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Rajkumar Venkatramani,
Lingyun Ji,
Joseph Lasky,
Kelley Haley,
Alexander Judkins,
Shengmei Zhou, Richard Sposto,
Randal Olshefski,
James Garvin,
Tanya Tekautz,
Gloria Kennedy,
Shahrad Rod Rassekh,
Theodore Moore,
Sharon Gardner,
Jeffrey Allen,
Richard Shore,
Christopher Moertel,
Mark Atlas,
Girish Dhall,
Jonathan Finlay
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ABSTRACT: This study investigates the outcome of children <10 years old with newly-diagnosed ependymoma treated on the prospective multinational "Head Start" III clinical trial. Between April 2004 and July 2009, 19 children with newly-diagnosed ependymoma were enrolled. All children were to receive five induction chemotherapy cycles followed by one consolidation cycle of myelo-ablative chemotherapy and autologous hematopoietic cell rescue. Children between 6 and 10 years of age or with residual tumor prior to consolidation were to receive irradiation thereafter. Median age of 19 children (8 female) was 20 months at diagnosis. Median follow up was 44 months. The primary site was infratentorial in 11 and supratentorial in 8 patients. Gross total resection was achieved in 10 patients. After induction chemotherapy, all three supratentorial ependymoma patients with residual disease achieved a complete response (CR), while only one of six infratentorial patients with residual disease achieved CR. Three infratentorial patients developed progressive disease during induction chemotherapy. All four infratentorial patients with residual disease who underwent autologous hematopoietic cell transplant, failed to achieve CR. Four patients received focal irradiation following chemotherapy. The 3-year event free survival (EFS) and overall survival (OS) for supratentorial ependymoma were 86 ± 13 % and 100 % respectively. The 3-year EFS and OS for infratentorial ependymoma were 27 ± 13 % and 73 ± 13 % respectively. The role of intensive induction and consolidation chemotherapy in deferring irradiation should be investigated further in children with supratentorial ependymoma with residual disease following surgery. This approach appears ineffective in children with infratentorial ependymoma in the absence of irradiation.
Journal of Neuro-Oncology 03/2013; · 3.21 Impact Factor
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ABSTRACT: PURPOSE: Adoptive transfer of natural killer (NK) cells combined with tumor-specific monoclonal antibodies (mAbs) has therapeutic potential for malignancies. We determined if large numbers of activated NK (aNK) cells can be grown ex vivo from peripheral blood mononuclear cells (PBMC) of children with high-risk neuroblastoma using artificial antigen-presenting cells (aAPC). EXPERIMENTAL DESIGN: Irradiated K562-derived Clone 9.mbIL21 aAPC were co-cultured with PBMC, and propagated NK cells were characterized with flow cytometry, cytotoxicity assays, Luminex® multi-cytokine assays, and a NOD/SCID mouse model of disseminated neuroblastoma. RESULTS: Co-culturing patient PBMC with aAPC for 14 days induced 2,363±443-fold expansion of CD56+CD3-CD14- NK cells with 83±4% purity (n=10). Results were similar with PBMC from normal donors (n=5). Expression of DNAM-1, NKG2D, FcγRIII/CD16 and CD56 increased 6±3, 10±2, 21±20, and 18±3-fold respectively on day 14 compared to day 0, demonstrating activation of NK cells. In vitro, aNK cells were highly cytotoxic against neuroblastoma cell lines, and killing was enhanced with GD2-specific monoclonal antibody ch14.18. When mediating cytotoxicity with ch14.18, release of TNFα, GM-CSF, IFNγ, sCD40L, CCL2/MCP-1, CXCL9/MIG, and CXCL11/I-TAC by aNK cells increased 4-, 5- 6-, 15-, 265-, 917- and 363-fold (151 to 9,121 pg/mL), respectively, compared to aNK cells alone. Survival of NOD/SCID mice bearing disseminated neuroblastoma improved when treated with thawed and immediately intravenously infused cryopreserved aNK cells compared to un-treated mice and was further improved when ch14.18 was added. CONCLUSION: Propagation of large numbers of aNK cells that maintain potent anti-neuroblastoma activities when cryopreserved supports clinical testing of adoptive cell therapy with ch14.18.
