9 results on '"Irwin, Meredith S."'
Search Results
2. Metastatic Neuroblastoma Confined to Distant Lymph Nodes (stage 4N) Predicts Outcome in Patients With Stage 4 Disease: A Study From the International Neuroblastoma Risk Group Database
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Morgenstern, Daniel A, London, Wendy B, Stephens, Derek, Volchenboum, Samuel L, Hero, Barbara, Di Cataldo, Andrea, Nakagawara, Akira, Shimada, Hiroyuki, Ambros, Peter F, Matthay, Katherine K, Cohn, Susan L, Pearson, Andrew DJ, and Irwin, Meredith S
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Cancer ,Pediatric ,Rare Diseases ,Neuroblastoma ,Neurosciences ,Clinical Research ,Cohort Studies ,Disease-Free Survival ,Humans ,Infant ,Loss of Heterozygosity ,Lymph Nodes ,Lymphatic Metastasis ,Neoplasm Metastasis ,Neoplasm Staging ,Prognosis ,Retrospective Studies ,Risk Factors ,Treatment Outcome ,Clinical Sciences ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
PurposeThe presence of distant metastases is one of the most powerful predictors of outcome in patients with neuroblastoma. However, the pattern of metastatic spread is not incorporated into current risk stratification systems. Small case series have suggested that patients with neuroblastoma who have metastatic disease limited to distant lymph nodes (4N disease) may have improved outcomes.Patients and methodsWe analyzed retrospective data from the International Neuroblastoma Risk Group database for patients diagnosed from 1990 to 2002. 4N patients were compared with the remaining stage 4 patients (non-4N), excluding those with missing metastatic site data.ResultsIn all, 2,250 International Neuroblastoma Staging System stage 4 patients with complete data were identified, of whom 146 (6.5%) had 4N disease. For 4N patients, event-free survival (EFS; 5-year, 77% ± 4%) and overall survival (OS; 5-year, 85% ± 3%) were significantly better than EFS (5-year, 35% ± 1%) and OS (5-year, 42% ± 1%) for non-4N stage 4 patients (P < .001). 4N patients were more likely to be younger (P < .001) and have tumors with favorable characteristics, including absence of MYCN amplification (89% v 69%; P < .001). In a multivariable analysis, 4N disease remained a significant predictor of outcome (hazard ratio for non-4N v 4N: 3.40 for EFS and 3.69 for OS). Within subgroups defined by age at diagnosis and tumor MYCN status, 4N disease was significantly associated with improved outcomes.Conclusion4N represents a subgroup with better outcome than that of other patients with metastatic disease. These findings suggest that the biology and treatment response of 4N tumors differ from other stage 4 tumors, and less intensive therapy should be considered for this cohort. Future exploration of biologic factors determining the pattern of metastatic spread is warranted.
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- 2014
3. Statistical Framework in Support of a Revised Children's Oncology Group Neuroblastoma Risk Classification System.
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Naranjo, Arlene, Irwin, Meredith S., Hogarty, Michael D., Cohn, Susan L., Park, Julie R., and London, Wendy B.
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NEUROBLASTOMA , *PROGRESSION-free survival , *REGRESSION analysis , *PROGNOSIS , *DIAGNOSIS - Abstract
Purpose: The International Neuroblastoma Risk Group (INRG) Staging System (INRGSS) was developed through international consensus to provide a presurgical staging system that uses clinical and imaging data at diagnosis. A revised Children's Oncology Group (COG) neuroblastoma (NB) risk classification system is needed to incorporate the INRGSS and within the context of modern therapy. Herein, we provide statistical support for the clinical validity of a revised COG risk classification system. Patients and Methods: Nine factors were tested for potential statistical and clinical significance in 4,569 patients diagnosed with NB who were enrolled in the COG biology/banking study ANBL00B1 (2006-2016). Recursive partitioning was performed to create a survival-tree regression (STR) analysis of event-free survival (EFS), generating a split by selecting the strongest prognostic factor among those that were statistically significant. The least absolute shrinkage and selection operator (LASSO) was applied to obtain the most parsimonious model for EFS. COG patients were risk classified using STR, LASSO, and per the 2009 INRG classification (generated using an STR analysis of INRG data). Results were descriptively compared among the three classification approaches. Results: The 3-year EFS and overall survival (± SE) were 72.9% ± 0.9% and 84.5% ± 0.7%, respectively (N = 4,569). In each approach, the most statistically and clinically significant factors were diagnostic category (eg, NB, ganglioneuroblastoma), INRGSS, MYCN status, International Neuroblastoma Pathology Classification, ploidy, and 1p/11q status. The results of the STR analysis were more concordant with those of the INRG classification system than with LASSO, although both methods showed moderate agreement with the INRG system. Conclusion: These analyses provide a framework to develop a new COG risk classification incorporating the INRGSS. There is statistical evidence to support the clinical validity of each of the three classifications: STR, LASSO, and INRG. [ABSTRACT FROM AUTHOR]
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- 2018
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4. Association of MYCN copy number with clinical features, tumor biology, and outcomes in neuroblastoma: A report from the Children's Oncology Group.
