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Background We reviewed clinical and biologic findings in a series of infants with neuroblastoma (NB) in liver. The aim was to gain insights into improving therapy. Patients and Methods Among 19 newly or recently diagnosed infants with NB in liver, 1987–2002, those with stage 4 involving bone received chemotherapy, while those without bone or extensive bone marrow (BM) involvement were observed or received limited treatment if NB caused life-threatening symptoms. We assessed results in the context of NB treatment risk stratification, which is based on age, stage, and selected biologic features (MYCN, ploidy, histology). Results Six of eight infants with bone involvement became long-term event-free survivors including 1/2 with MYCN amplification and four who received only 4–6 cycles of chemotherapy; at the end of treatment, four infants had abnormalities in liver ± the primary site, but these resolved. All 11 infants without bone lesions became long-term survivors with either no cytotoxic therapy or only one cycle of chemotherapy (± radiotherapy to liver), including four who had stage 4 and one stage 4S patient who still had NB in BM at age 15 months. Conclusions Treatment reduction should be considered for subsets of infants with non-MYCN-amplified widespread NB: stage 4 without bone or extensive BM involvement may not require cytotoxic therapy, stage 4S with symptomatic hepatomegaly may not require multiple cycles of chemotherapy, and classic stage 4 may do well with limited chemotherapy. Persistent liver abnormalities post-treatment may not require continued therapy to achieve a radiologic complete remission. © 2005 Wiley-Liss, Inc.

Mannitol is used for increased intracranial pressure and prevention of nephrotoxicity. We present a case report of a patient who experienced an anaphylactic response to mannitol and review the literature.

Purpose We previously reported a high response rate with a dose-intensive chemotherapy regimen in 24 children with high-risk neuroblastoma (NB). We now describe similar results with changes that reduce toxicity (fewer cycles, less vincristine, use of granulocyte colony-stimulating factor). Patients and Methods Eighty-seven consecutive newly diagnosed children with high-risk NB underwent induction that initially had seven cycles (57 patients) but was later limited to five (30 patients). Cycles 1, 2, 4, and 6 used cyclophosphamide (140 mg/kg)/doxorubicin (75 mg/m2)/vincristine (0.15 mg/kg in the first 27 patients, 0.067 mg/kg subsequently). Cycles 3, 5, and 7 used cisplatin (200 mg/m2)/etoposide (600 mg/m2). Tumor resection followed a minimum of three cycles. The induction was eventually modified to include anti-GD2 immunotherapy after each of the last three cycles (38 patients). Results Bone marrow disease resolved in 70 (91%) of 77 patients and was not detected pre- and postinduction in 10 patients. After cycle 3 or 4, 86% of primary tumors were more than 50% smaller. Postinduction metaiodobenzylguanidine scans showed normal radiotracer distribution in metastatic sites in 74 (87%) of 85 patients. Overall results were: 68 (79%) complete/very good partial responses (CR/VGPR); 14 (16%) partial responses (PR); three (3%) less than PR; one (1%) death from infection; and one patient not assessable for response. Five cycles yielded a CR/VGPR rate of 83%, compared with a 77% rate from seven cycles. Side effects were myelosuppression, mucositis, and hearing deficits; neurotoxicity was insignificant with the lower vincristine dosage. Four patients (each received seven cycles) developed myelodysplasia/leukemia. Conclusion Five cycles of this induction regimen, plus surgery, suffice to achieve CR/VGPR in ≈80% of children with high-risk NB.

Intrinsic biologic tumor features are critical prognosticators of survival in patients with neuroblastoma. Patients with localized neuroblastoma and favorable biologic parameters may be observed without treatment. Conversely, leptomeningeal metastases in patients with primary extracranial neuroblastoma are highly unusual and, despite aggressive multimodality therapies, invariably fatal. The authors describe a newly diagnosed infant with neuroblastoma and radiographic imaging suggestive of leptomeningeal metastases. The patient underwent partial surgical resection of the primary tumor. The primary tumor revealed favorable biologic characteristics. The patient was observed with no cytotoxic therapy and remained well with no evidence of disease progression more than 3 years since diagnosis. This case illustrates that some infants with favorable-biology neuroblastoma may be observed without treatment despite the advanced INSS stage.

