Makoto Iwafuchi

Treatment of advanced neuroblastoma with emphasis on intensive induction chemotherapy. A report from the study group of Japan

One hundred nine newly treated patients with advanced neuroblastoma were entered in this study between January 1985 and May 1989. The eligible patients included infants younger than 12 months of age with Stage IVA disease (bone cortex, distant lymph node, and/or remote organ metastases) and patients aged 12 months or older with Stage III or IV disease (IVA plus IVB with tumor crossing the mid‐line and with metastases confined to bone marrow, liver, and skin). The patients first received six cyclic course of intensive chemotherapy (regimen A1), consisting of cyclophosphamide (1200 mg/m2), vincristine (1.5 mg/m2), tetrahydropyranyl adriamycin (pyrarubicin; 40 mg/m2), and cisplatin (90 mg/m2). Original tumors and the regional lymph node metastases were removed some time during these first six cycles of chemotherapy. The patients were further divided into three groups. Patients in course 1 received alternating treatment by regimen B (cyclophosphamide and ACNU) and intensified regimen A1, and those in course 2 were treated with alternating administration of regimen C (cyclophosphamide and DTIC) and intensified A1. Patients in course 3 were treated with bone marrow transplantation (BMT) preceded by high‐dose preconditioning chemotherapy. Survival rates were 77% in Stage III and 54% in Stage IV at 2 years, and 70% in Stage III and 45% in Stage IV at 3 years. The major toxicities encountered were bone marrow suppression with leukocyte counts down to 100/mm3, mild cystitis, and hearing impairment. The 2‐year survival rate was 78% in 21 patients who underwent BMT when complete remission was achieved. We concluded that our intensive induction chemotherapy is of significant value in increasing the rate of complete response, and in widening the indications for and achieving improved results of treatment with BMT.

Intensified chemotherapy increases the survival rates in patients with stage 4 neuroblastoma with MYCN amplification.

Purpose Patients with high-risk neuroblastoma who have multiple copies of MYCN fare much worse than do those without MYCN amplification; however, it has not been clarified whether intensified chemotherapy with or without blood stem cell transplantation can alter the extremely poor prognosis of patients with amplified MYCN. Methods and Results Between 1985 and 1999, 301 patients older than age 12 months with stage 4 neuroblastoma were treated. From January 1985 to February 1991, 80 patients with stage 4 neuroblastoma with and without MYCN amplification uniformly received induction chemotherapy with regimen A1 (cyclophosphamide 1,200 mg/m2 and vincristine 1.5 mg/m2 on day 1, tetra-hydropyranyl [THP]-Adriamycin 40 mg/m2 on day 3, and cisplatin 90 mg/m2 on day 5). Among 22 patients with MYCN amplification, nine (40.9%) achieved a complete remission and seven (31.8%) underwent stem cell transplantation. Of 58 patients without MYCN amplification, 43 (74.1%) achieved a complete remission and 14 (24.1%) underwent stem cell transplantation. The 5-year relapse-free survival rates were 23.2% for stage 4 patients with MYCN amplification and 33.3% for those without MYCN amplification (P = 0.029); the 5-year overall survival rates were 32.8% for stage 4 patients with MYCN amplification and 42.8% for those without MYCN amplification (P > 0.05). From March 1991 to June 1998, patients with stage 4 neuroblastoma who had 10 or more copies of MYCN were treated with regimen A3 (cyclophosphamide 1,200 mg/m2 per day on days 1 and 2, THP-Adriamycin 40 mg/m2 on day 3, etoposide 100 mg/m2 per day on days 1 to 5, and cisplatin 25 mg/m2 per day on days 1 to 5); those with fewer than 10 copies of MYCN received regimen new A1 (cyclophosphamide 1,200 mg/m2 on day 1, THP-Adriamycin 40 mg/m2 on day 3, etoposide 100 mg/m2 per day on days 1 to 5, and cisplatin 90 mg/m2 on day 5), which is similar in intensity to regimen A1. Among 88 patients with MYCN amplification, 63 (71.6%) achieved a complete remission and 63 (71.68%) underwent stem cell transplantation. Of 133 patients without MYCN amplification, 93 (69.9%) achieved a complete remission and 71 (53.4%) underwent stem cell transplantation. The 5-year relapse-free survival rates were 36.0% for stage 4 patients with MYCN amplification and 32.2% for those without MYCN amplification (P > 0.05), the 5-year overall survival rates were 34.0% for stage 4 patients with MYCN amplification and 38.9% for those without MYCN amplification (P > 0.05). The difference in relapse-free survival rates was significantly different (P = 0.003) between patients with MYCN-amplified tumor treated before (regimen A1) versus after 1991 (regimen A3). Conclusions With the use of the more intensive induction regimen A3 plus blood stem cell transplantation for MYCN-amplified patients, survival curves for those with or without MYCN amplification now appear similar. Higher doses of chemotherapy may ameliorate the effect of MYCN amplification in patients with high-risk neuroblastoma.