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Campbell, Kevin, Gastier‐Foster, Julie M., Mann, Meegan, Naranjo, Arlene H., Ryn, Collin, Bagatell, Rochelle, Matthay, Katherine K., London, Wendy B., Irwin, Meredith S., Shimada, Hiroyuki, Granger, M. Meaghan, Hogarty, Michael D., Park, Julie R., DuBois, Steven G., Gastier-Foster, Julie M, and Van Ryn, Collin
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NEUROBLASTOMA ,DNA copy number variations ,CANCER chemotherapy ,CHROMOSOME abnormalities ,MYC oncogenes ,EPITHELIAL cell tumors ,GENE amplification ,PROGNOSIS ,REGRESSION analysis ,RESEARCH funding ,TUMOR classification ,PROPORTIONAL hazards models ,RETROSPECTIVE studies ,GENOTYPES - Abstract
Background: High-level MYCN amplification (MNA) is associated with poor outcome and unfavorable clinical and biological features in patients with neuroblastoma. To the authors' knowledge, less is known regarding these associations in patients with low-level MYCN copy number increases.Methods: In this retrospective study, the authors classified patients has having tumors with MYCN wild-type tumors, MYCN gain (2-4-fold increase in MYCN signal compared with the reference probe), or MNA (>4-fold increase). Tests of trend were used to investigate ordered associations between MYCN copy number category and features of interest. Log-rank tests and Cox models compared event-free survival and overall survival by subgroup.Results: Among 4672 patients, 3694 (79.1%) had MYCN wild-type tumors, 133 (2.8%) had MYCN gain, and 845 (18.1%) had MNA. For each clinical/biological feature, the percentage of patients with an unfavorable feature was lowest in the MYCN wild-type category, intermediate in the MYCN gain category, and highest in the MNA category (P<.0001), except for 11q aberration, for which the highest rates were in the MYCN gain category. Patients with MYCN gain had inferior event-free survival and overall survival compared with those with MYCN wild-type. Among patients with high-risk disease, MYCN gain was associated with the lowest response rate after chemotherapy. Patients with non-stage 4 disease (according to the International Neuroblastoma Staging System) and patients with non-high-risk disease with MYCN gain had a significantly increased risk for death, a finding confirmed on multivariable testing.Conclusions: Increasing MYCN copy number is associated with an increasingly higher rate of unfavorable clinical/biological features, with 11q aberration being an exception. Patients with MYCN gain appear to have inferior outcomes, especially in otherwise more favorable groups. Cancer 2017;123:4224-4235. © 2017 American Cancer Society. [ABSTRACT FROM AUTHOR]- Published
- 2017
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5. Regulation of endocytosis via the oxygen-sensing pathway.
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Yi Wang, Roche, Olga, Yan, Mathew S., Finak, Greg, Evans, Andrew J., Metcalf, Julie L., Hast, Bridgid E., Hanna, Sara C., Wondergem, Bill, Furge, Kyle A., Irwin, Meredith S., Kim, William Y., Teh, Bin T., Grinstein, Sergio, Park, Morag, Marsden, Philip A., and Ohh, Michael
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ENDOCYTOSIS ,HYPOXEMIA ,PROGNOSIS ,PROTEIN-tyrosine kinases ,CANCER treatment ,GROWTH factors - Abstract
Tumor hypoxia is associated with disease progression, resistance to conventional cancer therapies and poor prognosis. Hypoxia, by largely unknown mechanisms, leads to deregulated accumulation of and signaling via receptor tyrosine kinases (RTKs) that are critical for driving oncogenesis. Here, we show that hypoxia or loss of von Hippel–Lindau protein—the principal negative regulator of hypoxia-inducible factor (HIF)—prolongs the activation of epidermal growth factor receptor that is attributable to lengthened receptor half-life and retention in the endocytic pathway. The deceleration in endocytosis is due to the attenuation of Rab5-mediated early endosome fusion via HIF-dependent downregulation of a critical Rab5 effector, rabaptin-5, at the level of transcription. Primary kidney and breast tumors with strong hypoxic signatures show significantly lower expression of rabaptin-5 RNA and protein. These findings reveal a general role of the oxygen-sensing pathway in endocytosis and support a model in which tumor hypoxia or oncogenic activation of HIF prolongs RTK-mediated signaling by delaying endocytosis-mediated deactivation of receptors. [ABSTRACT FROM AUTHOR]
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- 2009
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6. Ceritinib in paediatric patients with anaplastic lymphoma kinase-positive malignancies: an open-label, multicentre, phase 1, dose-escalation and dose-expansion study.
