Epstein Barr virus associated pediatric nasopharyngeal carcinoma: its correlation with p53 and bcl-2 expression

BACKGROUND: Pediatric nasopharyngeal carcinoma (NPC) is relatively rare. The Epstein Barr virus (EBV) association with the oncogenesis of NPC is well established. Apoptosis-related proteins, p53 and bcl-2, have also been described in adult NPC pathogenesis. PROCEDURE: From 1988 to 1998, 16 patients with NPC were treated at R. Gutierrez Children's Hospital and the National J.P. Garrahan Pediatric Hospital. Their median age was 12 years (range 8-20), 2 females and 14 males. The presence of p53, bcl-2 and latent membrane protein-1 (LMP-1) of EBV expression was studied by immunohistochemistry and Epstein Barr encoded RNAs (EBERs) by in situ hybridization in tissue sections from formalin-fixed, paraffin-embedded NPC biopsies RESULTS: EBV presence and LMP-1 expression in epithelial tumor cells were detected in all the biopsies studied. p53 was expressed in 13/16 NPCs, but the frequency of positive malignant cells differed from case to case, ranging from less than 25 to 100% with heterogeneous staining intensity. Bcl-2 positive staining in tumor epithelial cells was detected in 2/16; whereas 10/16 cases showed bcl-2 positivity in infiltrating lymphocytes. CONCLUSIONS: Although our series is small, we conclude that the pathogenesis of pediatric NPC as a multistep process may well involve EBV infection. This leads to LMP-1 expression and p53 overexpression in epithelial tumor cells, whereas bc-2 seems unrelated to the development of this disorder.     

Combined radiation and chemotherapy for advanced undifferentiated nasopharyngeal carcinoma in children

Five children, 11–16 years of age at diagnosis, with advanced (stage IV) undifferentiated nasopharyngeal carcinoma, are reviewed. All had radiotherapy and chemotherapy, four at first treatment, are disease free in 8 months, 6, 10, and 13 years from diagnosis. One patient who had radiotherapy only as primary treatment and chemotherapy for metastases, died 15 months from diagnosis. One patient who received 60 Gy and chemotherapy according to the BACON protocol had severe early toxicity and severe late sequelae of treatment. Three patients who received chemotherapy according to a modified UICC-2 protocol for nasopharyngeal carcinoma and 50 to 54 Gy to the primary site had only mild early toxicity and mild late effects of treatment. With lower radiation doses, adjusted to the effect of preradiation chemotherapy, complete tumor control was achieved and acute and long-term morbidity reduced. Med. Pediatr. Oncol. 28:366–369, 1997. © 1997 Wiley-Liss, Inc.     

High-dose chemotherapy and autologous blood stem cell transplantation in children with metastatic neuroblastoma

High-dose chemotherapy (HDC) followed by autologous blood stem cell transplantation (ABSCT) was performed to improve the prognosis of children with metastatic neuroblastoma over 1 year of age at diagnosis. Seven stage IV neuroblastoma patients with a median age of 3.9 years (range 1.6–11.4 years) received conventional chemotherapy before leukapheresis for ABSCT. The median duration of chemotherapy before harvest was 8 months (range 3–23 months). Peripheral blood stem cells (PBSC) were harvested from them after the use of cytotoxic drugs plus granulocyte colony-stimulating factor. The median number of granulocyte-macrophage colony forming units collected after harvest was 23.2 × 10⁴/kg (range 10.1–45.3 × 10⁴/kg). The patients were administered HDC consisting of carboplatin, etoposide, and melphalan followed by ABSCT. Hematopoietic reconstitution after ABSCT was favorable; recovery of granulocytes count > 0.5 × 10⁹/L occurred within 2 weeks and stable platelet engraftment occurred at a median duration of 23 days (range 7–33 days). The toxicity of ABSCT was well tolerable. Two of the four patients who received ABSCT at their first complete remission remained in remission 67 and 68 months after ABSCT. One with partial remission also showed a good response for 8 months. The other two at first relapse showed a transient regression of the tumor. The prognosis of seven patients who received ABSCT was significantly better than that of 13 patients who received conventional therapy alone. These findings suggest that HDC followed by ABSCT is safe and useful as consolidation therapy for the treatment of patients with metastatic neuroblastoma.     