Treatment results of advanced neuroblastoma with the First Japanese Study Group protocol

PURPOSE To elucidate the efficacy of intensive induction and consolidation chemotherapy regimens (Study Group of Japan for Advanced Neuroblastoma [JANB] 85) for patients with advanced neuroblastoma aged 1 year or older. PATIENT AND METHODS One hundred fifty-seven patients with newly diagnosed advanced neuroblastoma were entered into this study between January 1985 and December 1990. Eligible patients were 12 months old or older with stage III or IV disease. The patients first received six cyclic courses of intensive induction chemotherapy (designated regimen A1) consisting of cyclophosphamide (1,200 mg/m2), vincristine (1.5 mg/m2), tetrahydro-pyranyl Adriamycin (pirarubicin; 40 mg/m2), and cisplatin (90 mg/m2). The patients were further treated with three different consolidation protocols: 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitrosour ea, dacarbazine, and bone marrow transplantation. RESULTS Overall survival rates for patients with stage III disease without reference to the consolidation protocols were 80.8%, 76.9%, and 66.3% at 2, 5, and 10 years, respectively. The overall survival rates for patients with stage IV disease were 58.8%, 34.4%, and 28.9% at 2, 5, and 10 years, respectively. There were no statistically significant differences between the three consolidation treatment groups. Patients who did not achieve complete remission (CR) with induction chemotherapy and surgery all died, suggesting that CR is essential for the cure of advanced neuroblastoma. The overall 5-year survival rate of the 24 patients with N-myc amplified stage III and IV disease was 33.3%, and the longest survival time of a relapse-free patient was 103 months. CONCLUSION The intensive induction chemotherapy regimen used in this study may be of significant value in increasing the CR rate and survival for patients with N-myc amplified and nonamplified advanced neuroblastoma.

Therapeutic significance of surgery in advanced neuroblastoma: A report from the study group of Japan

The role of surgery was evaluated in 19 stage III and 102 stage IV neuroblastoma patients, all of whom were treated with intensive induction chemotherapy by the Study Group of Japan between January 1985 and March 1990. For stage III neuroblastoma, surgical intervention at the primary site was performed in 18 of the 19 patients, 9 during and 9 after the first three cycles of A1 regimen, consisting of high-dose cyclophosphamide, vincristine, THP-adriamycin, and cis-platinum. Gross complete resection of primary tumor and regional lymph nodes was feasible in 17 of the 19 patients (89%), and the survival rate for the 17 patients were 79%, 70%, and 70% at 2 years, 3 years, and 4 years, respectively. For stage IV, surgical intervention at the primary site was performed in 92 of the 102 patients (90%): 30 cases during the first 3 cycles of A1 chemotherapy and 62 cases after that, with gross complete resection accomplished in 81 of the 102 patients (79%). The 81 patients with gross complete resection achieved had a better prognosis than those 11 patients with partial resection (P less than .05). Overall survival rate was 62% at 2 years for 27 patients who underwent complete resection after 3 cycles of A1 when resolution of all metastases was obtained, whereas the survival was 52% at 2 years for 31 patients who similarly underwent complete resection but when evidence of persistent metastases was present. Patients in whom the ipsilateral kidney was preserved at surgery had an outcome superior to that of those with associated nephrectomy (P less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Treatment of childhood renal cell carcinoma with lymph node metastasis: two cases and a review of literature.

Standard treatment for renal cell carcinoma (RCC) is radical nephrectomy with lymph node dissection. Stages I and II have encouraging prognoses, but Stage III with regional lymph node metastasis can be unfavorable. Adjuvant therapy for pediatric patients with advanced RCC with lymph node involvement or metastatic lesion has not been defined. Advanced pediatric RCC is reported in two patients (boys, aged 6 and 9 years: Stage IIIs, Robson; Stage III and IV, pTNM classification) treated by nephrectomy and lymph node dissection followed by postoperative interferon‐α (IFN), that can be used as an adjuvant therapy with side effects such as fever, bone marrow suppression, or decreased liver function. One is doing well for 7 years, another is suffered from lung metastases at 3 years after surgery. Although immunotherapy is expected to improve survival in pediatric patients with advanced RCC, surgical resection of renal and metastatic tumors remains the standard treatment. J. Surg. Oncol. 2000;75:266–269.