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Fischer, Matthias, Moreno, Lucas, Ziegler, David S, Marshall, Lynley V, Zwaan, C Michel, Irwin, Meredith S, Casanova, Michela, Sabado, Constantino, Wulff, Beate, Stegert, Mario, Wang, Luojun, Hurtado, Felipe K, Branle, Fabrice, Geoerger, Birgit, and Schulte, Johannes H
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ANAPLASTIC lymphoma kinase , *CHILD patients , *ANAPLASTIC large-cell lymphoma , *KARNOFSKY Performance Status , *OLDER patients , *THERAPEUTIC use of antineoplastic agents , *RESEARCH , *DRUG dosage , *GENETIC mutation , *HETEROCYCLIC compounds , *RESEARCH methodology , *PROGNOSIS , *MEDICAL cooperation , *EVALUATION research , *COMPARATIVE studies , *SULFONES , *TUMORS , *DRUG toxicity , *LONGITUDINAL method - Abstract
Background: Several paediatric malignancies, including anaplastic large cell lymphoma (ALCL), inflammatory myofibroblastic tumour (IMT), neuroblastoma, and rhabdomyosarcoma, harbour activation of anaplastic lymphoma kinase (ALK) through different mechanisms. Here, we report the safety, pharmacokinetics, and efficacy of ceritinib in paediatric patients with ALK-positive malignancies.Methods: This multicentre, open-label, phase 1 trial was done at 23 academic hospitals in ten countries. Children (aged ≥12 months to <18 years) diagnosed with locally advanced or metastatic ALK-positive malignancies that had progressed despite standard therapy, or for which no effective standard therapy were available, were eligible. ALK-positive malignancies were defined as those with ALK rearrangement, amplification, point mutation, or in the case of rhabdomyosarcoma, expression in the absence of any genetic alteration. Eligible patients had evaluable or measurable disease as defined by either Response Evaluation Criteria in Solid Tumours, version 1.1 for patients with non-haematological malignancies, International Neuroblastoma Response Criteria scan for patients with neuroblastoma, or International Working Group criteria for patients with lymphoma. Other eligibility criteria were Karnofsky performance status score of at least 60% for patients older than 12 years or Lansky score of at least 50% for patients aged 12 years or younger. This study included a dose-escalation part, followed by a dose-expansion part, in which all patients received treatment at the recommended dose for expansion (RDE) established in the dose-escalation part. Both parts of the study were done in fasted and fed states. In the dose-escalation part, patients were treated with once-daily ceritinib orally, with dose adjusted for body-surface area, rounded to the nearest multiple of the 50 mg dose strength. The starting dose in the fasted state was 300 mg/m2 daily and for the fed state was 320 mg/m2 daily. The primary objective of this study was to establish the maximum tolerated dose (ie, RDE) of ceritinib in the fasted and fed states. The RDE was established on the basis of the incidence of dose-limiting toxicities in patients who completed a minimum of 21 days of treatment with safety assessments and at least 75% drug exposure, or who discontinued treatment earlier because of dose-limiting toxicity. Overall response rate (defined as the proportion of patients with a best overall response of complete response or partial response) was a secondary endpoint. Activity and safety analyses were done in all patients who received at least one dose of ceritinib. This trial is registered with ClinicalTrials.gov (NCT01742286) and is completed.Findings: Between Aug 28, 2013, and Oct 17, 2017, 83 children with ALK-positive malignancies were enrolled to the dose-escalation (n=40) and dose-expansion (n=43) groups. The RDE of ceritinib was established as 510 mg/m2 (fasted) and 500 mg/m2 (fed). 55 patients (30 with neuroblastoma, ten with IMT, eight with ALCL, and seven with other tumour types) were treated with ceritinib at the RDE (13 patients at 510 mg/m2 fasted and 42 patients at 500 mg/m2 fed). The median follow-up was 33·3 months (IQR 24·8-39·3) for patients with neuroblastoma, 33·2 months (27·9-35·9) for those with IMT, 34·0 months (21·9-46·4) for those with ALCL, and 27·5 months (22·4-36·9) for patients with other tumour types. An overall response was recorded in six (20%; 95% CI 8-39) of 30 patients with neuroblastoma, seven (70%; 33-93) of ten patients with IMT, six (75%; 35-97) of eight patients with ALCL, and one (14%; <1-58) of seven patients with other tumours. The safety profile of ceritinib was consistent with that observed in adult patients. All patients had at least one adverse event. Grade 3 or 4 adverse events occurred in 67 (81%) of 83 patients and were mostly increases in aminotransferases (alanine aminotransferase increase in 38 [46%] patients and aspartate aminotransferase increase in 27 [33%] patients). At least one serious adverse event was reported in 40 (48%) of 83 patients and 31 (37%) of 83 patients had at least one grade 3 or 4 serious adverse event. 