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)

Chemoembolisation has been extensively used as primary treatment for unresectable hepatocellular carcinoma (HCC). In this unit, 185 patients with a new diagnosis of HCC not amenable to surgery were seen between 1988 and 1991. Intended therapy for these patients was chemoembolisation with doxorubicin (60 mg/m2) and lipiodol, repeated at six week intervals until it was technically no longer possible or until complete tumour response had been obtained. Chemoembolisation was possible in 67 of the 185 (37%). Reasons for exclusion were portal vein occlusion (n = 36), decompensated cirrhosis (n = 44), distant metastases (n = 5), diffuse tumour or unsuitable anatomy (tumour or vasculature) (n = 11), patient refusal (n = 11), and other (n = 11). Patients excluded from treatment survived for a median of 10 weeks (range 3 days-19 months). In patients treated, 18 had small HCC (< 4 cm) and 49 had large or multifocal HCC. Chemoembolisation was carried out a median of two sessions for small and three sessions for large tumours. Ten of 18 patients with small HCC showed a 50% or greater reduction in tumour size. Five of 49 patients with large or multifocal tumours showed a response to treatment. Median overall survival for treated patients was 36 weeks (range 3 days-4 years). One patient has subsequently undergone liver transplantation with no recurrence and minimal residual disease at transplantation. Two other patients are alive three years after chemoembolisation, one with no evidence of recurrent disease. No patient was thought suitable for surgery after their response to chemoembolisation. Chemotherapy related complications were seen in 22%. Complications were significantly more common in patients with larger tumours and poor liver reserve. Five patients died as a result of chemotherapy related complications. In conclusion, only one third of UK patients with unresectable HCC are treatable by chemoembolisation. Results with small tumours are encouraging, with a high response rate and the possibility of surgical intervention in previously inoperable disease. Large tumours, however, show a poor response and a significant incidence of side effects, suggesting that this treatment offers little benefit in advanced disease.
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PMID:Chemoembolisation with lipiodol and doxorubicin: applicability in British patients with hepatocellular carcinoma. 856 39

Despite considerable advancement in anticancer therapy, minimal residual disease (MRD) is still a major problem in the clinical management of cancer, including lymphoma. In this report, we have studied the antitumor effects of interleukin-12 (IL-12) against an aggressive liver metastatic murine RAW117-H10 lymphoma. Our results using three different doses of IL-12 (0.175, 0.35 and 0.7 micrograms/mouse) showed that a 0.35 micrograms dose is the most efficacious against lymphoma grown in intact mice. Furthermore, we have evaluated the therapeutic effects of IL-12 against residual lymphoma in a transplantation setting. BALB/c mice were treated with high-dose therapy (HDT) and transplanted with syngeneic bone marrow cells added with a known number of RAW117-H10 lymphoma cells to mimic the clinical situation of MRD. The mice were then treated with IL-12 (0.25 micrograms/mouse/day) alone or IL-12 plus activated cytotoxic effector cells. Our results showed that IL-12 had a significant (P < 0.05) antitumor therapeutic effect against liver metastatic lymphoma grown in intact mice as well as in lymphoma-bearing mice treated with HDT followed by stem cell transplantation as determined by survival period. The therapeutic effect of IL-12 was also demonstrated by a very significant decrease (P < 0.05) in the tumor burden in livers from the IL-12-treated mice. Mice that were treated with IL-12 following HDT and hematopoietic stem cell transplantation had a significant decrease in circulating white blood cells (P < 0.05), a significant increase in spleen weight and cellularity (P < 0.05), and hematopoietic progenitor cells (P < 0.05), a significant increase in the number of splenocytes expressing IL-2 alpha-chain receptor (P < 0.05), and an increase in the frequency of natural killer cells in their spleens. These studies suggest that cytokines such as IL-12 may have the potential to mediate antitumor effects against residual lymphoma without compromising lymphohematopoietic recovery.
Clin Exp Metastasis 1996 May
PMID:In vivo therapeutic effects of interleukin-12 against highly metastatic residual lymphoma. 867 76