Short-lived alpha-emitting isotopes individually conjugated to monoclonal antibodies have now reached human use, but little is still known about their toxicity. Use of antibody targetable (225)Ac nanogenerators is a new approach in the field of alpha-immunotherapy offering the advantage of a 10-d half-life (t(1/2)) and increased potency due to generation of 3 new atoms, yielding a total of 4 alpha-particles. However, the 3 alpha-emitting daughter elements generated have the potential for significant toxicity as these nuclides are no longer bound to the carrier IgG.Cynomolgus monkeys were used to evaluate the toxicity of prototype (225)Ac nanogenerators. Monoclonal antibody HuM195 (anti-CD33) is the carrier for planned human clinical trials of (225)Ac; there are no CD33 sites in cynomolgus monkeys. In one experiment, 2 monkeys received a single intravenous dose of (225)Ac-HuM195 at 28 kBq/kg. This dose level is approximately the planned initial human dose. In another experiment, 2 animals received a dose escalation schedule of 3 increasing (225)Ac-HuM195 doses with a cumulative activity of 377 kBq/kg. The whole-blood t(1/2) of (225)Ac, ratios of (225)Ac to its ultimate alpha-emitting daughter nuclide (213)Bi, generation of monkey anti-HuM195 antibodies (MAHA), hematologic indices, serum biochemistries, and clinical parameters were measured. Monkeys were euthanized and examined histopathologically when the dose escalation reached toxicity.The blood t(1/2) of (225)Ac-HuM195 was 12 d, and 45% of generated (213)Bi daughters were cleared from the blood. MAHA production was not detected. Approximately 28 kBq/kg of (225)Ac caused no toxicity at 6 mo, whereas a cumulative dose of approximately 377 kBq/kg caused severe toxicity. In the cumulative dosing schedule, single doses of approximately 37 kBq/kg resulted in no toxicity at 6 wk. After approximately 130 kBq/kg were administered, no toxicity was observed for 13 wk. However, 28 wk after this second dose administration, mild anemia and increases of blood urea nitrogen and creatinine were detected. After administration of an additional 185 kBq/kg, toxicity became clinically apparent. Monkeys were euthanized 13 and 19 wk after the third dose administration (cumulative dose was 377 kBq/kg). Histopathologic evaluation revealed mainly renal tubular damage associated with interstitial fibrosis.(225)Ac nanogenerators may result in renal toxicity and anemia at high doses. The longer blood t(1/2) and the lack of target cell antigens in cynomolgus monkeys may increase toxicity compared with human application. Therefore, a dose level of at least 28 kBq/kg may be a safe starting dose in humans. Hematologic and renal function will require close surveillance during clinical trials.

Neuroblastoma risk stratification is based on stage, age, and biology and prescribes surgery for low-risk disease, moderate-dose chemotherapy for intermediate-risk disease, and maximal therapy (including myeloablative treatment with stem cell transplantation) for high-risk disease. Four cases are described that depict pitfalls in risk assessment with potentially far-reaching consequences. This report focuses on a subset of four patients referred for second opinions. Stage was defined by the International Neuroblastoma Staging System. The first recommendations were for maximal therapy, but second opinions were radically different (ie, surgery alone). Ages at diagnosis were 15 to 25 months. Shimada histopathology was unfavorable in three of the four patients, but chromosomal, serum, and urine prognostic markers were favorable. All four patients did well without cytotoxic therapy (follow-up: 2 years 10 months plus to 4 years 8 months plus). Patient 1 had abdominal and upper thoracic/supraclavicular masses (stage 4); the former was resected and the latter spontaneously regressed. Patient 2 had retroperitoneal disease, without bone marrow involvement, but imaging studies showed lesions in vertebral bodies. Biopsies of the latter showed no neuroblastoma and the primary tumor (with regional lymph nodes) was resected, changing stage from 4 to 2B. Patient 3 had a retroperitoneal mass but no distant disease. Though initially deemed to be unresectable, the abdominal tumor was excised, changing the classification from high risk (stage 3 with unfavorable histopathology) to low risk (stage 1). Patient 4 had a pelvic mass, with unfavorable histopathology, and bilateral inguinal lymph node involvement (stage 3); all soft tissue disease was resected. The absence of cortical bone and extensive bone marrow metastatic involvement in a young neuroblastoma patient should cause a shift in attention to biologic prognostic markers. Some patients classified as having high-risk neuroblastoma might actually do well with no cytotoxic therapy.

Introduction: Considerable controversy exists regarding the appropriate management of spinal involvement in neuroblastoma (NB) patients. We review a large group of such patients and offer treatment recommendations. Methods: Forty-six patients with epidural and/or neural foraminal involvement treated between 1987 and 1998 were staged according to the International NB Staging System (INSS) and classified as high-risk (INSS stage 4; n = 31) or low-risk (INSS stage Conclusions: High-risk NB patients with spinal involvement but normal neurologic examinations should be offered chemotherapy. High-risk patients with HGSCC may respond to chemotherapy, but a small percentage will require operations for progressive neurologic deficits. Chemotherapy may be avoided in low-risk patients who are offered potentially curative operations. Patients treated with operations for epidural disease are at high risk of subsequently developing spinal deformity.

