Alveolar rhabdomyosarcoma has superior response rates to vinorelbine compared to embryonal rhabdomyosarcoma in patients with relapsed/refractory disease: A meta-analysis.

BACKGROUND: Patients with alveolar rhabdomyosarcoma (ARMS) have inferior outcomes compared to patients with embryonal rhabdomyosarcoma (ERMS) and more effective chemotherapy options are needed for these patients. Vinorelbine is a semisynthetic vinca alkaloid that has clinical activity in relapsed rhabdomyosarcoma (RMS) when used alone or in combination with cyclophosphamide. AIMS: The goal of our study was to evaluate whether RMS histology subtype influences response rate to vinorelbine alone or in combination. MATERIALS & METHODS: Five Phase 2 trials that enrolled RMS patients were included in the meta-analysis. Two studies evaluated vinorelbine alone, two studies evaluated vinorelbine in combination with low dose oral cyclophosphamide, and one study evaluated vinorelbine and intravenous cyclophosphamide in combination with temsirolimus or bevacizumab. All RMS patients had relapsed or refractory disease and had received at least one prior therapy. Response was reported according to RECIST1.1 and was defined as a complete or partial response. Response data was obtained from published results or from trial principal investigator. RMS NOS patients were grouped with ERMS patients for this analysis. Summary estimates comparing differences between ARMS and ERMS response rates were generated using a random-effects model to account for heterogeneity among the studies. RESULTS: One hundred fifty-six enrolled patients evaluable for response were included in the meta-analysis, 85 ARMS, 64 ERMS and 7 RMS-NOS. The combined effect generated from the random-effects model demonstrated a 41% increase (p = 0.001, 95% CI; 0.21-0.60) in response to vinorelbine as a single agent or in combination in patients with ARMS compared to patients with ERMS. There was no significant difference in the rate of progressive disease between patients with ARMS compared to ERMS (p = 0.1, 95%CI; -0.26-0.02). DISCUSSION: Vinorelbine is an active agent for the treatment of relapsed or refractory RMS and a meta-analysis of Phase 2 studies shows that radiographic responses in patients with ARMS were significantly higher than ERMS or RMS-NOS. CONCLUSION: These data support further investigation of vinorelbine in newly diagnosed patients with RMS particularly those with alveolar histology.

Predictors of cognitive function in pediatric brain tumor patients: Pre-surgery through 24-month follow-up.

The aim of this study was to examine the feasibility of cognitive assessment from pre-surgery through 2-year follow-up in a sample of pediatric brain tumor (BT) patients. We sought to investigate cognitive function over the course of diagnosis and treatment, and as a function of presenting problems, tumor location, treatment type, and tumor severity. Using a prospective, longitudinal design, standardized IQ measures were administered to pediatric BT patients (ages 6-16) prior to surgery (n = 25), 6 months post-diagnosis (n = 24), and 24 months post-diagnosis (n = 23). Group differences emerged based on tumor severity and treatment type at multiple time points, including prior to surgical intervention; children with high grade tumors performed more poorly than children with low grade tumors, and children receiving surgery plus adjuvant therapy performed more poorly than children who received surgery only. When considered together, an analysis of covariance demonstrated that tumor grade significantly accounted for variability in cognitive functioning, while treatment type did not. Although there is overlap clinically between tumor severity and treatment received, results suggest that tumor severity is an important factor contributing to variability in cognitive functioning and should also be considered when monitoring risk for cognitive deficits in children diagnosed with BT.

Associations among diffusion tensor imaging and neurocognitive function in survivors of pediatric brain tumor: A pilot study.

