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Solid tumor growth is dependent on angiogenesis, the formation of neovasculature from existing vessels. Endothelial activation of the extracellular signal–regulated kinase 1/2, c-jun NH2-terminal kinase, and p38 mitogen-activated protein kinase pathways is central to this process, and thus presents an attractive target for the development of angiogenesis inhibitors. Anthrax lethal toxin (LeTx) has potent catalytic mitogen-activated protein kinase inhibition activity. Preclinical studies showed that LeTx induced potent tumor growth inhibition via the inhibition of xenograft vascularization. However, LeTx receptors and the essential furin-like activating proteases are expressed in many normal tissues, potentially limiting the specificity of LeTx as an antitumor agent. To circumvent nonspecific LeTx activation and simultaneously enhance tumor vascular targeting, a substrate preferably cleaved by the gelatinases class of matrix metalloproteinases (MMP) was substituted for the furin LeTx activation site. In vivo efficacy studies showed that this MMP-activated LeTx inhibited tumor xenografts growth via the reduced migration of endothelial cells into the tumor parenchyma. Here we have expanded on these initial findings by showing that this MMP-activated LeTx reduces endothelial proangiogenic MMP expression, thus causing a diminished proteolytic capacity for extracellular matrix remodeling and endothelial differentiation into capillary networks. Additionally, our data suggest that inhibition of the c-jun NH2-terminal kinase and p38, but not extracellular signal–regulated kinase-1/2, pathways is significant in the antiangiogenic activity of the MMP-activated LeTx. Collectively, these results support the clinical development of the MMP-activated LeTx for the treatment of solid tumors. (Mol Cancer Res 2009;7(4):452–61)

Supplementary Data from Matrix Metalloproteinase–Activated Anthrax Lethal Toxin Inhibits Endothelial Invasion and Neovasculature Formation during In vitro Morphogenesis

Supplementary Figures S1-S3 from Matrix Metalloproteinase–Activated Anthrax Lethal Toxin Inhibits Endothelial Invasion and Neovasculature Formation during In vitro Morphogenesis

Infantile hemangiomas (IHs) are non-malignant, largely cutaneous vascular tumors affecting approximately 5-10% of children to varying degrees. During the first year of life, these tumors are strongly proliferative, reaching an average size ranging from 2 to 20 cm. These lesions subse- quently stabilize, undergo a spontaneous slow involution and are fully regressed by 5 to 10 years of age. Systemic treatment of infants with the non-selective β-adrenergic receptor blocker, propranolol, has demonstrated remarkable efficacy in reducing the size and appearance of IHs. However, the mechanism by which this occurs is largely unknown. In this study, we sought to understand the molecular mechanisms underlying the effectiveness of β blocker treatment in IHs. Our data reveal that propranolol treatment of IH endothelial cells, as well as a panel of normal primary endothelial cells, blocks endothelial cell proliferation, migration, and formation of the actin cyto- skeleton coincident with alterations in vascular endothelial growth factor receptor-2 (VEGFR-2), p38 and cofilin signaling. Moreover, propranolol induces major alterations in the protein levels of key cyclins and cyclin-dependent kinase inhibitors, and modulates global gene expression patterns with a particular affect on genes involved in lipid/sterol metabolism, cell cycle regulation, angiogenesis and ubiquitination. Interestingly, the effects of propranolol were endothelial cell-type independent, affecting the properties of IH endothelial cells at similar levels to that observed in neonatal dermal microvascular and coronary artery endothelial cells. This data suggests that while propranolol markedly inhibits hemangioma and normal endothelial cell function, its lack of endothelial cell specificity hints that the efficacy of this drug in the treatment of IHs may be more complex than simply blockage of endothelial function as previously believed.

Last minute review tables designed for a quick review before the exam; it helps the learner self-test their ability to the correct or most likely diagnosis and patient management in a very short time. Pediatric board study guide will offer further clarifications and additional information related to the topics on the last minute review section.