An indolent course is associated with neuroblastoma (NB) in adolescents and adults. In the current study, the authors analyzed this phenomenon in a large series of children with metastatic NB.The authors studied 38 patients who were diagnosed with NB in the first decade of life and had metastatic disease 5 years or more from diagnosis.The median age at diagnosis was 3 years 10 months. MYCN was amplified in 2 of 28 patients tested. Of 30 patients with classic Stage 4 NB, 9 had a late first recurrence of disease (4.3-13 years from diagnosis). Of eight patients who had atypical cases at diagnosis (one isolated mandibular lesion, two Stage 4-N, five non-Stage 4), six had a late first distant recurrence of disease (4 years 11 months-38 years 8 months). Nineteen patients were off therapy continuously for 3 years or more before disease recurred a first or second time. Myeloablative therapy was used to consolidate a first or second response in 27 patients. High-dose conventional therapy helped to achieve a second remission of disease in 9 of 20 patients assessable for response of first recurrence but achieved no major responses of second or third relapse in 10 of 11 patients. The combination of anti-G(D2) immunotherapy and/or cis-retinoic acid, targeted radiotherapy, and multiple cycles of chemotherapy with modest toxicity helped prolong survival. Twelve patients survive at 5 years 6 months+ to 19 years 4 months+ from diagnosis (median, 6 years 10 months+), including four with complete remission of disease; 10 received anti-G(D2) immunotherapy after recurrence. The other 26 patients died of disease (n = 22) or toxicity (n = 4) at 5 years-41 years 5 months from diagnosis (median, 6 years 5 months).The concept of indolent or smoldering NB should not be limited to adolescents/adults. The expanding repertoire of anti-NB treatments, including biologic therapies and chemotherapy regimens of modest toxicity, can convert childhood NB into a chronic disease with prolonged survival after recurrence.

e16506 Background: Individualized cancer therapy is a long held goal for patients and clinicians. We report the results of a commercially available precision medicine assay in recurrent gyn cancers...

e22115 Background: GI cancers account for about 20% of all cancers diagnosed in the US. Therapeutic options in relapsed/refractory disease are limited and the outcomes are poor. Advanced therapeuti...

PURPOSE: To describe oncolytic effects of treatment with anti-GD2 monoclonal antibody 3F8 plus granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients with neuroblastoma (NB). PATIENTS AND METHODS: Patients were eligible for 3F8/GM-CSF if intensive therapy had not eradicated potentially lethal NB. One cycle consisted of GM-CSF (subcutaneous bolus) on days 1 through 5, 11, and 12, and GM-CSF (2-hour intravenous [IV] infusion) followed after a 1-hour interval by 3F8 (1.5-hour IV infusion) on days 6 through 10 and 13 through 17. GM-CSF was dosed at 250 μg/m2/d on days 1 through 7 and at 500 μg/m2/d on days 8 through 17. 3F8 was dosed at 10 mg/m2/d (100 mg/m2/cycle). 3F8 was given with an opiate and an antihistamine. Patients without progressive disease (PD) or elevated human antimouse antibody titers could be treated again beginning 3 weeks after completion of a cycle. RESULTS: Among 19 patients treated for NB resistant to induction therapy, 12 of 15 had complete remission (CR) of bone marrow (BM) disease, and three others who had less than partial responses achieved prolonged progression-free survival (one remains on study at 21+ months, two had PD at 12 and 17 months). Among patients treated for recurrent NB resistant to retrieval therapy, five of 10 had CR in BM. The 15 patients treated for PD fared poorly, although two had scintigraphic findings suggestive of a short-term response. Side effects were limited to readily manageable pain and, less commonly, rash of short duration; hence, patients were treated as outpatients. CONCLUSION: 3F8/GM-CSF is well tolerated and shows promise for treatment of minimal residual NB in BM.

