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Background: In the tyrosine kinase inhibitor (TKI) era, outcomes after salvage therapy for relapsed or refractory Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) remain unclear., Procedure: The clinical courses of 19 patients with relapse (n = 13) or induction failure (n = 6) in the Japanese Pediatric Leukemia/Lymphoma Study Group Ph+ ALL04 study were retrospectively reviewed., Results: Fifteen male and four female patients had a median age of 8 (range 4-15) years at relapse or induction failure. Patients received imatinib in combination with hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) and methotrexate and cytarabine (MTX/Ara-C) (n = 9), imatinib in combination with other chemotherapy (n = 5), chemotherapy without imatinib (n = 2), imatinib alone (n = 2), or no additional chemotherapy (n = 1). Two patients underwent hematopoietic stem cell transplantation (HSCT) without achieving complete remission (CR) and died of leukemia. The remaining 17 patients achieved CR with salvage therapies and underwent HSCT whilst in CR: 10 patients remain alive in CR, five died of transplantation-related complications, and two died of relapse. In six of seven patients with available data on minimal residual disease (MRD), imatinib in combination with the first course of hyper-CVAD was more effective in achieving a favorable MRD response compared with the Ph+ ALL04 induction regimen., Conclusion: This study suggested that cross-resistance to imatinib failed to develop after conventional chemotherapy. Imatinib in combination with chemotherapy including hyper-CVAD+MTX/Ara-C was effective and safe for relapsed or refractory Ph+ ALL patients who received frontline therapy without imatinib., (© 2017 Wiley Periodicals, Inc.)

Two consecutive treatment protocols, NHL-89 and NHL-96, for pediatric diffuse large cell lymphoma (DLC) and lymphoblastic lymphoma (LBL) were conducted between March 1989 and December 2004 by Kyushu-Yamaguchi Children's Cancer Study Group. Forty-two patients (DLC: 15, LBL: 27) and 34 patients (DLC: 8, LBL: 26) were enrolled in NHL-89 and NHL-96, respectively. DLC patients received induction therapy of high-dose methotrexate (MTX) followed by repeated administration of intermediate MTX. LBL patients received a 4-drug induction followed by intensification, consolidation with cranial radiotherapy (15 to 24Gy), and maintenance. The maintenance phase consisted of multiple drug treatment; including prednisolone, vincristine, cyclophosphamide, and 6-mercaptopurine. With a median follow-up of 150 months for NHL-89 and 90.5 months for NHL-96, the estimated event-free survival at 5 years are 76.2±6.6% and 67.7±8.0%, respectively. Both studies improved the prognosis of DLC and LBL over our previous study of NHL-858.

The prognosis for patients with hepatocellular carcinoma (HCC) with progressive liver cirrhosis or extrahepatic metastases remains dismal. We report a case of HCC with liver cirrhosis and lung metastases who had been treated successfully by combination chemotherapy of 5-fluorouracil (5-FU) and interferon-alpha (IFN-alpha). A 67-year-old male with a history of hepatitis C, liver cirrhosis and HCC was hospitalized because of cough and dyspnea. Computed tomography (CT) of chest revealed multiple lung metastases. Systemic combination chemotherapy with 5-FU and IFN-alpha was begun, and lung metastases disappeared after one course of treatment. He died of liver failure one year later, but no recurrence of lung metastases was seen. Although systemic combination chemotherapy of 5-FU and IFN-alpha induced the bone marrow suppression, it was effective for lung metastases and palliates symptoms and signs in our case of HCC.