Response of therapy-associated acute nonlymphocytic leukemia to intensive induction chemotherapy

Among 31 consecutive patients who developed acute nonlymphocytic leukemia following treatment with chemotherapy or radiation therapy, 17 were treated with intensive chemotherapy aimed at inducing a complete remission. Seven of these 17 patients (41%) obtained a complete remission that ranged in duration from 2 to 11 (median 3) months. Two additional patients who failed to develop normal peripheral blood counts despite postinduction bone marrows that were normocellular and free of leukemia were classified as nonresponders. The median time to complete remission and median duration of leukopenia (WBC less than 1,000/mu 1) were 34 days and 23 days, respectively. Induction chemotherapy was complicated by fever in all patients, documented infection in six patients, and death secondary to sepsis in three. Survival of the 17 patients ranged from less than 1 to 39 (median 4) months. Patients achieving a complete remission had a median survival time of 10 months compared to 2 months for the nonresponders. The other 14 patients received only supportive care and had a median survival of 2 months. These findings indicate that therapy-associated acute nonlymphocytic leukemia (t-ANLL) can frequently respond to chemotherapy and that achieving a complete remission is associated with longer survival. Although these results are encouraging, patients with t-ANLL still have a relatively poor prognosis and efforts directed at improving treatment outcome need to be continued.     

Curability of recurrent disseminated disease after surgery alone for local-regional neuroblastoma using intensive chemotherapy and anti-G(D2) immunotherapy

PURPOSE: A reluctance to treat local-regional neuroblastoma by surgery alone derives partly from concern that if widespread neuroblastoma develops, the chance for cure is small, and partly from hope that mild chemotherapy will prevent relapse. The authors report on a series of patients who had distant recurrences after surgery alone for local-regional neuroblastoma. METHODS: Seven patients treated with surgery alone for local-regional neuroblastoma had widespread relapses 2.5 to 25 (median 7) months later and were treated at Memorial Sloan-Kettering Cancer Center (MSKCC). During the period of this study (1995-1999), MSKCC patients with high-risk neuroblastoma received the N7 protocol (dose-intensive chemotherapy, immunotherapy with the anti-G(D2) 3F8 antibody, targeted radiotherapy using 131I-3F8, local radiotherapy) if they had assessable disease, or 3F8 plus granulocyte-macrophage colony-stimulating factor (GM-CSF) followed by 13-cis-retinoic acid if they were in remission after treatment elsewhere. RESULTS: Five patients were in complete remission 3 years 11 months to 7 years 4 months from the start of retrieval therapy, including three who received all of their N7 treatment of relapsed neuroblastoma at MSKCC, one who received two cycles of chemotherapy elsewhere before starting N7, and one who was referred for 3F8/GM-CSF because of neuroblastoma cells in pretransplantation bone marrow. CONCLUSIONS: The encouraging survival results of our cohort are consistent with the concept that surgery alone for local-regional neuroblastoma might be beneficial to the overall neuroblastoma population because many patients will never need chemotherapy (and will therefore be spared its potential toxicities), and most of those who do have widespread relapses are likely to be cured with contemporary treatments.     