Clinical Cancer Research 02/2013; · 7.74 Impact Factor
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Mary Gerrard,
Ian M Waxman, Richard Sposto,
Anne Auperin,
Sherrie L Perkins,
Stanton Goldman,
Lauren Harrison,
Ross Pinkerton,
Keith McCarthy,
Martine Raphael,
Catherine Patte,
Mitchell S Cairo
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ABSTRACT: Mediastinal large B-cell lymphoma (MLBL) represents only 2% of mature B-cell non-Hodgkin lymphoma (B-NHL) in patients ≤18 years of age. Gene expression profiling demonstrates that MLBL in adults more closely resembles classical Hodgkin lymphoma than it does diffuse large B-cell lymphoma (DLBCL). We analyzed data from childhood and adolescent patients with Stage III MLBL (N=42) and non MLBL DLBCL (N=69) treated with Group B therapy on the FAB/LMB 96 study. Demographics of MLBL patients: M/F: 26/16; median age 15.7 yrs (12.5-19.7); LDH <2 vs. ≥2 ULN: 23:19. Six MLBL patients (14%) had <20% response to initial COP-therapy. Central pathology classification revealed approximately 50% with classical features of primary mediastinal B-cell lymphoma (PMBL). Five-year event-free survival (EFS) for Stage III MLBL and non-MLBL DLBCL groups were 66% (95% CI: 49-78%) and 85% (95% CI: 71-92%), respectively, p<0.001 (14%). The 5-year overall survival (OS) in the 42 MLBL patients was 73% (95% CI: 56-84%). MLBL in adolescent patients is associated with significantly inferior EFS compared with stage III non-MLBL DLBCL and can be of multiple histologies. Alternate treatment strategies should be investigated in the future taking into account both adult MLBL approaches and more recent biological findings in adult MLBL.
Blood 11/2012; · 9.90 Impact Factor
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James H Garvin,
Michael T Selch,
Emi Holmes,
Mitchell S Berger,
Jonathan L Finlay,
Ann Flannery,
Joel W Goldwein,
Roger J Packer,
Lucy B Rorke-Adams,
Tania Shiminski-Maher, Richard Sposto,
Philip Stanley,
Raymond Tannous,
Ian F Pollack
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ABSTRACT: PURPOSE: Standard therapy for childhood intracranial ependymoma is maximal tumor resection followed by involved-field irradiation. Although not used routinely, chemotherapy has produced objective responses in ependymoma, both at recurrence and in infants. Because the presence of residual tumor following surgery is consistently associated with inferior outcome, the potential impact of pre-irradiation chemotherapy was investigated. METHODS: Between 1995 and 1999, the Children's Cancer Group undertook a Phase II trial of pre-irradiation chemotherapy in children 3-21 years of age with intracranial ependymoma and radiological evidence of post-operative residual tumor. RESULTS: Of 84 patients, 41 had residual tumor, and were given four cycles of cisplatin-based chemotherapy prior to irradiation. Of 35 patients fully evaluable for response to chemotherapy, 14 (40%) demonstrated complete response, 6 (17%) partial response, 10 (29%) minor response or stable disease, and 5 (14%) demonstrated progressive tumor growth. For the entire group, 5-year overall survival (OS) and event-free survival (EFS) was 71 ± 6%, and 57 ± 6%, respectively. The pre-irradiation chemotherapy group demonstrated EFS comparable to that of patients with no residual tumor who received irradiation alone (55 ± 8% vs. 58 ± 9%, P = 0.45). Any benefit of chemotherapy was restricted to patients with greater than 90% tumor resection. CONCLUSIONS: Children with near total resection of ependymoma may benefit from pre-irradiation chemotherapy. Patients with subtotal resection have inferior outcome despite responses to chemotherapy, and should be considered for second-look surgery prior to irradiation. Pediatr Blood Cancer 2012; 59: 1183-1189. © 2012 Wiley Periodicals, Inc.