Background: Neonatal leukemia characterized by early stem cell origin and extramedullary infiltration in the first 4 weeks of life is rare. We analyzed the features and outcome of neonatal leukemia in Japan to establish an appropriate treatment strategy for this rare disorder., Procedure: Patients with infant leukemia registered and treated in the Japan Infant Leukemia Study between 1996 and 2001 were analyzed., Results: Among 162 infant leukemia patients, 11 exhibited neonatal leukemia; frequencies for all infant leukemias were 6.9% (8/116) for acute lymphoblastic leukemia (ALL) and 7.3% (3/41) for acute myeloid leukemia (AML). Positive MLL gene rearrangement was observed in all eight patients with ALL; a single patient with AML displayed germline configuration. Acute monoblastic leukemia was apparent in all three patients with AML (M5a in the FAB classification). Most of the patients demonstrated hepatoplenomegaly and hyperleukocytosis at diagnosis. Cutaneous and central nervous system involvement were detected in half of the patients. Four patients (one with AML, and three with ALL) have survived following stem cell transplantation (SCT); however, growth impairment related to SCT was observed in these patients., Conclusions: These results suggest an improvement attributable to treatment of neonatal leukemia. International-based collaborative studies are necessary to investigate the biology of this condition and to establish appropriate therapeutic strategies.

Background: The treatment outcome of multifocal childhood Langerhans cell histiocytosis (LCH) has not been satisfactory and has resulted in poor therapeutic responses with high mortality and a high incidence of reactivation with late sequelae. To overcome these issues, the Japan LCH Study Group-96 (JLSG-96) protocol was conducted prospectively from 1996 to 2001 in Japan., Methods: Newly diagnosed children with multifocal LCH were classified into 2 groups: a single-system multisite (SS-m) group and a multisystem (MS) group. All patients initially were treated on Protocol A, which consisted of 6 weeks of induction therapy with combined cytosine arabinoside, vincristine (VCR), and prednisolone (PSL) followed by 6 months of maintenance therapy. Patients who had a poor response to the induction of Protocol A were switched to a salvage regimen (Protocol B), which consisted of an intensive combination of doxorubicin, cyclophosphamide, VCR, and PSL., Results: In total, 91 patients were treated, including 32 patients in the SS-m group and 59 patients in the MS group. At the median 5-year follow-up, 96.9% of patients in the SS-m group and 78.0% of patients in the MS group had good response status. Diabetes insipidus developed in 3.1% of patients in the SS-m group and in 8.9% of patients in the MS group. The overall survival rate at 5 years for the SS-m and MS groups was 100% and 94.4% +/- 3.2%, respectively., Conclusions: The JLSG-96 protocol attained very low mortality for pediatric patients with multifocal LCH., (Copyright 2006 American Cancer Society.)

Although infants with acute lymphoblastic leukemia (ALL) and a germline MLL gene have a better prognosis than comparable infants with a rearranged MLL gene, their optimal therapy is controversial. In 2 consecutive studies, conducted between 1996 and 2002, we treated 22 cases of infant ALL with germline MLL using chemotherapy alone. The 5-year event-free survival rate was 95.5% with a 95% confidence interval of 86.9 to 100%. All 21 infants with precursor B-cell ALL have been in first complete remission for 3.5 to 8.8 years. Most treatment-related toxicities were predictable and well tolerated, and neither secondary malignancies nor physical growth impairments have been observed. These results indicate that chemotherapy of the type described here is both safe and highly effective against infant precursor B-cell ALL with MLL in the germline configuration.

Forty-four infants with acute lymphoblastic leukemia (ALL) characterized by MLL gene rearrangements were treated on a protocol of intensive chemotherapy followed by hematopoietic stem cell transplantation (HSCT) between November 1998 and June 2002. The remission induction rate was 91.0%, and the 3-year overall survival and event-free survival (EFS) rates, with 95% confidence intervals, were 58.2% (43.5%-72.9%) and 43.6% (28.5%-58.7%), respectively. Univariate analysis of EFS by presenting features indicated a poorer outcome in patients younger than 6 months of age with high white blood cell counts (>/= 100 x 10(9)/L; EFS rate, 9.4% versus 55.1% for all others, P = .0036) and in those with central nervous system invasion (EFS rate, 10.0% versus 56.9% for all others, P = .0073). The 3-year posttransplantation EFS rate for the 29 patients who underwent HSCT in first remission was 64.4% (46.4%-82.4%). In this subgroup, only the timing of HSCT (first remission versus others) was a significant risk factor by multivariate analysis (P < .0001). These results suggest that early introduction of HSCT, possibly with a less toxic conditioning regimen, may improve the prognosis for infants with MLL(+) ALL. Identification of subgroups or patients who respond well to intensified chemotherapy alone should have a high priority in future investigations.

