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Background The use of Ommaya catheters or ventriculoperitoneal shunts with programmable valves (pVP-shunts) for intraventricular drug administration is increasingly more common. Procedure We reviewed the safety and complication rate associated with ventricular access devices in patients receiving compartmental intraventricular radioimmunotherapy (cRIT). Results One hundred fifty one patients with recurrent primary or metastatic central nervous system (CNS) tumors (1–34 years) had a ventricular access device (143 Ommaya reservoirs, 8 VP shunts with programmable valves) placed for drug administration and cerebrospinal fluid acquisition. Patients received 2–5 serial injections 124I- or 131I- labeled monoclonal antibody 3F8 or 8H9. For each injection, catheters remained accessed for pharmacokinetic studies up to 48 hours or were individually accessed 3–6×/injection. Thereafter catheters were accessed for periodic routine cytology. Six patients (4%) had complications including three with catheter migration in the newly-placed setting requiring surgical revision. Two patients had pericatheter cyst formation (with cyst formation before radioimmunotherapy administration in one patient) resulting in elective removal and endoscopic cystoventriculostomy in both patients. There were no catheter-related infections, hemorrhages, seizures, focal deficits, or valve malfunctioning. Four patients later required Ommaya conversion to VP shunts because of hydrocephalus secondary to disease progression. Conclusions We report a long-term safety profile of ventricular access devices in patients receiving cRIT. Minimal acute complications are observed despite the frequency of cerebrospinal fluid acquisition; long-term complications are rare. Programmable VP shunts appear to be a safe and effective alternative to Ommaya catheters. Pediatr Blood Cancer 2014;61:1590–1592. © 2014 Wiley Periodicals, Inc.

Background To determine the prevalence of and risk factors for primary hypothyroidism following treatment with a radiolabeled monoclonal antibody (131I-3F8) in children with neuroblastoma. Procedure In the current study, we assessed thyroid function in 51 neuroblastoma patients who survived for ≥3 months after treatment with 131I-3F8 (a murine IgG3 monoclonal antibody that reacts with the ganglioside GD2) at 4 mCi/kg/day × 5 days (total 20 mCi/kg). Prior therapy in all subjects included dose-intensive chemotherapy; 13 subjects also received external beam radiation to the neck. Oral iodide and liothyronine sodium (T3) were administered for protection of the thyroid gland. Results Thirty-two of 51 subjects (63%) developed hormonal evidence of primary hypothyroidism. The median time to hypothyroidism after treatment with 131I-3F8 was 6.4 months. The probability of developing hypothyroidism was 56% at 2 years following treatment with 131I-3F8. There was evidence for an association between thyroidal uptake of 131I and development of hypothyroidism (hazard ratio 1.83, 95% confidence interval 0.91–3.30; P = 0.09). Conclusions We conclude that hormonal evidence of primary hypothyroidism developed in a majority of subjects treated with 131I-3F8, despite pretreatment with oral iodide plus liothyronine sodium. Alternative strategies for thyroid gland protection are needed. Pediatr Blood Cancer 2010;55:76–80. © 2010 Wiley-Liss, Inc.

