We used retroviral-mediated gene transfer of the human interleukin (IL)-2 gene into murine neuroblastoma cells to investigate whether locally-secreted IL-2 is able to influence the generation of anti-tumor immune responses. Supernatant obtained from cultures of approximately 1 x 10(6) IL-2 gene-transduced, G-418 selected neuro-2a cells was assayed for human IL-2 production by ELISA kit. First, to estimate whether the local secretion of IL-2 from the genetically-modified tumor cells would affect their tumorigenicity in vivo, IL-2-secreting neuro-2a cells were s.c. injected into A/J mice and tumor growth was measured weekly. And to estimate whether IL-2 transfected neuroblastoma cells protect mice from tumor development after wild-type tumor cell challenge, IL-2-secreting neuro-2a cells were s.c. injected into A/J mice. Seven days after IL-2 gene-transfected neuroblastoma cell injection, unmodified neuro-2a cells were s.c. injected into the contralateral site of A/J mice and tumor growth was measured weekly. Finally, to estimate IL-2 effect on pre-established large tumor burdens, IL-2-secreting neuro-2a cells were s.c. injected into A/J mice with established tumor and its growth was measured weekly. The IL-2 gene-transduced neuro-2a clones secreted 120.25-177.3 IU of IL-2 per ml per 10(6) cells during 24 hr. None of the mice injected with IL-2-secreting neuro-2a cells developed tumors within 6 weeks, while all of the mice injected with wild-type neuro-2a cells developed tumors. Immunization of mice with IL-2 gene-transfected, irradiated neuro-2a cells protected these animals against a subsequent challenge with wild-type tumor cells. Finally, the size of large neuroblastomas decreased after IL-2-secreting neuro-2a cell injection into mice. Local secretion of IL-2 gene-transduced tumor cells abrogates their tumorigenicity and induces protective immunity and may inhibit the growth of neuroblastoma.
Animal ; Antibody Formation ; Gene Transfer Techniques* ; Human ; Immunization/methods ; Interleukin-2/therapeutic use ; Interleukin-2/genetics* ; Mice ; Neoplasm Transplantation ; Neuroblastoma/therapy ; Neuroblastoma/prevention & control ; Neuroblastoma/pathology ; Neuroblastoma/genetics* ; Retroviridae/genetics* ; Tumor Cells, Cultured

Autologous stem cell transplantation (ASCT) for the treatment of high-risk neuroblastoma (NBL) is an accepted method for restoring bone marrow depression after high dose chemotherapy. We retrospectively analyzed eighty eight cases of NBL that underwent ASCT following marrow ablative therapy at 12 transplant centers of the Korean Society of Pediatric Hematology-Oncology between January 1996 and September 2000. Seventy nine children were of stage IV NBL and 9 were of stage III with N-myc amplification. Various cytoreductive regimens were used. However, the main regimen was 'CEM' consisting of carboplatin, etoposide and melphalan, and this was used in 66 patients. Total body irradiation was also added in 36 patients for myeloablation. To reduce tumor cell contamination, stem cell infusions after CD34+ cell selection were performed in 16 patients. Post-transplantation therapies included the second transplantation in 18 patients, interleukin2 therapy in 45, 13-cis retinoic acid in 40, 131-meta-iodobenzylguanidine in 4, conventional chemotherapy in 11, and local radiotherapy in 8. Twenty two patients died, sixty six patients are surviving 1 to 46 months after ASCT (median followup duration, 14.5 months). Although the follow-up period was short and the number of patients small, we believe that ASCT might improve the survival rate in high-risk NBL.
Adolescent ; Child ; Child, Preschool ; Combined Modality Therapy ; Female ; Human ; Korea ; Male ; Myeloablative Agonists/therapeutic use ; Neuroblastoma/mortality ; Neuroblastoma/pathology ; Neuroblastoma/therapy* ; Retrospective Studies ; Stem Cell Transplantation* ; Survival Rate ; Transplantation Conditioning ; Transplantation, Autologous ; Treatment Outcome

Adolescent ; Child ; Child, Preschool ; Female ; Humans ; Infant ; Longitudinal Studies ; Male ; Neoplasm Staging ; Neuroblastoma ; diagnosis ; pathology ; therapy ; Treatment Outcome

OBJECTIVEAt present there is no effective therapeutic approach for stage IV neuroblastoma. We report our experience with allogenic hematopoietic stem cell transplantation as a means of treating this disorder in one child.

