Aberrantly low STAT3 and STAT5 responses are associated with poor outcome and an inflammatory gene expression signature in pediatric acute myeloid leukemia

The relapse rate for children with acute myeloid leukemia is nearly 40% despite aggressive chemotherapy and often stem cell transplant. We sought to understand how environment-induced signaling responses are associated with clinical response to treatment. We previously reported that patients whose AML cells showed low G-CSF-induced STAT3 activation had inferior event-free survival compared to patients with stronger STAT3 responses. Here, we expanded the paradigm to evaluate multiple signaling parameters induced by a more physiological stimulus. We measured STAT3, STAT5 and ERK1/2 responses to G-CSF and to stromal cell-conditioned medium for 113 patients enrolled on COG trials AAML03P1 and AAML0531. Low inducible STAT3 activity was independently associated with inferior event-free survival in multivariate analyses. For inducible STAT5 activity, those with the lowest and highest responses had inferior event-free survival, compared to patients with intermediate STAT5 responses. Using existing RNA-sequencing data, we compared gene expression profiles for patients with low inducible STAT3/5 activation with those for patients with higher inducible STAT3/5 signaling. Genes encoding hematopoietic factors and mitochondrial respiratory chain subunits were overexpressed in the low STAT3/5 response groups, implicating inflammatory and metabolic pathways as potential mechanisms of chemotherapy resistance. We validated the prognostic relevance of individual genes from the low STAT3/5 response signature in a large independent cohort of pediatric AML patients. These findings provide novel insights into interactions between AML cells and the microenvironment that are associated with treatment failure and could be targeted for therapeutic interventions (AU)

Aberrantly low STAT3 and STAT5 responses are associated with poor outcome and an inflammatory gene expression signature in pediatric acute myeloid leukemia.

The relapse rate for children with acute myeloid leukemia is nearly 40% despite aggressive chemotherapy and often stem cell transplant. We sought to understand how environment-induced signaling responses are associated with clinical response to treatment. We previously reported that patients whose AML cells showed low G-CSF-induced STAT3 activation had inferior event-free survival compared to patients with stronger STAT3 responses. Here, we expanded the paradigm to evaluate multiple signaling parameters induced by a more physiological stimulus. We measured STAT3, STAT5 and ERK1/2 responses to G-CSF and to stromal cell-conditioned medium for 113 patients enrolled on COG trials AAML03P1 and AAML0531. Low inducible STAT3 activity was independently associated with inferior event-free survival in multivariate analyses. For inducible STAT5 activity, those with the lowest and highest responses had inferior event-free survival, compared to patients with intermediate STAT5 responses. Using existing RNA-sequencing data, we compared gene expression profiles for patients with low inducible STAT3/5 activation with those for patients with higher inducible STAT3/5 signaling. Genes encoding hematopoietic factors and mitochondrial respiratory chain subunits were overexpressed in the low STAT3/5 response groups, implicating inflammatory and metabolic pathways as potential mechanisms of chemotherapy resistance. We validated the prognostic relevance of individual genes from the low STAT3/5 response signature in a large independent cohort of pediatric AML patients. These findings provide novel insights into interactions between AML cells and the microenvironment that are associated with treatment failure and could be targeted for therapeutic interventions.

Merging of the National Cancer Institute-funded cooperative oncology group data with an administrative data source to develop a more effective platform for clinical trial analysis and comparative effectiveness research: a report from the Children's Oncology Group.

PURPOSE: The National Cancer Institute-funded cooperative oncology group trials have improved overall survival for children with cancer from 10% to 85% and have set standards of care for adults with malignancies. Despite these successes, cooperative oncology groups currently face substantial challenges. We are working to develop methods to improve the efficiency and effectiveness of these trials. Specifically, we merged data from the Children's Oncology Group (COG) and the Pediatric Health Information Systems (PHIS) to improve toxicity monitoring, to estimate treatment-associated resource utilization and costs, and to address important clinical epidemiology questions. METHODS: COG and PHIS data on patients enrolled on a phase III COG trial for de novo acute myeloid leukemia at 43 PHIS hospitals were merged using a probabilistic algorithm. Resource utilization summary statistics were then tabulated for the first chemotherapy course based on PHIS data. RESULTS: Of 416 patients enrolled on the phase III COG trial at PHIS centers, 392 (94%) were successfully matched. Of these, 378 (96%) had inpatient PHIS data available beginning at the date of study enrollment. For these, daily blood product usage and anti-infective exposures were tabulated and standardized costs were described. CONCLUSIONS: These data demonstrate that patients enrolled in a cooperative group oncology trial can be successfully identified in an administrative data set and that supportive care resource utilization can be described. Further work is required to optimize the merging algorithm, map resource utilization metrics to the National Cancer Institute Common Toxicity Criteria for monitoring toxicity, to perform comparative effectiveness studies, and to estimate the costs associated with protocol therapy.