PURPOSE: To assess prognostic factors for local control in high-risk neuroblastoma patients treated with hyperfractionated 21-Gy total dose to consolidate remission achieved by dose-intensive chemotherapy and surgery. PATIENTS AND METHODS: Patients with high-risk neuroblastoma in first remission received local radiotherapy (RT) totaling 21 Gy in twice-daily 1.5-Gy fractions. RT to the primary site followed dose-intensive chemotherapy and tumor resection; the target field encompassed the extent of tumor at diagnosis, plus 3-cm margins and regional lymph nodes. RT to distant sites followed radiologic evidence of response. Local failure was correlated with clinical factors (including other consolidative treatments) and biologic findings. RESULTS: Of 99 consecutively irradiated patients followed for a median of 21.1 months from RT, 10 relapsed in or at margins of RT fields at 1 to 27 months (median, 14 months). At 36 months after RT, the probability of primary-site failure was 10.1% ± 5.3%. No primary-site relapses occurred among the 23 patients whose tumors were excised at diagnosis, but there were three such relapses among the seven patients who were irradiated with evidence of residual disease in the primary site. Four of 18 patients with MYCN-amplified disease and serum lactate dehydrogenase greater than 1,500 U/L had local failures (23.4% ± 10.7% risk at 18 months). Acute radiotoxicities were insignificant, but three of 35 patients followed for ≥ 36 months had short stature from decreased growth of irradiated vertebra. CONCLUSION: Hyperfractionated 21-Gy RT is well tolerated and, together with dose-intensive chemotherapy and surgery, may help in local control of high-risk neuroblastoma. Extending the RT field to definitively encompass regional nodal groups may improve results. Visible residual disease may warrant higher RT dosing. Patients with biologically unfavorable disease may be at increased risk for local failure. RT to the primary site may not be necessary when tumors are excised at diagnosis.

Deletion of the short arm of chromosome 1 is frequently observed in neuroblastoma (NB). We performed loss of heterozygosity (LOH) analysis of 120 well characterized NB to better define specific regions of 1p loss and any association with clinical and biological prognostic features (DNA index, MYCN, age, and stage). All categories of disease were represented including 7 ganglioneuromas, 8 stage 4S, 33 local-regional (stages 1, 2, and 3), and 72 stage 4 NB according to the International Neuroblastoma Staging System. Patients were consistently treated with stage-appropriate protocols at a single institution. Sixteen highly informative, polymorphic loci mapping to chromosome 1 were evaluated using a sensitive, semi-automated, fluorescent detection system. Chromosome arm 1p deletions were detected in all categories of tumor except ganglioneuroma. Frequent LOH was detected at two separate regions of 1p and distinct patterns of losses were associated with individual clinical/biological categories. Clinically aggressive stage 4 tumors were predominantly diploid with extensive LOH frequently detected in the region of 1ptel to 1p35 (55%) and at 1p22 (56%). The shortest region of overlap for LOH at 1p36 was between D1S548 and D1S1592 and for 1p22 was between D1S1618 and D1S2766. Local-regional tumors were mostly hyperdiploid with short regions of loss primarily involving terminal regions of 1p36 (42%). Most spontaneously regressing stage 4S tumors (7/8) were hyperdiploid without loss of 1p36 or 1p22. These findings suggest that genes located on at least two separate regions of chromosome arm 1p play a significant role in the biology of NB and that distinct patterns of 1p LOH occur in individual clinical/biological categories.

PURPOSE To eradicate minimal residual disease with anti-G(D2) monoclonal antibody 3F8 in stage 4 neuroblastoma (NB) diagnosed at more than 1 year of age. PATIENTS AND METHODS Thirty-four patients were treated with 3F8 at the end of chemotherapy. Most had either bone marrow (n=31) or distant bony metastases (n=29). Thirteen patients were treated at second or subsequent remission (group I) and 12 patients in this group had a history of progressive/persistent disease after bone marrow transplantation (BMT); 21 patients were treated in first remission following N6 chemotherapy (group II). RESULTS Before 3F8 treatment, 23 patients were in complete remission CR, eight in very good partial remission (VGPR), one in partial remission (PR), and two had microscopic foci in marrow. Twenty-five had evidence of NB by at least one measurement of occult/minimal tumor (iodine 131[(131)I]-3F8 imaging, marrow immunocytology, or marrow reverse-transcriptase polymerase chain reaction [RT-PCR]). Acute self-limited toxicities of 3F8 treatment were severe pain, fever, urticaria, and reversible decreases in blood counts and serum complement levels. There was evidence of response by immunocytology (six of nine), by GAGE RT-PCR (seven of 12), and by (131)I-3F8 scans (six of six). Fourteen patients are alive and 13 (age 1.8 to 7.4 years at diagnosis) are progression-free (40 to 130 months from the initiation of 3F8 treatment) without further systemic therapy, none with late neurologic complications. A transient anti-mouse response or the completion of four 3F8 cycles was associated with significantly better survival. CONCLUSION Despite high-risk nature of stage 4 NB, long-term remission without autologous (A)BMT can be achieved with 3F8 treatment. Its side effects were short-lived and manageable. The potential benefits of 3F8 in consolidating remission warrant further investigations.