METHODSA 7-year-old boy with stage IV neuroblastoma received allogenetic hematopoietic stem cell transplantation. The donor was his mother who was haploid HLA-matched to the patient. Conditioning regimen consisted of fludarabin and melphalan. Stem cells were collected from peripheral blood and bone marrow of the donor.

RESULTSThe patient achieved hematopoietic reconstruction and was converted to full donor chimerism according to short tandem repeat sequence-polymerase chain reaction detection. The patient's neutrophil count recovered to more than 0.5 x 10(9)/L 10 days after transplantation. The patient's platelet count recovered to more than 20 x 10(9)/L 11 days after transplantation. Acute graft versus host disease occurred 8 days after transplantation and was improved after treatment. The patient survived in a 210-day-follow-up.

CONCLUSIONSHaploid HLA-matched allogeneic hematopoietic stem cell transplantation from parent donor was an alternative, safe and effective treatment for children with stage IV neuroblastoma.

Child ; Follow-Up Studies ; Graft vs Host Disease ; drug therapy ; Hematopoiesis ; Hematopoietic Stem Cell Transplantation ; Humans ; Male ; Neoplasm Staging ; Neuroblastoma ; pathology ; therapy ; Transplantation, Homologous

BACKGROUND: To evaluate the value of random urinary vanillylmandelic acid (VMA) as a surrogate marker for monitoring tumor response and predicting outcome in patients with neuroblastoma (NB). METHODS: Medical records of 91 patients newly diagnosed with NB at the Samsung Medical Center between June 2014 and August 2017 were reviewed. Clinical associations and other prognostic factors, including age at diagnosis, stage, pathologic subtype, MYCN amplification, and other cytogenetic aberrations, were analyzed. Furthermore, the significance of random urinary VMA level in predicting outcome and tumor response was also evaluated. RESULTS: The median random urinary VMA level at diagnosis was 27.9 (range: 1.7–600) mg/g creatinine. Abdominal primary site, male sex, advanced stage, less differentiated pathology (poorly differentiated, undifferentiated), 11q deletion, and high-risk tumor were associated with a higher VMA level at diagnosis. The VMA level decreased during chemotherapy (28.4%, 16.9%, and 9.6% of the VMA level at diagnosis after 3, 6, and 9 cycles of chemotherapy, respectively). A higher VMA level at diagnosis tends to be associated with a better overall survival in high-risk patients with borderline significance (58.3±18.6% vs. 76.5±13.4%, P=0.050). However, in the multivariate analysis, the VMA level was not a significant predictor of survival. A slower reduction in VMA level during chemotherapy was not associated with a worse overall survival. However, event free survival was significantly better in the rapid responder group. CONCLUSION: A higher VMA level was associated with high-risk features at diagnosis of NB. Random urinary VMA is a valuable marker for monitoring NB response during chemotherapy.
Biomarkers ; Chromosome Aberrations ; Creatinine ; Diagnosis ; Disease-Free Survival ; Drug Therapy ; Humans ; Male ; Medical Records ; Multivariate Analysis ; Neuroblastoma* ; Pathology ; Prognosis ; Vanilmandelic Acid*

Double high-dose chemotherapy (HDCT) was applied to 18 patients with highrisk neuroblastoma including 14 patients who could not achieve complete response (CR) even after the first HDCT. In 12 patients, successive double HDCT was rescued with peripheral blood stem cells collected during a single round of leukaphereses and in 6 patients, second or more rounds of leukaphereses were necessary after the first HDCT to rescue the second HDCT. The median interval between the first and second HDCT (76 days; range, 47-112) in the single harvest group was shorter than that (274.5 days; range, 83-329) in the double harvest group (p<0.01). Hematologic recovery was slow in the second HDCT. Six (33.3%) treatment-related mortalities (TRM) occurred during the second HDCT but were not related to the shorter interval. Disease-free survival rates at 2 years with a median follow-up of 24 months (range, 6-46) in the single and double harvest group were 57.1% and 33.3%, respectively. These results suggest that successive double HDCT using the single harvest approach may improve the survival of high-risk patients, especially who could not achieve CR after the first HDCT despite delayed hematologic recovery and high rate of TRM during the second HDCT.
*Antineoplastic Combined Chemotherapy Protocols ; Child ; Child, Preschool ; Combined Modality Therapy ; Disease-Free Survival ; Female ; *Hematopoietic Stem Cell Transplantation ; Humans ; Infant ; Leukapheresis ; Male ; Neuroblastoma/drug therapy/pathology/*therapy ; Pilot Projects ; Remission Induction ; Risk Factors ; Transplantation, Autologous ; Treatment Outcome