Molecular alterations of the IDH1 gene in AML: a Children's Oncology Group and Southwest Oncology Group study.

Recent whole-genome sequencing efforts led to the identification of IDH1(R132) mutations in acute myeloid leukemia (AML) patients. We studied the prevalence and clinical implications of IDH1 genomic alterations in pediatric and adult AML. Diagnostic DNA from 531 AML patients treated on Children's Oncology Group trial COG-AAML03P1 (N=257), and Southwest Oncology Group trials SWOG-9031, SWOG-9333 and SWOG-9500 (N=274), were tested for IDH1 mutations. Codon R132 mutations were absent in the pediatric cohort, but were found in 12 of 274 adult patients (4.4%, 95% CI 2.3-7.5). IDH1(R132) mutations occurred most commonly in patients with normal karyotype, and those with FLT3/ITD and NPMc mutations. Patients with IDH1(R132) mutations trended toward higher median diagnostic white blood cell counts (59.2 x 10(9) vs 29.1 x 10(9) per liter, P=0.19) than those without mutations, but the two groups did not differ significantly in age, bone marrow blast percentage, overall survival or relapse-free survival. Eleven patients (2.1%) harbored a novel V71I sequence alteration, which was found to be a germ-line polymorphism. IDH1 mutations were not detected in pediatric AML, and are uncommon in adult AML.

DNA repair polymorphisms and outcome of chemotherapy for acute myelogenous leukemia: a report from the Children's Oncology Group.

Polymorphisms of DNA repair genes RAD51 and XRCC3 increase susceptibility to acute myeloid leukemia (AML) in adults, an effect enhanced by deletion of the glutathione-S-transferase M1 (GSTM1) gene. In this study, we genotyped 452 children with de novo AML treated on CCG protocols 2941 and 2961 and compared genotype frequencies with those of normal blood donors, and analyzed the impact of genotype on outcome of therapy. XRCC3 Thr241Met, RAD51 G135C and GSTM1 genotypes did not increase susceptibility to AML when assessed singly. In contrast, when XRCC3 and RAD51 genotypes were examined together a significant increase in susceptibility to AML was seen in children with variant alleles. Analysis of outcome of therapy showed that patients heterozygous for the XRCC3 Thr241Met allele had improved post-induction disease-free survival compared to children homozygous for the major or minor allele, each of whom had similar outcomes. Improved survival was due to reduced relapse in the heterozygous children, and this effect was most marked in children randomized to therapy likely to generate DNA double-strand breaks (etoposide, daunomycin), compared with anti-metabolite (fludarabine, cytarabine) based therapy. In contrast, RAD51 G135C and the GSTM1 deletion polymorphism did not influence outcome of AML therapy in our study population.

Long-term results of children with acute myeloid leukemia: a report of three consecutive Phase III trials by the Children's Cancer Group: CCG 251, CCG 213 and CCG 2891.

The Children's Cancer Group (CCG) conducted three Phase III prospective clinical trials for children with de novo acute myeloid leukemia between the years 1979 and 1995. A total of 1903 eligible children ages birth to 21 years of age were enrolled on CCG 251 (n=485), CCG 213 (n=532) and CCG 2891 (n=886). Follow-up is ongoing, with medians of 7.9, 10.9 and 8.6 years, respectively. These three clinical trials developed dose- and time-intensive induction regimens based upon high-dose cytarabine and daunomycin and randomly assigned patients to allogeneic bone marrow transplantation in first remission if an HLA-matched related donor was identified. Despite dose- and time-intensive induction regimens, remission induction rates remained relatively stable at 77-78%. However, overall survival, event-free survival and disease-free survival (DFS) increased for patients receiving intensive-timing induction therapy in comparison to patients who received standard-timing induction, regardless of the type of postremission therapy. Outcomes were best for patients receiving intensive-timing induction followed by matched related donor allogeneic transplantation with DFS of 65+/-9% at 6 years. These three clinical trials have established a strong foundation for the development of future studies focusing on further risk group stratification and the development of novel, molecularly-targeted therapies.