Pediatric Blood & Cancer 09/2012; 59(7):1183-1189. · 1.89 Impact Factor
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Shahab Asgharzadeh,
Jill A Salo,
Lingyun Ji,
André Oberthuer,
Matthias Fischer,
Frank Berthold,
Michael Hadjidaniel,
Cathy Wei-Yao Liu,
Leonid S Metelitsa,
Roger Pique-Regi,
Peter Wakamatsu,
Judith G Villablanca,
Susan G Kreissman,
Katherine K Matthay,
Hiroyuki Shimada,
Wendy B London, Richard Sposto,
Robert C Seeger
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ABSTRACT: PURPOSE Children diagnosed at age ≥ 18 months with metastatic MYCN-nonamplified neuroblastoma (NBL-NA) are at high risk for disease relapse, whereas those diagnosed at age < 18 months are nearly always cured. In this study, we investigated the hypothesis that expression of genes related to tumor-associated inflammatory cells correlates with the observed differences in survival by age at diagnosis and contributes to a prognostic signature. METHODS Tumor-associated macrophages (TAMs) in localized and metastatic neuroblastomas (n = 71) were assessed by immunohistochemistry. Expression of 44 genes representing tumor and inflammatory cells was quantified in 133 metastatic NBL-NAs to assess age-dependent expression and to develop a logistic regression model to provide low- and high-risk scores for predicting progression-free survival (PFS). Tumors from high-risk patients enrolled onto two additional studies (n = 91) served as independent validation cohorts. Results Metastatic neuroblastomas had higher infiltration of TAMs than locoregional tumors, and metastatic tumors diagnosed in patients at age ≥ 18 months had higher expression of inflammation-related genes than those in patients diagnosed at age < 18 months. Expression of genes representing TAMs (CD33/CD16/IL6R/IL10/FCGR3) contributed to 25% of the accuracy of a novel 14-gene tumor classification score. PFS at 5 years for children diagnosed at age ≥ 18 months with NBL-NA with a low- versus high-risk score was 47% versus 12%, 57% versus 8%, and 50% versus 20% in three independent clinical trials, respectively. CONCLUSION These data suggest that interactions between tumor and inflammatory cells may contribute to the clinical metastatic neuroblastoma phenotype, improve prognostication, and reveal novel therapeutic targets.
Journal of Clinical Oncology 08/2012; 30(28):3525-32. · 18.37 Impact Factor
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Joann L Ater,
Tianni Zhou,
Emiko Holmes,
Claire M Mazewski,
Timothy N Booth,
David R Freyer,
Ken H Lazarus,
Roger J Packer,
Michael Prados, Richard Sposto,
Gilbert Vezina,
Jeffrey H Wisoff,
Ian F Pollack
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ABSTRACT: PURPOSE Surgery is curative therapy for pediatric low-grade gliomas (LGGs) in areas of the brain amenable to complete resection. However, LGGs located in areas where complete resection is not possible can threaten both function and life. The purpose of this study was to compare two chemotherapy regimens for LGGs in children younger than age 10 years for whom radiotherapy was felt by the practitioner to pose a high risk of neurodevelopmental injury. PATIENTS AND METHODS Previously untreated children younger than age 10 years with progressive or residual LGGs were eligible. Children were randomly assigned to receive carboplatin and vincristine (CV) or thioguanine, procarbazine, lomustine, and vincristine (TPCV). Children with neurofibromatosis are reported separately. Results Of 274 randomly assigned patients who met eligibility requirements, 137 received CV and 137 received TPCV. The 5-year event-free survival (EFS) and overall survival (OS) rates for all eligible patients were 45% ± 3.2% and 86% ± 2.2%, respectively. The 5-year EFS rates were 39% ± 4% for CV and 52% ± 5% for TPCV (stratified log-rank test P = .10; cure model analysis P = .007). On multivariate analysis, factors independently predictive of worse EFS and OS were younger age and tumor size greater than 3 cm(2). Tumor location in the thalamus was also associated with poor OS. CONCLUSION The difference in EFS between the regimens did not reach significance on the basis of the stratified log-rank test. The 5-year EFS was higher for TPCV on the basis of the cure model analysis. Differences in toxicity may influence physician choice of regimens.
Journal of Clinical Oncology 06/2012; 30(21):2641-7. · 18.37 Impact Factor
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ABSTRACT: Therapy of relapsed pediatric acute lymphoblastic leukemia (ALL) is hampered by low remission rates and high toxicity, especially in second and subsequent relapses. Our phase 1 study, T2005-003, showed that the combination of bortezomib with vincristine, dexamethasone, pegylated asparaginase, and doxorubicin had acceptable toxicity. We report the phase 2 expansion of this combination in patients with relapsed ALL who failed 2-3 previous regimens. Twenty-two patients with relapsed ALL were treated with bortezomib combined with this regimen; their ages ranged from 1 to 22 years, and they had either B-precursor ALL (n = 20) or T-cell ALL (n = 2). Grade 3 peripheral neuropathy developed in 2 (9%) patients. After 3 patients died from bacterial infections, treatment with vancomycin, levofloxacin, and voriconazole prophylaxis resulted in no further infectious mortality in the last 6 patients. Fourteen patients achieved complete remission (CR), and 2 achieved CR without platelet recovery, for an overall 73% response rate, meeting predefined criteria allowing for early closure. B-precursor patients faired best, with 16 of 20 (80%) CR + CR without platelet recovery, whereas the 2 patients with T-cell ALL did not respond. Thus, this combination of bortezomib with chemotherapy is active in B-precursor ALL, and prophylactic antibiotics may be useful in reducing mortality. Bortezomib merits further evaluation in combination therapy in pediatric B-precursor ALL. This study is registered at http://www.clinicaltrials.gov as NCT00440726.