Hepatoblastoma Producing Both Alpha-Fetoprotein and Human Chorionic Gonadotropin Clinicopathologic Analysis of Four Cases and a Review of the Literature

A clinicopathologic study was done of four cases of hepatoblastoma with precocious puberty, together with an analysis of 21 such cases reported in the literature. All four patients were males, the age ranging from 11 to 35 months. Three of the four patients died within 12 months after operation, but the fourth is living. Histologically, all patients had a hepatoblastoma with the coexistence of both fetal and embryonal type cells, although predominantly fetal in two and predominantly embryonal in the other two. Tumor giant cells were rarely encountered in all these cases. Both alpha‐fetoprotein (AFP) and human chorionic gonadotropin (hCG) in the serum or urine increased in our four cases and in five other cases reported in the literature. Though the serum AFP level paralleled the severity of clinical symptoms, the serum or urine hCG did not necessarily correspond to the clinical course. It is likely that these poorly prognostic virilizing hepatoblastomas secrete two different tumor markers, AFP and hCG, from different cells, and that these functioning tumor cells may not always exist concurrently in the recurrent or metastatic tumor. Cancer 56: 1636‐1642, 1985.

What is the benefit of aggressive chemotherapy for advanced neuroblastoma with N-myc amplification? A report from the Japanese study group for the treatment of advanced neuroblastoma

In 1985, a nationwide single protocol (cyclophosphamide, vincristine, tetrahydropyranyl Adriamycin, and cisplatin) for the treatment of advanced neuroblastoma was begun in Japan and was found to significantly increase the 3-year survival rate--to 70% for stage III, and to 45% for stage IV. In this study, the authors investigated the efficacy of this protocol for advanced neuroblastoma with or without N-myc amplification. In 159 of the 233 patients with advanced neuroblastoma treated with this protocol (between January 1985 and March 1993), genomic amplification of N-myc was determined. These 159 patients were divided into two groups according to the number of N-myc copies, ie, those with fewer than 10 copies (105 patients) and those with 10 or more copies (54 patients). The survival curves for the two groups were significantly different. The 5-year survival rate for patients with 10 or more copies was 43.9%; this is surprisingly high in comparison to results of previous studies in which no survivors were expected in cases of advanced neuroblastoma with highly amplified N-myc. Persistent bone marrow suppression was common, but there were no deaths attributable to drug side effects. Five patients with fewer than copies of N-myc amplification died more than 3 years after initial treatment. Three of the five had tumors with an unfavorable Shimada classification, and two had diploid nuclear DNA content. The authors conclude that the protocol resulted in dramatic improvement in the patients with advanced neuroblastoma, even with high N-myc amplification.(ABSTRACT TRUNCATED AT 250 WORDS)

A case of Currarino triad with familial sacral bony deformities.

Abstract We describe a male patient presenting with Currarino triad: a recto-urethral fistula, sacral bony deformity, and a presacral teratoma. Clinical screening of his family revealed three additional cases with incomplete forms of this association. Cytogenetic findings in the patient and his mother were normal. This case suggests that the occurrence of an anorectal malformation together with a sacral bony deformity should raise a physicians index of suspicion for associated presacral tumors, and that screening of the patients family members with sacral radiographs is necessary.

Flow cytometric DNA analysis of neuroblastoma: Prognostic significance of DNA ploidy in unfavorable group

Flow cytometric DNA content analyses were performed on samples of 54 patients with neuroblastoma. DNA aneuploidy was detected in 55.6% of the 54 patients. A high incidence of DNA aneuploidy was observed in patients with prognostically favorable variables such as age (less than 1 year), clinical stage (I, II, or IVs), and primary site (extraadrenal sites). DNA aneuploidy was predominant in surviving patients, even in those with unfavorable variables. In patients 1 year old or more, the survival rate among those with DNA aneuploidy was 58.8% compared with 28.6% in patients with diploidy. Likewise, in patients with advanced stage (III or IV) neuroblastoma, the survival rate among those with DNA aneuploidy was 63.2% compared with 30.4% in patients with DNA diploidy. It is concluded that DNA content analysis is of value in predicting the prognosis of patients with neuroblastoma.

Electrogastrography after operative repair of esophageal atresia

Esophageal atresia (EA) is a life-threatening disorder associated with operative complications. Post-operative gastric electrical control activity detected by a non-invasive electrogastrography (EGG) technique was investigated in 13 children aged 1–17 years to clarify whether gastric motility disorders were present. EGG abnormalities were present in 5 patients; persistent dysrhythmias were found in 3. Roentgenographic examinations showed mild gastroesophageal reflux in 3 (60%) of the dysrhythmic patients; 2 others had postprandial dysrhythmias. The mean spectral frequency (MSF) of EA cases with dysrhythmia was significantly higher than that of patients without dysrhythmia in both fasting and postprandial states (P < 0.05). The variability of the peak spectral frequencies (PSFV) in patients with dysrhythmia was significantly higher than in those without dysrhythmia in both fasting and postprandial states (P < 0.05). There were no significant differences in MSF and PSFV between EA patients without dysrhythmia and controls. These results suggest that gastric motor activity may be disordered in patients following operative repair of EA, although they remain asymptomatic. EGG may be a useful screening examination for postoperative gastric functional disorders.