Long-term neurologic outcome in children with opsoclonus-myoclonus associated with neuroblastoma: A report from the Pediatric Oncology Group

A retrospective data collection was performed on 29 children diagnosed with neuroblastoma and opsoclonus-myoclonus between 1983–1993 from Pediatric Oncology Group institutions. The aim was to describe neurologic outcome in children with neuroblastoma and opsoclonus-myoclonus. Age at diagnosis ranged from one month to 4 years (median age, 18 months). The duration of opsoclonus-myoclonus symptoms prior to the diagnosis of neuroblastoma ranged from 6 days to 17 months (median duration, 6 weeks). There was a prevalence of low stage disease according to the POG staging system; stage A (n = 18), stage B (n = 3), stage C (n = 7), stage D (n = 1). There was a predominance of paraspinal primary tumors. There was no case of N-myc amplification (0/17), and 2/8 cases were diploid. Treatment for neuroblastoma consisted of surgery alone in 19/29 (18 stage A, 1 stage C in thorax), and surgery plus chemotherapy in 10/29. No patient received radiotherapy. Treatment for opsoclonus-myoclonus ranged varied. Six children received no treatment for opsoclonus-myoclonus. The following agents were used aCTH (n = 14), prednisone (n = 12), IV IgG (n = 6), immuran (n = 2), depakote (n = 1), and inderal (n = 1). Eighteen of 29 children (62%) had resolution of opsoclonus-myoclonus symptoms. The range of time for recovery was a few days to 3 years. However the majority recovered over several months. Twenty of 29 children (69%) had persistent neurologic deficits including speech delay, cognitive deficits, motor delay, and behavioral problems. Of the 9 children who had complete recovery of opsoclonus-myoclonus without neurologic sequelae, age at diagnosis and duration of symptoms were not different from the entire group. Interestingly, 6/9 children with complete recovery received chemotherapy as part of their treatment. In conclusion, persistent neurologic deficits are characteristic for children with neuroblastoma and opsoclonusmyoclonus. Treatment with chemotherapy may improve the neurologic outcome. Med. Pediatr. Oncol. 28:284–288. © 1997 Wiley-Liss, Inc.     

Different Kinds of Paraneoplastic Syndromes in Childhood Neuroblastoma

Background:

Clinical presentations of paraneoplastic syndromes in neuroblastoma may multiply. Review of the clinical data and the literature on this syndrome may help in the diagnosis of neuroblastoma.

Objectives:

In order to make more accurate diagnosis, we reviewed the clinical data and the literature on this syndrome.

Patients and Methods:

Between April 2007 and April 2012, 68 children were diagnosed with neuroblastoma or ganglioneuroblastoma in our institution, 9 of which presented exclusively with paraneoplastic syndromes and were not treated with chemotherapy prior to diagnosis. After the diagnosis, all patients received chemotherapy and operation on NB97 protocol.

Results:

Among 68 pediatric patients with neuroblastoma or ganglioneuroblastoma, 4 (5.9%) patients suffered from neurological complications at diagnosis, 2 (2.9%) patients had digestive tract disorders, 2 (2.9%) patients had immune diseases, and 1 (1.5%) suffered from hematological disorder (without bone marrow involvement). All paraneoplastic syndrome patients achieved complete remission on paraneoplastic syndrome before completion of chemotherapy.

Conclusions:

Neuroblastoma may present with a range of non-specific neurologic symptoms in addition to the well-known opsoclonus-myoclonus syndrome and cerebellar ataxia. In any case, the presence of unexplained neurologic manifestations and other common clinical presentations such as rash, constipation, diarrhea, and especially immune disorders in an otherwise healthy child had raised the possibility of paraneoplastic syndrome due to the presence of an undiagnosed tumor.     

