Biomedical subjects
Publications and source records attributed to K K Matthay.
Current results suggest that purged autologous bone marrow transplant may improve outcome for some subsets of high risk neuroblastoma, but the risk of relapse is still high.
BACKGROUND: Neuroblastomas show different histopathologic phenotypes, and the tumor cells can carry normal or multiple copies of the N-myc proto-oncogene (MYCN). Studies of the N-myc gene and histopathology of untreated primary neuroblastomas have demonstrated that both these factors are important in risk assessment. PURPOSE: Our purpose was to determine if there are any associations between N-myc gene copy number, histopathologic features, clinical stage, and progression-free survival (PFS) and if joint analyses of histopathology and N-myc gene copy number improve risk assessment. METHODS: The histopathologic phenotype and N-myc gene copy number were determined for 232 biopsy/surgery specimens obtained from untreated primary neuroblastoma patients. Tumors were classified as having favorable or unfavorable histology on the basis of Schwannian stroma (rich versus poor), neuroblastic differentiation (differentiating versus undifferentiated), and mitosis-karyorrhexis (fragmenting nucleus) index (MKI; high, intermediate, or low) in the context of age at diagnosis (Shimada classification). N-myc gene amplification was considered significant when the gene copy number was at least 10-fold higher than normal as determined by Southern blot analysis. Otherwise, tumors were classified as nonamplified for N-myc. RESULTS: Among 19 stroma-rich tumors, 11 had grossly visible neuroblastic nodules, and two of these had N-myc amplification. Of 213 stroma-poor tumors, 51 had N-myc amplification, all of which were undifferentiated, and 45 (88% of 51) had high MKI. This histologic phenotype was present in less than 10% of tumors with nonamplified N-myc. Of 162 stroma-poor tumors that showed nonamplified N-myc, 45 (28%) were differentiating and 121 (75%) had low MKI. Neuroblastomas of clinical stages I, II, and IV-S nearly always had favorable histology and no amplification of N-myc. Stage III (regional) and particularly stage IV (metastatic) tumors, however, frequently had unfavorable histologic features with or without N-myc amplification. The estimated PFS at the end of 4 years after diagnosis was 83% for patients whose tumors had favorable histology and no N-myc amplification. The estimated PFS for the patients whose neuroblastomas had unfavorable histology, however, was 29% without and 13% with N-myc amplification, respectively. Subsets of patients with stage II, III, or IV disease were identified by both histologic evaluation and N-myc analysis. Multivariate Cox regression analysis indicated that both the histologic and N-myc-based stratifications provided prognostic information that was independent of staging. CONCLUSIONS: Neuroblastomas with N-myc amplification have a characteristic histopathologic phenotype and an aggressive clinical course. In contrast, neuroblastomas without N-myc amplification exhibit a wide range of histologic features that can define prognostic subsets.
Explore the source record for details and available documents.
BACKGROUND: The survival in neuroblastoma is influenced by patient age, disease stage, tumor site, and several biologic factors. This study was undertaken to determine if primary pelvic lesions are associated with an unusually favorable outcome. METHODS: Nine hundred eighty-six patients registered on Children's Cancer Group studies from 1980 to 1993 were reviewed, and 41 (4.3%) were found to have pelvic tumors. Survival was analyzed, and correlations among age, stage of disease, surgical resectability, histopathology, serum ferritin, and N-myc oncogene amplification were evaluated. RESULTS: Age at diagnosis was comparable between patients with pelvic and nonpelvic tumors. Disease distribution was similar, with stages III and IV comprising 78% (32 of 41) of pelvic lesions compared with 73% (692 of 945) for nonpelvic tumors. There was no outcome difference in favorable stages (I, II, and IV-S), with 3-year progression-free survival rates of 88% and 82% for pelvic and nonpelvic sites, respectively. However, in stages III and IV, the 3-year progression-free survival was 70% for pelvic lesions compared with 47% for nonpelvic tumors (p = 0.04). Some favorable biologic factors were more common in children with pelvic lesions. CONCLUSIONS: The pelvis is an unusual primary site for neuroblastoma but represents a more favorable prognostic subgroup, which is most evident in advanced-stage disease.
