hypertension, anemia, and dizziness were noted at 16.5 mg/m(2). At 25 mg/m(2), two of six evaluable patients had DLT. DLT was grade 4 constipation, neutropenia and grade 3 nausea/vomiting. At 21 mg/m(2) one of six evaluable patients had DLT (grade 3 nausea/vomiting). This dose was the MTD. Stable disease was noted in one patient with metastatic sarcoma to the lungs and in three patients with metastatic NSCLC. The pharmacokinetics of AVLB were linear, and well characterized by a two-compartment model, with a mean clearance of 26.4 l/h per m(2) and median terminal half-life of 18 h. CONCLUSIONS: The recommended phase II dose is 21 mg/m(2). A phase II study in NSCLC is being initiated.

Adult↗
PubMed2006

Radiation therapy with charged particles.

Charged particle beams can offer an improved dose conformation to the target volume as compared with photon radiotherapy, with better sparing of normal tissue structures close to the target. In addition, beams of ions heavier than (4)He exhibit a strong increase of the linear energy transfer in the Bragg peak as compared with the entrance region. These physical and biological properties are much more favorable than in photon radiotherapy. As a consequence, particle therapy with protons and heavy ions has gained increasing interest worldwide, and many clinical centers are considering introducing radiation therapy with charged particles. This contribution summarizes the physical and technical principles of charged particle therapy with protons and heavy ions. It briefly reviews the clinical experience gathered so far with proton therapy and gives a more detailed summary of the recent results in carbon ion therapy of skull base tumors, head and neck tumors, non-small-cell lung cancer, hepatocellular carcinomas, bone and soft-tissue sarcomas, and prostate cancer.

Humans↗
PubMed1990

The impact of osteonectin for differential diagnosis of bone tumors. An immunohistochemical approach.

75 osteosarcoma at various grades of histologic differentiation, including chondroblastic and small cell variants, and 5 fibrosarcomas of bone, 5 Ewing's sarcomas, 5 malignant fibrous histiocytomas of bone, 8 chondrosarcomas, and 2 dedifferentiated chondrosarcomas, were investigated immunohistochemically for evidence of osteonectin. According to the results of our study, osteonectin is present in all osteosarcomas, with special topographic preponderance in the osteoblastic and chondroblastic variants. Evidence of osteonectin was also found in all other bone tumors we had analysed so far. In chondrosarcomas, positive reactions appeared only in the vicinity of trabeculae and in dedifferentiated areas. Thus, osteonectin cannot be regarded as a bone-specific protein. Although a high affinity for the osseous matrix is one of its undoubted features, it is therefore unsuitable for differential diagnostic purposes.

Bone Neoplasms↗
PubMed1978

Evidence that tumor antigens enhance tumor growth in vivo by interacting with a radiosensitive (suppressor?) cell population.

The growth of a small number of cells from each of two chemically induced BALB/c sarcomas was enhanced when x-irradiated (15,000 rads) cells of the same sarcoma were mixed with the tumor inoculum. This enhancement did not occur if the recipients had been given a total body x-irradiation of 450 rads. Tumor neutralization (Winn) tests showed that tumor cells irradiated in vitro enhanced tumor growth only in the presence of radiosensitive cells present in the spleens of both nonimmune and tumor-bearing mice. On the basis of these findings we postulate that tumor antigen blocks effective tumor immunity by a mechanism that involves a suppressor cell population.

Animals↗
PubMed1988

A human inhibitor of tumor necrosis factor alpha.

Urine of some febrile patients exhibits a TNF-alpha inhibitory activity (TNF-alpha INH), sensitive to heat and trypsin, with an apparent mol wt of 40-60 X 10(3) and a pI range of 5.5-6.1. As for the Il-1 INH, the TNF INH activity involves a competitive mechanism of action suggesting the existence of a family of negative feedback-regulating molecules interfering with cytokines actions.

Carcinoma, Small Cell↗
PubMed1985

Skeletal muscle actin as tumor marker in the diagnosis of rhabdomyosarcoma in childhood.