The purpose of this study was to determine associations among neurocognitive outcomes and white matter integrity in the inferior fronto-occipital fasciculus (IFOF), uncinate fasciculus (UF), and genu of the corpus callosum (gCC) in survivors of pediatric brain tumor and healthy controls (HCs). Eleven survivors (ages 8-16; >2 years post-treatment) and 14 HCs underwent MRI; diffusion tensor imaging tractography (DSI Studio) was used to assess white matter integrity. Participants completed neuropsychological assessment of overall cognitive ability, executive function, processing speed, divided attention, and memory. As previously reported, survivors performed significantly worse than HCs on measures of overall IQ, working memory, processing speed, and executive function (ps < .01), but not on measures of long-delay memory. Mean fractional anisotropy was significantly lower in survivors than HC in the right IFOF, left UF, and gCC (ps < .05). Correlations with the total sample revealed a number of significant positive associations among white matter tracts and scores on neurocognitive measures. Survivors show deficits on measures of cognitive function and decreased white matter integrity compared to HCs. Results revealed a more general pattern of associations among white matter pathways and neurocognitive outcomes than initially hypothesized. It is possible that survivors with diffuse pathology from treatment effects (i.e., hydrocephalus or posterior fossa syndrome) show more general decreases in cognitive functioning and white matter integrity. Additional research with a larger and more diverse group of survivors is needed to better understand white matter integrity and neurocognitive outcome associations in this population.

Eutectic mixture of lidocaine and prilocaine versus 1% lidocaine injection for lumbar punctures in pediatric oncology patients.

BACKGROUND: The role of local analgesics for lumbar punctures (LPs) in pediatric oncology patients has not been specifically studied. AIM: To compare the efficacy of eutectic mixture of local anesthetics (EMLA) cream to 1% lidocaine injection for LPs. METHOD: This was a retrospective observational study of all patients receiving either EMLA cream (EMLA group) or 1% lidocaine subcutaneous injection (lidocaine group) in addition to fentanyl and propofol for LPs over 18 months. Demographics, vital parameters, procedural and recovery times, propofol and fentanyl doses, and adverse events were studied. RESULTS: Two hundred ninety LPs in 49 children were studied: 148 in the EMLA group and 142 in the lidocaine group. There was no difference in demographics or preprocedural parameters between the two groups. LPs in the EMLA group were completed in a shorter time (7.5 minutes [CI 7.0-8.1] vs 9.4 minutes [CI 8.9-9.9]) with a faster recovery time (38.7 minutes [CI 36.9-40.9] vs 43.9 minutes. [CI 41.9-45.9]) as compared with the lidocaine group (P < 0.001). The EMLA group required less maintenance doses (0.54 mg/kg [CI 0.47-0.62] vs 1.14 mg/kg [CI 1.06-1.21]) and total doses (2.58 mg/kg [CI 2.42-2.75] vs 3.12 mg/kg [CI 2.95-3.29]) of propofol as compared with the lidocaine group (P < 0.0001). Adverse events in the EMLA group were less (19% vs 41%) as compared with the lidocaine group (P < 0.0001). CONCLUSION: The addition of EMLA cream for procedural sedation for LPs in pediatric oncology patients significantly improves pain management in comparison with 1% lidocaine injection.

Fronto-limbic white matter microstructure, behavior, and emotion regulation in survivors of pediatric brain tumor.

PURPOSE: After treatment, pediatric brain tumor survivors (PBTS) face emotional and behavioral challenges, perhaps due to tumor or treatment-related changes in brain structures involved in emotion regulation, including those with fronto-limbic connections. We hypothesized that relative to healthy controls (HCs), PBTS would exhibit greater difficulties with behavior and emotional functioning, and display reduced mean fractional anisotropy (mFA) in white matter tracts with fronto-limbic connections including the cingulum bundle (CB), inferior fronto-occipital fasciculus (IFOF), and uncinate fasciculus (UF). We further predicted that mFA would account for variance in the relationship between group and emotional/behavioral outcome. METHODS: Eleven 8-16 year old PBTS and 14 HCs underwent MRI, including diffusion tensor imaging to assess white matter microstructure. Tractography quantified mFA of selected tracts. Parents rated children's emotional and behavioral functioning. RESULTS: Compared to HCs, caregivers of PBTS reported poorer behavioral regulation and greater internalizing and externalizing symptoms. Relative to HCs, PBTS had lower mFA within the bilateral CB, IFOF, and UF (ds = 0.59-1.15). Across groups, several medium-to-large correlations linked tract mFA and increased internalizing, externalizing, and poor behavioral regulation. Tract mFA also accounted for significant variance in the group-outcome association. CONCLUSIONS: Reduced mFA in fronto-limbic associated tracts may be associated with reduced behavioral regulation following pediatric brain tumor. PBTS with treatment known to impact white matter may be most susceptible. Research with larger, longitudinal samples should clarify this relationship, allow for multiple mediators across time, and consider factors like tumor and treatment type.