The Ewing's family of tumors is comprised of bone and soft tissue, small round blue cell neoplasms of neuroectodermal origin defined by the chromosomal aberration t(11;22)(q24;q12), and closely related variants. Molecular methods now exist to facilitate diagnosis and to defect minimal residual disease. Multiagent chemotherapeutic regimens in concert with adequate local control yield improved survival rates in patients with localized disease at diagnosis. Patients with metastatic disease still suffer poor survival rates; programs attempting to cure metastatic patients with intensive therapy as facilitated by peripheral stem cell and autologous marrow rescue have shown some promise. Intensive regimens with and without rescue are being explored for high-risk patients.
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PMID:Ewing's sarcoma and extracranial primitive neuroectodermal tumors. 886 5

To evaluate the role of affinity in monoclonal antibody (mAb)-mediated treatment of carcinomas, we compared the antibodies 17-1A and 323/A3 that bind with different affinities overlapping epitopes on the epithelial adhesion molecule Ep-CAM. This comparison was performed in several models for minimal residual disease in mice grafted with Ep-CAM transfected B16 melanoma cells originating from C57BL/6 mice. These cells were either grafted subcutaneously or injected intravenously into nude BALB/c mice, or grafted subcutaneously in immunocompetent C57BL/6 mice. In the BALB/c subcutaneous model, significant therapeutic results (p < 0.05) compared with the control mAb were obtained with both mAbs 17-1A and 323/A3. However, when treating lung metastases in nude BALB/c mice that had developed after intravenous injection of the B16/Ep-CAM tumor cells, only the high-affinity 323/A3 mAb could significantly (p < 0.05) reduce the number of metastases that appeared. In syngeneic C57BL/6 mice grafted subcutaneously with B16/ Ep-CAM cells, a single 323/A3 or 17-1A mAb injection had no effect, in contrast to that observed for the nude BALB/c mouse model. However, multiple injections of the 323/A3 mAb significantly (p < 0.005) reduced the mean tumor volume, although they did not prevent tumor development. The results show that in vivo antibody-mediated effector cell activation and subsequent tumor cell elimination is determined by mAb affinity and target antigen density. Therefore, treatment of minimal residual disease with high-affinity mAb 323/ A3 is expected to improve the clinical results obtained with mAb 17-1A.
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PMID:The role of monoclonal antibody affinity in tumor immunotherapy evaluated in in vivo models for minimal residual disease. 887 19

Based on a literature review and the SSG experience, the most important prognostic factors in high-grade osteosarcoma appear to be the presence of detectable metastases at diagnosis, tumour volume, old age, sex, histologic response, and possibly tumoral P-glycoprotein expression. However, for an adolescent patient with non-metastatic extremity disease, there is no consensus regarding prognostic factors at initial presentation, and currently there is thus no established method for dividing them into high- and low risk groups for the purpose of treatment differentiation. It should also be remembered that available prognostic factors have been identified only in a retrospective manner, following aggressive treatment of all patients. Thus patients in "favourable" prognostic groups may simply be patients who have had a good effect from aggressive treatment, and how they would have done with reduced treatment remains to be shown. Obviously the best method for prognostication would be the direct demonstration of micrometastatic disease in the lungs or in peripheral blood. In the relatively near future, this may become possible with immunoscintigrapy or immunohistochemistry utilizing monoclonal antibodies [29-31]. In Ewing's sarcoma, the most powerful factors indicating poor prognosis are metastases at diagnosis, poor histologic response, large tumour size and possibly pelvic localisation. There appears to be a somewhat better international consensus regarding prognostic factors in Ewing's sarcoma than in osteosarcoma. Although several studies have implemented intensified treatment for poor prognostic groups [8, 32], the role (if any) of high-dose treatment with stem cell rescue remains to be proven. The same factors are prognostic both for the development of metastases and local recurrence, but in addition, surgical treatment as opposed to radiotherapy appears to reduce local failure rate [12, 17, 33, 34]. As in osteosarcoma, the near future offers promise regarding the detection and quantification of micrometastatses and minimal residual disease, by means of PCR techniques recognizing specific genetic changes in the Ewing family of tumors [35].
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PMID:Prognostic factors in bone sarcomas. 905 8