This study analyzed data on 35 infants with acute myeloid leukemia (AML) who were treated with intensive chemotherapy between 1995 and 1998 in Japan. The incidence of boys, younger age (< 6 months old), and hyperleukocytosis at onset was high in patients with the M4/M5 subtype (n = 23) in the French-American-British classification, compared with the non-M4/M5 subtype (n = 12). Thirteen (56%) and 16 (70%) patients with the M4/M5 subtype also showed 11q23 translocations and MLL gene rearrangements, respectively, whereas only one patient with the non-M4/M5 subtype had this rearrangement. All 35 patients were treated with the ANLL91 protocol consisting of etoposide, high-dose cytarabine, and anthracyclines. Overall survival and the event-free survival (EFS) rates at 3 years of all patients were 76% (95% confidence interval [CI], 61.3%-90.7%) and 72% (95% CI, 56.4%-87.9%), respectively. EFS showed no significant difference between 2 subgroups divided by age, gender, presence of the MLL gene rearrangements, and white blood cell count at onset; EFS in patients with the M4/M5 subtype tended to be better than those with the non-M4/M5 subtype. Although all 6 patients who underwent allogeneic stem cell transplantation (SCT) have been in complete remission, no benefit of SCT was confirmed. These findings suggest that the intensive chemotherapy with the ANLL91 protocol might have been responsible for the observed good outcome of infant AML, even without SCT. The presence of the MLL gene rearrangements or the age at onset had no impact on the outcome of infant AML.

Background: In our previous studies, the outcome of high-risk ALL was still poor. In the present study, all children with ALL were classified into three groups and treated with a new regimen (AL90)., Patients and Methods: Between 1990 and 1996, 220 children with ALL, treated with the AL90 regimen, were classified into three risk groups: low, intermediate, and high: LR, IR, and HR, respectively. The protocol consisted of three- to five-drug induction, consolidation with intermediate-dose methotrexate and/or cytarabine, mercaptopurine and cyclophosphamide, four-drug intensification, and sequential maintenance therapies. Only intrathecal chemotherapy was used for CNS prophylaxis in the LR group, whereas cranial irradiation was added for the IR and HR groups., Results: The number of eligible patients was 91: LR group, 71: IR group, and 58: HR group. Complete remission (CR) was obtained in > 98% of the LR and IR groups, while only 88% achieved CR in the HR group. The 5-year event-free survival (EFS) rate was 67.4% in all patients: 70.4% in the LR group, 71.7% in the IR group, and 57.5% in the HR group. With respect to the previous study, EFS in the HR group who showed positive residual leukemia at 14 days was improved, whereas EFS in boys versus girls was significantly lower (48.8% : 85.7%, P = 0.02)., Conclusions: In high-risk ALL, the rate of induction failure was high and boys had a worse outcome, calling for improvements in induction therapy and a specific approach for boys., (Copyright 2001 Wiley-Liss, Inc.)

Purpose: We sought to identify the clinical variables most critical to successful treatment of Epstein-Barr virus (EBV)-associated hemophagocytic lymphohistiocytosis (HLH)., Patients and Methods: Among the factors tested were age at diagnosis (< 2 years or > or = 2 years), time from diagnosis to initiation of treatment with or without etoposide-containing regimens, timing of cyclosporin A (CSA) administration during induction therapy, and the presence or absence of etoposide., Results: By Kaplan-Meier analysis, the overall survival rate for the entire cohort of 47 patients, most of whom had moderately severe to severe disease, was 78.3% +/- 6.7% (SE) at 4 years. The probability of long-term survival was significantly higher when etoposide treatment was begun less than 4 weeks from diagnosis (90.2% +/- 6.9% v 56.5% +/- 12.6% for patients receiving this agent later or not at all; P <.01, log-rank test). Multivariate analysis with the Cox proportional hazards model demonstrated the independent prognostic significance of a short interval from EBV-HLH diagnosis to etoposide administration (relative risk of death for patients lacking this feature, 14.1; 95% confidence interval, 1.16 to 166.7; P =.04). None of the competing variables analyzed had significant predictive strength in the Cox model. However, concomitant use of CSA with etoposide in a subset of patients appears to have prevented serious complications from neutropenia during the first year of treatment., Conclusion: We conclude that early administration of etoposide, preferably with CSA, is the treatment of choice for patients with EBV-HLH.