A Congenital Case of Ependymoblastoma: A Rare and Aggressive Brain Tumor.

Congenital brain tumors are rare, representing <2% of all childhood brain tumors. Of these, ependymoblastoma is a profoundly aggressive embryonal brain tumor that is included in the diagnostic entity known as an embryonal tumor with multilayered rosettes. This report of a congenital ependymoblastoma diagnosed at birth aims to highlight how much remains unknown about embryonal tumor with multilayered rosettes and the devastating prognosis of this condition. Despite recent advancements made in identifying molecular targets for therapy, this tumor continues to have a high rate of recurrence with few successful treatment options, especially when diagnosed in the newborn period.

Early Testing of Serum Ferritin Facilitates Hemophagocytic Lymphohistiocytosis Diagnosis in Children.

The clinical and laboratory features of hemophagocytic lymphohistiocytosis (HLH) are nonspecific that makes the definitive diagnosis of HLH very challenging. The disease is almost universally fatal in the absence of early recognition and appropriate therapy. Elevated serum ferritin level is one of the diagnostic markers of HLH disease. We report the value of testing serum ferritin level early in the disease process in 3 pediatric patients who presented with persistent fever and sepsis-like features. Detection of elevated serum ferritin levels facilitated further testing to confirm the diagnosis of HLH and initiate early therapy with good outcomes.

Dynamic re-immunization of off-treatment childhood cancer survivors: An implementation feasibility study.

There are no universally approved re-vaccination guidelines for non-transplant pediatric cancer survivors. We hypothesized that by utilizing a response-based re-vaccination schedule, we could tailor vaccine schedules in off-treatment cancer survivors. Pre-vaccination antibody levels were obtained in 7 patients at an average of 20 days after the end of treatment date. In those without protective antibody levels, we administered vaccines 3 months after completion of treatment. Revaccinating patients 3 months after the end of treatment date resulted in protective antibody levels for most vaccines. We showed, on a preliminary basis, that vaccinating non-transplanted pediatric cancer survivors can be dynamically implemented in children with recovering immune function.

Functional neuroimaging of working memory in survivors of childhood brain tumors and healthy children: Associations with coping and psychosocial outcomes.

PURPOSE: Pediatric brain tumors are the second most common cancer diagnosis in individuals under age 20 and research has documented significant neurocognitive, psychosocial, and emotional late effects. Associations among these deficits have not been adequately considered and the role of survivors' coping with stress in relation to deficits is unknown. Further, research has yet to examine neurobiological processes related to neurocognitive, psychosocial, and emotional difficulties in survivors through the use of functional neuroimaging. METHOD: Questionnaire measures and functional neuroimaging were used to examine the neurocognitive, psychosocial, and emotional functioning and coping responses of survivors of pediatric brain tumors (N = 17; age 8-16) and healthy children (N = 15). RESULTS: Survivors experienced elevated levels of psychosocial and behavioral/emotional difficulties relative to healthy controls and normative data. Increases in brain activation in prefrontal and other anterior regions in response to a working memory task were associated with better psychosocial functioning, use of engagement coping strategies, and less use of disengagement coping strategies. Regression analyses suggest coping accounts for a significant portion of the association between brain activation and behavioral/emotional functioning. CONCLUSIONS: This study extends late-effects research by examining neurobiological processes associated with psychosocial and emotional difficulties. These findings contribute to our understanding of difficulties in survivors and provide a foundation for research exploring these associations and mediators of deficits in future longitudinal studies.

Pituitary blastoma: a pathognomonic feature of germ-line DICER1 mutations.