Blood Disorders covers disorders of red blood cells, white blood cells, platelets, and coagulation including congenital and acquired disorders. Neoplastic Disorders covers both Hematopoietic and Solid Tumors with information on epidemiology, clinical presentation, diagnosis, and treatment of these disorders.

This unusual mixed glioneuronal neoplasm of the spine resembling central neurocytoma is only the second reported example of a neoplasm of this type involving the spinal cord and is, seemingly, the first to present with diffuse leptomeningeal dissemination and communicating hydrocephalus. This 15-month-old boy presented with somnolence, bilateral sixth nerve palsy, and lower-extremity weakness and was found to harbor a primary neoplasm within the thoracic spine and associated syrinx, widespread leptomeningeal dissemination, and communicating hydrocephalus. The patient underwent cerebrospinal fluid shunt placement, thoracic laminectomy for tumor debulking and biopsy, chemotherapy, and radiation therapy to the neuraxis. Immunohistochemically, the tumor was marked by evidence of mixed glial (glial fibrillary acidic protein-positive) and neuronal (synaptophysin-positive) differentiation. Mitotic activity was inconspicuous. No areas of vascular proliferation, necrosis, or marked nuclear pleomorphism were noted. Mixed glioneuronal neoplasms are a heterogeneous group of tumors whose biological potential remains incompletely defined. The present case illustrates the reality that some of these neoplasms can be clinically aggressive, despite comparatively bland histological features. The authors' goal is to acquaint neurosurgeons with the expanding spectrum of mixed glioneuronal neoplasms and with the potential of some of these lesions to pursue an aggressive clinical course.

Purpose: Survivors of medulloblastoma, the most frequently occurring malignant brain tumor of childhood, suffer neuropsychological damage in the first decade after diagnosis. Cognitive performance, psychosocial functioning and quality of life were assessed in medulloblastoma survivors in the second decade after diagnosis. Methods: Ten year survivors were evaluated with a battery of neuropsychological tests, and self-report questionnaires regarding quality of life and emotional functioning. Clinical variables examined included the patient’s age at diagnosis, duration since diagnosis, treatment, and complications. Results: Sixteen medulloblastoma survivors [mean age at diagnosis: 7.2 years, range: 1–15 years; 6 males] were tested at a mean age of 22.2 years [range: 13.6–27.9 years]. All survivors had been treated with craniospinal radiation therapy; nine were treated with chemotherapy. Significant impairments were identified in more than 50 of survivors on tests within all neuropsychological domains, including attention, memory, visuospatial abilities, motor functioning, language, and executive functioning. Significant impairments were also identified in all psychosocial domains examined, including employment, ability to drive an automobile, participation in normal education, independent living, and dating history. Most importantly, quality of life scores, reported by both survivors and their caretakers, were in the normal range. Conclusion: Survivors of childhood medulloblastoma frequently suffer severe persistent deficits in a wide-range of neuropsychological functional domains. Nevertheless, survivors and their families do not report impaired quality of life. These severe neuropsychological and psychosocial deficiencies justify further attempts to reduce or delay the use of craniospinal radiation therapy for childhood medulloblastoma.

Purpose: The pilocytic astrocytoma (PA) is the most common childhood brain tumor. This report examines the MIB-1 labeling index (LI) as a predictor of progression-free survival (PFS) among childhood PAs. Patients and Methods: Consecutive PAs were examined to determine whether the MIB-1 LI was associated with tumor progression. Other variables evaluated included tumor location, use of adjuvant therapy, extent of resection, and age at diagnosis. Results: One hundred forty-one children were identified (mean ± SD age, 7.6 ± 4.7 years; range, 0.43 to 18.56 years); 118 children had adequate tissue for MIB-1 immunohistochemistry. The 5-year PFS was 61.25%. By log-rank analysis, an MIB-1 LI of more than 2.0 was associated with shortened PFS (P = .035). Patients with PAs who underwent complete surgical resection, had tumors located in the cerebellum, and were treated with surgery only also had more prolonged PFS (P = .001 for all). Tumors in the optic pathways were associated with a shorter PFS (P = .001). Restricting the evaluation of MIB-1 LI to only incompletely resected tumors revealed an insignificant trend of MIB-1 LI of more than 2.0 having a shortened PFS. Multivariate analysis demonstrated completely resected tumors and tumors located in the cerebellum as less likely to progress (P = .001 and .019, respectively). Conclusion: Children with PAs with an MIB-1 LI of more than 2.0 have a shortened PFS. PAs that are completely resected and are located in the cerebellum have a prolonged PFS. This initial study suggests that the MIB-1 LI identifies a more aggressive subset of PAs. Further work should focus on elucidating features of pilocytic astocytomas that will identify prospectively children at risk for progression.

