Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027819 (neuroblastoma)
 27,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Despite intensified chemotherapy protocols, including autologous bone marrow transplantation (ABMT), stage IV neuroblastoma has a poor prognosis, and modern therapeutic trends are aimed at the eradication of minimal residual disease, which is though to be the main factor leading to relapse. In this pilot study, we report the systemic administration of high doses of interleukin-2 after ABMT in four patients. Five day cycles of IL-2 at a dose of 18 x 10(6) IU/m2/day were administered at variable time intervals as frequent as it was necessary to maintain the levels of natural killer (NK) cytotoxic activity higher than the median control value (40 LU/ml blood) throughout 1 year from the start of first IL-2 treatment. After IL-2 infusion, NK and LAK activities increased significantly (median 742 x 10(-3) LU/ml blood and 186.8 x 10(-3) LU/ml blood, respectively). Toxicities were transient and no life-threatening complications were observed. Fever, anorexia, skin rash and enlarged liver were always present. Anaemia, thrombocytopenia, leukocytosis, lymphocytosis and and eosinophilia occurred following most of the IL-2 courses. Although the small number of patients does not allow an estimation of the immunomodulatory-antineoplasic effects of IL-2, the results seem promising for the management of neuroblastoma patients.
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PMID:High-dose systemic interleukin-2 therapy in stage IV neuroblastoma for one year after autologous bone marrow transplantation: pilot study. 888 13

We investigated the in vitro antitumor activity of monocytes derived from autologous bone marrow transplanted (ABMT) patients treated in vivo with granulocyte-macrophage colony-stimulating factor (GM-CSF). Thirty-four patients (17 female, 17 male), median age 42 (range 3-57) years, were enrolled in the study. Fourteen patients were diagnosed with non-Hodgkin's lymphoma (NHL), eight with Hodgkin's disease (HD), nine with breast cancer and three with neuroblastoma. Six patients who did not receive GM-CSF post-ABMT served as controls. We assessed cytotoxicity, antibody-dependent cellular cytotoxicity (ADCC), expression of the activation antigen CD16, and cytokine production by an enriched population of monocytes (> 90% CD+14) pre-, during and post-GM-CSF administration. Within the group of patients receiving treatment, ADCC was significantly higher during in vivo GM-CSF administration than post-therapy (P < 0.05) and in 50% of these patients, ADCC increased during in vivo GM-CSF administration over pretreatment values. In addition, in vivo GM-CSF administration caused the monocytes to secrete elevated levels of tumor necrosis factor-alpha (TNF-alpha) and GM-CSF (P < 0.05). We conclude that GM-CSF augments monocyte-mediated cytotoxicity post-ABMT, and therefore may have a role in controlling minimal residual disease post-transplant.
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PMID:Granulocyte-macrophage colony-stimulating factor dependent monocyte-mediated cytotoxicity post-autologous bone marrow transplantation. 891 16

Residual neuroblastoma (NB) cells in bone marrow or peripheral progenitor hematopoietic cells harvests may be a source of relapse after autologous transplantation in patients with high stage neuroblastoma. Therefore a sensitive method for detecting minimal residual disease (MRD) in the harvested product is important so that an appropriate purging techniques can be applied and optimized. We report on the detection of NB cells by fluorescence in situ hybridization (FISH) for N-myc amplification and compare the sensitivity of FISH with a semiquantitative polymerase chain reaction (PCR) assay. As a model of MRD we used the neuroblastoma cell line IMR-32 diluted with normal peripheral blood lymphocytes. We were able to detect a single NB cell in 1000 normal mononuclear cells by FISH. The PCR method, using ethidium-bromide-stained gels, required at least 10% NB cells to be present for detection of an amplified band of the N-myc oncogene. Thus, FISH is ten to one hundred times more sensitive in detection of N-myc amplification than a differential PCR and thus it is the method of choice for detection of MRD in NB patients.
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PMID:Comparison of fluorescent in situ hybridization (FISH) and the polymerase chain reaction (PCR) for detection of residual neuroblastoma cells. 899 48