Although precise anatomic staging is prognostically important in neuroblastoma, most widely employed staging systems remain incompatible. The International Neuroblastoma Staging System (INSS) was formulated to incorporate the basic elements of several systems to and define the significance of tumor resectability, anatomic "midline," and lymph node involvement. The authors sought to determine the applicability and value of the INSS compared with the classic Evans system. Between 1980 and 1992, 424 children with the diagnosis of local or regional neuroblastoma were entered in Childrens Cancer Group (CCG) clinical trials. The patients were assigned to Evans stage I, II, or III, by clinical and surgicopathologic assessment, and were treated uniformly by Group-wide therapy protocols. INSS stage 1, 2A, 2B, or 3, was applied, by retrospective analysis, to the children in the earlier studies, and by prospective evaluation of recent patients in the current studies. Survival and relapse-free survival (RFS) rates were determined and compared, based on age at diagnosis, extent of resection, and staging reassignment. All 87 Evans stage I patients were classified as INSS stage 1 and had a 92% 3-year RFS rate. Of the 144 Evans stage II patients, 65 also qualified as INSS stage 1 patients, with an 82% RFS rate. The other 79 stage II children remained in INSS stage 2A or 2B and had a 70% RFS rate (P = .10). Of the 193 Evans stage III patients, 24 were reassigned to INSS stage 1 (85% RFS rate) and 33 to stage 2A or 2B (65% survival rate; 61% RFS rate).(ABSTRACT TRUNCATED AT 250 WORDS)
The use of new strategies for dose intensification using peripheral blood stem cell or autologous purged bone marrow rescue has raised expectations for cure in advanced neuroblastoma, although conflicting reports exist regarding the efficacy of these approaches. Using risk groups based on both biological and clinical staging, the Children's Cancer Group (CCG) has conducted a series of pilot studies to test new induction, consolidation and myeloablative regimens to attempt to improve outcome. We summarise below the outcome and prognostic factor analysis for the pilot chemotherapy trial, CCG-(CCG-321P2), and the use of high dose myeloablative chemoradiotherapy with allogeneic (CCG-321P1) or autologous purged bone marrow rescue (CCG-321P3) for high risk neuroblastoma patients who were progression-free at the end of induction chemotherapy. After autologous bone marrow transplantation (ABMT), progression-free survival (PFS) at 4 years was 38% (median follow-up 4 years). Prognostic factors for relapse after ABMT included pre-BMT disease status, bone marrow tumour content at harvest, extent of primary resection at diagnosis, and time to ABMT. MYCN amplification, age, stage, and pre-BMT myeloablative regimen were not significant. Allogeneic BMT did not have a better outcome than ABMT. In a retrospective, non-randomised comparison of ABMT and chemotherapy, there was a significant difference in PFS for stage IV patients. High risk subgroups possibly benefiting from ABMT could be identified, including those with tumour MYCN amplification, over 2 years at diagnosis, and those not in complete remission at the end of induction. A randomised prospective trial comparing myeloablative therapy with ABMT to continuous infusion consolidation chemotherapy is currently underway in CCG to determine the relative benefit.
PURPOSE: Treatment of neuroblastoma cell lines with 13-cis-retinoic acid (cis-RA) can cause sustained inhibition of proliferation. Since cis-RA has demonstrated clinical responses in neuroblastoma patients, it may be effective in preventing relapse after cytotoxic therapy. This phase I trial was designed to determine the maximal-tolerated dosage (MTD), toxicities, and pharmacokinetics of cis-RA administered on an intermittent schedule in children with neuroblastoma following bone marrow transplantation (BMT). PATIENTS AND METHODS: Fifty-one assessable patients, 2 to 12 years of age, were treated with oral cis-RA administered in two equally divided doses daily for 2 weeks, followed by a 2-week rest period, for up to 12 courses. The dose was escalated from 100 to 200 mg/m2/d until dose-limiting toxicity (DLT) was observed. A single intrapatient dose escalation was permitted. RESULTS: The MTD of cis-RA was 160 mg/m2/d. Dose-limiting toxicities in six of nine patients at 200 mg/m2/d included hypercalcemia (n = 3), rash (n = 2), and anemia/thrombocytopenia/emesis/rash (n = 1). All toxicities resolved after cis-RA was discontinued. Three complete responses were observed in marrow metastases. Serum levels of 7.4 +/- 3.0 mumol/L (peak) and 4.0 +/- 2.8 mumol/L (trough) at the MTD were maintained during 14 days of therapy. The DLT correlated with serum levels > or = 10 mumol/L. CONCLUSION: The MTD of cis-RA given on this intermittent schedule was 160 mg/m2/d. Serum levels known to be effective against neuroblastoma in vitro were achieved at this dose. The DLT included hypercalcemia, and may be predicted by serum cis-RA levels. Monitoring of serum calcium and cis-RA levels is indicated in future trials.