Opsoclonus-myoclonus syndrome in a 2 year old boy with prenatally diagnosed retroperitoneal tumour

Opsoclonus-myoclonus syndrome, also named Myoclonic Encephalopathy of Infants, Opsoclonus- Myoclonus Ataxia, Dancing Eyes - Dancing Feet Syndrome, Dancing Eyes Syndrome, Kinsbourne syndrome, is a rare, paraneoplastic or possibly post-viral chronic neurological disorder. The age of presentation ranges from 6 months to 3 years. In 50% of affected children the syndrome is associated with an underlying occult or clinically apparent neuroblastoma. In most patients the tumour is localized, small and well differentiated, with no NMYC gene copy number amplification. The syndrome may also occur after tumour resection or at relapse. The opsoclonus-myoclonus syndrome can occur in children without neuroblastoma, in such idiopathiccases, the onset of neurological symptoms is related to infection. It is assumed, that in idiopathic cases the syndrome could have developed in the course of neuroblastoma which had undergone a complete spontaneous regression. The most characteristic clinical features of opsoclonus-myoclonus syndrome are: opsoclonus, myoclonus, ataxia, irritability, mutism and sleep disturbances. The disease course is usually long-term with episodes of remission and relapses. Approximately 80% of children with opsoclonus-myoclonus syndrome suffer from mild to severe neurological handicaps, mainly cognitive impairment. The authors present a 2-year old boy with opsoclonus-myoclonus syndrome preceded by involution of prenatally documented retroperitoneal area tumour.     

Long-term outcome of patients with intraspinal neuroblastoma

BACKGROUND: Chemotherapy, radiotherapy, and surgical decompression with laminectomy are effective therapeutic options in the treatment of cord compression from neuroblastoma (NB). We report the long-term outcome of patients with intraspinal NB treated with or without laminectomy at two large pediatric oncology centers. PROCEDURE: We reviewed the medical records and radiographs of 26 children with intraspinal NB treated at Children's Memorial Hospital in Chicago, Illinois, between 1985 and 1994 or at St. Jude Children's Research Hospital in Memphis, Tennessee, between 1967 and 1992. RESULTS: Twenty-four of the 26 patients are alive and disease-free (follow-up of 2-29 years; median, 10 years 2 months). Fifteen of the 23 patients with neurologic impairment underwent initial laminectomy. Nine of these 15 patients recovered neurologic function, including 3 patients who presented with paraplegia. Eleven of the 15 patients who underwent laminectomy have developed mild to severe spinal deformities. Eight patients with neurologic symptoms consequent to cord compression were treated with initial chemotherapy and/or surgery, but did not undergo laminectomy. Three patients with mild to moderate deficits recovered neurologic function. Four of 11 patients with intraspinal NB who did not undergo laminectomy have mild to severe scoliosis. CONCLUSIONS: A low incidence of neurologic recovery was seen in patients with long-standing severe cord compression regardless of treatment modality. For patients with partial neurologic deficits, recovery was seen in most patients following chemotherapy or surgical decompression with laminectomy. A higher incidence of spinal deformities was seen in the patients treated with initial laminectomy.     

Chemotherapy as an alternative to laminectomy and radiation in the management of epidural tumor

Nine children with neuroblastoma and five with Ewing sarcoma were found at diagnosis to have epidural extension of tumor. Five children underwent laminectomy prior to referral, with good neurologic recovery in only one. Management in the other nine children did not include laminectomy. All 14 patients were given chemotherapy without radiotherapy. Rapid regression of tumor with neurologic recovery occurred in response to chemotherapy in all patients with neurologic deficits. The responses observed in these children indicate that for chemotherapy-sensitive tumors, effective chemotherapy is a feasible alternative to laminectomy and radiation therapy in the management of epidural disease.     