14 (17%) deaths occurred during the study, of which 12 were on-treatment deaths and two were after 30 days of the last dose. Of the 12 on-treatment deaths, ten were due to disease progression (neuroblastoma), one due to sepsis, and one due to intractable hypotension.Interpretation: Ceritinib 500 mg/m2 once daily with food is the recommended dose for paediatric patients with ALK-positive malignancies. Ceritinib showed promising preliminary antitumour activity in patients with ALK-positive refractory or recurrent IMT or ALCL, and in a subset of patients with relapsed or refractory neuroblastoma, with a manageable safety profile. Our data support the notion that ALK inhibitors should be considered in therapeutic strategies for paediatric patients with malignancies with genetic ALK alterations.Funding: Novartis Pharmaceutical Corporation. [ABSTRACT FROM AUTHOR]- Published
- 2021
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7. Association of heterogeneous MYCN amplification with clinical features, biological characteristics and outcomes in neuroblastoma: A report from the Children's Oncology Group.
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Campbell, Kevin, Naranjo, Arlene, Hibbitts, Emily, Gastier-Foster, Julie M., Bagatell, Rochelle, Irwin, Meredith S., Shimada, Hiroyuki, Hogarty, Michael, Park, Julie R., and DuBois, Steven G.
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CHI-squared test , *CONFIDENCE intervals , *FISHER exact test , *GENE amplification , *LONGITUDINAL method , *NEUROBLASTOMA , *RETROSPECTIVE studies , *DESCRIPTIVE statistics , *LOG-rank test , *DISEASE complications - Abstract
MYCN amplification (MNA) is associated with poor outcomes in neuroblastoma. Less is known about heterogeneous MNA within a tumour. We compared clinical characteristics, biologic features and clinical outcomes of patients with heterogeneous MNA to patients with either homogeneous MNA or MYCN wild-type tumours. In this retrospective cohort study, we categorized patients as having tumours with MYCN wild-type, homogeneous MNA (>20% amplified tumour cells) or heterogeneous MNA (≤20% amplified tumour cells). We used chi-squared or Fisher's exact tests to compare features between groups. We used log-rank tests and Cox models to compare event-free survival (EFS) and overall survival (OS) between groups. MYCN status and heterogeneity status (if amplified) could be ascertained in diagnostic tumour samples from 5975 patients, including 57 (1%) with heterogeneous MNA, 981 (16.4%) with homogeneous MNA, and 4937 (82.6%) with MYCN wild-type tumours. Multiple clinical and biological features differed between patients with heterogeneous vs. homogeneous MNA, including enrichment for thoracic primary sites and paucity of 1p loss of heterozygosity with heterogeneous MNA (p < 0.0001). Importantly, EFS and OS were not significantly different between patients with heterogeneous vs. homogeneous MNA. Further, EFS and OS for patients with heterogeneous MNA were significantly inferior to patients with wild-type MYCN. Although neuroblastomas with heterogeneous MNA demonstrate significantly different biological and clinical patterns compared with homogeneous MNA, prognosis is similar between the two groups. These results support current practice that treats patients with heterogeneous MNA similarly to patients with homogeneous MNA. • MYCN amplification (MNA) is a known adverse prognostic factor in neuroblastoma. • Only 1% of neuroblastomas have heterogeneous MNA, with MNA in ≤20% of tumour cells. • Clinical and biological features are distinct for heterogeneous MNA. • Outcomes with heterogenous MNA are worse than with wild-type MYCN. [ABSTRACT FROM AUTHOR]
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- 2020
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8. Prognostic significance of pattern and burden of metastatic disease in patients with stage 4 neuroblastoma: A study from the International Neuroblastoma Risk Group database.