OBJECTIVE: The purposes of our study were to investigate the use of MR angiography with two- (2D) and three-dimensional (3D) displays in evaluating vascular morphology of musculoskeletal neoplasms for preoperative planning of limb-salvage surgery and to assess the use of MR angiography for monitoring changes in neovascularity and evaluating response to chemotherapy. SUBJECTS AND METHODS: We used MR angiography (2D time-of-flight) to study 13 patients with primary bone tumors (nine osteogenic sarcomas, two Ewing's sarcomas, and two primary lymphomas of bone) at the time of initial presentation. Eight patients (all of whom had osteogenic sarcoma) also underwent MR angiography following chemotherapy before limb-salvage surgery. Two-dimensional maximum intensity projections were obtained. Three-dimensional reconstructions of vascular structures were created from the angiographic source images and were displayed simultaneously with 3D reconstructions of tumor and normal bone generated from conventional MR images. RESULTS: Two-dimensional maximum intensity projections were useful for evaluating small vessel neovascularity; 3D displays demonstrated spatial relationships of tumor, feeder vessels, and normal vascular structures. Tumor encroachment onto or encasement of normal vascular structures was shown in four patients on 2D maximum intensity projections and on 3D displays. The eight patients with osteogenic sarcoma who had follow-up imaging showed marked neovascularity prior to chemotherapy. Five patients responded to chemotherapy (> or = 90% tumor necrosis at histology); MR angiography showed marked reduction in tumor neovascularity in these patients. Three patients did not respond to chemotherapy; MR angiography showed unchanged neovascularity in one and increased neovascularity in two of these patients. CONCLUSION: MR angiography provides good visualization of peripheral vascular branches and tumor neovascularity in patients with primary bone tumors. MR angiography demonstrates encroachment onto and encasement of major vessels by the tumor mass and appears to be useful for assessing response to chemotherapy in osteogenic sarcoma and possibly other primary bone tumors by detecting treatment-induced changes in tumor neovascularity.
PURPOSE: We have compared the toxicity, relapse rate, and progression-free survival (PFS) of high-risk neuroblastoma patients receiving identical induction therapy and myeloablative chemotherapy plus total-body irradiation (TBI) followed by allogeneic or autologous purged bone marrow transplantation (BMT). PATIENTS AND METHODS: Fifty-six patients with high-risk neuroblastoma underwent BMT at investigator and parent option if they did not have progressive disease after induction chemotherapy with cisplatin, cyclophosphamide, doxorubicin, and etoposide. After surgery and local radiation to residual tumor, myeloablative therapy consisting of etoposide, melphalan, cisplatin, and TBI was given followed by BMT. Patients with human leukocyte antigen (HLA)-compatible siblings received allogeneic bone marrow (n = 20). The remaining patients (n = 36) received autologous bone marrow that had undergone multimodality purging and had no remaining detectable tumor cells by immunocytology. RESULTS: Four of 20 allogeneic patients had a treatment-related death, compared with three of 36 autologous patients (P = .21). The relapse rate among allogeneic BMT patients was 69%, compared with 46% for autologous BMT patients (P = .14). The estimated PFS rates 4 years after BMT were 25% for allogeneic BMT patients and 49% for autologous BMT patients (P = .051). CONCLUSION: Overall outcome for patients with neuroblastoma given this same induction therapy followed by autologous purged marrow was similar to that with allogeneic marrow, although bias in patients selection cannot be excluded in a nonrandomized comparison.
