Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The most serious problem in current gene therapy is that clinical applications have often led to unsatisfactory results. Here we show novel concepts and crucial factors that have been missing for successful cytokine gene therapy. A clinically-relevant mouse model of primary and micro-metastatic osteosarcoma was generated by subcutaneously and intravenously injecting murine osteosarcoma LM8 cells, in which adenoviral gene transduction efficiencies were extremely low; current therapies remain less effective for such disseminated micro-metastases. A single injection of adenoviral vector encoding interleukin-2 gene (Ad.IL-2) was given only into the established primary tumor. Notably, antitumoral immunity was successfully elicited by IL-2 secretion from connective tissues adjacent to the primary tumor, and this immunity not only suppressed primary tumor growth but also eradicated disseminated micro-metastases in distant organs. Most importantly, not only minimal side effects but also maximal therapeutic effects were exerted only in the case of injecting the optimal (i.e., not the highest) dose of Ad.IL-2, because spleen injuries caused by excessive levels of circulating IL-2 might diminish the therapeutic effect. Although the narrow range of the optimal therapeutic expression level of IL-2 may be crucial, it was feasibly determined by serum IL-2 levels. Thus, a crucial factor for successful cytokine gene therapy is not the high gene transduction efficiency in the tumor, which has been generally recommended, but the use of the optimal therapeutic expression level. In conclusion, just a single injection of Ad.IL-2 into a primary tumor lesion, which is feasible, not invasive and cost effective, is potently therapeutic for distant disseminated micro-metastases, as long as the optimal therapeutic level is monitored. These novel concepts, which contradict those of previous studies, warn researches about the possible problems with the ongoing clinical cytokine gene therapy.
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PMID:Gene therapy eradicating distant disseminated micro-metastases by optimal cytokine expression in the primary lesion only: novel concepts for successful cytokine gene therapy. 1476 39

A number of genes are implicated in the initiation and progression of osteosarcoma; however, cytogenetic and comparative genomic hybridization studies indicate the involvement of additional unidentified genes. An examination of gene expression profiles in 22 high-grade osteosarcoma tumor specimens from 15 patients (including paired primary and metastatic samples from five patients) indicated that von Willebrand factor (vWF) mRNA expression may increase during tumor progression. vWF, a large glycoprotein previously considered to be expressed exclusively by endothelial cells and megakaryocytes, is involved in platelet aggregation and adhesion to the subendothelial matrix, processes critical to hematogenous tumor cell metastasis to the lung. Analysis of paired primary and metastatic osteosarcoma tumor samples from 10 patients revealed an increase in vWF gene expression in metastases (P=0.005). Immunohistochemistry showed that, in addition to the endothelial cells, vWF protein was also detected in osteosarcoma cells in vivo in 13 of 29 tumor specimens as well as in SAOS2, an osteosarcoma cell line. The tumor cell staining correlated positively with high vWF expression in the sample (P=0.006). Although vascular endothelial cells contribute to the vWF mRNA detected in the tumor samples, there was neither any correlation between vascular density (VD) and vWF mRNA expression nor between VD and clinical outcome. These findings suggest that vWF expression is deregulated in osteosarcoma tumors, potentially contributing to metastasis.
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PMID:von Willebrand factor expression in osteosarcoma metastasis. 1546 17

We report on the management and outcome of 96 patients who developed local recurrence (LR) after having definitive primary treatment with chemotherapy and surgery for non-metastatic osteosarcoma. LR developed at a median of 11 months from initial surgical treatment. 18% of patients had metastases prior to the diagnosis of LR and 23% were found to have metastases synchronously. The prognosis for this group with metastases was 14% survival at 2 years. In the 57 patients without metastases at the time of development of LR, survival was 51% at 2 years and 41% at 5 years. Treatment was by excision of the LR and radiotherapy or by amputation. The only significant prognostic factors identified were the presence of metastases at the time of development of LR (P < 0.0001) and small size of the LR. The role of adjuvant chemotherapy was unclear. Whilst every attempt should be made to avoid LR, patients who develop LR are curable, particularly if they do not have metastases at the time of diagnosis of the LR.
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PMID:Management and outcome after local recurrence of osteosarcoma. 1573 63