In contrast to MYCN amplification, expression of either trk-A or CD44 in neuroblastoma is a favourable prognostic factor and were therefore investigated in tumours from 250 patients. One hundred and eleven localised/4s (Group 1) and 139 stage 4 (Group 2) tumours were analysed. MYCN copy number was obtained by Southern blotting or PCR amplification and was detected in 28 stage 4 tumours. Trk-A and CD44 expression was detected by immunoperoxidase staining using murine monoclonal antibodies 5C3 and L178, respectively. Expression was scored as positive (homogeneous), mixed (heterogeneous) or non-reactive (negative). Trk-A expression was found in 95% of Group 1 tumours and 49% of Group 2 tumours. CD44 expression was found in 100% of Group 1 tumours, the majority of which had a strong homogeneous expression. Lack of CD44 expression occurred in 25% of tumours, all stage 4 neuroblastoma. Of the 28 MYCN amplified tumours, 27/28 (96%) were trk-A negative, and 13/28 (46%) CD44 negative. We conclude that (1) a significant percentage of stage 4 neuroblastoma express either or both trk-A and CD44, (2) the absence of CD44 expression is highly restricted to stage 4 neuroblastoma and is associated with the lack of trk-A expression, (3) trk-A negativity among CD44-positive tumours is associated with stage 4 neuroblastoma and (4) the absence of trk-A expression is highly correlated with MYCN amplification.

A, Retinal masses of metastatic neuroblastoma found 7months after multiagent chemotherapy following initial diagnosis at 6 weeks of age for favorable histology metastatic neuroblastoma. B, After treatment including chemotherapy, craniospinal radiation, immunotherapy, and intra-Ommaya radiotherapy, the patient has no evidence of systemic or retinal neuroblastoma. Fungal Endophthalmitis Original Investigation Research

β-glucans are complex, naturally-occurring polysaccharides that prime leukocyte dectin and complement receptor 3. Based on our preclinical findings, indicating that oral barley-derived (1 → 3),(1 → 4)-β-D-glucan (BG) synergizes with the murine anti-GD2 antibody 3F8 against neuroblastoma, we conducted a Phase I clinical study to evaluate the safety of this combinatorial regimen in patients affected by chemoresistant neuroblastoma. In this setting, four cohorts of six heavily pre-treated patients bearing recurrent or refractory advanced-stage neuroblastoma were treated with 3F8 plus BG. Each cycle consisted of intravenous 3F8 at a fixed dose of 10 mg/m2/day plus concurrent oral BG, dose-escalated from 10 to 80 mg/Kg/day, for 10 d. Patients who did not develop human anti-mouse antibodies could be treated for up to 4 cycles. Twenty-four patients completed 50 cycles of therapy. All patients completed at least one cycle and were evaluable for the assessment of toxicity and responses. The maximum tolerated dose of BG was not reached, but two patients developed dose-limiting toxicities. These individuals developed grade 4 thrombocytopenia after one cycle of BG at doses of 20 mg/Kg/day and 40 mg/Kg/day, respectively. Platelet counts recovered following the administration of idiopathic thrombocytopenic purpura therapy. There were no other toxicities of grade > 2. Eleven and 13 patients manifested stable and progressive disease, respectively. Thirteen out of 22 patients with pre-treatment positive 123I-MIBG scans demonstrated clinical improvement on semiquantitative scoring. Responses did not correlate with BG dose or with in vitro cytotoxicity. In summary, 3F8 plus BG is well tolerated and shows antineoplastic activity in recurrent or refractory advanced-stage neuroblastoma patients. Further clinical investigation of this novel combinatorial immunotherapeutic regimen is warranted.

Introduction Injection of 131I-3F8 directly into the cerebrospinal fluid (CSF) through an Ommaya reservoir is a safe form of radioimmunotherapy (RIT) treatment for leptomeningeal metastasis (JCO, 25:5465, 2007). Recently, we described a one-compartment pharmacokinetics model that showed good fitting to CSF sampling data from 6 patients (JNM 50:1324, 2009). We now describe an improved two-compartment model to take into account the ventricular reservoir before 131I-3F8 distribution into the subarachnoid space and to explore limiting factors that may significantly affect the efficacy of the therapy. Methods The distribution and binding of 131I-3F8 in the cerebral spinal fluid were modeled using a system of rate equations derived from the principle of mass conservation. The model was fitted to CSF sampling data from an expanded cohort of patients (39 injections in 25 patients). Three sets of criteria were used to examine the effect of each parameter on the efficacy of the treatment. These criteria were (1) the area under the radioactivity concentration curve of the bound antibody (AUC[CIAR]) (2) the unbound antibody AUC[CIA], and (3) their therapeutic ratio (AUC[CIAR]/AUC[CIA]). In addition to parameters tested in the previous model, immunoreactivity, tumor distribution, and nonspecific binding were also tested. Results The two-compartment model showed improved fitting to patient data when compared to the one compartment model (R=0.92±0.11 versus 0.77±0.21, p=0.005). Predictions from the one compartment model were confirmed. Furthermore, we made these new observations: (1) Increasing immunoreactivity of 131I-3F8 from 10% to 90% increased both (AUC[CIAR]) and therapeutic ratio ([AUC[CIAR]/AUC[CIA]) by 7.4 fold, (2) The presence of ≤ 5% tumor cells in the ventricles or ≤ 10% of nonspecific 131I-3F8 binding to normal tissues had no appreciable effect on the therapeutic ratio. When extrapolated to a clinical setting, the model predicted that if 131I-3F8 could be split into 4 doses of 1.4 mg each and given at ≥ 24 hours apart, an antibody affinity of KD of 4 × 10−9 and immunoreactivity of 50% were adequate in order to deliver ≥10,000 Rad to tumor cells while keeping normal CSF exposure to Conclusion The two compartment model of intra-ommaya radioimmunotherapy showed better fitting to patient data than the one-compartment model. This model predicted that immunoreactivity and affinity were crucial in improving therapeutic efficacy. Nevertheless, an optimal scheduling of antibody injections should permit highly favorable therapeutic ratio even with 4 nM affinities and suboptimal immunoreactivity. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5633.