Blood 05/2012; 120(2):285-90. · 9.90 Impact Factor
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ABSTRACT: PURPOSE In 1995, the Children's Cancer Group (CCG) opened a trial for patients with Hodgkin's lymphoma evaluating whether low-dose involved-field radiation therapy (IFRT) improved event-free survival (EFS) for patients achieving a complete response after chemotherapy. We present the long-term study outcome using final data through March 2007. PATIENTS AND METHODS Between January 1995 and December 1998, 826 eligible patients were enrolled onto CCG 5942. Four hundred ninety-eight patients achieving an initial complete response to chemotherapy were randomly assigned to receive IFRT or no further therapy. EFS and overall survival (OS) were assessed from the date of study entry or random assignment, as appropriate. Results Ten-year EFS and OS rates for the entire cohort were 83.5% and 92.5%, respectively. In an as-treated analysis for randomly assigned patients, the 10-year EFS and OS rates were 91.2% and 97.1%, respectively, for IFRT and 82.9% and 95.9%, respectively, for no further therapy. For EFS and OS comparisons, P = .004 and P = .50, respectively. Bulk disease, "B" symptoms, and nodular sclerosis histology were risk factors for inferior EFS. CONCLUSION With a median follow-up of 7.7 years, IFRT produced a statistically significant improvement in EFS but no improvement in OS. For individual patients, the relative risks of relapse versus late effects of IFRT must be considered. Patient and disease characteristics and early response assessment will aid in deciding which patients are most likely to benefit from IFRT.
Journal of Clinical Oncology 05/2012; 30(26):3174-80. · 18.37 Impact Factor
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ABSTRACT: To describe the serial histopathology of intermediate risk stage 3 neuroblastoma after chemotherapy, and correlate with residual mass at therapy completion and outcome.
A retrospective review of intermediate risk stage 3 neuroblastoma patients treated 1989-2005 at Children's Hospital Los Angeles according to CCG 3881 or CCG 3961 protocols was performed, with central review of histopathology, radiology, and surgery.
Eighteen patients treated per CCG 3881 (n = 9) or CCG 3961 (n = 9), with including 1 (n = 5), 2 (n = 9), ≥ 3 (n = 3), or unknown number (n = 1) of surgical procedures were included. At therapy completion, 10 patients had residual tumor: <10% original size (n = 3), >10% original size (n = 6) (5 MIBG avid; 4 with elevated catecholamines), and CT non-measurable MIBG avid tumor (n = 1). Post-chemotherapy histology showed tumor regression (n = 4); or maturation with (n = 6) or without (n = 2) Schwannian development. Histologic changes correlated with median tumor shrinkage of 80% (regressing tumors) and <25% (maturing tumors). Tumor size increased in one patient with maturing tumor and Schwannian development. Overall survival was 100%.
Post-chemotherapy histopathology of intermediate risk stage 3 neuroblastoma was characterized by regression or maturation. Persisting residual and maturing tumors were not associated with tumor progression, despite MIBG uptake and/or elevated catecholamines, supporting observation only. Histopathology should be obtained in future studies to confirm these findings, and guide length of chemotherapy.
Pediatric Blood & Cancer 05/2012; 58(5):675-81. · 1.89 Impact Factor
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ABSTRACT: Interleukin-6 (IL-6) is a pleiotropic cytokine with a broad range of physiologic and pathologic functions. Because in cancer, IL-6 contributes to a microenvironment that promotes tumor cell survival, angiogenesis, and inflammation, understanding the mechanism responsible for its production is important. In neuroblastoma, the second most common solid tumor in children, IL-6 is produced not by tumor cells but by stromal cells such as monocytes and bone marrow mesenchymal stem cells (BMMSC). Here we show that the production of IL-6 in BMMSCs is in part stimulated by galectin-3 binding protein (Gal-3BP) secreted by neuroblastoma cells. We identified a distal region of the IL-6 promoter that contains 3 CCATT/enhancer binding protein (C/EBP) binding domains involved in the transcriptional upregulation of IL-6 by Gal-3BP. Gal-3BP interacted with Galectin-3 (Gal-3) present in BMMSCs, and a Gal-3BP/Gal-3/Ras/MEK/ERK signaling pathway was responsible for the transcriptional upregulation of IL-6 in BMMSCs in which Gal-3 has a necessary function. In support of the role of this pathway in human neuroblastoma tumors, Gal-3BP was found to be present in tumor cells and in the adjacent extracellular matrix of 96% of 78 primary neuroblastoma tumor samples examined by immunohistochemistry. Considering the protumorigenic function of IL-6 in cancer, this tumor cell-stromal cell interactive pathway could be a target for anticancer therapy.