Immunoaffinity-purified and tissue-specific antibodies against carp skeletal muscle actin have been assessed for their usefulness in diagnosing rhabdomyosarcoma. Routinely processed formaldehyde-fixed tissue and the avidin--biotinyl--peroxidase complex technique were used. Thirty-six tumors of patients varying in age from less than 1 year to 17 years were diagnosed as rhabdomyosarcoma on the basis of routine histological stains or electron microscopy, and on clinical grounds. Among them were 20 poorly differentiated tumors. All moderately and well-differentiated rhabdomyosarcomas and the majority of the poorly differentiated tumors (13 of 20) showed positive immunostaining for actin. Positive staining was observed in all three types of rhabdomyosarcoma, i.e., embryonal, alveolar, and pleomorphic. Besides rhabdomyosarcomas, the only other positive neoplasms were those that contained rhabdomyoblastic differentiation such as malignant "triton" tumors and malignant mixed müllerian tumors. Our results indicate that antibodies against skeletal muscle actin are a powerful tool for diagnosing rhabdomyosarcoma and that they can be used to distinguish the poorly differentiated forms from other types of small round cell tumors in childhood such as neuroblastoma, Ewing's sarcoma, and malignant lymphoma. The results are discussed in the light of the embryogenesis of cross-striated skeletal muscle.

Actins↗
PubMedDate not supplied

Pheochromocytoma combined with malignant schwannoma: unusual neoplasm of the adrenal medulla.

A 38-year-old woman was operated on to remove a large tumor that replaced the left adrenal gland. The tumor was encapsulated and showed small areas typical of pheochromocytoma, and spindle cell or undifferentiated round cell sarcoma in most areas. Metastases of primitive round cell appearance were operated from the abdominal cavity and abdominal wall shortly after the initial surgery. Eighteen months after the first operation, the patient was alive with metastases in liver and retroperitoneal space. The pheochromocytomalike component showed a typical ultrastructural and immunohistochemical profile of pheochromocytoma and was positive for neurofilaments, synaptophysin, neuron-specific enolase, and S-100 protein in the sustentacular cells. The sarcomatous areas showed fibroblastoid spindle cells that were often surrounded by a basal lamina. Immunohistochemistry revealed S-100 protein positivity in many spindle cells, but markers of pheochromocytoma or epithelial differentiation were absent. The metastases lacked all markers except for vimentin, and the cells were undifferentiated by electron microscopy. These findings suggest that the neoplasm was a compound tumor with a typical pheochromocytoma component and a sarcoma resembling a malignant schwannoma. Neoplastic proliferation of the S-100 protein-positive Schwann-cell-like sustentacular cells of the pheochromocytoma would be an explanation for the genesis of this sarcoma associated with pheochromocytoma.

Abdominal Neoplasms↗
PubMed1978

Phase I clinical study of quelamycin.

A phase I clinical study was done with quelamycin, a recently synthesized triferric derivative of adriamycin. Twenty-one good-risk patients were studied: 19 patients with non-small cell carcinoma of the lung and two patients with metastatic sarcoma. Acute toxicity occurred in all patients and consisted of high fever, flushing, hypertension, generalized body aches, tremors, and confusion, which lasted 3-6 hours. Potentially dangerous cardiotoxicity occurred in eight patients who had previous minor rhythm disturbances, and was characterized by tachycardia, atrial extrasystoles, atrial fibrillation, and branch block which lasted 6-14 hours. The dose-limiting hematologic toxicity was found to occur at 125 mg/m2 iv single-dose. Objective responses were observed in three of 19 patients with lung cancer and in one patient with metastatic osteogenic sarcoma resistant to adriamycin therapy. In conclusion, quelamycin is a new derivative of adriamycin with potential interest. However, the acute generalized toxicity and the immediate cardiotoxicity found in the presently used schedule are excessive. Further studies directed to suppress these side effects are in progress.

Adolescent↗
PubMed1981

Cytotoxic T cells in small intestine epithelial, lamina propria and lung lymphocytes.

We have examined the development of specific cytotoxic T-cell activity in the lungs and the epithelium and lamina propria of the small intestine following tumour cell inoculation by subcutaneous or intraperitoneal routes. After an intraperitoneal injection of tumour cells, large amounts of cytotoxic activity are detectable in the lungs and lamina propria. In comparison, the epithelial lymphocytes of the small intestine display low cytotoxic activity. After a subcutaneous injection, little cytotoxicity is detectable except in the lungs and the development of such cytotoxicity has a much shorter time course compared with that induced by an intraperitoneal inoculation of tumour cells. The data indicate a marked difference in the functional capacity of lymphocytes from the epithelium and lamina propria of the small intestine.

Animals↗
PubMed1975

Distinctive intestinal mast cell neoplasms of domestic cats.