In our report, we did not discuss how relapses were documented— we assumed it would be self-evident that they must be confirmed unequivocably before salvage therapy is initiated. Satharasinghe et al raise concern about the 27% of patients whose relapse was detected only by iodine-123 (I) metaiodobenzylguanidine (MIBG) scan. Among those 25 patients, 24 had abnormal radiotracer uptake in one or more osteomedullary sites and one patient had new uptake in a small postoperative paraspinal site. Relapse was deemed unequivocal when multiple skeletal sites of abnormal MIBG uptake were present (n 7). In contrast, with a single new abnormal MIBG-avid osteomedullary site (n 17), the finding was judged as indicative of relapse only after magnetic resonance imaging revealed a corresponding lesion and follow-up MIBG scan remained abnormal (by which time other staging studies often also showed new disease). The paraspinal relapse was confirmed by disease resection after follow-up I-MIBG scintigraphy remained abnormal. None of the above patients had the most common form of I-MIBG false positivity, that is, uptake in the abdomen after retroperitoneal tumors are resected and renal function is impaired, leading to delayed or altered excretion of the radiotracer. Uncertainty in these situations is rare with tomographic (SPECT) imaging techniques or fusion MIBG/computed tomography (CT) that correlate uptake to anatomy; hybrid [F]fluorodeoxyglucose-positron emission tomography/CT can also be helpful in clarifying disease status. Relapse of high-risk neuroblastoma (NB) has long been viewed as a systemic event and tantamount to eventual death from disease or toxicity of retrieval therapy. Developments in the past decade, however, raise the welcome possibility that the absolute equivalence between relapse in these patients and a lethal outcome may no longer hold true. Thus, close monitoring using sensitive techniques may now be detecting focal or well-localized relapses. These might be controlled by surgery and/or radiotherapy, supplemented by relatively nontoxic systemic therapies that are noncrossresistant with prior treatments. For patients with no evidence of disease after treatment of highrisk NB, we continue to advocate close monitoring for recurrence. Despite being the most common study to reveal unsuspected relapse, I-MIBG scan was falsely negative in 16% of cases. Clearly, this scintigraphic evaluation cannot serve as a “stand-alone surveillance test” but should be part of a battery of tests required for accurately assessing relapse-free survival.

10050 Background: CNS relapse in high-risk NB is on the rise as extracranial disease control improves. Management of CNS relapse with radiotherapy (RT) that does not address the entire neuraxis has...

2022 Background: NB metastatic to the CNS (NB-CNS) is difficult to control. We describe a salvage regimen incorporating intra- Ommaya RIT delivered to the CSF. Methods: 37 patients (pts) with NB-CNS (parenchymal masses and/or leptomeningeal [LM] carcinomatosis) treated at MSKCC from 1988 through 2006 were reviewed. Nine (group #1) of 37 pts developed NB-CNS metastasis (median age 3.8 years) and were treated with a salvage regimen: resection of parenchymal masses, 2160 cGy craniospinal irradiation (CSI), intravenous irinotecan and oral temozolomide, and RIT with 131I-8H9 and or 131I-3F8 targeting tumor associated antigens on phase I/II studies. Immunotherapy (intravenous anti-GD2 monoclonal antibody 3F8 plus subcutaneous GM-CSF) was also given for systemic control. Survival was compared to the other 28 (group #2) pts who developed NB-CNS (median age 4.2 years) treated with combinations of surgery, chemotherapy, and radiation but without CSI + RIT. Results: All 37 pts had high risk disease at initial diagnosis of NB. 9 of 9 group #1 pts had marrow and/or bony involvement; 6 of 9 had MYCN amplification and 5 of 9 had serum LDH >1500 U/ml. All had intensive chemotherapy and radiotherapy prior to CNS relapse. Despite this, the CNS salvage regimen was well-tolerated. Myelosuppression following CSI and chemotherapy was common; 2 pts received stem cell support. All 9 pts in the RIT group are alive and well, disease-free at 3+, 11+, 15+, 18+, 18+, 20+, 22+, 31+, 42+ months since CNS relapse. In contrast, pts in group #2 had a median time to death of 5.5 months, (p131I-3F8 or 131I-8H9 is well-tolerated and improves the prognosis for these high risk patients. No significant financial relationships to disclose.