Postremission therapy for children with acute myeloid leukemia: the children's cancer group experience in the transplant era.

We reviewed consolidation therapy results and analyzed postremission outcomes for 1464 children less than 21 years old at diagnosis in five consecutive Children's Cancer Group acute myeloid leukemia trials between 1979 and 1996. Children in remission were allocated to allogeneic bone marrow transplantation (BMT) (N=373) in first remission, if a matched family donor was available. Remaining children were assigned consolidation chemotherapy (N=688) or autologous purged BMT (N=217), or withdrew from study before assignment, or with unknown data (N=186). Overall and disease-free survival were superior for children assigned allogeneic transplants. High (>50,000/microl) diagnostic white blood cell (WBC) count was prognostic for inferior outcome, but French-American-British (FAB) subtypes were not. Inv(16) is a favorable karyotypic feature for children in first remission and t(8;21) is not. Allogeneic transplantation benefit was evident in most children, including those with high or low diagnostic WBC count, each FAB subtype, and t(8;21), but was not seen in children with inv(16). Therefore, these data suggest reserving matched related donor allogeneic transplantation for children with inv(16) for second remission, but not those with t(8;21).

PTPN11 mutations in pediatric patients with acute myeloid leukemia: results from the Children's Cancer Group.

The PTPN11 gene encodes SHP-2, a nonreceptor protein tyrosine phosphatase that relays signals from activated growth factor receptors to p21(ras) (Ras) and other signaling molecules. Somatic PTPN11 mutations are common in patients with juvenile myelomonocytic leukemia (JMML) and have been reported in some other hematologic malignancies. We analyzed specimens from 278 pediatric patients with acute myelogenous leukemia (AML) who were enrolled on Children's Cancer Group trials 2941 and 2961 for PTPN11 mutations. Missense mutations of PTPN11 were detected in 11 (4%) of these samples. None of these patients had mutations in NRAS; however, one patient had evidence of a FLT3 alteration. Four of the patients with PTPN11 mutations (36%) were boys with French-American-British (FAB) morphology M5 AML (P=0.012). Patients with mutations also presented with elevated white blood cell counts. There was no difference in clinical outcome for patients with and without PTPN11 mutations. These characteristics identify a subset of pediatric AML with PTPN11 mutations that share clinical and biologic features with JMML.

Histopathology (International Neuroblastoma Pathology Classification) and MYCN status in patients with peripheral neuroblastic tumors: a report from the Children's Cancer Group.

BACKGROUND: The International Neuroblastoma Pathology Classification (International Classification), which was established in 1999, is significant prognostically and is relevant biologically for the evaluation and analysis of patients with neuroblastic tumors (NTs). MYCN amplification is a known molecular marker for aggressive progression of NTs. These have been used together as important prognostic factors to define risk groups for patient stratification and protocol assignment. METHODS: A total of 628 NTs (535 neuroblastomas [NBs]); 21 ganglioneuroblastoma, intermixed [GNBi]; 9 ganglioneuromas [GN]; and 63 ganglioneuroblastoma, nodular [GNBn]) from the Children's Cancer Group studies were evaluated histologically (favorable histology [FH] tumors vs. unfavorable histology [UH] tumors) according to the International Classification and were tested molecularly for MYCN status (amplified vs. nonamplified). Four tumor subsets (FH-nonamplified, FH-amplified, UH-nonamplified, and UH-amplified) were defined by histopathology and MYCN status, and their prognostic effects were analyzed. Detailed analysis between morphologic indicators (grade of neuroblastic differentiation and mitosis-karyorrhexis index [MKI]) and MYCN status was done by using tumors in the NB category. RESULTS: There were 339 FH-nonamplified tumors (5-year event free survival [EFS], 92.1%); 8 FH-amplified tumors (EFS, 37.5%); 172 UH-nonamplified tumors (EFS, 40.9%); and 109 UH-amplified tumors (EFS, 15.0%). The prognostic effects on patients with tumors in the four subsets were independent from the factors of patient age and disease stage (P < 0.0001). MYCN amplification was seen almost exclusively in tumors of the NB category, and no patients with tumors in either the GNBi category or in the GN category and only two patients with tumors in the GNBn category had amplified MYCN. Among the patients with tumors in the NB category, patients with FH-nonamplified tumors (309 patients) had an excellent prognosis, and patients with UH-amplified tumors (107 patients) had the poorest clinical outcome in any age group. The prognosis for children with UH-nonamplified tumors (111 patients) was poor when they were diagnosed at age > 1.5 years. It was also noted that patients with UH-amplified tumors (median age, 2.14 years) were diagnosed at a significantly younger age compared with the patients with UH-nonamplified tumors (median age, 3.55 years). Histologically, MYCN-amplified tumors lacked neuroblastic differentiation regardless of the age of patients. MYCN amplification also was linked generally to increased mitotic and karyorrhectic activities. However, MKI classes in patients with MYCN-amplified tumors varied significantly, depending on the age at diagnosis, and younger patients had higher MKI classes. CONCLUSIONS: The combination of histopathologic evaluation and MYCN status distinguishes four clinical and biologic tumor subsets in patients with NTs. MYCN amplification seems to be the powerful driving force for preventing cellular differentiation regardless of patient age and for increasing mitotic and karyorrhectic activities in an age dependent manner.

