Medical and pediatric oncology最新文献

We evaluated the toxicity and maximum tolerated dose of topotecan in a novel myeloablative regimen as treatment for high-risk pediatric tumors. Patients received an assigned topotecan dosage in combination with fixed doses of carboplatin and thiotepa, followed by autologous hematopoietic stem cells infusion. Topotecan dose was escalated in cohorts of four patients until the maximum tolerated dose of topotecan was defined or until accrual of 30 patients. Pharmacokinetics of topotecan were examined, and event-free survival was estimated. We describe preliminary results following treatment of 25 pediatric patients with high-risk solid tumors.

Background: High-affinity somatostatin receptors (SRs) have been characterized in neuroblastomas and may be used as target structures for in vivo detection of SR.

Procedure: Eighty-eight children with histologically proven neuroblastoma were investigated at diagnosis or relapse by (123)I-mIBG and (111)In-pentetreotide scintigraphy. All tumors were investigated for MYCN copy number, chromosome 1p36 status, and 68/88 also for DNA content, followed for a median follow-up of 35 months (range 1-88 months).

Results: SR expression was detected in 56/88 tumors and (123)I-mIBG showed positivity in 83/88. (111)In-pentetreotide was less sensitive in detecting tumor tissue than was (123)I-mIBG (64% vs. 94%, P = 0.005). Survival (SUR) and event-free survival probability (EFS) according to Kaplan-Meier was significantly better for children with positive SR scintigraphy than for the children with a negative SR scan (SUR: 90% vs. 48% at 4 years log rank P < 0.003, EFS: 83% vs. 39% at 4 years, log rank P < 0.0002).

Conclusions: (123)I-mIBG scintigraphy remains the best scintigraphic method for detecting neuroblastoma tumor tissue, whereas additional SR scintigraphy is able to provide significant prognostic information with a minimum of invasiveness.

Background: Intrathecal antibody-based targeted therapies may have clinical potential for patients with leptomeningeal (LM) cancer.

Procedure: Five patients with GD2-positive LM tumors were injected with 1-2 mCi intra-Ommaya (131)I-3F8, a murine IgG3 antibody specific for GD2. Serial cerebrospinal fluid (CSF) and serum samples and SPECT imagings (4, 24, and 48 hr) were performed to predict radiation doses to the tumor and normal brain and blood prior to the administration of larger therapeutic doses.

Results: Side effects included self-limited fever, headache, and vomiting. Focal (131)I-3F8 uptake consistent with tumors was seen along the craniospinal axis in four patients. Calculated radiation dose to the CSF was 14.9-56 cGy/mCi and to blood and other organs outside the CNS less than 2 cGy/mCi.

Conclusions: Intraventricular (131)I-3F8 successfully detected LM disease and resulted in a large favorable CSF/blood ratio. Intraventricular (131)I-3F8 may have clinical utility in the diagnosis and radioimmunotherapy of GD2-positive LM cancers. Med. Pediatr. Oncol. 35:716-718. 2000.

Current study shows that about 50% of neuroblastomas (NBs) detected through mass screening had factor(s) indicating an unfavorable biological nature and that early intervention after the screening might improve clinical outcome of the patients. On the other hand, favorable properties were detected in the remaining half of the mass-screening NBs. Some of them might have the ability to regress spontaneously. Therapeutic modality should be determined according to their biological nature. Further investigation for their biologic properties is necessary to evaluate the benefits of the mass screening.

Background: Immunotherapy using cytokine-expressing tumor cells has shown promise as an anticancer strategy. We have recently begun a trial of interleukin-2 (IL-2) gene-modified allogeneic neuroblastoma cells administered in a sequence of eight injections to patients with high-risk neuroblastoma following completion of primary therapy. Six patients to date have completed treatment.

Procedure: We examined humoral responses to the immunizing cell line and, when available, to the patients' autologous tumor cells using an in vitro binding assay.

Results: Five of six patients developed a rise in antitumor antibodies to the immunizing neuroblastoma cell line following vaccination. Two of these patients had autologous tumor available; both demonstrated a humoral response to these cells as well.

Conclusions: Our results demonstrate that vaccination with IL-2-expressing allogeneic tumor cells after intensive primary therapy can elicit a humoral response to the immunizing line. These antibodies are cross-reactive with the patients' own tumor cells in the two cases in which autologous cells were available. This suggests that different patients' tumors may share common antigens that can be exploited in immunotherapy strategies and supports the continued exploration of allogeneic tumor cells as tumor vaccines.

Background: The suitability of CD34 selection for purging peripheral blood progenitor cells (PBPC) collected from patients with neuroblastoma (NB) has been called into question, largely because of reports of detection of low levels of CD34 on the surface of some NB cell lines and tumors.