儿童异基因造血干细胞移植后淋巴细胞增殖性疾病的临床研究

目的探讨儿童异基因造血干细胞移植（allo-HSCT）后淋巴细胞增殖性疾病（PTLD）的诊治及预后。方法回顾性分析4例allo-HSCT后EBV相关性PTLD（EBV．PTLD）患儿的临床资料。其中,急性淋巴细胞白血病（高危）（ALL—HR）2例,重型再生障碍性贫血（SAA）2例。异基因外周血造血干细胞移植（allo-PBSCT）3例,异基因脐血造血干细胞移植（allo-UCBSCT）1例。结果4例患儿分别于allo．HSCT后第53、101、22、42d发生PTLD。临床表现为发热、鼻塞、扁桃体肿大、淋巴结肿大和肝脾肿大,移植前均EBNA-1-IgG（＋）、VCA．IgG（＋）;移植后EBV．DNA1．69×10^4～8．62×10^8 copies／mL。经淋巴结病理活检确诊为EBV-PTLD,其中1例为T细胞来源,3例为B细胞来源。例1予减停免疫抑制剂、使用利妥昔单抗、联合COP方案化疗及供者淋巴细胞输注（DU）治疗,PTLD反复且发生严重皮肤GVHD、肺部感染,移植后第193d死亡。余3例予减停免疫抑制剂及利妥昔单抗治疗,临床表现消失且EBV．DNA转阴,分别随访17、12、7个月均无病存活。结论动态监测EBV—DNA对PTLD早期发现具有重要意义。减停免疫抑制剂联合利妥昔单抗治疗EBV-PTLD疗效明显。化疗可导致严重感染,DLI治疗存在严重GVHD危险,不宜作为一线治疗。     

A single institution experience with pediatric nasopharyngeal carcinoma: high incidence of toxicity associated with platinum-based chemotherapy plus IMRT

BACKGROUND: Chemotherapy and intensity-modulated radiotherapy (IMRT) have decreased treatment-related complications in adult patients with nasopharyngeal carcinoma (NPC). Our aim was to evaluate the toxicity profile of IMRT plus chemotherapy in pediatric NPC patients. OBSERVATIONS: Five patients were treated with chemotherapy and IMRT. All patients experienced grade 3-4 acute toxicities. With a median follow-up of 6.3 years, all patients experienced >or=3 long-term toxicities. The most common toxicities were hypothyroidism, xerostomia, hearing loss, and dental disease. CONCLUSIONS: We did not observe a significant decrease in long-term toxicities with IMRT plus chemotherapy in our small cohort of pediatric NPC patients.     

Nasopharyngeal carcinoma in the pediatric age group: the northern Israel (Rambam) medical center experience, 1989-2004

Nasopharyngeal carcinoma (NPC) is rare in children, accounting for less than 1% of all malignancies. Radiation therapy has been the mainstay of treatment of many years, but to improve survival, the use of chemotherapy has been advocated. This is a retrospective analysis of 13 patients less than 20 years of age treated for NPC the Rambam Medical Center during 1989 to 2004. Eight boys and five girls with a median age of 14.5 years (range 10-19) were included. Median follow up (including patients who died) was 6.15 years (range 1-15 years). Duration of symptoms was 1 to 24 months (median 5 months). Of the 13 patients, one patient had stage I, 6 had stage III, 5 had stage IV-A, and 1 had stage IV-B disease. Ten patients (77%) had undifferentiated carcinoma (WHO type III) and three patients (23%) had nonkeratinizing carcinoma (WHO type II). Most of the children received two or three courses of neoadjuvant multiagent chemotherapy consisting of cisplatin and 5-FU, followed by radiotherapy with doses in excess of 60 Gy. One child received concomitant chemoradiation. Ten of the 13 patients (77%) are alive without disease 6 years after diagnosis (range 1-15 years). One patient developed local and distant metastases 1 year after diagnosis and is currently receiving combined radiochemotherapy. Two patients died. Overall survival was 84%; event-free survival was 77%. Nine patients (69%) developed moderate to severe long-term complications. Pediatric NPC is curable by combined radiation and chemotherapy, with doses of radiation in excess of 60 Gy. Long-term follow-up is important for early detection of second malignancies as well as for radiation-induced endocrinologic deficiencies and other normal tissue complications.     