OBJECTIVETo investigate the efficacy of high dose chemotherapy combined with autologous peripheral blood stem cell transplantation (APBSCT) for the treatment of neural ectodermal solid tumor originated from neural crest in children.

METHODSTwenty-three children at a medium age of 5.8 + or - 3.5 years with neural ectodermal solid tumor originated from neural crest were enrolled. Of the 23 children, 20 with stage IV neuroblastoma (9 were in complete remission, 7 were in partial remission and 4 were in progressive disease), 2 with stage IV primitive neuroectodermal tumor (PNET) in complete remission, and 1 with retinoblastoma in partial remission. Before APBSCT the children received 8.0 + or - 4.3 courses of chemotherapy. During chemotherapy the autologous peripheral blood stem cells were harvested and the tumor excision was performed. Then APBSCT was performed.

RESULTSThe reconstruction of the hematopoietic system was noted in 19 of 20 children with stage IV neuroblastoma 16.5 + or - 0.9 days after transplantation. A follow-up (median 15.8 months) was done in these children. The follow-up showed that the survival rate in children in complete remission before transplantation was 100%, 57% in those in partial remission, and none of children in progressive disease survived (P<0.05). The total survival rate was 67% in children with neuroblastoma. The child with retinoblastoma had complete remission in a 6-months follow-up. The tumors recurred in children with PNET 5 to 8 months after transplantation and all died within one year after transplantation.

CONCLUSIONSHigh dose chemotherapy combined with APBSCT can result in a good outcome in children with neural ectodermal solid tumor originated from neural crest in complete remission before transplantation and can improve the outcome in patients in partial remission before transplantation. However, the children with PNET, even in complete remission before transplantation, do not respond to the therapy.

Antigens, CD34 ; analysis ; Antineoplastic Agents ; therapeutic use ; Combined Modality Therapy ; Female ; Follow-Up Studies ; Humans ; Male ; Neural Crest ; pathology ; Neuroblastoma ; therapy ; Neuroectodermal Tumors, Primitive ; therapy ; Peripheral Blood Stem Cell Transplantation ; Transplantation, Autologous

OBJECTIVETo investigate the basic clinical characteristics of paraneoplastic neurological syndrome (PNS) in children.

METHODTo retrospectively analyze the clinical data of 12 PNS children who were hospitalized in neurology department in Beijing Children's Hospital from 2010 to 2011. Some patients were followed up after surgery.

RESULTIn 12 patients with PNS, 11 were male and 1 was female. The mean onset age were (30.5 ± 15.3) months. The mean duration from neurological symptom onset to finding out of tumor was (112.7 ± 154.4) days. The onset of the disease in 2 patients was acute, in 3 was subacute and in the other 7 was chronic (2 of 7 had 2 to 3 relapses). Of 12 patients, 11 had symptoms of ataxia (3 patients also had opsoclonus and myoclonus, OMS), 1 had weakness of limbs at onset and then had ataxia. Nine of 12 patients had surgery, and pathologic diagnosis was neuroblastoma and ganglioneuroma. Six patients were followed-up for 8 to 21 months. One patient had a little improvement and 5 almost recovered.

CONCLUSIONThe PNS children can have neurological symptoms only at the onset and there were no particular evidence of tumor. It is prone to misdiagnosis. The prognosis of PNS in children was poor.