Individuals harboring germ-line DICER1 mutations are predisposed to a rare cancer syndrome, the DICER1 Syndrome or pleuropulmonary blastoma-familial tumor and dysplasia syndrome [online Mendelian inheritance in man (OMIM) #601200]. In addition, specific somatic mutations in the DICER1 RNase III catalytic domain have been identified in several DICER1-associated tumor types. Pituitary blastoma (PitB) was identified as a distinct entity in 2008, and is a very rare, potentially lethal early childhood tumor of the pituitary gland. Since the discovery by our team of an inherited mutation in DICER1 in a child with PitB in 2011, we have identified 12 additional PitB cases. We aimed to determine the contribution of germ-line and somatic DICER1 mutations to PitB. We hypothesized that PitB is a pathognomonic feature of a germ-line DICER1 mutation and that each PitB will harbor a second somatic mutation in DICER1. Lymphocyte or saliva DNA samples ascertained from ten infants with PitB were screened and nine were found to harbor a heterozygous germ-line DICER1 mutation. We identified additional DICER1 mutations in nine of ten tested PitB tumor samples, eight of which were confirmed to be somatic in origin. Seven of these mutations occurred within the RNase IIIb catalytic domain, a domain essential to the generation of 5p miRNAs from the 5' arm of miRNA-precursors. Germ-line DICER1 mutations are a major contributor to PitB. Second somatic DICER1 "hits" occurring within the RNase IIIb domain also appear to be critical in PitB pathogenesis.

Phase 2 study of safety and efficacy of nimotuzumab in pediatric patients with progressive diffuse intrinsic pontine glioma.

BACKGROUND: The prognosis of diffuse intrinsic pontine glioma (DIPG) remains poor, with no drug proven to be effective. METHODS: Patients with clinically and radiologically confirmed, centrally reviewed DIPG, who had failed standard first-line therapy were eligible for this multicenter phase II trial. The anti-epidermal growth factor receptor (EGFR) antibody, nimotuzumab (150 mg/m(2)), was administered intravenously once weekly from weeks 1 to 7 and once every 2 weeks from weeks 8 to 18. Response evaluation was based on clinical and MRI assessments. Patients with partial response (PR) or stable disease (SD) were allowed to continue nimotuzumab. RESULTS: Forty-four patients received at least one dose of nimotuzumab (male/female, 20/24; median age, 6.0 years; range, 3.0-17.0 years). All had received prior radiotherapy. Treatment was well tolerated. Eighteen children experienced serious adverse events (SAEs). The majority of SAEs were associated with disease progression. Nineteen patients completed 8 weeks (W8) of treatment: There were 2 PRs, 6 SDs, and 11 progressions. Five patients completed 18 weeks (W18) of treatment: 1 of 2 patients with PR at W8 remained in PR at W18, and 3 of 6 children with SD at W8 maintained SD at W18. Time to progression following initiation of nimotuzumab for the 4 patients with SD or better at W18 was 119, 157, 182 and 335 days, respectively. Median survival time was 3.2 months. Two patients lived 663 and 481 days from the start of nimotuzumab. CONCLUSIONS: Modest activity of nimotuzumab in DIPG, which has been shown previously, was confirmed: A small subset of DIPG patients appeared to benefit from anti-EGFR antibody treatment.

Neuroimaging of executive function in survivors of pediatric brain tumors and healthy controls.

OBJECTIVE: Research on the long-term sequelae of treatment for pediatric brain tumors has identified significant neurocognitive deficits experienced by many survivors. Despite indications of deficits based on cognitive assessment, the identification of specific neurobiological mechanisms of these deficits using neuroimaging techniques has yet to be considered. METHOD: This study used norm-referenced standardized assessment and functional MRI (fMRI) to examine attention and executive functioning deficits of survivors of pediatric brain tumors, as compared with healthy children. RESULTS: Survivors of pediatric brain tumors performed more poorly than healthy children on measures of overall cognitive ability, attention, and executive function during testing, as well as on a working memory task during fMRI. Survivors showed lower blood-oxygen level dependent (BOLD) signal in bilateral frontal regions associated with sustained attention (BA6/8) and greater BOLD signal in left cingulate regions associated with complex problem-solving and performance monitoring (BA32) during working memory task completion. Both group and brain activation accounted for significant variance in neurocognitive functioning. CONCLUSIONS: Survivors of pediatric brain tumor and healthy children differed in brain activation during completion of a working memory task, and brain activation was associated with deficits noted in testing. These findings may improve understanding of mechanisms of cognitive deficits and avenues for intervention for children with brain tumors.

Neurocognitive late effects of pediatric brain tumors of the posterior fossa: a quantitative review.