Multifocal osteosarcoma represents a rare and aggressive type of osteosarcoma in which multiple bone lesions are detected simultaneously in the absence of pulmonary or any other visceral organ involvement. Despite a multidisciplinary approach, overall survival remains poor and disease progresses, leading to death within 1 yr of diagnosis. Here we report a case of an 18-yr-old patient with extensively metastatic osteosarcoma developing diffuse calcification in lung, pleural, diaphragm, pericardial, subcutaneous metastases, and mediastinal lymph nodes after intensive multiagent chemotherapy. We provide an extensive review of the literature together with presentation of different aspects regarding the debate on the multicentric versus metastatic hypotheses for multifocal osteosarcoma. An update on the current understanding of the molecular features of this disease is also included.
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PMID:Diffuse calcification of metastases after intensive multiagent chemotherapy in widespread osteosarcoma leading to death in a 18-year-old male: report of a case and literature review. 1730 3

The incidence of metastatic osteosarcoma is increasing because of improved results following multi-agent chemotherapy and resection of the primary tumour. Metastases occur most commonly in the lungs, whereas bowel metastases are rare. We describe a 25-year-old female who presented with melaena six years after successful resection of an osteosarcoma of her right femur, and one year after resection of a solitary pulmonary metastasis. Imaging revealed a lesion arising within both the duodenum and the pancreas for which a Whipple's pancreatoduodenectomy was carried out, achieving complete resection. Histological examination confirmed the diagnosis of metastatic osteosarcoma. We believe this is only the second such case reported. At 11 months post-operatively she had no detectable disease. Although rare, osteosarcoma can metastasise to the intestine. The surgeon must be aware of this complication, and that bowel metastases are potentially resectable.
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PMID:Osteosarcoma metastasising to the duodenum and pancreas. 1746 28

Historically, osteosarcoma has been a problematic metastatic disease, with 40-80% of patients developing pulmonary metastasis after primary tumor resection. Recent treatment advancements have reduced the occurrence of metastatic lesions to less than 30%. Using attenuated Salmonella typhimurium, we previously demonstrated regression in tumor burden in murine solid tumor and metastatic models. We established a murine model for metastatic osteosarcoma to determine the effect of treatment with a single oral dose of attenuated S. typhimurium with (SalpIL2) and without (Sal-NG) a gene for a truncated human interleukin-2. Female balb/c mice were administered 2 x 10(5) (ATCC K7M2) osteosarcoma cells via tail vein injection from culture and treated by oral gavage of Salmonella species 3 days later. Mice were harvested for splenic lymphocytes and tumor enumeration by intratracheal injection with India ink 21 days after injection. Treatment with attenuated SalpIL2 reduced pulmonary metastases in number and volume compared to saline controls. Furthermore, splenic natural killer cell populations were increased 93% with SalpIL2 and 114% with Sal-NG compared to nontreated groups. This pulmonary metastasis model demonstrates attenuated Salmonella typhimurium with human interleukin-2 reduced metastatic osteosarcoma in mice and confirm the need for further investigation into the immunologic properties of SalpIL2 as a possible treatment for metastatic osteosarcoma.
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PMID:Attenuated Salmonella typhimurium with IL-2 gene reduces pulmonary metastases in murine osteosarcoma. 1842 36

An understanding of differential gene expression in highly metastatic osteosarcoma could provide gene targets for treatment of metastases. We compared gene expression profiles of high- (LM7) and low- (LM2) metastatic SaOS2-derived cell lines in an in vitro tissue culture model and examined several differentially regulated genes in vivo in a murine orthotopic xenograft model. We hypothesized an orthotopic inoculation of LM2 and LM7 cells would establish a primary lesion and the gene expression profile of cells grafted in this fashion would resemble the gene expression profile observed in an in vitro model. Thirty-five days after inoculation, animals were euthanized and both tibiae were harvested and rapidly frozen in liquid nitrogen. Human-specific GAPDH mRNA was present in two of four tibias inoculated with LM2 cells and three of four tibias inoculated with LM7 cells. Tibiae displaying the presence of human cells were assayed by semiquantitative reverse transcriptase polymerase chain reaction. We observed poor correspondence of in vitro to in vivo gene expression for either cell line. Accordingly, in vitro osteosarcoma gene expression data must be interpreted with caution until confirmed in vivo. Our orthotopic injection model allowed in vivo study of differential gene expression between these two cell lines but did not show radiographic evidence of an established primary lesion.
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PMID:Metastatic osteosarcoma gene expression differs in vitro and in vivo. 1851 56