We analyzed the long-term outcome and late effects of treatment in 187 patients with childhood acute lymphoblastic leukemia (ALL) diagnosed between 1984 and 1990. Overall survival and event-free survival rates were 68.2% +/- 3.7% and 63.2% +/- 3.6% at 15 years, respectively. Of 55 patients who relapsed after achieving the first complete remission (CR), only 17.4% were rescued by salvage therapy. The advantage of stem cell transplantation over chemotherapy was observed only in those patients with bone marrow relapse during therapy. The SD for score height in patients maintaining the first CR significantly decreased at the time of final follow-up compared with that at diagnosis: 0.059 to -0.800 (P < .0001). The decrease was remarkable in patients younger than 5 years at diagnosis. Other late effects included mild liver dysfunction in 18% and hepatitis C virus infection in 9%. Congestive heart failure was observed in only 2.9% of patients despite the high cumulative dose of daunorubicin (450 mg/m2). Although the survival rates of patients on our protocols were comparable to those of other study groups, some modification, including reduction in dose of cranial irradiation and/or anticancer drugs, should be considered to reduce late adverse effects in survivors of childhood ALL.

In recent pediatric collaborative studies of acute myeloid leukemia (AML), patients with Down's syndrome (DS) have better outcome than other patients when they were treated according to their intensive AML protocols. This may be attributed to enhanced sensitivity of DS AML cells to selected chemotherapeutic agents. We evaluated a less intensive chemotherapeutic regimen which was specifically designed for children with AML-DS. Remission induction chemotherapy consisted of daunorubicin (25 mg/m2/day for 2 days), cytosine arabinoside (100 mg/m2/day for 7 days), and etoposide (150 mg/m2/day for 3 days). Patients received one to seven courses of consolidation therapy of the same regimen. Thirty-three patients were enrolled on the study and their clinical, hematologic and immunophenotypic features were analyzed. Of the 33 patients, all were younger than 4 years and diagnosed as having acute megakaryoblastic leukemia or myelodysplastic syndrome. All patients achieved a complete remission and estimated 8 year event-free survival rate was 80+/-7%. Three patients relapsed and two died due to cardiac toxicity and one due to septic shock. The results of our study showed that patients with AML-DS constitute a unique biologic subgroup and should be treated according to a less intensive protocol designed for AML-DS.

A total of 62 patients with standard-risk acute lymphoblastic leukemia received three-drug induction consisting of vincristine, prednisolone, and L-asparaginase (l-Asp) followed by consolidation therapy with intermediate-dose methotrexate (MTX), intrathecal MTX, and 18 Gy of cranial irradiation. Maintenance therapy consisting of 6 drugs including daunorubicin (DNR, 450 mg/m2 in total) was continued for 3 years. Patients were randomized and half of them received weekly l-Asp during maintenance therapy as a late intensification. Complete remission (CR) was achieved in 61/62 (98.4%), and 11 of 61 patients relapsed. At 10 years, the event-free survival (EFS) was 80.6 +/- 5.0% and overall survival was 88.7 +/- 4.0%; median follow-up time was 9.3 years. The 10-year EFS of patients with additional l-Asp (84.8 +/- 6.2%) was superior to that without l-Asp (75.9 +/- 7.9%), although it was not statistically significant. No patients who received a full dose of DNR and maintained CR developed heart failure, although the shortening fraction decreased from 41.0% at diagnosis to 35.2% (median). The protocol AL841 provided good long-term disease control without severe late cardiac dysfunction.