Deficits in neurocognitive functioning are an important area of late effects in survivors of pediatric brain tumors; however, a quantitative analysis of the magnitude of these deficits in survivors of brain tumors of the posterior fossa has not been conducted. Despite tumor locations in the posterior regions of the brain, individual studies have documented deficits in a variety of domains, reflective of impairment in other brain regions. The current study provides a comprehensive meta-analysis of literature on neurocognitive late effects found in survivors of posterior fossa tumors. Results indicated significant deficits in both specific and broad indices of neurocognitive functioning, and the overall magnitude of effects across domains ranged from medium to large (g = -0.62 to -1.69) with a large mean overall effect size (g = -1.03). Moderator analyses indicated significantly greater effects for survivors diagnosed at a younger age and those who received radiation therapy. These findings underscore the importance of monitoring neurocognitive late effects in survivors of pediatric brain tumors of the posterior fossa, as well as the need for more consistent consideration of demographic, diagnostic, and treatment-related variables to allow for examination of factors that moderate these deficits.

Treatment of recurrent diffuse intrinsic pontine glioma: the MD Anderson Cancer Center experience.

Recurrent diffuse intrinsic pontine gliomas (DIPG) are traditionally treated with palliative care since no effective treatments have been described for these tumors. Recently, clinical studies have been emerging, and individualized treatment is attempted more frequently. However, an informative way to compare the treatment outcomes has not been established, and historical control data are missing for recurrent disease. We conducted a retrospective chart review of patients with recurrent DIPG treated between 1998 and 2010. Response progression-free survival and possible influencing factors were evaluated. Thirty-one patients were identified who were treated in 61 treatment attempts using 26 treatment elements in 31 different regimens. The most frequently used drugs were etoposide (14), bevacizumab (13), irinotecan (13), nimotuzumab (13), and valproic acid (13). Seven patients had repeat radiation therapy to the primary tumor. Response was recorded after 58 treatment attempts and was comprised of 0 treatment attempts with complete responses, 7 with partial responses, 20 with stable diseases, and 31 with progressive diseases The median progression-free survival after treatment start was 0.16 years (2 months) and was found to be correlated to the prior time to progression but not to the number of previous treatment attempts. Repeat radiation resulted in the highest response rates (4/7), and the longest progression-free survival. These data provide a basis to plan future clinical trials for recurrent DIPG. Repeat radiation therapy should be tested in a prospective clinical study.

Induction treatment for diffuse intrinsic pontine glioma, experience of M.D. Anderson Cancer Center.

BACKGROUND: The biology of diffuse intrinsic pontine glioma remains poorly understood and the dismal prognosis has not changed despite various attempts to add chemotherapy to standard radiation. PATIENTS AND METHODS: A retrospective chart review was carried out of patients with diffuse intrinsic pontine glioma treated at M.D. Anderson Cancer Center from 1998 to 2010, and the data analyzed comparing drug effects aiming to generate hypotheses. RESULTS: A total of 64 patients had diffuse intrinsic pontine glioma as confirmed by radiology review; 28 were male, and age at diagnosis ranged from 1.5 to 16.5 years. All patients received radiation as initial treatment, and 44 had additional treatment during the radiation, with a total of 15 different drug combinations obtained from 15 different individual drugs. The median overall survival after diagnosis was 0.79 years (SD 0.123). Patients treated with the anti-inflammatory agent rofecoxib had inferior survival (p=0.00002). CONCLUSION: Based on these data, we hypothesize that inflammatory/reactive processes in the tumor might play a beneficial role during radiation and suggest that this be tested in animal models.

Orbital pleomorphic liposarcoma in an eight-year-old boy.

Adult-type sarcomas are, as the name indicates, rare tumors in the pediatric population. Although soft tissue sarcomas as a group are not uncommon diagnoses, nonrhabdomyosarcoma soft tissue sarcomas are much rarer and encompass a wide range of diagnoses. A few of these tumors are commonly found in the adult population and are thus referred to as adult-type sarcomas. We present a case of a pleomorphic liposarcoma, an adult-type sarcoma, arising as a primary tumor in the orbit of an 8-year-old boy. The histologic analysis revealed bizarre tumor giant cells and definitive lipoblastic differentiation. The atypical cells were positive for S100, and negative for CD34, desmin, MyoD1, and myogenin. This is a high-grade sarcoma, very rarely encountered in the pediatric population. We present the histologic findings of this unusual pediatric sarcoma and review the literature.

A quantitative meta-analysis of neurocognitive sequelae in survivors of pediatric brain tumors.