A recombinant humanized antibody-interleukin 2 fusion protein (huKS1/4-IL-2) was used to direct IL-2 to the tumor microenvironment and elicit a T cell-mediated eradication of established pulmonary and hepatic CT26-KSA colon carcinoma metastases in syngeneic BALB/c mice. This antitumor effect was specific because a fusion protein, which was nonreactive with these tumor cells, failed to exert any such effect. The efficacy of the huKS1/4-IL-2 fusion protein in eliminating metastases was documented because mixtures of monoclonal antibody huKS1/4 with recombinant human IL-2 were ineffective and, at best, only partially reduced tumor load. Two lines of evidence indicated the eradication of metastases and the absence of minimal residual disease in animals treated with the fusion protein: first, the lack of detection of CT26-KSA cells by reverse transcription-PCR, which can detect one tumor cell in 10(6) liver cells; and second, the tripling of life span. The effector mechanism involved in this tumor eradication is dependent on T cells because the IL-2-directed therapy is ineffective in T cell-deficient SCID mice. The essential effector cells were further characterized as CD8+ T cells by in vivo depletion studies. Such T cells, isolated from tumor-bearing mice after fusion protein therapy, elicited MHC class I-restricted cytotoxicity in vitro against colon carcinoma target cells. Taken together, these data indicate that fusion protein-directed IL-2 therapy induces a T cell-dependent host immune response capable of eradicating established colon cancer metastases in an animal tumor model.
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PMID:Elimination of established murine colon carcinoma metastases by antibody-interleukin 2 fusion protein therapy. 935 62

Chemoembolisation has been extensively used as primary treatment for unresectable hepatocellular carcinoma (HCC). In this unit, 185 patients with a new diagnosis of HCC not amenable to surgery were seen between 1988 and 1991. Intended therapy for these patients was chemoembolisation with doxorubicin (60 mg/m2) and lipiodol, repeated at six week intervals until it was technically no longer possible or until complete tumour response had been obtained. Chemoembolisation was possible in 67 of the 185 (37%). Reasons for exclusion were portal vein occlusion (n = 36), decompensated cirrhosis (n = 44), distant metastases (n = 5), diffuse tumour or unsuitable anatomy (tumour or vasculature) (n = 11), patient refusal (n = 11), and other (n = 11). Patients excluded from treatment survived for a median of 10 weeks (range 3 days-19 months). In patients treated, 18 had small HCC (4 cm) and 49 had large or multifocal HCC. Chemoembolisation was carried out a median of two sessions for small and three sessions for large tumours. Ten of 18 patients with small HCC showed a 50% or greater reduction in tumour size. Five of 49 patients with large or multifocal tumours showed a response to treatment. Median overall survival for treated patients was 36 weeks (range 3 days-4 years). One patient has subsequently undergone liver transplantation with no recurrence and minimal residual disease at transplantation. Two other patients are alive three years after chemoembolisation, one with no evidence of recurrent disease. No patient was thought suitable for surgery after their response to chemoembolisation. Chemotherapy related complications were seen in 22%. Complications were significantly more common in patients with larger tumours and poor liver reserve. Five patients died as a result of chemotherapy related complications. In conclusion, only one third of UK patients with unresectable HCC are treatable by chemoembolisation. Results with small tumours are encouraging, with a high response rate and the possibility of surgical intervention in previously inoperable disease. Large tumours, however, show a poor response and significant incidence of side effects, suggesting that this treatment offers little benefit in advanced disease.
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PMID:Is chemoembolisation of value in inoperable primary hepatocellular carcinoma. 951 40