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??Abstract??Objective??To identify the clinical features of opsoclonus-myoclonus syndrome and its response to adrenocorticotropic hormone ??ACTH??. Methods??Fourteen OMS cases who were diagnosed during 2006??2010 in Peking University First Hospital were enrolled in this study. Data on medical history?? neurological signs??laboratory tests??response to ACTH and the relapse were evaluated. Results??Among 14 cases?? eight were male and six were female. Age at presentation ranged from 12 to 44 months ??average 20.7 months??. Main symptoms at presentation were opsoclonus ??14/14????myoclonus and ataxia ??14/14????poor sleeping ??14/14????irritability ??14/14??. Neuroblastoma was found in one of the fourteen cases. EEGs of all showed no epileptic discharges. Before the diagnosis of OMS??7 cases were ever misdiagnosed as acute cerebellar ataxia??4 were misdiagnosed as epilepsy?? 4 were misdiagnosed as encephalitis and 1 was misdiagnosed as hereditary metabolic disease. All patients received ACTH therapy. Neurologic function improved in all children?? but seven children had relapse within 3??12months ??average 5.7 months??. Conclusion??OMS is a rare autoimmune neurological disorder which is often present in young chlidren.Neuroblastoma is common in children with OMS.OMS is characterized by rapid??involuntary and irregular conjugate eye movements ??opsoclonus????myoclonic jerking of the limbs and trunk??ataxia??poor sleep and behavioral disturbances. Due to the possible immune-mediated mechanisms?? treatment with ACTH can be successful?? but relapse rate is high and the outcome is unfavourable. Neurological sequelae such as behavioral?? language and cognitive problems occur in the majority.     

Neuroblastome surrénalien bilatéral et syndrome de Pepper : à propos de quatre observations

4S neuroblastoma with bilateral adrenal involvement is defined by small primitive tumors (stage 1 or 2) with disseminated disease restricted to the liver, skin, and/or bone marrow. Children are less than one year old. These tumors are rare and of multicentric origin. PATIENTS AND METHODS: Our multicentric study analyzed four children less than four months old at diagnosis. RESULTS: All had a favourable histology, with normal MYC-N copy number, and one case had a diploid tumor. The four patients had first supportive care at the beginning, but three cases received chemotherapy because of progressive disease, with liver radiotherapy in two cases because of massive hepatomegaly; three cases had surgery (unilateral adrenal resection in two cases and bilateral in one case) and one had only a biopsy. Surgery was the only treatment in one case. One patient relapsed 17 months after initial treatment and was treated with intensive chemotherapy and stem cell rescue. The outcome is favorable for the four patients, without evidence of recurrent disease. CONCLUSION: Children with 4S neuroblastoma with bilateral adrenal tumors have a good prognosis. Treatment should be the less aggressive as possible. The group with favorable prognostic parameters should have supportive care if spontaneous regression occurs. But we have to treat with chemotherapy neonates with massive hepatomegaly and children with one or more unfavorable prognostic factors (unfavorable histology, high MYC-N copy number).     

Barrett esophagus in long-term survivors of childhood solid tumors

We report on 2 cases of long-term survivors of childhood solid tumors, who developed Barrett esophagus (BE) after treatment for neuroblastoma and Hodgkin lymphoma, respectively. Case 1: A stage 3 neuroblastoma was treated with surgery, carboplatin/etoposide chemotherapy, and supradiaphragmatic radiotherapy (30 Gy). Twelve years later, based on endoscopic and histologic findings, BE was diagnosed on the middle segment. Case 2: A stage IIIB Hodgkin lymphoma received mechloretamine, oncovin, procarbazine, prednisone/adriamycin, bleomycin, vinblastine, dacarbazine chemotherapy and supra/subdiaphragmatic radiotherapy (25 Gy). Nineteen years later, BE was diagnosed associated with an esophageal stricture. In long-term survivors of childhood tumors who had received chest/neck radiotherapy and chemotherapy, the risk of BE may be increased, therefore the diagnosis should be considered in the presence of gastroesophageal symptoms.     

The association between neuroblastoma and opsoclonus-myoclonus syndrome: a historical review

An association between neuroblastoma and opsoclonus-myoclonus syndrome (OMS) was described as early as 1927 within the first report on the transformation of malignant neuroblastoma to a benign ganglioneuroma. It was not recognized at that time nor was it appreciated in the subsequent follow-up report on the same patient in 1959. Myoclonic encephalopathy of infancy, an alternative name for OMS, was described by a pediatric neurologist in 1962; however, its connection to neuroblastoma was not known. It was only in 1968 that the association between these two conditions was first reported. The neuroblastoma tumors associated with OMS are almost all small, stage I–II with no associated MYCN amplification or metastases. OMS occurs in 2–3% of patients with neuroblastoma, but neuroblastoma is found in as many as 50% of children who present with OMS. Nearly 100% of the children with neuroblastoma associated with OMS survive, and this has led to speculation that the OMS is a result of an autoimmune process, not metastases. Affected children are treated with steroids, ACTH, or intravenous immunoglobulin, but many have persistent neurologic and developmental deficits. Using the original case reported in 1927, we summarize a century of literature in this review on OMS and its association with neuroblastoma.     