39例儿童头颈部横纹肌肉瘤临床特点及治疗转归

目的：探讨儿童头颈部横纹肌肉瘤的（RMS）临床特点及治疗转归。方法：回顾性分析北京同仁医院2004年11月至2010年11月收治的39例原发于头颈部的RMS患儿临床资料及治疗随访结果,其中男23例,女16例,年龄3个月至14岁,中位年龄6.0岁。结果：39例患儿临床主要表现为眼球突出及眼睑肿胀(56%,22/39),鼻塞及鼻出血占28%（11/39）,面颊包块占15%（6/39）。39例患儿中,原发部位以眼睑及眼眶为主（56%,22/39）,其次为鼻咽部及筛窦（28%,11/39）。37例有明确病理分型,大多数患儿为胚胎型（89%,33/37）。39例患儿中位随访时间为38个月(10~80个月),放弃治疗4例,获随访35例。35例患儿中,行单纯手术4例,单纯化疗1例, 手术+化疗12例,手术+放疗2 例,手术+化疗+放疗13例(其中8例行125I放射性粒子植入术治疗),手术+化疗+放疗+自体外周血造血干细胞移植（APBSCT）2例,化疗+APBSCT 1例。其中7例复发,5例死亡,总生存率86%（30/35）,完全缓解率达66%（23/35）,部分缓解率达20%（7/35）,8例粒子植入术治疗患儿6例达无瘤生存。结论：RMS患儿临床表现主要为眼球突出及眼睑肿胀;眼部及鼻咽是儿童头颈部RMS多发部位;病理分型以胚胎型为主;包括化疗、手术、125I粒子组织间植入及APBSCT等多种综合治疗方法可有效提高RMS患儿缓解率。     

Serial intense chemotherapy combining topotecan, etoposide, carboplatin and cyclophosphamide (TECC) followed by autologous hematopoietic stem cell support in patients with high risk soft tissue sarcoma (STS)

In nine patients (pts) with soft tissue sarcoma refractory to conventional therapy (incomplete response or relapse) intensified chemotherapy was administered combining 0.75 mg/m (2) topotecan, 100 mg/m (2) etoposide, 100 mg/m (2) carboplatin and 200 mg/m (2) cyclophosphamide on day 1-5 (TECC). To avoid prolonged intervals between the serial TECC courses autologous hematopoietic stem cell supports (median 1.0 x 10(6) CD34+ cells per kg body weight (bw), range 0.5-2.8 x 10(6) CD34+ cells/kg bw, SD 0.6 x 10(6) CD34+ cells/kg bw) were given on day 7. All pts received granulocyte colony stimulating factor (GCSF) from day 8 in addition. All together 39 TECC courses (minimum 2 courses, maximum 6 courses per pt) were administered, with a median interval of 32 (range 21-52) days until recovery. Leukopenia (<1000/microl) occurred 9 days (range 3-13 days; SD 2.4 days) after end of chemotherapy and persisted for 9 (range 3-15 days; SD 3 days) days. In 31/39 TECC courses readmission to hospital was required for supportive therapy mainly due to neutropenic fever. In this period pts received 0.83 (range 0-1) red blood cell units and 2.35 (range 1-4) platelet units. C-reactive protein in neutropenic pts as an indicator for infection after TECC chemotherapy was detectable after 36 of 39 chemotherapy courses leading to further supportive therapy (median 10.4 mg/dl, range 1.1-28.3 mg/dl; SD 6.67 mg/dl). Duration of total inpatient treatment per TECC course including supportive therapy was in median 13.5 days (range 7-53 days; SD 4.3 days). Only two children had a prolonged infection (77 and 100 days). Clinical and objective tumor responses, defined as complete remission, very good partial response and partial response were observed in 9/9 pts at eight weeks after the last TECC course and were maintained at six months in 7/9 pts. Median time to progression and median overall survival time after TECC chemotherapy were 20.3 months and 25.2 months, respectively. These data provide evidence that in very high risk pts refractory to standard high risk therapy, a combination of TECC chemotherapy and stem cell support is feasible in pts with incomplete remission respectively relapsed STS pts and demonstrates promising antineoplastic activity. Therefore, this regimen warrants further investigation in prospective trials.     