Adrenocorticotropic Hormone ; therapeutic use ; Biomarkers, Tumor ; analysis ; Brain ; diagnostic imaging ; pathology ; Child, Preschool ; Female ; Ganglioneuroma ; diagnosis ; pathology ; therapy ; Humans ; Immunoglobulins, Intravenous ; therapeutic use ; Infant ; Magnetic Resonance Imaging ; Male ; Neuroblastoma ; diagnosis ; pathology ; therapy ; Opsoclonus-Myoclonus Syndrome ; diagnosis ; pathology ; therapy ; Paraneoplastic Syndromes, Nervous System ; diagnosis ; pathology ; therapy ; Prognosis ; Radiography ; Retrospective Studies

OBJECTIVES: To investigate the effectiveness of high-dose chemotherapy combined with autologous hematopoietic stem cell transplantation (ASCT) in the treatment of children with high-risk neuroblastoma (NB). METHODS: A retrospective analysis was performed on 29 children with high-risk NB who were admitted to Shanghai Children's Hospital and were treated with high-dose chemotherapy combined with ASCT from January 2013 to December 2021, and their clinical features and prognosis were analyzed. RESULTS: Among the 29 children treated by high-dose chemotherapy combined with ASCT, there were 18 boys (62%) and 11 girls (38%), with a median age of onset of 36 (27, 59) months. According to the International Neuroblastoma Staging System, 6 children (21%) had stage III NB and 23 children (79%) had stage IV NB, and the common metastatic sites at initial diagnosis were bone in 22 children (76%), bone marrow in 21 children (72%), and intracalvarium in 4 children (14%). All 29 children achieved reconstruction of hematopoietic function after ASCT. After being followed up for a median time of 25 (17, 45) months, 21 children (72%) had continuous complete remission and 8 (28%) experienced recurrence. The 3-year overall survival rate and event-free survival rate were 68.9%±16.1% and 61.4%±14.4%, respectively. Presence of bone marrow metastasis, neuron-specific enolase ≥370 ng/mL and positive bone marrow immunophenotyping might reduce the 3-year event-free survival rate (P<0.05). CONCLUSIONS Children with high-risk NB who have bone marrow metastasis at initial diagnosis tend to have a poor prognosis. ASCT combined with high-dose chemotherapy can effectively improve the prognosis of children with NB with a favorable safety profile.
Child, Preschool ; Female ; Humans ; Male ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; Bone Marrow Neoplasms/drug therapy* ; China ; Combined Modality Therapy ; Disease-Free Survival ; Hematopoietic Stem Cell Transplantation ; Neuroblastoma/pathology* ; Prognosis ; Retrospective Studies ; Stem Cell Transplantation ; Transplantation, Autologous

OBJECTIVENeuroblastoma is a highly malignant tumor. Stage IV neuroblastoma has a very poor long-term outcome by conventional chemotherapy and surgery and better therapies are essential. This study aimed to explore the long-term effect of high dose induction chemotherapy combined with autologous peripheral blood stem cell transplantation and 13-cis retinoid acid treatment on stage IV neuroblastoma in children.

METHODSTwenty-eight children with stage IV neuroblastoma, aged 2.1-11.5 years (mean 3.3 +/- 1.9 years), were employed for the study. Primary sites of the tumors included adrenal (n=23), chest (n=3), chest-abdomen (n=1) and sacrum (n=1). Before autologous peripheral blood stem cell transplantation the patients received 6 courses of intensive induction chemotherapy. During chemotherapy the autologous peripheral blood stem cells were harvested and the tumor excision was done. After transplantation the local radiation and 13-cis retinoid acid therapy were administered.

RESULTSAfter 6 courses of induction chemotherapy 13 patients got complete remission (CR), 11 got partial remission (PR), and 4 had no response. The 24 patients who received CR or PR completed the full therapy. A 3.5 +/- 0.7 years follow-up showed that the 4-year event-free survival of the CR and PR patients was 29.2%. The median no-relapse survival time in CR patients was 4.1 +/- 0.7 years but 2.8 +/- 0.5 years in PR patients (t= 3.9, P < 0.01).

CONCLUSIONSHigh dose chemotherapy combined with autologous peripheral stem cell transplantation and 13 cis-retinoid acid treatment can improve the long-term outcome of patients with stage IV neuroblastoma. The patients in CR before transplantation had better outcomes than those in PR.

Antineoplastic Combined Chemotherapy Protocols ; adverse effects ; therapeutic use ; Child ; Child, Preschool ; Combined Modality Therapy ; Female ; Humans ; Male ; Neoplasm Staging ; Neuroblastoma ; pathology ; therapy ; Peripheral Blood Stem Cell Transplantation ; Transplantation, Autologous