RESPONSE TO RITUXIMAB AND PREDNISOLONE FOR OPSOCLONUS-MYOCLONUS-ATAXIA SYNDROME IN A CHILD WITH GANGLIONEUROBLASTOMA

Opsoclonus-myoclonus-ataxia (OMA) syndrome is a rare neurobehavioral paraneoplastic disorder in children with neuroblastic tumors. The neurologic symptoms are generally treated with a number of immunosupressive and immunomodulating agents. A 4-year-old previously healthy male patient was admitted to the authors’ center with progressive ataxia, gait disturbance, diffuculty of speech, and opsoclonus. He had a diagnosis of ganglionueroblastoma at the thoracal paraspinal region. Following surgey, the patient received IVIG and prednisolone but his cerebellar symptoms progressed. Rituximab therapy was started and continued for total 8 weeks without any side effect. The authors observed excellent neurologic response in the patient at the 4th week of treatment. Rituximab is a new, promising, and safe therapy for OMA syndrome in children with neuroblastoma.     

Opsoclonus-myoclonus-ataxia syndrome in neuroblastoma: clinical outcome and antineuronal antibodies-a report from the Children's Cancer Group Study

BACKGROUND: Opsoclonus-myoclonus-ataxia (OMA) is a paraneoplastic neurologic syndrome affecting 2-3% of children with neuroblastoma. Although children with OMA and neuroblastoma may have higher survival, many experience a significant amount of late neurologic impairment, which may be immunologically mediated. The aim of this study was to compare the outcome of neuroblastoma patients with and without OMA, relating to prognostic factors, treatment, and the presence or absence of anti-neuronal antibodies. PROCEDURE: Questionnaires were mailed out requesting information on the current neurologic status of patients who submitted sera at diagnosis to the Children's Cancer Group serum bank from 1980 to 1994. Information was requested on clinical and biological patient characteristics as well as clinical aspects of the patients identified as having OMA syndrome, including presentation and treatment for OMA, late sequelae of OMA, the presence or absence of antineuronal antibodies, and survival. Sera from 16 of the OMA patients and 48 case-controls with neuroblastoma were assayed for anti-neuronal antibodies. RESULTS: Of the 675 responses received, 21 patients had OMA. Ninety percent of OMA patients presented with non-metastatic disease, vs. 35% of non-OMA patients. Estimated 3-year survival for the OMA patients with nonmetastatic disease (stage I, II, III) greater than 1 year of age was 100% vs. 77% for similar non-OMA patients (P = 0.0222). At follow-up, 14/19 evaluable OMA patients displayed some form of developmental or neurologic abnormality. There was no significant correlation of late sequelae with antineuronal antibodies, age, time between OMA symptoms and diagnosis, or treatment given for tumor or OMA. There was a significant correlation of late sequelae with lower stage disease (I and II) compared to more advanced disease (III and IV). CONCLUSIONS: Patients with OMA and neuroblastoma have excellent survival but a high risk of neurologic sequelae. Favorable disease stage correlates with a higher risk for development of neurologic sequelae. The role of anti-neuronal antibodies in late sequelae of OMA needs further clarification.     

Myoclonic encephalopathy of infancy: A 10 year review

Myoclonic encephalopathy of infancy (MEI) is a unique cause of acute ataxia in infants and is a rare presentation of neuroblastoma. Five cases presenting to a tertiary referral children's hospital during a 10 year period are reviewed. Two cases were associated with a neuroblastoma. All children were treated with intramuscular injections of adrenocorticotropic hormone, with symptomatic improvement. One child died from an opportunistic infection following chemotherapy for neuroblastoma. The four survivors have mild to moderate clinical and intellectual deficits. Investigation and continuing observation for occult neural crest tumours is emphasized for all cases of MEI, though no underlying cause was found in 60% of children in this study.     