Purpose. Original articles and abstracts published between January 1991 and January 1997 were selected according to specified criteria and reviewed to provide answers to five interesting questions about the systemic treatment of metastatic osteosarcoma.Results.(1) In patients with metastatic disease at presentation, what is the outcome after intensive multi-agent chemotherapy?Historically, survival has been poor, but may be improving with the use of ifosfamide-containing regimens.(2) Can response to new agents be evaluated better in patients who have received no previous chemotherapy?Based on limited data, this is probably true.(3) Is the response to neo-adjuvant chemotherapy, as determined by histopathology, similar for the primary tumor and synchronous pulmonary metastases?With intensive multi-agent chemotherapy, good histological response rates are in the range 70-90% for both groups.(4) What is the outcome, after intensive combined modality treatment with chemotherapy and surgery, in patients relapsing with metastases after previous adjuvant chemotherapy, and what are the important prognostic factors?Outcome is highly variable, but 5-year survival ranges between 25 and 50% and a good outcome is more likely if recurrent disease is limited to resectable lung metastases.(5) Can a biological agent (L-MTP-PE) prolong the time to relapse in patients with resected metastatic osteosarcoma?Preliminary data suggest that this is possible, but more studies are required.
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PMID:Metastatic osteosarcoma: a review of current issues in systemic treatment. 1852 Dec 13

Purpose. To report the outcome of 37 patients with metastatic osteosarcoma entered into a large randomized trial (EOI 80831/MRC B002) comparing two different regimens of chemotherapy in patients with osteosarcoma.Methods. Patients with biopsy-proven osteosarcoma localized and metastatic, age 40 years or younger, were randomized to receive either two-drug treatment with doxorubicin/cisplatin (DOX 25 mg m(-2) day(-1) x 3 + DDP 100 mg m(-2) on day 1 q 3 weeks x 6 courses) or three-drug treatment comprising high-dose methotrexate (HDMTX 8 mg m(-2) administered every 4.5 weeks x 4 courses) given 10 days before DOX/DDP.Results. Twenty-four patients with metastatic disease received the two-drug arm treatment and 13 received three-drug treatment. Despite chance imbalance in numbers, there were no major differences in age, sex, primary site or performance status. Baseline alkaline phosphatase (AP) was elevated more frequently (96 vs 42%) in the two-drug arm. Twenty-one of 24 patients in the two-drug arm and 11/13 patients in the three-drug arm had evaluable primary tumors concurrent with metastases. Respective clinical response rates for the two- and three-drug arms were 48% and 40% for primary tumors, and 33% and 55% for metastases. Respective survivals at 2 and 4 years were 36% and 9% for the two-drug arm, and 69% and 52% for the three-drug arm, and survival was better for patients with normal AP at presentation. When adjusted for AP, survival was not significantly different between the two treatments (hazard ratio 0.52, 95% confidence interval 0.22-1.23, p = 0.14). There were three long-term survivors among the metastatic patients, all of whom received the three-drug therapy.Discussion. It is likely that random bias in the population (small numbers, imbalance in size of groups, uneven distribution of AP) accounts for the difference in outcome favoring the three-drug treatment in patients with metastatic disease. More reliance can be placed on the finding that disease-free and overall survival in the adjuvant component of this study (Bramwell et al., J Clin Oncol 1992; 10: 1579-91) were better after two-drug treatment.
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PMID:A Randomized Comparison of two Short Intensive Chemotherapy Regimens in Children and Young Adults With Osteosarcoma: Results in Patients With Metastases: A Study of the European Osteosarcoma Intergroup. 1852 Dec 18

This report discusses a rare case of nephrectomy for metastatic osteosarcoma, the first performed laparoscopically, and proposes such management as a standard of care. A 21-year-old woman with a history of metastatic osteosarcoma involving her right kidney was referred to our institution for evaluation. She was managed with a hand-assisted laparoscopic nephrectomy. An exhaustive review of the English literature pertaining to this disease was performed. To our knowledge, this case represents only the sixth nephrectomy ever reported for metastatic osteosarcoma and the first performed by a laparoscopic approach. In addition, this is the first reported case of this disease invading the renal vein. The literature suggests that the incidence of renal involvement in osteosarcoma is significant and that renal imaging should be mandatory in such patients. When renal metastases are diagnosed, prompt nephrectomy is warranted. A minimally invasive approach in these patients should be considered.
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PMID:Nephrectomy in the management of metastatic osteosarcoma. 1882 37


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