Cancer Research 03/2012; 72(9):2228-38. · 7.86 Impact Factor
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ABSTRACT: Axillary lymph node status continues to be among the most important prognostic variables regarding breast cancer survival. We were interested in our ability to accurately predict axillary nodal involvement by using physical examination and standard breast imaging studies in combination.
A retrospective review was performed of 244 consecutive patients diagnosed with invasive breast carcinoma between May 2008 and December 2010 who underwent physical examination of the axilla, digital mammography, axillary ultrasonography, and contrast-enhanced breast magnetic resonance imaging and who had subsequent histopathologic evaluation of one or more axillary lymph nodes.
A total of 62 (25%) of 244 women were found to have positive axillary lymph nodes on final histopathologic examination, 42% of whom were able to be identified preoperatively. The sensitivity for predicting axillary metastasis if any one or more examination modalities were suspicious was 56.5%. The specificity for predicting axillary metastasis if any three or more modalities were suspicious was 100%. Of the patients who had all four modalities negative, 14% were ultimately found to have histologically positive nodes at the time of surgery.
Physical examination and multimodal imaging in combination are useful for preoperative axillary staging and treatment planning. However, they remain inadequate definitive predictors of axillary lymph node involvement.
Annals of Surgical Oncology 01/2012; 19(6):1825-30. · 4.17 Impact Factor
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Mitchell S Cairo, Richard Sposto,
Mary Gerrard,
Anne Auperin,
Stanton C Goldman,
Lauren Harrison,
Ross Pinkerton,
Martine Raphael,
Keith McCarthy,
Sherrie L Perkins,
Catherine Patte
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ABSTRACT: Adolescents (age 15 to 21 years) compared with younger children with mature B-cell non-Hodgkin's lymphoma (NHL) have been historically considered to have an inferior prognosis. We therefore analyzed the impact of age and other diagnostic factors on the risk of treatment failure in children and adolescents treated on the French-American-British Mature B-Cell Lymphoma 96 (FAB LMB 96) trial.
Patients were divided by risk: group A (limited), group B (intermediate), and group C (advanced), as previously described. Prognostic factors analyzed for event-free survival (EFS) included age (< 15 v ≥ 15 years), stage (I/II v III/IV), primary site, lactate dehydrogenase (LDH), bone marrow/CNS (BM/CNS) involvement, and histology (diffuse large B-cell lymphoma v mediastinal B-cell lymphoma v Burkitt lymphoma or Burkitt-like lymphoma).
The 3-year EFS for the whole cohort was 88% ± 1%. Age was not associated as a risk factor for increased treatment failure in either univariate analysis (P = .15) or multivariate analysis (P = .58). Increased LDH (≥ 2 × upper limit of normal [ULN] v < 2 × ULN), primary site, and BM-positive/CNS-positive disease were all independent risk factors associated with a significant increase in treatment failure rate (relative risk, 2.0; P < .001, P < .012, and P < .001, respectively).
LDH level at diagnosis, mediastinal disease, and combined BM-positive/CNS-positive involvement are independent risk factors in children with mature B-cell NHL. Future studies should be developed to identify specific therapeutic strategies (immunotherapy) to overcome these risk factors and to identify the biologic basis associated with these prognostic factors in children with mature B-cell NHL.
Journal of Clinical Oncology 01/2012; 30(4):387-93. · 18.37 Impact Factor
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Mark A Lones,
Martine Raphael,
Keith McCarthy,
Andrew Wotherspoon,
Marie-Josee Terrier-Lacombe,
Alan D Ramsay,
Ken Maclennan,
Mitchell S Cairo,
Mary Gerrard,
Jean Michon,
Catherine Patte,
Ross Pinkerton,
Leonard Sender,
Anne Auperin, Richard Sposto,
Claire Weston,
Nyla A Heerema,
Warren G Sanger,
Daniel von Allmen,
Sherrie L Perkins
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ABSTRACT: This study reports 6 cases of primary follicular lymphoma of the testis (PFLT) in children and adolescents correlated with clinical presentation, pathologic features, treatment, and outcome. All 6 patients (age, 3 to 16 y; median, 4 y) had PFLT grade 3 with disease limited to the testis, completely resected and treated with 2 courses of chemotherapy (cyclophosphamide, vincristine, prednisone, doxorubicin). Event-free survival was 100% (follow-up: median, 73 mo; mean, 53 mo; range, 6 to 96 mo). In conclusion, clinical outcome in children and adolescents with PFLT is excellent with treatment including complete surgical resection and 2 courses of cyclophosphamide, vincristine, prednisone, doxorubicin.