BACKGROUND: Deficits in neurocognitive functioning are an important area of late effects in survivors of pediatric brain tumors, but a quantitative analysis of the magnitude of these deficits has yet to be conducted. PROCEDURE: The purpose of the current article is to provide a comprehensive meta-analysis of the literature on long-term neurocognitive effects found in these survivors. RESULTS: Results indicated significant deficits in both narrow and broad indices of neurocognitive functioning, and the overall magnitude of the effects across all domains ranged from small to large in magnitude (g = -0.45 to -1.43) with a large mean overall effect size of g = -0.91. CONCLUSIONS: These findings underscore the importance of monitoring the neurocognitive late effects in survivors of pediatric brain tumors, and the need for more consistent consideration of demographic, diagnostic, and treatment-related variables in future research to allow for examination of factors that may moderate these deficits.

Phase I and pharmacokinetic study of cetuximab and irinotecan in children with refractory solid tumors: a study of the pediatric oncology experimental therapeutic investigators' consortium.

PURPOSE: To determine the dose of cetuximab that can be safely combined with irinotecan for treatment of pediatric and adolescent patients with refractory solid tumors. PATIENTS AND METHODS: This open-label, phase I study enrolled patients ages 1 to 18 years with advanced refractory solid tumors, including tumors of the CNS. Patient cohorts by age group (children, ages 1 to 12 years; adolescents, ages 13 to 18 years) received escalating weekly doses of cetuximab (75, 150, 250 mg/m(2)) in a 3 + 3 design, plus irinotecan (16 or 20 mg/m(2)/d) for 5 days for 2 consecutive weeks every 21 days. The primary end points were establishing the maximum-tolerated dose (MTD), recommended phase II dose (RPIID), and pharmacokinetics of the combination. Preliminary safety and efficacy data were also collected. RESULTS: Twenty-seven children and 19 adolescents received a median of 7.1 and 6.0 weeks of cetuximab therapy, respectively. Cetuximab 250 mg/m(2) weekly plus irinotecan 16 mg/m(2)/d (pediatric) or 20 mg/m(2)/d (adolescent) have been established as the MTD/RPIID. Dose-limiting toxicities included diarrhea and neutropenia. Mild to moderate (grade 1 to 2) acneiform rash occurred in a majority of patients; no grade 3 to 4 rashes were observed. Cetuximab demonstrated dose-dependent clearance in both children and adolescents, similar to that in adults. There were two confirmed partial responses, both in patients with CNS tumors. Stable disease was achieved in 18 patients overall, including 10 patients with CNS tumors (38.5%). CONCLUSION: The cetuximab/irinotecan combination can be given safely to children and adolescents with cancer. Promising activity, particularly in CNS tumors, warrants phase II evaluation of this regimen.

Phase II evaluation of intravenous vinorelbine (Navelbine) in recurrent or refractory pediatric malignancies: a Children's Oncology Group study.

BACKGROUND: A Phase II trial was developed to determine the efficacy and toxicity of intravenous vinorelbine, a semi-synthetic vinca alkaloid, in children, adolescent, and young adults with recurrent or refractory solid malignancies. PROCEDURES: Fifty patients were enrolled among three strata: soft tissue sarcomas [rhabdomyosarcoma (RMS), non-rhabdomyosarcoma, primitive neuroepithelial tumor] (20 patients); brain tumors [astrocytoma (4 patients), medulloblastoma (2 patients), other (16 patients)] (22 patients); neuroblastoma (8 patients). Vinorelbine was given weekly for 6 consecutive weeks during an 8-week interval. The response rate and toxicity profile was assessed. RESULTS: Among the first 35 patients treated at 33.75 mg/m(2)/dose, 25 experienced grades 3-4 neutropenia (75%). The dose was decreased to 30 mg/m(2)/dose in the remaining 15 patients. The median age was 10 years (range, 1-25). Four responses (one complete, three partial) occurred within the soft tissue sarcoma strata (all with RMS) and two occurred in the brain tumor group (medulloblastoma and astrocytoma). The most common toxicities were hematological and neurological. CONCLUSION: Vinorelbine at dose of 30 mg/m(2) can be safely administered to children with recurrent or refractory solid malignancies. The study design identified vinorelbine to be active in the sarcoma category, with a response rate of 36% (4/11) among RMS patients.