9566 Background: Beta glucans are complex, naturally occurring polysaccharides that prime leucocyte dectin and CR3 receptors. Based on our preclinical observations that oral barley-derived (1→3,1→4)-β-D-Glucan (BG) synergizes with the murine anti-GD2 antibody 3F8 against neuroblastoma (NB) (Clin Cancer Res 8:1217), we conducted a phase I study to determine the safety of the combination of BG and 3F8 in patients with resistant NB. Methods: Heavily pre-treated patients with recurrent or refractory advanced stage NB were treated with 3F8/BG. Each cycle consisted of intravenous (IV) 3F8 at a fixed dose of 10 mg/m2/day ×10 days, plus oral BG dose escalated from 10 to 80 mg/kg/day ×10 days in 4 cohorts of 6 patients each. Patients without human anti-mouse antibody (HAMA) could be re-treated up to a total of 4 cycles. Results: Twenty-three patients with stage 4 and one with stage 3 NB (M:F = 11:13; median age 8 (range 2–19) years completed 47 cycles of therapy with 3F8/BG. 8 patients had progressive disease (PD) while 16 had stable refractory NB (SD) at enrollment. All patients completed at least one cycle of therapy and were evaluated for toxicity and response. Maximum tolerated dose for BG was not reached. Two patients developed dose-limiting toxicities (DLT). Both had grade 4 thrombocytopenia after completing one cycle of treatment: one at BG dose of 20mg/kg/day and the other at 40 mg/kg/day. Both cases responded to therapy with a short course of ITP (idiopathic thrombocytopenic purpura) therapy; one subsequently developed chronic ITP. There were no other >grade 2 toxicities related to 3F8/BG therapy. 14, 4, 2 and 6 patients completed 1, 2, 3 and 4 cycles respectively. Reasons for withdrawal in patients who did not complete 4 cycles were PD in 10, persistently elevated HAMA in 6 and DLT in 2. Overall 11 patients had SD and 13 PD. 14/23 patients with positive MIBG scans prior to therapy demonstrated improvement after one cycle. Responses did not correlate with BG dose received. 7 patients, all with residual disease survive at a median of 40 (range 24–45) months post-treatment. Conclusions: 3F8/BG is well tolerated and shows activity against resistant NB. Further clinical investigation of this novel combination is warranted. No significant financial relationships to disclose.

5C3 is a murine IgG 1 antibody specific for the nerve growth factor (NGF) docking site of the human p140 trk-A receptor, with no cross-reactivity with human trk-B. In vitro , 5C3 and its Fab mimic the effects of NGF, a neurotrophin mediating growth and differentiation of neural crest-derived cells. When labelled with radioisotope, 5C3 images human trk-A positive tumours in vivo . More importantly, 5C3 induces regression of human trk-A positive tumours in rodents. We therefore investigated the value of 5C3 in detecting trk-A expression in human neuroblastoma by immunohistochemistry. 5C3 reactivity was detected in 73 of 113 neuroblastoma specimens and correlated strongly with localised/4s disease (55/60) with either a homogeneous or mixed pattern. Among stage 4 neuroblastoma, only 18/53 had homogeneous or mixed trk-A expression. 5C3 did not react with 46/48 other human malignancies, but was positive in 1 melanoma and 1 Wilms' tumour specimen. The prognostic, imaging and NGF-mimetic properties of antibody 5C3 and its derivatives may offer alternatives for the diagnosis and treatment of neuroblastoma.