Journal of Pediatric Hematology/Oncology 01/2012; 34(1):68-71. · 1.16 Impact Factor
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ABSTRACT: The recently proposed Rolling 6 Phase I study design is an alternative to the standard 3+3 patient cohort design. It was proposed as a way to reduce the time necessary to complete a trial by reducing the downtime during which Phase I trials are suspended for evaluation of dose-limiting toxicity (DLT). We performed a paired comparison of the Rolling 6 and 3+3 designs via a large simulation study over a wide spectrum of conditions defined by inter-patient arrival time, number of doses, DLT dose response slope, DLT dose response shape, and starting dose. Our results in general confirm that, on average, trials will be completed more quickly with the Rolling 6, with negligible penalty in terms of patient safety during the trial or as a result of the selected MTD, although the Rolling 6 on average will require more patients and thus will incur higher research costs. While the reduction in average trial duration with the Rolling 6 can be notable in absolute terms, in relative terms the reduction may be modest, in contrast to the relative increase in numbers of patients treated, which can be substantial. For identical sequences of patients, the difference between the two designs in trial duration and numbers of patients treated is highly variable. Therefore it is not so predictable whether the Rolling 6 will result in more rapid completion of a single trial or of a small series of trials.
Contemporary clinical trials 04/2011; 32(5):694-703. · 1.51 Impact Factor
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Sharon O'Neil,
Lingyun Ji,
Cathliyn Buranahirun,
Jaye Azoff,
Girish Dhall,
Soumen Khatua,
Sunita Patel,
Ashok Panigrahy,
Mark Borchert, Richard Sposto,
Jonathan Finlay
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ABSTRACT: Evaluation of neurocognitive outcomes after a treatment strategy of chemotherapy followed by reduced-dose and volume irradiation for primary central nervous system (CNS) germinoma.
Neuropsychological evaluations including measures of verbal and nonverbal intellectual functioning, working memory, processing speed, verbal and nonverbal memory, executive functioning, depression, anxiety, and social functioning were analyzed for all patients (N = 20) with histologically diagnosed CNS germinoma diagnosed at our institution between 2003 and 2009. All 20 patients underwent at least one neuropsychological evaluation, 14 patients had at least two evaluations, 7 patients had at least three, and 2 had four, generating a total of 43 test batteries at a mean of 3.0 years from diagnosis.
The 20 patients performed as a group in the average range on all neurocognitive measures administered when compared to the nonmedical normative group. No decline over time was indicated on any of the neurocognitive measures. An improvement over time was indicated for nonverbal reasoning, nonverbal memory, processing speed, working memory, response inhibition, and cognitive flexibility. No significant differences were found by tumor location, age at diagnosis, or hydrocephalus at presentation.
For pediatric and adolescent patients with newly diagnosed CNS germinoma, modest chemotherapy followed by reduced dose ventricular field irradiation with simultaneous integrated boost to the primary site, is associated with preservation of neurocognitive, social and emotional functioning.
Pediatric Blood & Cancer 04/2011; 57(4):669-73. · 1.89 Impact Factor
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Alekist Quach,
Lingyun Ji,
Vikash Mishra,
Aimee Sznewajs,
Janet Veatch,
John Huberty,
Benjamin Franc, Richard Sposto,
Susan Groshen,
Denice Wei,
Paul Fitzgerald,
John M Maris,
Gregory Yanik,
Randall A Hawkins,
Judith G Villablanca,
Katherine K Matthay
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ABSTRACT: (131) I-Metaiodobenzylguanidine ((131) I-MIBG) provides targeted radiotherapy for children with neuroblastoma, a malignancy of the sympathetic nervous system. Dissociated radioactive iodide may concentrate in the thyroid, and (131) I-MIBG is concentrated in the liver after (131) I-MIBG therapy. The aim of our study was to analyze the effects of (131) I-MIBG therapy on thyroid and liver function.