The murine monoclonal antibody 3F8 mediates lysis of neuroblastoma (NB) by complement and leukocytes (including neutrophils) but is neutralized if human anti-mouse antibody (HAMA) forms. We assessed the impact on rapid HAMA formation of prior chemotherapy in NB patients.For the 153 patients treated with 3F8 after conventional therapy (Group 1), the analysis included time from chemotherapy to the start of 3F8. For the 103 patients treated with 3F8 after myeloablative alkylator-based therapy (MAT) (Group 2), the analysis included both chemotherapy administered before stem-cell collection and time from MAT to the start of 3F8.In Group 1, the incidence of HAMA-positivity was significantly lower if patients received high-dose cyclophosphamide (HD-Cy,or = 4,000 mg/m2) before 3F8 treatment (P0.001). In addition, HAMA-positivity was least likely if 3F8 treatment was initiated90 days post-HD-Cy (2/76 compared to 3/19 first treated at 90-120 days, and 17/27 first treated at120 days, P0.001). In Group 2 patients who were transplanted with stem cells collected after HD-Cy, HAMA-positivity occurred in 1/60 patients treated90 days post-MAT versus 13/23 treated90 days post-MAT (P0.001). Among Group 2 patients transplanted with stem cells collected after no prior HD-Cy, the incidence of HAMA-positivity was significantly higher (15/19, P0.001), including 5/7 whose 3F8 treatment began90 days post-MAT.HD-Cy reliably blocks humoral responses to a murine antibody. This capacity to prevent host rejection of foreign or not fully humanized proteins raises the possibility of a broad role for HD-Cy in immunotherapeutic strategies.

Background Few studies have assessed late effects in neuroblastoma (NB) survivors, particularly those with advanced stage disease. Methods Retrospective analysis of a cohort of advanced stage NB survivors followed in a late effect clinic at a single institution. Screening tests to detect late effects were tailored depending on the individual's treatment exposures. Results The study included 63 survivors (31 males). The median age at diagnosis was 3.0 years. The median follow-up from diagnosis was 7.06 years. All patients had surgery and received chemotherapy, 89% received radiation therapy (RT), 62% immunotherapy, and 56% autologous stem cell transplant. Late complications were detected in 95% of survivors and included: hearing loss (62%), primary hypothyroidism (24%), ovarian failure (41% of females), musculoskeletal (19%), and pulmonary (19%) abnormalities. The majority of complications were moderate, with only 4% being life-threatening. Survivors who received cisplatin were at greater risk to develop hearing loss compared to those not so treated (OR 9.74; 95% CI: 0.9–101.6). A total dose of cyclophosphamide greater than 7.4 g was associated with ovarian failure (P = 0.02). Conclusions Late complications occur frequently in survivors of advanced stage NB. The majority of these problems are of mild-moderate severity. Long-term follow-up (LFTU) and screening of this population is essential. © 2005 Wiley-Liss, Inc.

Background Affected patients with neonatal alloimmune thrombocytopenia (AIT) are often severely thrombocytopenic and, if so, may suffer an intracranial hemorrhage (ICH). This study was undertaken to compare the outcome of cases of AIT to cases of neonatal thrombocytopenia shown not to be AIT and to identify clinical features that would facilitate the diagnosis. Procedure Two hundred twenty two cases of neonatal thrombocytopenia for which serologic testing was obtained by the referring physician were accrued for this study from 11 testing laboratories. The relevant clinical information was pursued. Results The mean birth platelet count in 110 neonates with AIT was 26,000/mm3 × 109/L and the rate of ICH was 11% (not all neonates had head sonos). Three criteria distinguished cases of AIT from other causes of neonatal thrombocytopenia (n = 56): (1) severe thrombocytopenia 5, birthweight >2,200 g, grade >1, antenatal occurrence, or signs of bleeding, that is, petechiae, ecchymoses; and (3) no additional, non-hemorrhagic neonatal medical problems. Conclusions AIT is a unique type of neonatal thrombocytopenia with significant hemorrhagic consequences. Identification of AIT at the bedside should guide institution of appropriate treatment and lead to serologic testing for confirmation. Pediatr Blood Cancer 2005 © 2004 Wiley-Liss, Inc.