We previously described SL/MDS in 3/53 newly-diagnosed NB patients (pts) who received 4 cycles of high-dose cyclophosphamide (4200 mg/m2)-doxorubicin (75 mg/m2)-vincristine (CAV) and 3 cycles of high-dose cisplatin (200 mg/m2)-etoposide (600 mg/m2) (P/E), ± local radiotherapy (RT), ± immunotherapy using the anti-GD2 3F8 antibody, ± targeted RT using 131-I-3F8. With longer follow-up and the addition of a further 11 pts who received 7 cycles and 5 pts who received 6 cycles, there are 3 more cases of SL/MDS (Table1), which gives SL or MDS in 6/69 pts. Table 1. Pts with Secondary Leukemia or MDS | Age | From Dx | Presentation | Type | Cytogenetics | |:----------------------------------------------------------- | ------- | ---------------- | ---- | ---------------------------------------- | | * all 3 received 7 cycles; 2 also received local RT and 3F8 | | ** all 3 received 7 cycles, local RT, 3F8, and 131-I-3F8 | | Previously reported cases (J Clin Oncol 16:3880, 1998)* | | 4y | 15m | surveillance BM | M2 | del(9)(q13q34),del(11)(q23q25) | | 5y | 27m | thrombocytopenia | MDS | del(5)(q11), der(7)t(7;17)(q11,q11), −17 | | 12y | 7m | monocytosis | M5 | del(11)(q23) (rearranged MLL gene) | | New cases** | | 3y | 12m | leukocytosis | ALL | t(4;11)(q21;q23) (rearranged MLL) | | 8y | 50m | thrombocytopenia | MDS | del(5q) and del(7q) | | 25y | 24m | thrombocytopenia | MDS | del(7q) | This SL risk was a reason for subsequently limiting induction to 3 CAV and 2 P/E. At 4+-to-72+ months (median, 19+), SL/MDS has not occurred in 46 pts treated with 5 cycles, including 19 who received thiotepa-topotecan-carboplatin (TTC) with an autologous stem-cell transplant and 11 who received both TTC and oral etoposide (E) maintenance. In routine surveillance studies, 4 pts in the 6/7-cycle group had BM cytogenetic changes (worrisome for SL) that spontaneously resolved, and 1 pt in the 5-cycle group had a cytogenetic aberration that has persisted in >90% of BM cells for 15+ months, without morphologic or clinical evidence of SL/MDS (Table 2). Allo-transplant was recommended, but not done, for this patient and for the 10 yr old with a t(3;6) translocation that was documented in 20%-to-100% of BM mitoses for 26 months before finally disappearing (Table 2). Table 2. Pts with chromosomal aberrations but no SL or MDS | Age | From Dx | # of Cycles, other Rx* | Cytogenetics, Duration | |:------------------------------------ | ------- | ------------------------ | --------------------------------------- | | * all of these pts also received 3F8 | | 18y | 10m | 7, local RT | inv(11)(q21q23) (rearranged MLL), 1m | | 6y | 21m | 7, local RT, 131-I-3F8 | t(2;16)(q31;q22) t(6;10)(q21;p13), 4m | | 10y | 22m | 6, local RT, 131-I-3F8 | der(6) t(3,6)(q23, p25), 26m | | 6y | 24m | 7, local RT, 131-I-3F8 | dup(1)(q21q32), 14m | | 5y | 17m | 5, local RT, TTC, oral E | t(4;11)(p12;q23) (rearranged MLL), 15m+ | In prior-treated NB pts, we also found transient BM cytogenetic abnormalities, some associated with leukemia or MDS, including del(16) (q22) and del(7q), though others are not, including inv(17) (p13q23). We conclude that fewer cycles of dose-intensive induction may reduce risks of SL/MDS and that BM cytogenetic abnormalities do not invariably evolve into SL or MDS. The nature of other genetic or epigenetic abnormalities that underlie such a transformation is currently unknown.

8543 Background: Few studies have assessed late effects in neuroblastoma (NB) survivors. Methods: 63 high risk NB patients were seen at the Long Term Follow-Up Clinic since 1991. Results: Median age at diagnosis was 3.0 years. 11 patients had stage 3 disease and 52 stage 4 (2 stage 2B initially). Median follow-up was 7.06 years. All patients had surgery and received chemotherapy, 56 (89%) radiation therapy, 38 (60%) immunotherapy and 35 (56%) autologous stem cell transplant. 60 patients (95%) had late effects and 18 (29%) had more than three. The most frequent complications were: hearing loss (62%), primary hypothyroidism (24%), ovarian failure (41% of females), musculoskeletal (21%), pulmonary (19%), neurocognitive (14%), visual (14%), dental (13%) and secondary neoplasms (6%). Grades of severity were: 1 (24%), 2 (44%), 3 (28%) and 4 (4%) (CTCAE v 3.0). Survivors who received cisplatinum were more at risk to develop hearing loss compared to those who did not receive it ( OR, 9.74; 95% CI: 0.9–101.6). A t...

Diganglioside G D2 and Antigen 8H9: Potential Targets for Antibody-Based Immunotherapy against Desmoplastic Small Round Cell Tumor and Rhabdomyosarcoma