International neuroblastoma pathology classification for prognostic evaluation of patients with peripheral neuroblastic tumors: a report from the Children's Cancer Group.

BACKGROUND: The International Neuroblastoma Pathology Classification was established in 1999 for the prognostic evaluation of patients with neuroblastic tumors (NTs). METHODS: Pathology slides from 746 NTs (the Children's Cancer Group [CCG]-3881 and CCG-3891 studies) were evaluated according to the International Classification. First, prognostic effects of the morphologic indicators (grade of neuroblastic differentiation: undifferentiated [U], poorly differentiated [PD] and differentiating [D]; and mitosis-karyorrhexis index [MKI]: low [L-MKI], intermediate [I-MKI], and high [H-MKI]) for tumors in the neuroblastoma (NB) category were tested. Then, prognostic significance of the International Classification for all NTs in four categories (neuroblastoma [NB]; ganglioneuroblastoma, intermixed [GNBi]; ganglioneuroma [GN]; and ganglioneuroblastoma, nodular [GNBn]) was analyzed. Finally, age distribution of the patients in the four categories as well as three subtypes (based on the grade of differentiation) in the NB category was compared. RESULTS: There were 630 NB tumors, 30 GNBi tumors, 10 GN tumors, and 76 GNBn tumors. In the NB category, prognostic effects of the indicators (three grades of differentiation and three mitosis-karyorrhexis index [MKI] classes: low [L], intermediate [I], and high [H]) were affected significantly by the age of the patients. The age-linked evaluation of the indicators according to the International Classification successfully distinguished two prognostic subgroups: the favorable histology (FH) subgroup (PD/D and L/I-MKI tumors in patients age < 1.5 years, D and L-MKI tumors in patients ages 1.5-5.0 years; 90.4% 5-year event free survival [EFS]) and the unfavorable histology (UH) subgroup (U and/or H-MKI tumors in patients of any age, PD and/or I-MKI tumors in patients ages 1.5-5.0 years, any grade of differentiation, and any MKI class in patients age > or = 5 years; 26.9% EFS) (P < 0.0001). The International Classification also distinguished the FH group (FH subgroup with NB, GNBi, and GN tumors) and the UH group (UH subgroup with NB and GNBn tumors) for all NTs (90.8% EFS and 31.2% EFS, respectively; P < 0.0001) and provided independent prognostic information on both patient age and disease stage (P < 0.0001). Among patients with FH tumors, the median ages of patients with the PD and D subtype tumors in the NB category were 0.43 years (range, 0-1.50 years) and 1.50 years (range, 0.02-4.65 years), respectively, and the median ages of patients with GNBi and GN tumors were 3.51 years (range, 0.96-14.85 years) and 4.80 years (range, 1.94-17.05 years), respectively. In contrast, patients with UH tumors generally were older when they were diagnosed, and with median ages of 2.99 years (range, 1.30-8.84 years) for patients with U subtype tumors, 2.59 years (range, 0.0-12.57 years) for patients with PD subtype tumors, 2.16 years (range, 0.35-9.90) for patients with D subtype tumors, and 3.26 years (range, 0.57-15.90 years) for patients with GNBn tumors. CONCLUSIONS: This study confirmed the prognostic significance of the International Classification, substantiated age-linked prognostic effects of the morphologic indicators for patients with the tumors in the NB category, and supported the concept of an age-appropriate framework of maturation for patients with the tumors in the FH group.