Therapy of advanced ovarian juvenile granulosa cell tumors

BACKGROUND: Gonadal sex cord-stromal tumors are rare tumors that develop from the gonadal non-germ cell component such as granulosa, Sertoli or Leydig cells. Among these, juvenile granulosa cell tumors (JGCT) constitute the largest subgroup of ovarian sex cord-stromal tumors during childhood and adolescence. In local disease (FIGO stage I), the beneficial role of tumor-ovarectomy is well established. In contrast, life expectancy in patients with advanced JGCT (FIGO stage >/= II) is short even after complete tumor resection. The current literature provides only limited and inconclusive data regarding the value of adjuvant chemotherapy in such patients with advanced disease. PATIENTS AND METHODS: Therefore, we analyzed the patients with FIGO stage >/= II JGCT who were prospectively documented as follow-up patients of the German MAKEI trials for non-testicular germ cell tumors and received the recommended cisplatin-based chemotherapy in an adjuvant setting. From 1988 until 2000, 7 patients (age, 4;2 - 18;11 years, median 14;8 years) were registered. Three patients were stage IIc, one stage IIIa, and three stage IIIc. 5 patients underwent laparatomy with adnectomy, which was complete in only two patients. Two patients received laparoscopic tumor resection, which was incomplete in both. All patients received 4 or 6 cycles of adjuvant cisplatin-based three-agent chemotherapy in analogy to the current therapeutic concept applied in malignant germ cell tumors. One patient with a large tumor and multiple peritoneal metastases additionally received 40 Gy abdominal irradiation. RESULTS: All patients achieved complete clinical remission after initial surgery and adjuvant chemotherapy. 4 out of 7 patients are currently remaining in first continuous complete remission after 15 to 111 months follow-up. One patient developed a metachronous tumor of the contralateral ovary after 126 months follow-up and is still alive but currently in therapy of another recurrence. Another patient suffered a tumor recurrence after 12 months but achieved a second complete remission with cisplatin chemotherapy after a follow-up of currently 4 months. One patient achieved complete clinical remission but suffered a diffuse peritoneal tumor recurrence with massive ascites and finally died as a result of tumor progression. In summary, at the time of this report 6 of 7 patients are alive after a median of 47 (15 - 138) months. CONCLUSION: This analysis clearly demonstrates that advanced JGCT can be successfully treated with surgery followed by adjuvant cisplatin-based chemotherapy. Therefore, this study reveals encouraging therapeutic perspectives in these otherwise fatal tumors that merit further investigation in a prospective cooperative trial.     

自体外周血造血干细胞移植在小儿恶性晚期实体肿瘤的临床应用(英文)

目的　小儿晚期实体肿瘤对常规化疗效果欠佳 ,该文探讨大剂量化疗并自体外周血干细胞移植(APBSCT)治疗小儿高危晚期实体瘤的可行性及疗效。方法　 1 3例恶性实体肿瘤患儿 (恶性淋巴瘤 7例、神经母细胞瘤 6例 ) ,在其完全缓解 (1 2例 ) ,部分缓解 (1例 )后进行了APBSCT治疗。移植时病程中位时间 1 0月。 1 1例用化疗加重组人粒 单细胞集落刺激因子 (rhGM CSF)或重组人粒细胞集落刺激因子 (rhG CSF)动员 ,2例采用常规化疗方案作为动员剂。所采集单个核细胞 (MNC)为 (6 .85± 2 .6 5 )× 1 0 8/kg。CD34+ 细胞为 (1 5 .82± 1 2 .93)×1 0 6/kg。CFU GM集落为 (1 7.87± 1 7.94 )个 / 1 0 4细胞。预处理方案中 6例基本方案为全身放疗加环磷酰胺。 7例未用TBI ,仅以马法兰为主做为预处理方案 (马法兰 +卡铂 +足叶乙甙 5例 ,白消胺 +马法兰 2例 )。结果　移植后白细胞 >0 .5× 1 0 9/L、>1 .0× 1 0 9/L、血小板 >2 0× 1 0 9/L的中位时间分别为 1 2天、1 5天、1 9天。中位随访时间4 8月 (1月～ 1 4 4月 )。至今总生存率 77% (1 0 / 1 3) ,死亡率 2 3% (3/ 1 3) ,无移植相关死亡。结论　APBSCT是治疗小儿晚期实体肿瘤 ,明显改善其预后的重要治疗方法。     