We conducted a multicenter study to improve the treatment of B-cell non-Hodgkin's lymphoma and acute lymphoblastic leukemia (NHL/ALL) in Japanese children. The subjects were a total of 57 untreated patients with the B-cell type of either NHL (27 Burkitt's and 9 diffuse large) or ALL between 2 and 15 years old (median: 8 years) seen between 1988 and 1994. All patients received the same cytoreductive therapy (half doses of vincristine and prednisolone) and the same first and second induction courses (vincristine, prednisolone, high-dose methotrexate, repetitive high-dose cyclophosphamide, and adriamycin). Three cycles of consolidation blocks A and B (consisting of reduced doses of similar agents used in the second induction course) followed for patients with stage III or IV NHL or B-ALL, while only one cycle was given for stage I or II disease. Fifty-three patients (93.0%) achieved complete remission. Eight patients had relapse all occurring within 1 year. Another patient had secondary myelodysplastic syndrome. The median follow-up period was 48 months (range: 24-94 months). The overall survival and event-free survival (EFS) rates for all patients were, respectively, 75.9% (S.E.: 5.9) and 70.1 (S.E.: 6.1). The relapse-free interval rate of the 53 patients who achieved CR was 83.5% (S.E.: 5.3). EFS was 75.0% (S.E.: 21.7) in stage I, 84.6% (S.E.: 10.0) in stage II, 78.63% (S.E.: 11.0) in stage III, 80.0% (S.E.: 17.9) in stage IV, and 52.4% (S.E.: 10.9) in ALL. Among the stage IV NHL and ALL patients, EFS was significantly worse in patients with initial CNS involvement than in those without it (14.3% (S.E.: 13.2) vs. 73.7% (S.E.: 10.1); P = 0.0025). In conclusion, our regimen (AT-B88) produced a more than 70% cure-rate for children with any stage of B-cell NHL/ALL without initial CNS involvement. However, a new regimen is needed for patients with initial CNS involvement.

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 x 10(4)/kg (range 10.1-45.3 x 10(4)/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 x 10(9)/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.

This is the first report of successful treatment of recurrent retinoblastoma with vitreous seeding by a combination of ranimustine (MCNU) and carboplatin. The patient was diagnosed with bilateral retinoblastoma at 3 years of age. Although he received photocoagulation and radiotherapy for the left eye after enucleation of the right eye, a recurrent tumor associated with vitreous seeding developed 6 years later. The child underwent chemotherapy with cyclophosphamide and nimustine hydrochloride (ACNU), and a transient decrease of tumor cells in the vitreous was seen. We then changed the chemotherapy regimen to MCNU (70 mg/m2/ day for 1 day) and carboplatin (400 mg/m2/day for 2 days). After five courses of this chemotherapy, the tumor in the vitreous completely disappeared. No recurrence has been observed for > 4 years. Side effects, including myelosuppression, general fatigue, and vomiting, were observed during the course of chemotherapy, but they were ameliorated with supportive therapy. Neither nephro- nor ototoxicity was observed. The patient has useful vision. These results warrant further study of this novel drug combination in patients with recurrent, or even primary, retinoblastoma.

A total of 125 children, who were diagnosed as having high-risk acute lymphoblastic leukemia (ALL), were treated with two consecutive protocols designated as AL851 (1985-1988) and ALHR88 (1988-1990). All patients received induction therapy consisting of vincristine (VCR), prednisolone (PSL), daunorubicin (DNR), and I-asparaginase (I-Asp). In the ALHR88 protocol, the patients whose blasts in the bone marrow (BM) were > or = 25% on day 14 of induction therapy and who were classified into T-cell type received additional cytosine arabinoside (AraC). After consolidation with intermediate-dose methotrexate (MTX), reinduction therapy including VCR, dexamethasone, and adriamycin followed by high-dose AraC was done for all patients. Intrathecal MTX and 24Gy of cranial irradiation were used to prevent central nervous system leukemia. A maintenance therapy consisting of 6-mercaptopurine, cyclophosphamide, MTX, DNR, VCR, and AraC was administered for 3 years after achieving a complete remission (CR). CR was achieved in 51/55 (92.7%) for AL851 and 68/70 (97.1%) for ALHR88. The 5-year event-free survival rates were 49.1 +/- 6.7% in AL851 and 62.5 +/- 6.1% in ALHR88. The factors related to a poor prognosis were a high initial leukocyte count of greater than 50 x 10(9)/L (P < 0.001), an L2 morphology of leukemic cells by FAB classification (P = 0.009), the chromosomal abnormality (P = 0.004) and high residual leukemic cells in BM (> or = 25%) on day 14 of induction therapy (P < 0.001). Taking these factors into consideration, more intensive protocols were started in 1990 for the patients with high-risk ALL.