High-dose melphalan, etoposide, total-body irradiation, and autologous stem-cell reconstitution as consolidation therapy for high-risk Ewing's sarcoma does not improve prognosis.

PURPOSE: To determine whether consolidation therapy with high-dose melphalan, etoposide, and total-body irradiation (TBI) with autologous stem-cell support would improve the prognosis for patients with newly diagnosed metastatic Ewing's sarcoma (ES). PATIENTS AND METHODS: Thirty-two eligible patients with newly diagnosed ES metastatic to bone and/or bone marrow were enrolled onto this study. Treatment was initially comprised of five cycles of induction chemotherapy (cyclophosphamide, doxorubicin, and vincristine alternating with ifosfamide and etoposide) and local control. Peripheral-blood stem-cell collection was performed after the second cycle of chemotherapy, with delay if the bone marrow was persistently involved. If patients had a good response to initial therapy, they proceeded to consolidation therapy with melphalan, etoposide, TBI, and stem-cell support. RESULTS: Of the 32 eligible patients, 23 proceeded to high-dose therapy consolidation. Of the nine patients who did not proceed to consolidation, four were secondary to progressive disease and two were secondary to toxicity. Three patients died from toxicity during the high-dose phase of the therapy. The majority of the patients who underwent high-dose consolidation therapy experienced relapse and died with progressive disease. Two-year event-free survival (EFS) for all eligible patients is 20%. The 2-year post-stem-cell reconstitution EFS for the subset of 23 patients who received consolidation therapy is 24%. Analysis of peripheral-blood stem-cell collections by molecular techniques for minimal residual disease showed contamination of at least some samples by tumor cells in all three patients with available data. CONCLUSION: Consolidation with high-dose melphalan, etoposide, TBI, and autologous stem-cell support failed to improve the probability of EFS in this cohort of patients with newly diagnosed metastatic ES.

Opsoclonus-myoclonus-ataxia syndrome in neuroblastoma: clinical outcome and antineuronal antibodies-a report from the Children's Cancer Group Study.

BACKGROUND: Opsoclonus-myoclonus-ataxia (OMA) is a paraneoplastic neurologic syndrome affecting 2-3% of children with neuroblastoma. Although children with OMA and neuroblastoma may have higher survival, many experience a significant amount of late neurologic impairment, which may be immunologically mediated. The aim of this study was to compare the outcome of neuroblastoma patients with and without OMA, relating to prognostic factors, treatment, and the presence or absence of anti-neuronal antibodies. PROCEDURE: Questionnaires were mailed out requesting information on the current neurologic status of patients who submitted sera at diagnosis to the Children's Cancer Group serum bank from 1980 to 1994. Information was requested on clinical and biological patient characteristics as well as clinical aspects of the patients identified as having OMA syndrome, including presentation and treatment for OMA, late sequelae of OMA, the presence or absence of antineuronal antibodies, and survival. Sera from 16 of the OMA patients and 48 case-controls with neuroblastoma were assayed for anti-neuronal antibodies. RESULTS: Of the 675 responses received, 21 patients had OMA. Ninety percent of OMA patients presented with non-metastatic disease, vs. 35% of non-OMA patients. Estimated 3-year survival for the OMA patients with nonmetastatic disease (stage I, II, III) greater than 1 year of age was 100% vs. 77% for similar non-OMA patients (P = 0.0222). At follow-up, 14/19 evaluable OMA patients displayed some form of developmental or neurologic abnormality. There was no significant correlation of late sequelae with antineuronal antibodies, age, time between OMA symptoms and diagnosis, or treatment given for tumor or OMA. There was a significant correlation of late sequelae with lower stage disease (I and II) compared to more advanced disease (III and IV). CONCLUSIONS: Patients with OMA and neuroblastoma have excellent survival but a high risk of neurologic sequelae. Favorable disease stage correlates with a higher risk for development of neurologic sequelae. The role of anti-neuronal antibodies in late sequelae of OMA needs further clarification.

Opsoclonus-myoclonus-ataxia syndrome in neuroblastoma: histopathologic features-a report from the Children's Cancer Group.