Venoocclusive liver disease (VOD) as a complication of Wilms' tumour management in the series of consecutive 206 patients.

In 4 years (1993-1996) 206 pts. with nephroblastoma were treated. All children were treated according to SIOP 93-01 protocol. Overall survival was 92%. In 27 cases hepatotoxic events occurred. In 10 cases, venoocclusive liver disease (VOD) was diagnosed. VOD is a syndrome associated with hepatomegaly, sudden weight gain or ascites and jaundice. It results from damage to the endothelium of hepatic venules and necrosis of central hepatocytes with subsequent proliferation of fibrous tissue and occlusion of the central hepatic veins. Dactinomycin is one of the drugs considered responsible for its development. Mean age of VOD patients was 4 yrs, however 3 of them were below 1 yr. In all cases, VOD occurred during postoperative chemotherapy (mean 16 th week of treatment). All patients received dactinomycin and vincristine. Five children with right kidney tumors underwent post-operative abdominal irradiation. Main VOD symptoms were hepatomegaly and ascites (80%). Hypertransaminasaemia, as well as, on ultrasound, gallbladder wall thickening and/or free abdominal fluid were observed. Median VOD duration was 27 days and its course was usually temporary and self-limiting. However, in 2 cases recurrent VOD episodes were noted. All children received supportive treatment only. In 6 cases, VOD resulted in chemotherapy delay or drug reductions, while in 4 others chemotherapy was completed preliminarily. Nevertheless it did not affect patients' outcome overall survival in VOD group was 90%. CONCLUSIONS: Total 5% VOD frequency is similar to other reports. Infants and children receiving abdominal irradiation seem to be at special risk of VOD development.     

Opsoclonus-myoclonus-ataxia syndrome in neuroblastoma: histopathologic features-a report from the Children's Cancer Group

BACKGROUND: Opsoclonus-myoclonus-ataxia (OMA) is a paraneoplastic syndrome that occurs in about 2-3% of all cases of neuroblastoma. The histopathologic characteristics of neuroblastoma tumors associated with this syndrome were evaluated in a series of cases and controls. PROCEDURE: Pathology slides from a total of 54 neuroblastoma tumors were reviewed blindly. They included 13 tumors associated with opsoclonus-myoclonus and 41 age- and stage-matched controls. All tumors were classified into either the favorable (FH) or unfavorable histology (UH) group according to the International Neuroblastoma Pathology Classification (the Shimada system). Grade of lymphocytic infiltration was evaluated and presence or absence of lymphoid follicles was recorded in the individual tumor tissues. RESULTS: Twelve of 13 cases with opsoclonus-myoclonus were in the FH group. Twelve of 13 cases had diffuse (found in every section prepared from the multiple portions of the primary tumor) and extensive (occupying more than 50% of a single of multiple microscopic fields with x 100 magnification) lymphocytic infiltration with lymphoid follicles. Of the 41 control cases (27 FH and 14 UH tumors), 18 had focal areas of lymphocytic infiltration and six showed lymphoid follicles, but none had diffuse or extensive infiltration in their primary tumors. CONCLUSIONS: Diffuse and extensive lymphocytic infiltration with lymphoid follicles is a characteristic histologic feature of neuroblastic tumors with opsoclonus-myoclonus. This observation suggests an immune-mediated mechanism for this rare paraneoplastic syndrome.     