Background. To determine the maximumtolerated duration and dose-limiting toxicity of a daily schedule of orally administered cyclophosphamide and topotecan in pediatric patients with recurrent or refractory malignant solid tumors. Methods. Patients received oral cyclophosphamide (50 mg/m 2 /dose) in the morning followedbytopotecan(0.8mg/m 2 /dose)8–12hr later for an escalating number of consecutive days (10, 14, and 17 days). Results. Seventeen pediatric patients were treated with oral cyclophosphamide and topotecan for durations of 10–17 days for a total of 58 treatment courses. Reversible hematologic toxicity (neutropenia and thrombocytopenia) was the dose-limiting toxicity. Nonhematologic toxicities of greater than grade 3 were not observed. A partial response (neuroblastoma following myeloablative chemotherapy and stem cell rescue) and prolonged stable disease (medulloblastoma) were each observedin one patient.Conclusions. The recommended duration of therapy with a daily schedule of both oral cyclophosphamide (50 mg/m 2 /day) and topotecan (0.8 mg/m 2 /day) for previously treated pediatric patients with recurrent or refractory solid tumors is 14 consecutive days. The observed dose limiting toxicity (DLT) was reversible neutropenia. This regimen was well tolerated in heavily pretreated patients and demonstrated activity against recurrent pediatric solid tumors. Pediatr Blood Cancer 2004;42:93–98. 2003 Wiley-Liss, Inc.

Few reports exist describing the progression-free and overall survival of children with low-grade (WHO grade II) oligodendrogliomas treated uniformly with aggressive surgery but without adjuvant chemotherapy or radiation therapy. Furthermore, significant prognostic features, including the MIB-1 labeling index (LI), have not been reported for children with oligodendrogliomas. The medical records of 20 consecutive patients with low-grade oligodendrogliomas were reviewed. All patients had been treated with aggressive surgical resection. Adjuvant chemotherapy and radiation therapy were reserved for radiographic or clinical progression. These patients have been followed for a median of 5.5 years (range 0.5–11.5 years) after diagnosis. To date, there have been no patient deaths. Six of the 20 patients experienced tumor progression at a median of 2.2 years (range 0.4–4.8 years) following the initial surgery. The MIB-1 LI was infrequently greater than 5. Of several prognostic factors for subsequent tumor progression that were examined, only tumors located within the parietal lobes were associated with a worse progression-free survival. Other risk factors, including presenting symptoms, age at diagnosis, MIB-1 LI and the extent of tumor resection, were not associated with an increased frequency of tumor progression.

Purpose: Children with recurrent or progressive central nervous system (CNS) tumors have an unfavorable prognosis. Based on Pediatric Oncology Group (POG) institutional pilot data, low-dose oral methotrexate (MTX) was studied. Methods: Eight dosages of MTX 7.5 mg/m 2 every 6 hours were administered on a weekly schedule for as long as 18 months. Patients in six different brain tumor strata were accrued. Results: The response rates (complete or partial responses) were as follows: astrocytoma 2 of 10, malignant glioma 1 of 19, medulloblastoma 0 of 18, brainstem tumor 0 of 12, ependymoma 1 of 7, and miscellaneous histologic types 0 of 12. The main toxicities, mucositis, myelosuppression, and hepatic transaminase elevation were considered tolerable. Conclusion: Low-dose oral MTX showed no significant activity against malignant glioma, medulloblastoma, brainstem tumors, and miscellaneous histologic types. Indeterminate but low response rates were observed in children with astrocytoma and ependymoma. This regimen will not be recommended for front-line therapy.