BACKGROUND: Opsoclonus-myoclonus-ataxia (OMA) is a paraneoplastic syndrome that occurs in about 2-3% of all cases of neuroblastoma. The histopathologic characteristics of neuroblastoma tumors associated with this syndrome were evaluated in a series of cases and controls. PROCEDURE: Pathology slides from a total of 54 neuroblastoma tumors were reviewed blindly. They included 13 tumors associated with opsoclonus-myoclonus and 41 age- and stage-matched controls. All tumors were classified into either the favorable (FH) or unfavorable histology (UH) group according to the International Neuroblastoma Pathology Classification (the Shimada system). Grade of lymphocytic infiltration was evaluated and presence or absence of lymphoid follicles was recorded in the individual tumor tissues. RESULTS: Twelve of 13 cases with opsoclonus-myoclonus were in the FH group. Twelve of 13 cases had diffuse (found in every section prepared from the multiple portions of the primary tumor) and extensive (occupying more than 50% of a single of multiple microscopic fields with x 100 magnification) lymphocytic infiltration with lymphoid follicles. Of the 41 control cases (27 FH and 14 UH tumors), 18 had focal areas of lymphocytic infiltration and six showed lymphoid follicles, but none had diffuse or extensive infiltration in their primary tumors. CONCLUSIONS: Diffuse and extensive lymphocytic infiltration with lymphoid follicles is a characteristic histologic feature of neuroblastic tumors with opsoclonus-myoclonus. This observation suggests an immune-mediated mechanism for this rare paraneoplastic syndrome.

Quantitative tumor cell content of bone marrow and blood as a predictor of outcome in stage IV neuroblastoma: a Children's Cancer Group Study.

PURPOSE: This study investigated the prognostic value of quantifying tumor cells in bone marrow and blood by immunocytology in children with high-risk, metastatic neuroblastoma. PATIENTS AND METHODS: Patients with stage IV neuroblastoma (N = 466) registered on Children's Cancer Group study 3891 received five cycles of induction chemotherapy and were randomized either to myeloablative chemoradiotherapy with autologous purged bone marrow rescue or to nonmyeloablative chemotherapy. Subsequently, they were randomized to 13-cis-retinoic acid or no further treatment. Immunocytologic analyses of bone marrow and blood were performed at diagnosis, week 4, week 12, bone marrow collection, and end induction and were correlated with tumor biology, clinical variables, treatment regimen, and event-free survival (EFS). RESULTS: Immunocytology identified neuroblastoma cells in bone marrow of 81% at diagnosis, 55% at 4 weeks, 27% at 12 weeks, 19% at bone marrow collection, and 14% at end induction. Tumor cells were detected in blood of 58% at diagnosis and 5% at collection. There was an adverse effect on EFS of increasing tumor cell concentration in bone marrow at diagnosis (P =.04), at 12 weeks (P =.006), at bone marrow collection (P <.001), and at end induction (P =.07). Positive blood immunocytology at diagnosis was associated with decreased EFS (P: =.003). The prognostic impact of immunocytology was independent of morphologically detected bone marrow disease, MYCN status, and serum ferritin level in bivariate Cox analyses. CONCLUSION: Immunocytologic quantification of neuroblastoma cells in bone marrow and blood at diagnosis and in bone marrow during induction chemotherapy provides prognostic information that can identify patients with very high-risk disease who should be considered for experimental therapy that might improve outcome.

Multidrug resistance-associated protein 1 (MRP1) expression in neuroblastoma cell lines and primary tumors.

BACKGROUND AND PROCEDURE: MRP1 expression by neuroblastomas was evaluated by Northern blot analysis in 21 cell lines and 90 primary untreated tumors. Cytotoxicity assay in cell lines was performed for five anticancer drugs used in treating neuroblastoma. RESULTS: MRP1 expression did not correlate with drug resistance or with MYCN RNA expression in cell lines. MRP1 expression was higher in drug-sensitive cell lines established after chemotherapy relative to cell lines at diagnosis, but highly drug-resistant cell lines showed low MRP1 expression. Positive expression of MRP1 RNA in primary tumors was associated with a poorer survival relative to MRP1-negative tumors. However, MRP1 expression levels did not correlate with age, stage, MYCN amplification, or MYCN expression, and higher MRP1 expression was not associated with a worse outcome. CONCLUSIONS: In neuroblastoma, positive MRP1 RNA expression at diagnosis has prognostic significance, but high drug resistance is conferred by mechanisms other than MRP1.