Intrathecal thiotepa: reappraisal of an established therapy

PURPOSE: Intrathecal thiotepa is recommended as a treatment of leptomeningeal metastases (LM) in children, although published data to support this approach are limited. The authors sought to determine the efficacy of intrathecal thiotepa for pediatric LM. PATIENTS AND METHODS: The authors reviewed all children treated with intrathecal thiotepa for LM at two tertiary children's hospitals, assessing outcome by cerebrospinal fluid cytology, neuroimaging, neurologic examination, and overall survival rate. RESULTS: Fifteen children with LM evidenced by malignant cells in the cerebrospinal fluid (mean age 7.3 years; five medulloblastoma, one anaplastic astrocytoma, one glioblastoma, one retinoblastoma, one neuroblastoma, two rhabdomyosarcoma, one non-Hodgkin lymphoma, two acute lymphoblastic leukemia, and one acute myelogenous leukemia) were treated with intrathecal thiotepa at 5 to 11.5 mg/m2 per dose for two to seven doses. Five children received concomitant craniospinal irradiation; 12 received simultaneous systemic or other intrathecal chemotherapy, or both. Four children experienced clearance of malignant cells from the spinal fluid, but this response was sustained in only two. All four children with cytologic response received concurrent radiotherapy, chemotherapy, or both. No patients showed partial or complete response on neuroimaging. Only one child had improvement on the neurologic examination; six were unchanged and eight had worsening neurologic signs. Median survival was 15.1 weeks, with a 1-year overall survival rate of 26.7% (standard error 11.4%). CONCLUSIONS: The unfavorable outcomes observed suggest that intrathecal thiotepa adds little to combination therapy for pediatric LM.     

Analysis of status epilepticus related presumed encephalitis in children.

OBJECTIVE: Encephalitis is an acute infection of brain parenchyma characterized clinically by fever, headache, and an altered level of consciousness. There may also be focal or multifocal neurologic deficits, and focal or generalized seizure activity. Here we report an analysis of status epilepticus (SE) related presumed encephalitis in a series of children. METHODS: We retrospectively reviewed cases of SE related presumed encephalitis treated in the pediatric intensive care unit, between February 2002 and June 2006. Factors evaluated included age, sex, clinical symptoms, seizure type, presence of SE or refractory status epilepticus (RSE), initial electroencephalogram (EEG) finding, neuroimaging study, cerebrospinal fluid (CSF) and outcome. RESULTS: There were 46 patients (19 girls and 27 boys), aged 8 months to 16 years. Twenty (43.4%) of 46 children developed RSE. The major clinical symptoms included fever (100%), upper respiratory symptoms (56.5%) and altered level of consciousness (45.6%). The initial seizure type was categorized as focal (23.9%), generalized (34.8%), primary focal and secondary generalized (41.3%). Initial EEG revealed a focal (30.8%), or multifocal (19.2%) epileptiform discharge in the SE group and a focal (5%), or multifocal (70%) or generalized (25%) epileptiform discharge in the RSE group. The time of follow-up for this study was 6 months to 51 months. In the SE group, 4 died, 16 developed epilepsy and/or neurologic deficits, and 6 returned to baseline. In the RSE group, 6 died, 13 developed epilepsy and/or neurologic deficits, and none returned to baseline. All survivors were discharged on antiepileptic medications. CONCLUSIONS: Our data indicated that children of SE related presumed encephalitis had a high mortality and morbidity. Outcome was related to multifocal or generalized abnormalities of the initial EEG and presence of RSE.     

Autologous stem cell transplantation for refractory opsoclonus myoclonus ataxia syndrome

Opsoclonus, myoclonus, ataxia syndrome (OMA) is a severe neurologic disorder often associated with neuroblastoma. It is challenging to treat and can have long‐term neurologic sequelae. Current recommended therapies include intravenous immunoglobulin, corticosteroids, rituximab, and chemotherapy (cyclophosphamide). We present two cases who were refractory to conventional therapy and underwent autologous stem cell transplantation (ASCT). One patient had complete resolution of symptoms following ASCT and the other patient had minimal change in symptoms with this therapy. These findings support consideration of ASCT as a therapeutic option for patients with refractory OMA after failure of known effective therapies.     

儿童眼球阵挛-肌阵挛综合征14例临床特征及治疗分析

总结儿童眼球阵挛-肌阵挛综合征（OMS）的临床特征及对促肾上腺皮质激素（ACTH）治疗反应。方法　对北京大学第一医院儿科2006—2010年收治的14例OMS患儿的临床表现、体征、实验室检查及治疗效果、复发情况进行评估。结果　14例OMS中男8例,女6例。发病年龄12～44个月（平均20.7个月）,主要症状为眼球阵挛、肌阵挛、共济失调、睡眠障碍、易激惹。其中1例合并神经母细胞瘤。所有患儿脑电图均未见异常放电。明确诊断前14例均被误诊,其中7例误诊为急性小脑共济失调,3例误诊为癫痫,3例曾误诊为脑炎,1例误诊为遗传代谢病。14例均予ACTH治疗且均有效,7例在ACTH治疗后3～12个月（平均5.7个月）复发。结论　OMS是一种罕见的神经系统自身免疫性疾病,多见于婴幼儿,且与神经母细胞瘤相关。临床表现为快速、不自主、无规律的眼球运动（眼球阵挛）、肌阵挛、共济失调、睡眠障碍、行为改变,因目前对本病认识不足,易被误诊。ACTH治疗有效,但易复发且神经系统后遗症明显,远期预后不良。     