Procedure: We used three approaches to address the issue of purging of NB from stem cell specimens and possible labeling of NB: 1) Flow cytometric detection of CD34 on NB cell lines. We assessed CD34 expression using a panel of anti-CD34 monoclonal antibodies (MoAbs) including 9C5, 12.8, and QBend10 and showed no increase in labeling over secondary-only control. 2) Spiking experiments with the Isolex 50 system. NB cell lines were used to contaminate aliquots of PBPC collections, after which the products were purified using the Isolex 50. Purging of NB was assessed by quantitative multiplex RT-PCR (TaqMan system) using a tumor-specific transcript, GAGE. We demonstrated >2 logs of tumor cell depletion from these specimens. 3) Analysis of clinical specimens. PBPC pre- and post-CD34 selection were analyzed from patients treated on the CHP-594 transplant trial.

Results: In nine specimens selected using the Ceprate LC CD34 selection system where tumor was detectable by immunocytochemistry preselection, we observed >2.4 to >4.6 logs of NB purging after selection. We then analyzed 23 aliquots of PBPC infused into patients post-CD34 selection and compared them to the product preselection; 20/23 specimens showed depletion of NB, although some level of GAGE message was observed in most post-CD34 selection specimens.

Conclusion: These data show that purging of NB from PBPC specimens using CD34 selection is feasible, yielding infused products that are negative at the level of ICC but often positive at the level of RT-PCR.

Background: The purpose was to investigate the influence of metastatic pattern and primary extension over midline on prognosis of infants with metastatic neuroblastoma.

Procedure: Data of 317 consecutive infants with metastatic neuroblastoma were analyzed.

Results: The amount of bone marrow infiltration (<10% vs. >10%) proved to be the most important factor and was more important than the presence of bone metastases. A disadvantage in outcome for patients with distant lymph node, intracranial, or atypical metastases or for patients with primary extension over midline could not be demonstrated. However, in the subgroup of patients treated with limited treatment, primary extension over midline proved a risk factor.

Conclusion: A redefinition of Stage 4S on an international basis is suggested.

Background: The aims of this study were to determine whether the introduction and expression of the noradrenaline transporter (NAT) gene into NAT-negative neuroblastoma cell lines would make them amenable to targeted radiotherapy using [(131)I]MIBG.

Procedure: Neuroblastoma cell lines were transfected with a eukaryotic expression vector containing the bovine noradrenaline transporter cDNA under the expression of the CMV promoter. Stable transfectants were created by selection in geneticin (G418) and were characterised for their MIBG uptake ability and susceptibility to [(131)I]MIBG therapy.

Results: The cell line SK-N-MC, which normally shows no ability to take up MIBG, was successfully transfected with bNAT. SK-N-MC.bNAT transfectants exhibited uptake and release kinetics similar to those of the natural NAT-expressing cell line SK-N-BE(2c). Levels of [(131)I]MIBG uptake were 33% of those of the highest naturally NAT-expressing cell line SK-N-BE(2c). Growth delay assays using multicellular spheroids indicated that this degree of [(131)I]MIBG uptake was sufficient to inhibit growth at radioactive concentrations of 4 Mbq/ml.

Conclusions: These results demonstrate the feasibility of combining gene therapy with targeted radiotherapy to enhance uptake, and hence radiation dose, to neuroblastoma tumours using [(131)I]MIBG. With the appropriate delivery vehicle and tumour-specific control of expression, the introduction of noradrenaline transporter molecules may be a viable means of enhancing the response of neuroblastoma tumours to [(131)I]MIBG therapy.

Background: Despite intensive-alkylator based regimens, >50% of patients with high-risk neuroblastoma (NB) die from recurrent disease that is probably due, in part, to acquired alkylator resistance.

Procedure: Using buthionine sulfoximine (BSO)-mediated, glutathione (GSH) depletion to modulate melphalan (L-PAM) resistance, we examined six NB cell lines established after progressive disease following either standard chemotherapy, BSO/L-PAM therapy, or myeloablative therapy and autologous hematopoietic stem cell transplant (AHSCT).

Results: Four of the six cell lines (three p53-nonfunctional and one p53-functional) showed high-level L-PAM resistance.

Conclusions: Fixed ratio analysis demonstrated BSO/L-PAM synergy (combination index >1) for all cell lines tested. In L-PAM-resistant cell lines, the minimal cytotoxicity observed for BSO combined with nonmyeloablative concentrations of L-PAM was markedly enhanced (>4 logs total cell kill) when BSO was combined with myeloablative concentrations of L-PAM. In alkylator-resistant NB, the optimal use of BSO may require dose escalation of L-PAM to levels requiring AHSCT.