Pre- and post-therapy thyroid and liver functions were reviewed in a total of 194 neuroblastoma patients treated with (131) I-MIBG therapy. The cumulative incidence over time was estimated for both thyroid and liver toxicities. The relationship to cumulative dose/kg, number of treatments, time from treatment to follow-up, sex, and patient age was examined.
In patients who presented with Grade 0 or 1 thyroid toxicity at baseline, 12 ± 4% experienced onset of or worsening to Grade 2 hypothyroidism and one patient developed Grade 2 hyperthyroidism by 2 years after (131) I-MIBG therapy. At 2 years post-(131) I-MIBG therapy, 76 ± 4% patients experienced onset or worsening of hepatic toxicity to any grade, and 23 ± 5% experienced onset of or worsening to Grade 3 or 4 liver toxicity. Liver toxicity was usually transient asymptomatic transaminase elevation, frequently confounded by disease progression and other therapies.
The prophylactic regimen of potassium iodide and potassium perchlorate with (131) I-MIBG therapy resulted in a low rate of significant hypothyroidism. Liver abnormalities following (131) I-MIBG therapy were primarily reversible and did not result in late toxicity. (131) I-MIBG therapy is a promising treatment for children with relapsed neuroblastoma with a relatively low rate of symptomatic thyroid or hepatic dysfunction.
Pediatric Blood & Cancer 02/2011; 56(2):191-201. · 1.89 Impact Factor
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ABSTRACT: Central nervous system neoplasms are the most common solid tumors in children, and more than 40% are low-grade gliomas. Variable locations, extent of resection, postoperative neurodiagnostic evaluation, and histology have confounded therapy and outcome.
To investigate disease control and survival after surgery.
A prospective natural history trial from 1991 to 1996 produced a subset of patients with low-grade gliomas managed by primary surgery and subsequent observation. Patients were evaluable if eligibility, tumor location, and extent of resection were confirmed by pathological diagnosis, preoperative and postoperative imaging, and the surgeon's report. Primary end points were overall survival (OS), progression-free survival (PFS), and postprogression survival.
Of 726 patients enrolled, 518 were fully evaluable for analysis. The 5- and 8-year OS rates were 97% ± 0.8% and 96% ± 0.9%, respectively, and PFS rates were 80% ± 1.8% and 78% ± 2.0%. In univariate analyses, histological type, extent of residual tumor, and disease site were significantly associated with PFS and OS. In multivariate analysis, gross total resection (GTR) without residual disease was the predominant predictor of PFS. In patients with limited residual disease, 56% were free of progression at 5 years.
GTR should be the goal when it can be achieved with an acceptable functional outcome. The variable rate of progression after incomplete resection highlights the need for new predictors of tumor behavior.
Neurosurgery 02/2011; 68(6):1548-54; discussion 1554-5. · 2.79 Impact Factor
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Alekist Quach BA,
Lingyun Ji MS,
Vikash Mishra MD,
PNP Aimee Sznewajs MS,
MN Janet Veatch RN,
John Huberty MS,
Benjamin Franc MD,
Richard Sposto PhD,
Susan Groshen PhD,
Denice Wei MS, [......],
Benjamin Franc, Richard Sposto,
Susan Groshen,
Denice Wei,
Paul Fitzgerald,
John M. Maris,
Gregory Yanik,
Randall A. Hawkins,
Judith G. Villablanca,
Katherine K. Matthay
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ABSTRACT: Background131I-Metaiodobenzylguanidine (131I-MIBG) provides targeted radiotherapy for children with neuroblastoma, a malignancy of the sympathetic nervous system. Dissociated radioactive iodide may concentrate in the thyroid, and 131I-MIBG is concentrated in the liver after 131I-MIBG therapy. The aim of our study was to analyze the effects of 131I-MIBG therapy on thyroid and liver function.ProcedurePre- and post-therapy thyroid and liver functions were reviewed in a total of 194 neuroblastoma patients treated with 131I-MIBG therapy. The cumulative incidence over time was estimated for both thyroid and liver toxicities. The relationship to cumulative dose/kg, number of treatments, time from treatment to follow-up, sex, and patient age was examined.ResultsIn patients who presented with Grade 0 or 1 thyroid toxicity at baseline, 12 ± 4% experienced onset of or worsening to Grade 2 hypothyroidism and one patient developed Grade 2 hyperthyroidism by 2 years after 131I-MIBG therapy. At 2 years post-131I-MIBG therapy, 76 ± 4% patients experienced onset or worsening of hepatic toxicity to any grade, and 23 ± 5% experienced onset of or worsening to Grade 3 or 4 liver toxicity. Liver toxicity was usually transient asymptomatic transaminase elevation, frequently confounded by disease progression and other therapies.Conclusion
The prophylactic regimen of potassium iodide and potassium perchlorate with 131I-MIBG therapy resulted in a low rate of significant hypothyroidism. Liver abnormalities following 131I-MIBG therapy were primarily reversible and did not result in late toxicity. 131I-MIBG therapy is a promising treatment for children with relapsed neuroblastoma with a relatively low rate of symptomatic thyroid or hepatic dysfunction. Pediatr Blood Cancer 2011;56:191–201. © 2010 Wiley-Liss, Inc.