The observed response to [131I]MIBG therapy in advanced neuroblastoma after conventional therapy, the noninvasiveness of the procedure, and the high metabolic activity which is frequently observed in untreated tumors led to the concept of substituting [131I]MIBG therapy for combination chemotherapy at diagnosis prior to surgery in patients with advanced disease/high risk neuroblastoma. The objective of this approach is to reduce the tumor volume, enabling adequate surgical resection of the tumor, and to avoid toxicity and the induction of early drug resistance. Chemotherapy is reserved to treat minimal residual disease postoperatively. Thirty-one children who presented with inoperable neuroblastoma were treated according to this protocol. After an objective response to [131I]MIBG therapy at diagnosis, 19 of 27 evaluable patients (70%) had complete or > 95% resection of the primary tumor or did not require surgery at all. Only mild hematological toxicity was observed. It is concluded that [131I]MIBG therapy of neuroblastoma at diagnosis is feasible; its effectiveness in attaining operability of the primary tumor is at least equal to that of combination chemotherapy, but its toxicity is considerably less.
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PMID:[131I]MIBG as a first line treatment in advanced neuroblastoma. 900 52

Targeted interleukin-2 (IL-2) therapy with a genetically engineered antidisialoganglioside GD2 antibody-IL-2 fusion protein induced a cell-mediated antitumor response that effectively eradicated established bone marrow and liver metastases in a syngeneic model of neuroblastoma. The mechanism involved is exclusively natural killer (NK) cell-dependent, because NK-cell deficiency abrogated the antitumor effect. In contrast, the fusion protein remained completely effective in the T-cell-deficient mice or immunocompetent mice depleted of CD8+ T cells in vivo. A strong stimulation of NK-cell activity was also shown in vitro. Immunohistology of the leukocytic infiltrate of livers from treated mice revealed a strong staining for NK cells but not for CD8+ T cells. The therapeutic effect of the fusion protein was increased when combined with NK-cell-stimulating agents, such as poly I:C or recombinant mouse interferon-gamma. In conclusion, these data show that targeted delivery of cytokines to the tumor microenvironment offers a new strategy to elicit an effective cellular immune response mediated by NK cells against metastatic neuroblastoma. This therapeutic effect may have general clinical implications for the treatment of patients with minimal residual disease who suffer from T-cell suppression after high-dose chemotherapy but are not deficient in NK cells.
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PMID:Natural killer cell-mediated eradication of neuroblastoma metastases to bone marrow by targeted interleukin-2 therapy. 947 37

The increase in the number of patients treated with high-dose chemotherapy/autologous stem cell transplantation (HDC/ASCT) for solid tumor malignancies has generated concern about the infusion of tumor cell contamination in the graft. In an effort to study so-called minimal residual disease (MRD) in the HDC/ASCT setting, a variety of assay methods have been used. Although these assays vary in terms of sensitivity and specificity of tumor detection, they are in agreement as to the presence and viability of tumor cells in ASCT grafts. A growing body of evidence indicates that MRD is present in ASCT grafts from neuroblastoma, breast cancer, and ovarian cancer patients. More importantly, several retrospective studies have determined that the infusion of tumor cells with the ASCT graft is strongly associated with post-ASCT relapse. Gene-marking studies have directly demonstrated that infused tumor cells are present at sites of disease relapse. Thus, the issue of tumor contamination of autologous grafts is an area of growing concern. This review article details the current status of MRD in solid tumor malignancies, with emphasis on assay methodology, clinical utility, and clinical relevance in transplantation medicine.
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PMID:Minimal residual disease in solid tumor malignancies: a review. 950 77