Background. Children diagnosed with medulloblastoma whose tumor involves the brain stem or has spread through the cerebrospinal fluid pathways to other areas of the brain or spinal cord have a poor prognosis despite therapy with surgery, craniospinal irradiation (CSI), and chemotherapy. Preradiation chemotherapy may improve the outlook for these patients. Methods. To further study the role and feasibility of preradiation chemotherapy, children between the ages of 4 and 21 years diagnosed with advanced medulloblastoma and measurable disease were enrolled in the Pediatric Oncology Group 8695 study. Patients were treated with a 9-week course of vincristine, cisplatin, and cyclophosphamide followed by CSI. Imaging films were reviewed centrally for eligibility and response to chemotherapy. Toxicity to chemotherapy and radiation as well as delays and modifications in subsequent CSI were recorded. Results. Thirteen of 30 fully evaluable patients achieved complete or partial response (43%) to chemotherapy. Toxicity was mostly fever and neutropenia after cyclophosphamide, which is predictable and tolerable. Radiation therapy was delivered in full doses and volumes in most patients but was delayed in its start in most patients. Central review of films revealed frequent use of different imaging modalities at baseline and after therapy, making accurate assessment of tumor response difficult. Conclusion. Preradiation chemotherapy with vincristine, cisplatin, and cyclophosphamide is active in patients with advanced medulloblastoma but should be modified to minimize the risk of progressive disease while on therapy and to avoid delays in starting radiation therapy. Consistent use of the same neuroimaging modality is essential in documenting response.

Solid tumor growth is dependent on angiogenesis, the formation of neovasculature from existing vessels. Endothelial activation of the extracellular signal–regulated kinase 1/2, c-jun NH2-terminal kinase, and p38 mitogen-activated protein kinase pathways is central to this process, and thus presents an attractive target for the development of angiogenesis inhibitors. Anthrax lethal toxin (LeTx) has potent catalytic mitogen-activated protein kinase inhibition activity. Preclinical studies showed that LeTx induced potent tumor growth inhibition via the inhibition of xenograft vascularization. However, LeTx receptors and the essential furin-like activating proteases are expressed in many normal tissues, potentially limiting the specificity of LeTx as an antitumor agent. To circumvent nonspecific LeTx activation and simultaneously enhance tumor vascular targeting, a substrate preferably cleaved by the gelatinases class of matrix metalloproteinases (MMP) was substituted for the furin LeTx activation site. In vivo efficacy studies showed that this MMP-activated LeTx inhibited tumor xenografts growth via the reduced migration of endothelial cells into the tumor parenchyma. Here we have expanded on these initial findings by showing that this MMP-activated LeTx reduces endothelial proangiogenic MMP expression, thus causing a diminished proteolytic capacity for extracellular matrix remodeling and endothelial differentiation into capillary networks. Additionally, our data suggest that inhibition of the c-jun NH2-terminal kinase and p38, but not extracellular signal–regulated kinase-1/2, pathways is significant in the antiangiogenic activity of the MMP-activated LeTx. Collectively, these results support the clinical development of the MMP-activated LeTx for the treatment of solid tumors. (Mol Cancer Res 2009;7(4):452–61)

The object of this study was to identify prognostic factors for survival among children with recurrent medulloblastoma.Postprogression survival and patient, tumor, and treatment factors were examined in 46 cases of recurrent medulloblastoma (mean age of patients at diagnosis 6.5 years, mean age at progression 8.4 years). Differences were calculated by Kaplan-Meier log-rank analysis. Multivariate analysis was performed using the Cox proportional hazard model.The probability of 5-year survival was 26.3%. Forty-one patients received salvage therapy and five patients received hospice care only. Log-rank analysis showed an association between prolonged patient survival and recurrence limited to the primary site (p = 0.008), initial therapy including the Pediatric Oncology Group (POG) regimen for the treatment of brain tumors in infants ("Baby POG;" p = 0.037), and treatment with radiation therapy (RT) following initial progression (p = 0.015). Cox regression analysis showed a significant association between prolonged survival and only one variable--tumor recurrence restricted to the primary site (p = 0.037). There was no significant association between prolonged survival and any other variables, including patient sex, age at progression, interval from tumor diagnosis to progression, initial tumor stage, and salvage treatment with chemotherapy. Subgroup analysis revealed that site of tumor progression was also prognostic for survival among the subgroup of patients older than 3 years of age at diagnosis who were initially treated with RT and chemotherapy (p = 0.017, log-rank test).Some children with recurrent medulloblastoma will be long-term survivors, and certain features are associated with likelihood of survival. Patients whose tumors recur at only the primary tumor site have an increased chance of prolonged survival.