Mutations of the Epstein-Barr virus LMP-1 oncogene in a 10-year-old Japanese girl with nasopharyngeal carcinoma

A 10-year-old patient with nasopharyngeal carcinoma (NPC) was studied for mutations within the carboxy-terminal portion of the Epstein-Barr virus (EBV) latent membrane protein (LMP)-1 gene. The EBV genome, defined as type A, was detected in biopsied tumor specimens by Southern hybridization with specific probes. Sequence analysis of the carboxy-terminal part of the LMP-1 gene revealed no deletions but seven single-base substitutions, four of which were found to be identical to those previously detected in codons for amino acids 322 to 366 in the Chinese NPC CAO. Although yet unresolved, the observed mutations may be associated with the pathogenesis of NPC.     

Lamivudine Facilitates Optimal Chemotherapy in Hepatitis B Virus-Infected Children with Hematological Malignancies: A Preliminary Report

Hepatitis B virus (HBV) reactivation is well documented in infected patients who have hematologic malignancies, precluding appropriate chemotherapy courses and, therefore, increasing the possibility of relapse of malignancies. The objective of this study was to evaluate lamivudine treatment to prevent hepatitis B reactivation in children with cancer who acquired infection with HBV and so allow completion of optimal chemotherapy. Ten children (7:3 M:F; median age: 9.8 years), undergoing chemotherapy for hematological malignancies and suffering from immunosuppressive-induced hepatitis B virus reactivation, were treated concurrently with lamivudine (3 mg/kg bw,od) for up to 18 months. All were HBsAg+ve, HBsAb?ve, HBV-DNA+ve. Serology markers (HBsAg/Ab, HBeAg/Ab, HBV-DNA) and ALT were tested 3 monthly. Histological assessments were performed pre- and 18 months post-lamivudine therapy. During lamivudine therapy chemotherapy courses were completed for all children, and none of the patients suffered reactivation of hepatitis. After a median follow-up of 10 months, remission of malignancy was maintained in 7/10 patients while 3 patients relapsed. HBeAg+ve seroconversion occurred in 4/9 HBeAg+ve children within 3 months. After 9 months of therapy, 8/10 were HBV-DNA?ve. Six out of 7 children with histological evidence of chronic hepatitis showed marked improvement post-therapy. Lamivudine therapy for up to 18 months in children receiving chemotherapy helped prevent recurrence of hepatitis B exacerbations and improved the underlying chronic hepatitis, while facilitating completion of appropriate chemotherapy regimens without compromise.     

Lamivudine facilitates optimal chemotherapy in hepatitis B virus-infected children with hematological malignancies: a preliminary report