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Morgenstern, Daniel A., London, Wendy B., Stephens, Derek, Volchenboum, Samuel L., Simon, Thorsten, Nakagawara, Akira, Shimada, Hiroyuki, Schleiermacher, Gudrun, Matthay, Katherine K., Cohn, Susan L., Pearson, Andrew D.J., and Irwin, Meredith S.
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NEUROBLASTOMA , *HEMATOPOIETIC stem cell transplantation , *METASTASIS , *STATISTICS , *DATA analysis , *CHILDREN , *THERAPEUTICS - Abstract
Neuroblastoma is a childhood cancer with remarkably divergent tumour behaviour and the presence of metastatic disease is a powerful predictor of adverse outcome. However, the importance of the involvement of specific metastatic sites or overall metastatic burden in determining outcome has not been fully explored. We analysed data from the International Neuroblastoma Risk Group database for 2250 patients with stage 4 disease treated from 1990 to 2002. Metastatic burden was assessed using a ‘metastatic site index’ (MSI), a score based on the number of metastatic systems involved. Overall, involvement of bone marrow, bone, lung, central nervous system, or other sites was associated with worse outcome. For patients aged ≥18 months, involvement of liver had the greatest impact on outcome and was associated with tumour MYCN amplification and adrenal primary and lung metastases. Increased MSI was associated with worse outcome and higher baseline ferritin/lactate dehydrogenase. We explored the impact of initial treatment approach on these associations. Limiting the analysis to patients allocated to protocols including stem cell transplant (SCT), there was no longer an association of outcome with metastatic involvement of any individual system or increasing MSI. Thus, treatment escalation with SCT (and the addition of differentiating agents to maintenance therapy) appears to have provided maximal benefit to patients with greatest metastatic disease burden. These findings underscore the importance of examining prognostic factors in the context of specific treatments since the addition of new therapies may change or even negate the predictive impact of a particular variable. [ABSTRACT FROM AUTHOR]
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- 2016
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9. Characteristics and outcome of patients with ganglioneuroblastoma, nodular subtype: A report from the INRG project
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Angelini, Paola, London, Wendy B., Cohn, Susan L., Pearson, Andrew D.J., Matthay, Katherine K., Monclair, Tom, Ambros, Peter F., Shimada, Hiroyuki, Leuschner, Ivo, Peuchmaur, Michel, Irwin, Meredith S., and Baruchel, Sylvain
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NEUROBLASTOMA , *HEALTH outcome assessment , *SURVIVAL analysis (Biometry) , *TREATMENT effectiveness , *DESCRIPTIVE statistics , *KAPLAN-Meier estimator , *EVALUATION , *PROGNOSIS - Abstract
Abstract: Aim: Describe characteristics and outcome of INRG patients with ganglioneuroblastoma, nodular subtype (GNBn). Patients and methods: Amongst 4071 patients in the INRG database with known INPC histological category, 232 patients with GNBn were identified. Patients were categorised by clinical, pathological and genetic characteristic. For event-free survival (EFS) and overall survival (OS), Kaplan–Meier curves and lifetables were generated, and the outcome of subgroups was compared using log rank test. Results: Patients with GNBn were older (83% >18 months), a higher proportion had unfavourable INPC pathology (83%), and rarely had MYCN gene amplified tumours (2%). Otherwise, the distribution of clinical and biological risk factors including stage, ferritin, initial treatment, grade of NB differentiation, MKI, 11q, 1p, and 17q were similar between patients with GNBn and the overall INRG cohort. EFS and OS were 54%±5% and 68%±5%, respectively. A cohort with superior outcome was identified: OS for GNBn patients younger than 18 months was 95%±5% (n =39) and for GNBn patients with stage 1, 2, 3, 4s was 95%±3% (n =125). Conversely, a poor outcome sub-group could also be identified: OS for stage 4 was 35%±7% (n =107). Conclusions: Patients with GNBn tumours are rare and have a very heterogeneous outcome. Except for LDH and MKI, the factors prognostic in the overall NB cohort are also prognostic in patients with GNBn. Similar to the overall NB cohort, patients with GNBn older than 18 months of age, with stage 4 disease represent a high-risk sub-group and should be considered for aggressive treatment upfront. [Copyright &y& Elsevier]
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- 2012
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