Background: Supratentorial primitive neuroectodermal tumors (sPNET) are highly-malignant and rare brain tumors that primarily affect young children. Despite multimodal treatment that includes surgery, radiotherapy and chemotherapy, less than half of affected patients will survive 5 years post-diagnosis. Moreover, neurocognitive impairment associated with current treatment protocols is a significant complication in survivors. Therefore, new molecular targeted therapies that are effective and less toxic are needed to further improve outcomes in sPNET patients. Tyrosine kinase inhibitors (TKI) have emerged as an important class of molecular targeted anti-cancer agents with demonstrated clinical efficacy and generally favorable toxicity profiles. Dasatinib, an orally-administered TKI that is FDA approved for Ph+ CML/ALL, has been reported in off-label use for cancers of the head and neck, breast, colon, prostate and lung. Dasatinib targets multiple tyrosine kinases that are involved in numerous cancers, including ABL, SRC family tyrosine kinases (SFKs), and receptor tyrosine kinases c-KIT and PDGFR. Notably, SFKs have been implicated in driving the development and progression of numerous solid tumors, including PNET and medulloblastoma. Methods: Here we report the successful use of dasatinib with informed consent in multimodal treatment of a 32 month old, ex-29 week twin B female patient. She was diagnosed with sPNET that demonstrated high tumor SFK-activity, had progressed on standard chemotherapy, and for whom irradiation was avoided due to the unwanted side effects of radiation on the developing brain. Multiplex kinase-activity profiling, and electron microscopy analysis was performed on pre- and post-dasatinib treatment tumor tissue after partial resections. Additionally, pre-and post-treatment MRI was done to quantitate the clinical response with dasatinib. Results: Ex vivo multiplex analysis revealed aberrant activation of SFKs SRC, LYN and FYN in the sPNET tumor, which was shown to be significantly reduced following dasatinib therapy. In addition, blockade of SFK activity with dasatinib correlated with greatly reduced activation of downstream proliferative transcription factors STAT1 and STAT3. Electron microscopy analysis of the tumor upon surgical resection revealed phenotypic changes with significant presence of autophagocytic vacuoles, indicative of cellular sequestration, and increased prominence of nuclear heterochromatin. Dasatinib therapy over a 4-month period was very well-tolerated by the patient and resulted in significant tumor reduction as determined by radiographic detection. Conclusions: We have demonstrated how tyrosine kinase activity-based tumor profiling can be utilized to devise a successful personalized molecular targeted multimodal treatment strategy in a patient for whom standard therapy had failed. Dasatinib was clinically and molecularly effective in the treatment of a progressive refractory sPNET displaying high-SFK activity. These results could aid future patient stratification schemes that direct targeted therapies based upon an aberrant molecular pathway strategy, therefore larger clinical studies using this approach are warranted. Citation Format: Lisa LR Hartman, Diba Farah, Arlynn F. Mulne, Bruce B. Storrs, Harry L. Wilson, Staci Bryson, Derrick M. Oaxaca, Robert A. Kirken, Jeremy A. Ross. Integration of a personalized molecular targeted therapy into the multimodal treatment of refractory early childhood sPNET. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr B73.