Hepatitis B virus (HBV) reactivation is well documented in infected patients who have hematologic malignancies, precluding appropriate chemotherapy courses and, therefore, increasing the possibility of relapse of malignancies. The objective of this study was to evaluate lamivudine treatment to prevent hepatitis B reactivation in children with cancer who acquired infection with HBV and so allow completion of optimal chemotherapy. Ten children (7:3 M:F; median age: 9.8 years), undergoing chemotherapy for hematological malignancies and suffering from immunosuppressive-induced hepatitis B virus reactivation, were treated concurrently with lamivudine (3 mg/kg bw,od) for up to 18 months. All were HBsAg+ve, HBsAb-ve, HBV-DNA+ve. Serology markers (HBsAg/Ab, HBeAg/Ab, HBV-DNA) and ALT were tested 3 monthly. Histological assessments were performed pre- and 18 months post-lamivudine therapy. During lamivudine therapy chemotherapy courses were completed for all children, and none of the patients suffered reactivation of hepatitis. After a median follow-up of 10 months, remission of malignancy was maintained in 7/10 patients while 3 patients relapsed. HBeAg+ve seroconversion occurred in 4/9 HBeAg+ve children within 3 months. After 9 months of therapy, 8/10 were HBV-DNA-ve. Six out of 7 children with histological evidence of chronic hepatitis showed marked improvement post-therapy. Lamivudine therapy for up to 18 months in children receiving chemotherapy helped prevent recurrence of hepatitis B exacerbations and improved the underlying chronic hepatitis, while facilitating completion of appropriate chemotherapy regimens without compromise.     

High dose melphalan and autologous bone marrow transplantation for solid tumours of childhood

Between October, 1977 and December, 1984, 61 children aged 5 months to 18 years (median 6.5) with solid tumours have been treated with high dose melphalan (HDM) 100–240 mg/m² with autologous non-cryo-preserved bone marrow “rescue” to increase the rate of haematological recovery. Of these 61, 60 were evaluable on December 31st 1984; one patient was lost to follow up. Thirty-two patients received HDM and marrow autograft after conventional chemotherapy with or without radiotherapy (16 neuroblastoma, 6 rhabdomyosarcoma, 9 Ewings, 1 osteosarcoma) while 28 patients received this treatment after relapse following conventional chemotherapy (7 neuroblastoma, 9 rhabdomyosarcoma, 6 Wilms, 2 Ewings, 1 histiocytosis X, 1 carcinoma of the ovary, 1 yolk sac tumour, and 1 nasopharyngeal carcinoma). The median duration of leucopenia was 11 days (range 5–36 days). The other immediate toxicities due to melphalan were severe vomiting and nausea, mucositis in most patients and convulsions in 6. Of the 32 patients treated in first remission, 9 are now disease-free at 1 to 82 months. Of the 28 patients treated after relapse, 3 are alive without disease at 6–86 months. HDM produces responses in patients with disease resistant to other agents, particularly with Wilms' tumours and rhabdomyosarcoma, and occasionally these responses are durable. It seems to be less effective for children with Stage IV neuroblastoma.     

HIT-LGG: effectiveness of carboplatin-vincristine in progressive low-grade gliomas of childhood--an interim report

BACKGROUND: The rationale of the HIT-LGG protocol is to delay standard radiotherapy through administration of chemotherapy for children with progressive low grade glioma at an age under 5 years and in older children upon individual decision. PATIENTS AND METHOD: Until October 10th., 1999, 402 patients from 69 hospitals were registered. 130 children with progressive tumors were treated after a median observation time of 5 months: 46 patients received primary radiotherapy and 84 primary chemotherapy. A ten week induction period with weekly Vincristine and pulses of Carboplatin at weeks 1, 4, 7 and 10 is followed by consolidation with simultaneous application of both drugs every 4 weeks until week 53. RESULTS: Of 84 patients in the chemotherapy arm of the study (49 male, 35 female, 23 NF I, median age 2.99 years) 36 received treatment at diagnosis and 43 after a median observation time of 19.7 months. 94.3% achieved a clinical and neuroradiological response according to protocol criteria (5 CR, 30 PR/OR, 31 SD) after a median of 5.1 months. 4 tumors showed primary progression (9 too early, 5 not known). Only 6 of 84 children received radiation therapy for progressive disease during (2) or after termination (4) of chemotherapy, after a median delay of 25.6 months at a median age of 6.0 years. At a median observation time of 21.0 months, 6 children are in CR, 11 in PR, 48 have SD, 4 tumors are progressive and 3 children died of their tumor. (9 too early, 3 not known). PFS is at 72% after 36 months. 24 of 27 children experiencing allergic reactions to Carboplatin had to interrupt chemotherapy prematurely. CONCLUSIONS: Combination therapy with Carboplatin and Vincristine can effectively delay the start of radiotherapy in children with progressive low-grade glioma. The high rate of hypersensitivity reactions has to prompt future modifications of treatment.     