In the I-131 MIBG scans of 14 patients with neuroblastoma (86%) or pheochromocytoma/paraganglioma (14%) that were studied more than 48 hours after administration of the radiopharmaceutical, 12 (86%) had discernible cerebellar MIBG localization. A few had midbrain or diffuse cerebral uptake as well. None of the patients had cerebellar or other central nervous system signs or symptoms, and the localization is consistent with the known distribution density of central nervous system catecholamine receptors. This suggests that cerebellar MIBG localization is normal in delayed scans and that it should not be confused with neuraxial metastasis of adrenergic neuronal neoplasms.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
PURPOSE: The goal of this investigation was to determine if comparing sites of neuroblastoma at relapse after myeloablative chemoradiotherapy and purged autologous bone marrow transplantation (ABMT) with sites of disease at diagnosis and before ABMT could provide insight to the reasons for treatment failure. PATIENTS AND METHODS: Ninety-nine patients with high-risk neuroblastoma underwent ABMT after induction chemotherapy, surgery +/- local radiation (RT) and then myeloablative therapy with teniposide (or etoposide), melphalan, doxorubicin, cisplatin, and total-body irradiation (TBI). RESULTS: Forty-one of 84 assessable patients (15 toxic deaths) developed progressive disease 1 to 44 months after ABMT. The overall probability of relapse 36 months after ABMT was 49%. Tumor recurred in primary (n = 22), bone (n = 20), bone marrow (n = 18), lung (n = 3), and other sites (n = 9). Eight patients relapsed in the primary site alone, 14 in primary and distant sites, and 19 in distant sites only. Of 41 patients with progressive disease, 33 have died, with a median interval from relapse to death of 4 months. Both bone and bone marrow involvement at diagnosis correlated with specific relapse in that site (P < .05). Bone marrow tumor content at harvest greater than 0.1% also correlated with bone marrow relapse (P = .001). There was an association between incomplete resection of the primary tumor at diagnosis and relapse in that site (P = .06). CONCLUSION: Neuroblastoma normally recurs in multiple sites after ABMT, particularly in areas of previous disease. More intensive treatment to known areas of disease (aggressive early surgery, effective myeloablative consolidation therapy) and post-ABMT therapy for minimal residual disease should be studied for their potential to decrease the frequency of relapse.
PURPOSE: This trial was undertaken to determine if a continuous infusion format with increased dose-intensity had antitumor activity with tolerable toxicity in patients with advanced neuroblastoma. PATIENTS AND METHODS: Forty heavily pretreated patients with refractory or progressive neuroblastoma received continuous infusion doxorubicin, cisplatin, and etoposide along with bolus ifosfamide in a dose-escalation format. A total of 79 courses of chemotherapy were administered at five different dose levels. RESULTS: Fifteen of 35 assessable patients (43%) achieved either a partial response (PR) or complete response (CR), including five patients with a CR, three with a very good PR (VGPR), and seven with a PR. Hematologic toxicity was severe, but reversible, and other toxicities, although significant, were tolerable and much less than that accepted in a bone marrow transplantation (BMT) setting. CONCLUSION: This investigation illustrates that response is possible even in an extremely poor-prognosis group of patients, and it suggests that such a regimen may be effective if given before disease progression occurs.
Infantile myoclonic encephalopathy (opsoclonus-myoclonus or IME) is a rare clinical syndrome associated with occult neuroblastoma in 20%-50% of all cases. IME is the initial presentation of neuroblastoma in 1%-3% of children. Imaging approaches including chest radiography and abdominal computed tomography (CT) have been proposed to detect neuroblastoma in IME. Metaiodobenzylguanidine (MIBG) is highly effective in the detection of neuroblastoma. These scans can identify both soft-tissue and skeletal lesions anywhere in the body. Our purpose was to attempt to determine the best screening method for detection of occult neuroblastoma in patients with IME. Records of all neuroblastoma patients from 1983 to May 1991 were reviewed. Four cases of IME with neuroblastoma were identified in which imaging studies included an MIBG scan. All four patients had positive MIBG scans (100%) while only two had masses on initial CT (50%). In the three patients initially evaluated by traditional methods, the mean time to diagnosis and the mean number of advanced radiologic studies were 7.5 mo and 7.3 studies respectively. The patient screened with MIBG had only cranial and abdominal CT prior to surgery. Although based on a limited number of patients, results suggest that MIBG may prove to be a useful screening procedure in patients with IME. Traditional imaging modalities can then be directed to evaluate sites of disease identified by MIBG scans.