BACKGROUND: High-risk and recurrent medulloblastoma (MB) is associated with significant mortality. The murine monoclonal antibody 3F8 targets the cell-surface disialoganglioside GD2 on MB. We tested the efficacy, toxicity, and dosimetry of compartmental radioimmunotherapy (cRIT) with intraventricular(131)I-labeled 3F8 in patients with MB on a phase II clinical trial. METHODS: Patients with histopathologically confirmed high-risk or recurrent MB were eligible for cRIT. After determining adequate cerebrospinal fluid (CSF) flow, patients received 2 mCi (where Ci is Curie) (124)I-3F8 or (131)I-3F8 with nuclear imaging for dosimetry, followed by up to four therapeutic (10 mCi/dose) (131)I-3F8 injections. Dosimetry estimates were based on serial CSF and blood samplings over 48 hr plus region-of-interest analyses on serial imaging scans. Disease evaluation included pre- and posttherapy brain/spine magnetic resonance imaging approximately every 3 months for the first year after treatment, and every 6–12 months thereafter. RESULTS: Forty-three patients received a total of 167 injections; 42 patients were evaluable for outcome. No treatment-related deaths occurred. Toxicities related to drug administration included acute bradycardia with somnolence, headache, fatigue, and CSF pleocytosis consistent with chemical meningitis and dystonic reaction. Total CSF absorbed dose was 1,453 cGy (where Gy is Gray; 350.0–2,784). Median overall survival from first dose of cRIT was 24.9 months (95% confidence interval [CI]:16.3–55.8). Patients treated in radiographic and cytologic remission were at a lower risk of death compared to patients with radiographically measurable disease (hazard ratio: 0.40, 95% CI: 0.18–0.88, P = 0.024). CONCLUSIONS: cRIT with (131)I-3F8 is safe, has favorable dosimetry to CSF, and when added to salvage therapy using conventional modalities, may have clinical utility in maintaining remission in high-risk or recurrent MB.

Current therapies for high-risk neuroblastoma (NB) necessitate the availability of several aliquots of autologous peripheral blood stem cells to reverse-associated myelosuppression. Priming with the CXCR4 inhibitor plerixafor plus G-CSF was associated with successful stem cell harvest in 5/7 heavily prior-treated patients with stage 4 NB who had previously failed G-CSF priming. Minimal residual disease was not detected in harvested cells from any patient despite the presence of disease in bone/bone marrow in 6/7. Hematopoietic reconstitution was achieved in all three patients receiving plerixafor-primed stem cells after myeloablative therapy. Plerixafor is an effective and safe agent for stem cell collection in patients with NB. Pediatr Blood Cancer 2012; 58: 469–471. © 2011 Wiley Periodicals, Inc.

Background The PI3K/AKT/mTOR pathway is aberrantly activated in many pediatric solid tumors including gliomas and medulloblastomas. Preclinical data in a pediatric glioma model demonstrated that the combination of perifosine (AKT inhibitor) and temsirolimus (mTOR inhibitor) is more potent at inhibiting the axis than either agent alone. We conducted this study to assess pharmacokinetics and identify the maximum tolerated dose for the combination. Procedure We performed a standard 3+3 phase I, open-label, dose-escalation study in patients with recurrent/refractory pediatric solid tumors. Four dose levels of perifosine (25–75 mg/m2/day) and temsirolimus (25–75 mg/m2 IV weekly) were investigated. Results Twenty-three patients (median age 8.5 years) with brain tumors (diffuse intrinsic pontine glioma [DIPG] n = 8, high-grade glioma n = 6, medulloblastoma n = 2, ependymoma n = 1), neuroblastoma (n = 4), or rhabdomyosarcoma (n = 2) were treated. The combination was generally well tolerated and no dose-limiting toxicity was encountered. The most common grade 3 or 4 toxicities (at least possibly related) were thrombocytopenia (38.1%), neutropenia (23.8%), lymphopenia (23.8%), and hypercholesterolemia (19.0%). Pharmacokinetic findings for temsirolimus were similar to those observed in the temsirolimus single-agent phase II pediatric study and pharmacokinetic findings for perifosine were similar to those in adults. Stable disease was seen in 9 of 11 subjects with DIPG or high-grade glioma; no partial or complete responses were achieved. Conclusions The combination of these AKT and mTOR inhibitors was safe and feasible in patients with recurrent/refractory pediatric solid tumors.