Background A robotically guided linear accelerator has recently been developed which provides frameless radiosurgery with high precision. Potential advantages for the pediatric population include the avoidance of the cognitive decline associated with whole brain radiotherapy, the ability to treat young children with thin skulls unsuitable for frame-based methods, and the possible avoidance of general anesthesia. We report our experience with this system (the “Cyberknife”) in the treatment of 21 children. Procedures Cyberknife radiosurgery was performed on 38 occasions for 21 patients, age ranging from 8 months to 16 years (7.0 ± 5.1 years), with tumors considered unresectable. Three had pilocytic astrocytomas, two had anaplastic astrocytomas, three had ependymomas (two anaplastic), four had medulloblastomas, three had atypical teratoid/rhabdoid tumors, three had craniopharyngiomas, and three had other pathologies. The mean target volume was 10.7 ± 20 cm3, mean marginal dose was 18.8 ± 8.1 Gy, and mean follow-up is 18 ± 11 months. Twenty-seven (71%) of the treatments were single-shot and eight (38%) patients did not require general anesthesia. Results Local control was achieved in the patients with pilocytic and anaplastic astrocytoma, three of the patients with medulloblastoma, and the three with craniopharyngioma, but not for those with ependymoma. Two of the patients with rhabdoid tumors are alive 16 and 35 months after this diagnosis. There have been no procedure related deaths or complications. Conclusion Cyberknife radiosurgery can be used to achieve local control for some children with CNS tumors without the need for rigid head fixation. © 2004 Wiley-Liss, Inc.

Nonperioperative strokes are rare yet potentially devastating events for children with central nervous system (CNS) tumors. The incidence of and risk factors for nonperioperative strokes in children with CNS tumors is unknown.The authors performed a retrospective review of children from their institution with CNS tumors. The incidence of stroke in the nonperioperative period and the influence of patient demographic factors, coexisting genetic diseases, tumor type, and treatment modality on the subsequent occurrence of a stroke were determined.Eight hundred seven consecutive patients from the authors' institution with CNS tumors were observed for a combined 3224 nonperioperative years. Thirteen patients (1.6%) had a nonperioperative stroke, for an incidence of 4.03 strokes/1000 years of nonperioperative patient follow-up. Eight patients were males, and the median age at diagnosis of a CNS tumor was 4.8 years (range, 0.3-18.6 years). The median duration from diagnosis of a CNS tumor until the occurrence of stroke was 2.3 years (range, 0.3-15.8 years). Among numerous potential risk factors individually examined by chi-square analysis, only treatment with radiation therapy was associated with the subsequent development of a stroke (chi-square, P = 0.007). By logistic regression analysis, treatment with radiation therapy and a diagnosis of an optic pathway glioma were the only statistically significant variables associated with a stroke.Strokes are much more common among children with CNS tumors. Children treated with radiation therapy and those with optic pathway gliomas have a higher association with the occurrence of a subsequent nonperioperative stroke. Because children with optic pathway gliomas may be at particularly high risk of stroke after radiation therapy, the desired beneficial therapeutic effects of irradiation must always be weighed against its potentially adverse effects, including stroke.

Thirty-two children with medulloblastoma were evaluated postoperatively with conventional and gadolinium-enhanced MR imaging. Eleven patients had abnormal cranial MR studies; nine of these had recurrent tumor. In six patients recurrent tumor enhanced with Gd, while in the other three patients recurrent tumor did not enhance. The remaining two patients had areas of abnormal Gd enhancement that were caused by radiation-induced breakdown of the blood-brain barrier rather than by recurrent tumor. This study shows that not all recurrent medulloblastoma enhances and that the absence of Gd enhancement does not necessarily indicate the absence of recurrent tumor.

1556 Background: Despite improvement in therapies, a substantial number of children with medulloblastoma experience tumor progression. The objectives of this single institution report are to report...

Seventeen children with severe pain due to malignant neoplasm were successfully treated with a subcutaneous infusion of morphine sulfate using a syringe pump. Pain relief was adequate in every case without major side effects. The median dosage required was 0.06 mg/kg/hr (range, 0.025 to 1.79 mg/kg/hr). Three patients received the subcutaneous infusion at home. No patient required an intravenous line for pain control.