Histopathology defines prognostic subsets of ganglioneuroblastoma, nodular.

BACKGROUND: Ganglioneuroblastoma, nodular (GNBn) is a rare subtype of the family of neuroblastic tumors (neuroblastoma, ganglioneuroblastoma, and ganglioneuroma) that are classified in the unfavorable histology group according to the International Neuroblastoma Pathology Classification (Shimada system). Tumors of this subtype have been considered to represent a prototypic example of biologically and clinically nonaggressive (Schwannian stroma-rich and stroma-dominant) components combined with biologically and clinically aggressive nodular (Schwannian stroma-poor) components. However, detailed histopathologic analysis as well as thorough prognostic evaluation of patients with this subtype has not been reported. METHODS: Pathology slides and reports from a total of 70 GNBn patients from the Children's Cancer Group (CCG)-3881 and CCG-3891 studies were reviewed. Sixty-eight tumors were classified in the favorable subset (FS) or the unfavorable subset (US) based on the evaluation of nodular components by applying the same histopathologic criteria (patient age, grade of neuroblastic differentiation, mitosis-karyorrhexis index) that are used for neuroblastomas in the International Neuroblastoma Pathology Classification. Patient prognosis as well as clinical and biologic characteristics within the subsets were analyzed, and the results were compared with those from 654 non-GNBn patients who were enrolled in the same CCG studies during the same period. RESULTS: Patients with GNBn tumors, usually diagnosed at age > 1 year, had a significantly lower overall 5-year event free survival (EFS) rate than patients with non-GNBn subtypes (44.7% EFS vs. 65.0% EFS; P = 0. 0073). A significant difference in the outcome of the patients between the FS (22 patients; 86.1% EFS; 95.0% survival rate) and the US (46 patients; 29.0% EFS; 40.7% survival rate) of the GNBn subtype (P < 0.0005) was shown. When the cohort of patients with GNBn tumors was subdivided into FS and US, the outcomes were similar to those of patients with tumors of favorable histology (397 patients; 90.5% EFS; 97.6% survival rate) and with tumors of unfavorable histology (257 patients; 27.0% EFS; 35.7% survival rate) of the non-GNBn type. The patients with US tumors frequently (63.0%) presented with distant metastasis. CONCLUSIONS: The current study demonstrates that the nodular components in GNBn tumors are not always aggressive. The prognosis of these patients can be determined by the analysis of age-linked histopathologic features.

Loss of heterozygosity at 1p36 independently predicts for disease progression but not decreased overall survival probability in neuroblastoma patients: a Children's Cancer Group study.

PURPOSE: To determine the independent prognostic significance of 1p36 loss of heterozygosity (LOH) in a representative group of neuroblastoma patients. PATIENTS AND METHODS: Diagnostic tumor specimens from 238 patients registered onto the most recent Children's Cancer Group phase III clinical trials were assayed for LOH with 13 microsatellite polymorphic markers spanning chromosome band 1p36. Allelic status at 1p36 was correlated with other prognostic variables and disease outcome. RESULTS: LOH at 1p36 was detected in 83 (35%) of 238 neuroblastomas. There was a correlation of 1p36 LOH with age at diagnosis greater than 1 year (P = .026), metastatic disease (P<.001), elevated serum ferritin level (P<.001), unfavorable histopathology (P<.001), and MYCN oncogene amplification (P<.001). LOH at 1p36 was associated with decreased event-free survival (EFS) and overall survival (OS) probabilities (P<.0001). For the 180 cases with single-copy MYCN, 1p36 LOH status was highly correlated with decreased EFS (P = .0002) but not OS (P = .1212). Entering 1p36 LOH into a multivariate regression model suggested a trend toward an independent association with decreased EFS (P = .0558) but not with decreased OS (P = .3687). Furthermore, allelic status at 1p36 was the only prognostic variable that was significantly associated with decreased EFS in low-risk neuroblastoma patients (P = .0148). CONCLUSION: LOH at 1p36 is independently associated with decreased EFS, but not OS, in neuroblastoma patients. Determination of 1p36 allelic status may be useful for predicting which neuroblastoma patients with otherwise favorable clinical and biologic features are more likely to have disease progression.