Multifocal osteogenic sarcoma patients without familial histories of increased tumor predisposition were examined for mutations in the highly conserved regions of the p53 gene. p53 point mutations were found in tumor DNA from each of the four patients we examined. A germ-line p53 mutation was detected in one of these patients, and a further rearrangement of the residual wild-type allele was detected in tumor tissue. p53 germ-line mutations can contribute to the enhanced predisposition to tumor development manifest in patients with multifocal osteosarcoma.
Efforts to overcome rapid uptake of liposomes by cells of the mononuclear phagocytic system (MPS) have identified that lipids derivatized with the hydrophilic polymer poly(ethylene glycol) (PEG) have many advantages. The structure-function relationship of PEG-derivatized phosphatidylethanolamine (PEG-PE) has been examined by studies of blood lifetime and tissue distribution in both mice and rats. Liposomes composed of phosphatidylcholine (PC), cholesterol, and 7.5 mol% of PEG-PE show prolonged circulation and reduced MPS uptake when the PEG has a molecular weight in the range of 1000 to 5000. Up to 35% of the injected dose remains in the blood and less than 10% is taken up by the MPS (liver plus spleen) after 24 h in the best cases as compared to 1% and 40%, respectively, for liposomes without PEG-PE. Prolonged circulation with PEG-PE is independent of cholesterol, degree of saturation in either the PC or the PE lipid anchor, lipid dose, or addition of other negatively charged lipids, phosphatidylglycerol or cholesterol sulfate. This versatility in lipid composition and dose without alteration of blood lifetime or tissue distribution is essential for controlling drug dosage and release properties in a liposome-based therapeutic agent.
Prophylactic central nervous system treatment has dramatically improved the disease-free survival of children with acute lymphoblastic leukemia (ALL). Long-term neuropsychological sequelae are documented in children who received 2400 cGy prophylactic cranial irradiation. The dose was reduced to 1800 cGy. Available reports on developmental consequences, with short follow-up, have yielded inconsistent results. This study assesses radiation dose effects on cognitive function in children with leukemia who received central nervous system prophylaxis with 2400 cGy versus 1800 cGy whole brain radiotherapy. All leukemic children also received intrathecal methotrexate. A control group of children (treated for Wilms' tumor) received no central nervous system therapy. Nineteen children were treated with 2400 cGy, 16 children with 1800 cGy. The 12 control children received no irradiation. All patients were off therapy for at least 70 months. The 1800 cGy and 2400 cGy patient groups were off therapy for equivalent periods of time (range 70-123 mo) at follow-up testing. Mean age at diagnosis was 49 months, at testing: 142 months. The male to female ratio was 1/1. Standardized psychological tests were administered. Full-Scale, Verbal, and Performance IQ were measured with the Wechsler Intelligence Scale for Children-Revised. Wide Range Achievement Testing evaluated reading, spelling, and arithmetic abilities. Children treated with 1800 cGy performed significantly better than those who received 2400 cGy, and at the same level as controls. There were statistically significant differences between the 1800 cGy and 2400 cGy subjects in all measures. 2400 cGy patients had deficiencies in IQ and academic performance. 1800 cGy patients scored approximately 12 points higher than 2400 cGy children. Eleven children, two in the control group, two in the 1800 cGy, and seven in the 2400 cGy group had IQ scores of less than 90. Eight of the nine irradiated children with deficits had radiotherapy before age 5. These results indicate a mild, but diffuse information processing deficit in children who received 2400 cGy, but not in children who received 1800 cGy. These findings with a minimum of 6 years of follow-up provide new information on late effects of CNS prophylaxis in ALL. Reducing the cranial RT dose from 2400 cGy to 1800 cGy reduced neurotoxicity to acceptable levels.