Seventy-three children with acute nonlymphocytic leukemia (ANLL) have been treated with ANLL-85 and ANLL-88 protocol at Kyushu-Yamaguchi Children's Cancer Study Group between June, 1985 and February, 1993. Ten boys and 10 girls (0y4m-16ylm) were treated with the ANLL-85 protocol. The complete remission (CR) rate was 75% and the 5-year event free survival (EFS) was 20 +/- 9%. It was terminated because of frequent early relapse (within 6 months after CR). Thirty-four boys and 19 girls (0y3m-17ylm) were treated with the ANLL-88 protocol. The CR rate was 85% and the 5-year EFS was 32 +/- 7%. Early relapse rate with ANLL-88 was lower than that of ANLL-85, however 9 cases relapsed after terminating therapy. Although bone marrow transplantation (BMT) from related donors during the first CR was effective in ANLL-88, EFS was not improved. Recognition of risk factors and appropriate chemotherapy regimens with or without the support of stem cell transplantation may be necessary to cure children with ANLL.

Fifty five children diagnosed as having high-risk acute lymphoblastic leukemia (ALL) between 1985 and 1988 were treated with protocol AL851. The agents used in the protocol were as follows: induction therapy: vincristine (VCR), prednisolone, daunorubicin (DNR) and l-asparaginase, consolidation therapy: an intermediate-dose methotrexate (MTX), central nervous system (CNS) leukemia prophylaxis: intrathecal MTX and 24Gy cranial irradiation, reinduction therapy: VCR, adriamycin, dexamethasone and high dose cytarabine (AraC), maintenance therapy: 6-mercaptopurine, cyclophosphamide, MTX, DNR, VCR and AraC. Patients received chemotherapy for 3 years after achieving complete remission (CR). CR was obtained in 51 patients (92.7%). Twenty-four of them relapsed after achieving CR (bone marrow 16, CNS 3 and testis 5). At median follow-up of 79 (range 64-102) months, the estimated 8-year disease free survival rate was 49.1 +/- 6.7%. Four patients relapsed at bone marrow during the first 6 months of the treatment, indicating that more intensive combination chemotherapy should be included in earlier stage of the protocol. The high incidence of testicular relapse (14.3% in boys) suggests that high-dose MTX or AraC should be needed for improvement of the prognosis of high-risk ALL patients.

Eight pediatric patients with acute lymphoblastic leukemia (ALL) were treated with intermediate-dose cytosine arabinoside (ID-AraC, 1 g/m2) in combination with adriamycin except one patient. Of the eight patients, four refractory to the initial induction therapy and one in bone marrow relapse gained complete remission with two to three cycles of this therapy. Four of the five patients have been in continuous remission for 4 to 24 months with the maintenance therapy of monthly administration of ID-AraC. One patient in central nervous system (CNS) relapse has continued in remission from CNS leukemia after two cycles of the therapy. Side effects of ID-AraC and adriamycin were generally mild to moderate and tolerable in all children. These results suggest that the use of ID-AraC and adriamycin might prove effective in the treatment of ALL refractory to other regimens.

Thirty-one children with leukemia or lymphoma treated with multi-drug chemotherapy for more than 2 years were reviewed to identify and characterize the occurrence of febrile episodes related to vincristine (VCR) injection. In nine of the 31 children, more than two febrile episodes apparently attributable to VCR during maintenance therapy were identified. No such episodes were found to have occurred during induction therapy. The median age at diagnosis of these nine children was 3.2 +/- 1.6 years, significantly lower than the 6.8 +/- 4 years of the other 22 children (P less than 0.01). No significant difference was observed between these two groups in laboratory data obtained before the VCR injections, and the drugs used in combination with VCR were apparently unrelated to the incidence of febrile episodes. All of these febrile episodes began within 24 hours after VCR injection. Peak levels of 38 degrees C to 39 degrees C occurred 6 to 24 hours after onset. The episodes also were accompanied by mild, general fatigue and a loss of appetite. They ranged in duration from half of a day to 4 days, but those persisting more than 3 days occurred in three of the five children whose regimens did not include corticosteroid. The results thus suggest that fever is an immediate reaction to the toxicity of VCR in young children, and that the duration of fever can be shortened by combining VCR with corticosteroid.