Infants with stage 4 neuroblastoma: the impact of the chimeric anti-GD2-antibody ch14.18 consolidation therapy

BACKGROUND: Antibody treatment is considered tolerable and potentially effective in the therapy of neuroblastoma. We have analyzed the clinical data of infants < 1 year with stage 4 neuroblastoma with regard to the consolidation treatment. PATIENTS AND METHODS: Infants < 1 year with stage 4 neuroblastoma who completed initial treatment (6-8 chemotherapy cycles followed either by 4 cycles low dose oral chemotherapy or high dose chemotherapy with stem cell transplantation) without event were eligible for this trial. Consolidation therapy consisted of 6 cycles of antibody ch14.18 (20 mg/m(2) x d ch14.18 for 5 days every 2 months) or 12 months oral maintenance chemotherapy (MT). RESULTS: Of 59 evaluable patients, 31 received a total of 159 ch14.18 cycles, 16 received MT instead, and 12 had no further treatment. Fever (47 % of cycles), abnormal CRP without infection (25 %), rash (23 %), cough (16 %), and pain (8 %) were the main side effects. Univariate analysis found no difference in event free survival (3-year-EFS 80.5 +/- 7.1 %, 87.5 +/- 8.3 %, and 75.0 +/- 12.5 % for patients treated with antibody ch14.18, MT, and no further therapy, p = 0.433) and overall survival (3-year-OS 90.1 +/- 5.4 %, 93.8 +/- 6.0 %, and 91.7 +/- 8.0 % for patients treated with antibody ch14.18, MT, and no further therapy, p = 0.931). Multivariate analysis failed to demonstrate an advantage of antibody treatment. CONCLUSION: The outcome of infants with stage 4 neuroblastoma is good. Consolidation treatment with ch14.18 was tolerable but associated with fever, elevated CRP, rash, cough, and pain as side effects. Compared to oral maintenance chemotherapy and no consolidation treatment, ch14.18 treatment had no impact on the patients' outcome which confirms the results found in children > 1 year.     

大剂量化疗造血干细胞移植治疗IV期神经母细胞瘤的长期疗效研究

目的：目前IV期神经母细胞瘤患儿无论采用何种方法治疗均疗效差,长期生存率低,需要探索新的治疗途径。该文采用大剂量化疗、自体外周血造血干细胞移植及13-顺式维甲酸治疗等方法,试图提高IV期神经母细胞瘤的长期疗效。方法：选择IV期神经母细胞瘤患儿28例,年龄2.1~11.5岁,平均3.3±1.9岁,发病时间1~7个月,平均3.1±0.7个月。原发部位:肾上腺23例,胸部3例,胸腹联合1例,骶骨1例。强烈化疗6疗程,期间进行外周血造血干细胞采集、手术切除,然后进行自体外周血造血干细胞移植,术后行局部放疗及13-顺式维甲酸治疗,定期随访。结果：28例患儿诱导化疗结束时13例取得完全缓解,11例取得部分缓解,4例化疗中病情进展。完全缓解及部分缓解的24例患儿完成治疗进入本研究。随访3.5±0.7年,两组4年无病生存率29.2%。完全缓解组中位无复发生存时间4.1±0.7年;部分缓解组中位无复发生存时间2.8±0.5年,两组中位无复发生存时间差异有显著性(t=3.9,P<0.01)。结论：大剂量化疗、自体外周血造血干细胞移植及13-顺式维甲酸治疗IV期神经母细胞瘤可取得较好疗效,4年无病生存率29.2%,移植前达到完全缓解时可取得更好疗效