Pediatric Blood & Cancer 01/2011; 56(2):191 - 201. · 1.89 Impact Factor
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ABSTRACT: As p53 loss of function (LOF) confers high-level drug resistance in neuroblastoma, p53-independent therapies might have superior activity in recurrent neuroblastoma. We tested the activity of vorinostat, a histone deacetylase inhibitor, and flavopiridol, a pan-Cdk inhibitor, in a panel of multidrug-resistant neuroblastoma cell lines that included lines with wild-type (wt) and transcriptionally active TP53 (n = 3), mutated (mt), and LOF TP53 (n = 4) or p14(ARF) deletion (n = 1). The combination of vorinostat and flavopiridol was synergistic and significantly more cytotoxic (P < 0.001) in cell lines with p53-LOF and in the clones stably transfected with dominant-negative p53 plasmids. Cell cycle analysis by flow cytometry showed prominent cell-cycle arrest in G(2)/M (37%) for a cell line with wt TP53 (SK-N-RA) at 16 to 20 hours, while cells with mt TP53 (CHLA-90) slipped into sub-G(1) at 6 to 24 hours (25%-40% specific cell death). The morphological hallmarks of mitotic cell death, including defective spindle formation and abnormal cytokinesis, were detected by confocal microscopy after the treatment with vorinostat + flavopiridol combination in CHLA-90. The combination caused reduction in the expression of G(2)/M proteins (cyclin B1, Mad2, MPM2) in 2 cell lines with mt TP53 but not in those with wt TP53. Plk1 expression was reduced in all treated lines. Small interfering RNA knockdown of Mad2 and cyclin B1 or Plk1 synergistically reduced the clonogenicity of CHLA-90 cells. The combination of HDAC inhibitor and flavopiridol may be a unique approach to treating neuroblastomas with p53 LOF, one that evokes induction of mitotic failure.
Molecular Cancer Therapeutics 12/2010; 9(12):3289-301. · 5.23 Impact Factor
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Aaron Cooper,
John van Doorninck,
Lingyun Ji,
Darren Russell,
Marc Ladanyi,
Hiroyuki Shimada,
Mark Krailo,
Richard B Womer,
Jessie Hao-ru Hsu,
Dafydd Thomas,
Timothy J Triche, Richard Sposto,
Elizabeth R Lawlor
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ABSTRACT: Ewing sarcoma family tumors (ESFT) are aggressive tumors of putative stem cell origin for which prognostic biomarkers and novel treatments are needed. In several human cancers, high expression of the polycomb protein BMI-1 is associated with poor outcome. We have assessed the potential clinical significance of BMI-1 expression level in ESFT.
BMI-1 expression was assessed in 130 tumors by immunostaining and associations with clinical features and outcome determined. The molecular signatures of BMI-1-low and BMI-1-high tumors were compared using microarrays and differentially activated canonical pathways identified by gene-specific enrichment analysis. Automated quantitative analysis of phosphoproteins was used to assess relative levels of pathway activation. Sensitivity to IGF1-R inhibition was determined using MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium] assays.
BMI-1 is overexpressed by the vast majority of ESFTs. However, in 20% of cases, BMI-1 levels are low to undetectable. Significantly, although clinical presentation and outcome were similar between BMI-1-high and BMI-1-low tumors, whole genome expression array analysis showed marked differences in their respective gene expression profiles. Gene-specific enrichment analysis identified that several cancer-associated canonical biological pathways, including IGF1, mTOR, and WNT, are significantly downregulated in BMI-1-low compared with BMI-1-high tumors. Consistent with these in vivo data, the response to IGF1-R inhibition in vitro was diminished in BMI-1-low compared with BMI-1-high ESFT cells.
ESFT that do not overexpress BMI-1 represent a novel subclass with a distinct molecular profile and altered activation of and dependence on cancer-associated biological pathways.
Clinical Cancer Research 11/2010; 17(1):56-66. · 7.74 Impact Factor