Combined chemotherapeutic regimens of (1) cyclophosphamide (40 mg/kg x two days), (2) cisplatinum (20 mg/m2 x five days) plus VM-26 (100 mg/m2), and (3) Adriamycin (60 mg/m2) plus DTIC (250 mg/m2 x five days) were prescribed for 42 Japanese children greater than 1 year of age with stage III or IV neuroblastoma. The protocol was separated into three forms (A, B, and C) from the combination pattern of three such high-dose courses. The cumulative survival rates for those with stages III and IV 48 months after initiation of therapy were 76.2% and 20.1%, respectively, and the overall rate was 36.7%. The tumor disappeared during the course of treatment in 25 of 42 children (59.5%). The 48-month survival rate was superior in patients greater than 5 years of age than younger patients (P less than .01). Even in patients with a tumor originating in the suprarenal region, the 48-month survival rate was 30.5%. Among 12 patients in whom the N-myc oncogene was measured, one of five with one to ten copies of amplification died, whereas all seven with greater than ten copies died or had a recurrence. Thus, the present chemotherapeutic regimens, in particular alternate administration of each high-dose course, considerably improved the survival of patients with stage III neuroblastoma. More aggressive protocols are needed for those with stage IV neuroblastoma who are greater than 1 year of age, particularly in those with an amplified N-myc oncogene.

A 37y/o male developed mass formation in right tibia in Oct. 1986. He had generalized lymphadenopathy. Diagnosis of malignant lymphoma of B cell type (follicular, large cell type) stage IV B was made because of bone marrow involvement. Surface marker analysis of pathologic cells in the peripheral blood, bone marrow, lymph nodes revealed that they were of B cell type with positive EA gamma rosette formation, positive surface immunoglobulin with IgM-kappa and cytoplasmic immunoglobulin with IgM-kappa and positive responses to monoclonal antibodies of OKIal and B1. He responded partially to VEPAM therapy but in Jan. 1987 he developed Ga accumulation in heart and ECG abnormalities such as depression of ST and inverted T in II, III, AVF, V1-V6 leads. After treatment with VEP, ECG abnormalities disappeared in a month. The same ECG abnormalities recurred once more and disappeared again. Autopsy findings revealed accumulation of lymphoma cells in epicardium and myocardial degeneration in right ventricle. Ga scan appears to be a valuable method for detection of early cardiac involvement by malignant lymphoma.

A 12-year-old patient with non-Hodgkin's lymphoma, who developed central nervous system (CNS) relapse, was successfully treated with the following new regimen: cerebrospinal irradiation (CSpRT), high-dose chemotherapy, and autologous bone marrow transplantation (ABMT). He received remission induction therapy comprising intrathecal methotrexate and systemic chemotherapy, followed by cranial and spinal irradiations in doses of 2,000 cGy in 10 fractions over 5 days, and 1,200 cGy in 6 fractions over 3 days, respectively. He then received chemotherapy comprising 4 infusions of 1 g/m2 cytosine arabinoside and an intravenous injection of 4 mg/kg ACNU. His bone marrow, collected and cryopreserved after the remission induction therapy, was infused immediately after the high-dose chemotherapy. The granulocyte and platelet counts reached the nadir level on days 10 and 6 after ABMT, respectively, gradually recovering to the normal level in about 1 month. Neither severe infection nor bleeding was noted during the aplastic phase. No neurological deficits have been observed for 12 months. The short-time CSpRT and high-dose chemotherapy followed by ABMT are thus demonstrated to reduce neurotoxicities and bone marrow toxicities and to produce a good therapeutic effect against CNS involvement in lymphoma.