By use of histologic, histochemical, and ultrastructural techniques a group of distinctive intestinal neoplasms of domestic cats, previously thought to arise from enterochromaffin cells, were redefined as mast cell neoplasms. Although these tumors differed histologically from the more typical visceral mast cell neoplasm of cats, ultrastructural and histochemical similarities between cells comprising both tumors were encountered. Differences in granule morphology and histochemical characteristics were, however, consistently demonstrated when the neoplasms were compared. The intestinal neoplasms are not associated with ulceration of the gastrointestinal tract unlike many mast cell tumors involving viscera. We suggest that the differences between the cells in the typical visceral and intestinal tumors confirm and extend the concept of the existence of morphologic and functionally heterogeneous populations of mast cells occurring in different anatomical locations of the body.

Animals↗
PubMed1996

A pneumovitrector for the diagnostic biopsy of the vitreous.

A full-function vitrectomy instrument (pneumovitrector) developed by the author is described. This instrument is composed of an aspirating and cutting system combined with an infusion line for injecting air or gas into the vitreous cavity. Simultaneous injection of gas and removal of the vitreous pneumovitrectomy allows for a large vitreous biopsy specimen that has not been diluted with infusion fluid and does not reduce the intraocular pressure. A biopsy of the vitreous is performed for the diagnosis of intraocular infection and ocular involvement in reticulum cell sarcoma (non-Hodgkin's lymphoma). While aspiration of a small amount of liquid vitreous is often sufficient for the diagnosis of bacterial endophthalmitis, a larger volume of liquid and solid vitreous is needed for the establishment of diagnoses such as fungal endophthalmitis and intraocular lymphoma. Diagnostic vitrectomy is performed using either a 20-gauge needle or a 22-gauge needle or a miniaturized vitrectomy system. In the latter case, vitrectomy instruments are often combined with either an infusion cannula or an infusing fiber optic light probe. In most situations, 0.1 to 0.2 ml of vitreous is removed prior to injection and replacement of the volume of the vitreous , in order to obtain the maximum amount of undiluted vitreous for culture or histologic evaluation. Although a complete vitrectomy can be performed and the aspirate collected in the vitrectomy cassette can be spun down to obtain solid material, this procedure is generally done in the operating room. Aspiration of the vitreous for the biopsy without simultaneous replacement of the vitreous volume limits the amount of biopsy specimen that can be taken and is accompanied by the collapse of the eye as a result of hypotony. To overcome this problem, a miniaturized instrument (pneumovitrector) has been developed by this author.

Biopsy↗
PubMed1983

Studies on the in vivo synthesis of methotrexate polyglutamates and their efflux properties in normal, proliferative, and neoplastic mouse tissues.

Synthesis of poly-gamma-glutamyl metabolites of methotrexate was demonstrated in mouse small intestine, liver and bone marrow, and in L1210 leukemia, Sarcoma 180 and Ehrlich tumor cells after sc injections of [3H]methotrexate to tumor bearing mice. Ion exchange chromatography of tissue extracts resolved six peaks of radioactivity believed to represent methotrexate and metabolites with up to 4 additional glutamyl residues. Polyglutamate formation in L1210 cells and small intestine was shown to be independent of dose at least to 400 mg/kg as long as intracellular levels of drug in excess of the dihydrofolate reductase binding capacity (exchangeable) were maintained. Both the total amount of polyglutamates and the average length of the polyglutamyl chain increased with time as long as exchangeable level of drug were present intracellularily. The results also showed differences in the extent of metabolism of methotrexate polyglutamates among the tissues examined. Although, these differences were at times very large, there was no consistent correlation between these differences and other pharmacologic parameters or cytoxicity. Tumor cells appeared to synthesize more polyglutamates than the normal tissues examined. However, differences in total drug persistence and sensitivity to drug among tumor cells and among normal tissues did not reflect the relative extent of polyglutamate synthesis in each group. We observed no selective retention of polyglutamates as compared to methotrexate by L1210 cells in vitro as indicated by the extracellular accumulation during efflux of methotrexate and the polyglutamates. This could only be demonstrated by allowing efflux of intracellular drug in the presence of extracellular dihydrofolate reductase, which averted hydrolysis of the polyglutamates. It is concluded that the extent of polyglutamate synthesis per se may not be a determinant of drug sensitivity in murine tissues. However, the accumulation of these metabolites may contribute in some way to overall therapeutic response or relative cytotoxicity.