Methotrexate polyglutamation may lack prognostic significance in children with B-cell precursor acute lymphoblastic leukemia treated with intensive oral methotrexate

BACKGROUND: The purpose of this study was to determine if a correlation exists between clinical outcome and accumulation and polyglutamation of methotrexate by lymphoblasts in vitro in children with B-cell precursor acute lymphoblastic leukemia (BCP-ALL). PATIENTS AND METHODS: The amount of accumulated methotrexate and of long-chain methotrexate polyglutamates (MTXPG(3-7)) by lymphoblasts was determined in 52 children newly diagnosed with BCP-ALL after incubation with 1 micromol/L [(3)H]MTX for 24 hours in vitro. All patients then received intensive multiagent chemotherapy that used divided-dose oral methotrexate during consolidation and intensive continuation and standard oral weekly methotrexate during maintenance. RESULTS: Eight patients had a bone marrow relapse at a median of 40.4 months (range 18.5-48.3 months) after diagnosis. The median follow-up for the remaining 44 patients is 69.0 months (range 22-92.8 months). There was no significant difference in the amount of accumulated methotrexate (1450.0 +/- 896.3 vs. 640 +/- 472.5 pmol/10 cells) or of accumulated MTXPG (1450.0 +/- 919.4 vs. 617.4 +/- 482.7 pmol/10(9) cells) (median +/- semi-interquartile ranges) between patients who relapsed and those who remained in continuous complete remission. The estimated 5-year event-free survival rate for patients whose lymphoblasts accumulated more than 500 pmol MTXPG(3-7)/10(9) cells was 80.0% +/- 7.3% versus 90.5% +/- 6.4% for those whose lymphoblasts accumulated less than 500 pmol MTXPG(3-7)/10(9) cells. CONCLUSIONS: In the context of effective prolonged divided-dose oral methotrexate-based therapy in the treatment of BCP-ALL, methotrexate accumulation and polyglutamation no longer seem to have prognostic significance.     

The usefulness of bone marrow aspiration in the diagnosis of Niemann-Pick disease type C in infantile liver disease.

BACKGROUND: Niemann-Pick disease type C (NPC) is a fatal, autosomal recessive lysosomal storage disease which may present in infancy with cholestatic jaundice and/or hepatosplenomegaly. In cholestatic patients with splenomegaly, a bone marrow aspirate has been advocated as a relatively accessible tissue to demonstrate storage phenomena. Typically in patients with NPC, macrophages with abnormal cholesterol storage, so called foam cells, can be detected in the bone marrow. AIM: To review our experience of bone marrow aspiration in children with NPC presenting with infantile liver disease. METHODS: A retrospective analysis of 11 consecutive children (8 males) from Birmingham Children's Hospital with NPC presenting with infantile liver disease was undertaken. The diagnosis of NPC was confirmed in all cases by demonstrating undetectable or low rates of cholesterol esterification and positive filipin staining for free cholesterol in cultured fibroblasts. RESULTS: The median age at presentation was 1.5 months (range 0.5-10). Bone marrow aspirates showed storage cells in only 7/11 cases. Bone marrow aspirates which had storage cells were undertaken at a median age of 11 months while those with no storage cells were undertaken at median age 2.3 months. The overall sensitivity of bone marrow aspirates for detecting storage cells in children presenting with infantile liver disease was 64%; however, for children who had bone marrow aspirates in the first year of life it was only 57%. CONCLUSIONS: The sensitivity of bone marrow aspirate for the diagnosis of NPC disease in patients presenting with infantile liver disease was lower than previously reported. Where NPC is suspected clinically, definitive investigations should be undertaken promptly. There is a need to develop sensitive screening methods for NPC in children presenting with infantile liver disease.