The purpose of this study was to evaluate in a phase I-II trial whether low doses of recombinant human interleukin 2 (rHuIL-2) over a prolonged period of time are safe and effective in eradicating or controlling minimal residual disease in children with neuroblastoma given high-dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT). From January 1992 to July 1996, 17 consecutive patients, with either stage IV or relapsed neuroblastoma, were enrolled. Patients received rHuIL-2 after a median time interval (min-max) of 105 days (56-153) after HDCT and ASCT. The protocol consisted of 2 'priming' courses of rHuIL-2 at escalating doses administered intravenously at 72-h intervals, followed by 'maintenance' with 11 monthly and six bimonthly boosting 5-day courses administered subcutaneously on an outpatient basis. At April 1997, 7 out of the 17 patients had completed the treatment schedule, four had discontinued treatment because of toxicity and four because of relapse; the remaining two patients are still on treatment, having completed 15 courses. Expansion of T lymphocytes, together with an increase in both natural killer cells and in activated T lymphocytes was evidenced. After a median (min-max) follow-up time of 30 (16-64) months, 12 out of 17 patients are alive and well. Two patients relapsed and died 14 and 35 months after transplant. Three patients are alive after having relapsed at 41, 21 and 13 months. The actuarial 2-year event-free survival and overall survival are 67% and 92% respectively. Intermittent administration of low doses of rHuIL-2 given for a long period of time is well tolerated and seems capable of controlling minimal residual disease after HDCT and ASCT in children with high-risk neuroblastoma.
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PMID:Immunotherapy with low-dose recombinant interleukin 2 after high-dose chemotherapy and autologous stem cell transplantation in neuroblastoma. 971 39

Bone marrow biopsy is very important in diagnosis and follow-up of children affected by neuroblastoma (NB). Between June 1995 and May 1997 we studied 55 patients with NB stage 4. Specimens were obtained at the diagnosis (in 8 patients) and after chemotherapy (in 55 patients) in order to evaluate the effects of treatment on bone marrow disease. 88% of 343 biopsies were representative versus 99% of 639 aspirates. Of 8 stage 4 patients evaluated at diagnosis, 15/16 biopsies versus 9/15 aspirates were positive. Following chemotherapy, out of 298 evaluable sites examined, 111 biopsies versus 30 aspirates (37 versus 10%) were positive. Of 111 positive biopsies 53 showed a focal pattern (35 differentiated, 18 undifferentiated), while 51 showed a diffuse pattern (18 differentiated, 40 undifferentiated). Our results confirm previous literature data indicating a better efficacy of histology versus morphology in detecting residual bone marrow disease (especially in case of focal differentiated pattern). The recent introduction of a specific monoclonal antibody, called anti-GD2, has improved our capacity to detect minimal residual disease in patients' bone marrow. The inclusion of anti-GD2 immunohistochemistry in our evaluation will possibly increase our overall sensitivity to detect minimal residual disease and may provide information capable to direct the physician's decision into a more rational patient's treatment.
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PMID:[The morphological assessment of bone marrow infiltration in neuroblastoma]. 974 6

Bone marrow infiltration if documented at diagnosis in the majority of children with neuroblastoma. Despite its chemosensitivity it is difficult to eradicate. In addition, current methods to detect it following treatment are inadequate. The following two articles report improved results in evaluating the minimal residual disease in the bone marrow. The prognostic and therapeutic relevance will be presented and discussed.
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PMID:[Bone marrow infiltration in neuroblastoma]. 974 8

Recombinant antibody-cytokine fusion proteins are immunocytokines that achieve high cytokine concentrations in the tumor microenvironment and thereby effectively stimulate cellular immune responses against malignancies. The activation and expansion of immune effector cells, such as CD8+ T lymphocytes, by interleukin-2 immunocytokines resulted in the eradication of established pulmonary and hepatic metastases of murine melanoma and colorectal carcinoma in syngeneic mouse models. These immunocytokines were equally effective in eliminating established bone marrow and liver metastases of murine neuroblastoma by activating natural killer cells. The effective eradication of metastases by immunocytokines resulted in significant prolongation in life span of mice over that of controls receiving equivalent mixtures of antibody and interleukin-2, which failed to reduce the growth of disseminated metastases. Proof of concept was established, indicating that immunocytokine-induced activation and expansion of immune effector cells in the tumor microenvironment can effectively eradicate established tumor metastases. This promising new approach to cancer immunotherapy may lead to clinical applications that improve treatment of cancer patients with minimal residual disease in an adjuvant setting.
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PMID:Immunocytokines: a promising approach to cancer immunotherapy. 988 98


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