Animals↗
PubMed1990

Differing specificities for 4-aminofolate analogues of folylpolyglutamyl synthetase from tumors and proliferative intestinal epithelium of the mouse with significance for selective antitumor action.

Folylpolyglutamyl synthetase (FPGS), partially purified from murine L1210 leukemia and Sarcoma 180 cells and the proliferative fraction of luminal epithelium from mouse small intestine (the site of limiting toxicity to folate analogues), was examined for its ability to utilize various 4-aminofolates as substrates. For tumor-derived FPGS, aminopterin was the most preferred substrate overall, exhibiting the lowest value for apparent Km and highest Vmax. The other analogues and folic acid exhibited nearly 2-fold lower Vmax. Folic acid exhibited a 3-fold higher Km than aminopterin. Alkylation of aminopterin (methotrexate) or carbon for nitrogen substitution (10-deazaaminopterin) at N-10 increased Km 3- to 6-fold, while alkylation at C10 (10-ethyl-10-deazaaminopterin) restored Km to near equivalency with aminopterin. For FPGS derived from proliferative intestinal epithelium, aminopterin was also the preferred substrate, but the value for Vmax (derived with crude cell-free extract) was 6-fold lower than for tumor cell FPGS. Values for Vmax (derived with partially purified FPGS) for the other 4-aminofolate analogues and folic acid were similar (methotrexate) or 2-fold (10-ethyl-10-deazaaminopterin) and 5-fold (folic acid) lower than for aminopterin. The value for Km derived with aminopterin was similar to that derived for either tumor cell FPGS. The value for folic acid was 2-fold higher, and alkylation of aminopterin (methotrexate) or carbon to nitrogen substitution (10-deazaaminopterin) at N-10 with (10-ethyl-10-deazaaminopterin) or without alkylation markedly increased Km (27-, 90-, and greater than 100-fold, respectively, for methotrexate, 10-ethyl-10-deazaaminopterin, and 10-deazaaminopterin). In other studies, it was found that the diglutamate of aminopterin (aminopterin +G1) was a relatively poor substrate for FPGS derived from all three sources compared with methotrexate diglutamate, both in respect to values for Km and Vmax that were measured in each case. Findings with FPGS derived from L1210 cells were confirmed by high-pressure liquid chromatography analysis of product formation during the reaction with the parent compounds. The significance of the results presented here to the question of relative toxicity and therapeutic activity of these analogues is discussed.

Animals↗
PubMed1988

Diagnosis of neuroblastoma metastasis in bone marrow with a panel of monoclonal antibodies.

Neuroblastoma, along with rhabdomyosarcoma, Ewing's sarcoma, and acute lymphoblastic leukemia/lymphoma, is one of the small, round-cell tumors of childhood. All of these malignancies show a propensity to metastasize to bone marrow. Occasionally when the clinical picture is unclear and the tumor is particularly anaplastic, it can be difficult to arrive at a diagnosis by conventional histological and biochemical procedures. In the present study, a panel of nine monoclonal antibodies was used to undertake a detailed analysis of seven bone marrows contaminated with tumor cells: six cases of stage IV neuroblastoma, and one case of stage IV-S neuroblastoma. The antibody profiles obtained were compared with those deduced from the studies of over 20 marrows from patients with acute lymphoblastic leukemia. A comparison of these data with those obtained from the studies of rhabdomyosarcoma and Ewing's sarcoma cell lines and tissues suggests that when high levels of tumor cells are present in the marrow, it is possible to obtain a confident diagnosis of either neuroblastoma or acute lymphoblastic leukemia. In addition, the immunocytological identification of neuroblasts in bone marrow enables accurate staging without histological examination.

Antibodies, Monoclonal↗
PubMed1997

Peripheral primitive neuroectodermal tumor involving the paravertebral and retroperitoneal regions.

A rare case of peripheral primitive neuroectodermal tumor (PNET) is reported. A 68-year-old woman complaining of lumbago was admitted to our hospital. Diagnosis was made based on pathological findings characterized by Homer Wright-type rosettes. Ultrastructural examination showed the presence of neurosecretory granules and short cytoplasmic processes, which were highly suggestive of neural differentiation. Chromosomal analysis of the neoplastic cells revealed translocation (11;22)(q24;q12), which is often found in Ewing's sarcoma and Askin tumor. These results strengthen the hypothesis of a common histogenesis for these small round cell tumors, and suggest common oncogenesis for these neoplasms.

Aged↗