Recently, cytokine gene transfer into tumour cells has been shown to mediate tumour regression in animal models via immunomodulation. Consequently, a number of clinical protocols have been developed to treat cancer patients with cytokine gene-modified tumour cells. Here, we report the results of a clinical phase I trial using for the first time autologous, interleukin 7 gene-modified tumour cells for vaccination of ten patients with disseminated malignant melanoma. Melanoma cells were expanded in vitro from surgically removed metastases, transduced by a ballistic gene transfer technique and were then injected after in vitro irradiation s.c. at weekly intervals. Clinically, there was no major toxicity except for mild fever, and no major clinical response towards vaccination was observed. Eight of ten patients completed the initial three s.c. vaccinations and were eligible for immunological evaluation. Post vaccination, peripheral mononuclear cells (PBMCs) were found to contain an increased number of tumour-reactive proliferative as well as cytolytic cells, as determined by a limiting dilution analysis. In three of six patients, the frequencies of anti-melanoma cytolytic precursor cells increased between 2.6- and 28-fold. Two of these patients showed a minor clinical response. Analysis of the autologous tumour cell vaccines regarding IL-7 secretion after gene transfer, HLA class I and class II cell surface expression, secretion of immunosuppressive mediators (TGF-beta1, IL-10) and various melanoma-associated tumour antigens revealed a very diverse expression profile. In conclusion, vaccination using gene-modified autologous melanoma cells induced immunological changes in a group of advanced, terminally ill patients. These changes can be interpreted as an increased anti-tumour immune response. However, immunological modulation was most pronounced in patients in good physical condition. Therefore, patients with minimal tumour load or minimal residual disease might preferentially benefit from tumour cell vaccination in further studies. In order to evaluate the effects of the cytokine gene-modified tumour cell vaccines more precisely, an antigenically better defined vaccine is needed.
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PMID:Vaccination with IL-7 gene-modified autologous melanoma cells can enhance the anti-melanoma lytic activity in peripheral blood of patients with a good clinical performance status: a clinical phase I study. 966 67

The induction of tumor-specific T-cell responses that are effective in eradicating disseminated tumors and in mounting a persistent tumor-protective immunity is one of the major goals of tumor immunotherapy. Here, we demonstrate that we achieved this goal by directing interleukin 2 (IL-2) to the tumor microenvironment of colon carcinoma metastases in syngeneic mice with a recombinant antibody-IL-2 fusion protein (huKS1/4-IL-2). Eradication of established pulmonary metastases is induced by a CD8+ T cell-mediated immune response, which can be transmitted to naive syngeneic severe combined immunodeficient mice by adoptive transfer of CD8+ T cells from immune animals. This immune response was followed by the induction of a long-lived immunity against challenge up to 5 months later with CT26-KSA or wild-type CT26 murine colon carcinoma cells in BALB/c mice. This memory immune response was confirmed by flow cytometric analyses of CD8+ T cells isolated from secondary lymphoid tissue that revealed a phenotypic profile typical of early memory T cells. This long-lived protective tumor immunity was successfully boosted to become optimally effective in all experimental animals by injections of noncurative doses of IL-2 fusion protein 4 days after challenge with tumor cells. Taken together, our results indicate that the huKS1/4-IL-2 fusion protein elicits a long-lived cellular memory immune response that can be amplified by additional applications of IL-2 fusion proteins. This approach could become useful for the treatment of colorectal carcinoma in an adjuvant setting, particularly in patients with minimal residual disease.
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PMID:Induction of persistent tumor-protective immunity in mice cured of established colon carcinoma metastases. 973 3

Immunocytokines are antibody-cytokine fusion proteins that combine the unique targeting ability of antibodies with the multifunctional activities of cytokines to activate effector cells in the tumor microenvironment. Here, we demonstrate the therapeutic efficacy of a tumor-specific immunocytokine, huKS1/4-IL2, which effectively inhibited growth and dissemination of lung and bone marrow metastases of human prostate carcinoma in severe combined immunodeficient mice. This antitumor effect was specific and highly effective, irrespective of reconstitution of these mice with human lymphokine-activated killer cells. Survival times of mice treated with huKS1/4-IL2 were increased 4-fold as compared with animals treated with a mixture of the corresponding antibody and recombinant human interleukin-2 (rhIL2). A persistent antitumor response after treatment with the huKS1/4-IL2 immunocytokine in B, T, and natural killer cell-deficient severe combined immuodeficient-BEIGE mice, depleted of granulocytes, implies a major role for macrophages in this treatment effect. Our data demonstrate that immunocytokine-directed interleukin-2 therapy to tumor sites is an immunotherapeutic approach with potent effects against disseminated metastases of human prostate carcinoma and suggest that this treatment could be effective in an adjuvant setting for patients with minimal residual disease.
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PMID:Suppression of human prostate carcinoma metastases in severe combined immunodeficient mice by interleukin 2 immunocytokine therapy. 979 90


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