Yoshiaki Tsuchida

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.

Spontaneous regression of patent omphalomesenteric duct: From a fistula to Meckel's diverticulum

A newborn with a patent omphalomesenteric duct is described in this report. This anomaly is a very rare one. Regression of the omphalomesenteric duct occurs as a normal embryonic event in the intrauterine life between the fifth and ninth week of gestation; however, in this case regression occurred spontaneously in the neonatal period and resulted in a Meckels diverticulum with no connection with the umbilicus. This is the first case to be reported.

Radical excision of primary tumor and lymph nodes in advanced neuroblastoma: combination with intensive induction chemotherapy

The role of surgery in the management of children with advanced neuroblastoma is still unclear; no radical surgical technique for resection of primary tumor and lymph nodes has been established. A radical procedure was developed and has been employed in 13 patients over 1 year of age with stage III or IV disease since 1985, together with intensive induction chemotherapy. For abdominal neuroblastoma, the area of retroperitoneal lymph node dissection was divided into six sections: to the left of the abdominal aorta, between the aorta and vena cava, and to the right of the vena cava, with further subdivision according to the level of the renal vein. After excision of the primary tumor, lymph node dissection was carried out systematically in all six sections; gross complete resection was possible in 12 of the 13 patients. All 12 patients attained complete remission at least once in the course of treatment, and 7 underwent autologous bone marrow transplantation. It is noteworthy that local control of the disease was satisfactory in all but 1 patient who had extensive involvement of both renal hila and showed recurrence in the remaining kidney. Eight patients are alive with an average follow-up of 44 months; 7 of them show no signs of disease. After reviewing the results of our previous series and this series, it was concluded that advances in operative techniques and the introduction of intensive induction chemotherapy did increase surgical resectability, the rate of complete remission, and the number of candidates for bone marrow transplantation. Improvement of survival in patients with advanced neuroblastoma may thus be expected.

Anorectal malformations associated with a presacral tumor and sacral defect

The triad of anorectal malformation, presacral mass, and sacral bony defect is quite rare. During the past 18 years, five patients with this triad were treated in our institutions. Four had covered anal or anorectal stenosis, while one infant had anorectal agenesis. There was a central defect of the sacral bone in three and sacral hemivertebrae in two patients. An additional case that had an intact sacrum but was otherwise associated with the same anomalies is also reported. In the literature, we could find 51 cases (including 5 cases of our own) that fall under this symptom complex. All patients had a presacral tumor, the commonest being teratomas and meningoceles (20 cases each). Anal or anorectal stenoses were most frequently encountered (46 cases), while malformations such as anorectal agenesis (3) or anorectal stenosis plus rectovaginal fistula (2) were seen less frequently. We therefore contend that the spectrum of this symptom complex is broader than was previously considered. Among these patients, constipation was the most common presenting symptom. Barium enema and computer tomographic studies were helpful in identifying the presence, extent, and nature of the mass. The embryogenesis is discussed, reviewing the clinical and pathological characteristics of these patients.

Renin Production in Congenital Mesoblastic Nephroma in Comparison with that in Wilms' Tumor

The case of an infant with congenital mesoblastic nephroma and associated reninism is presented. The patient was a 39-day-old boy who presented with a left abdominal mass and mild hypertension (112/70 mm Hg). Both plasma renin activity (PRA) and plasma total renin concentration (PTRC) were elevated; the PTRC value of 1458 pg/mL of this case was the highest we had seen in patients with childhood renal tumors. The tumor was successfully removed and histologically confirmed as a congenital mesoblastic nephroma (cellular variant). The patients PRA and PTRC returned to normal after nephrectomy. Indirect immunoperoxidase staining showed renin localized predominantly in the juxtaglomerular apparatuses adjacent to the glomeruli entrapped by the tumor. No positive staining was seen in the tumor cells. These findings indicate that the entrapped glomeruli may play a significant role in producing renin. More important, PTRC was extremely high compared to the moderate increase of PRA and to the mild elevation of blood pressure. The mechanism of renin production by childhood renal tumors is discussed, and the importance of studying inactive renin and total renin is emphasized.

Analysis of Lectin Affinity Immunoelectrophoretic Profiles of Serum Alpha-Fetoprotein from Patients with Yolk Sac Tumors and Carcinomas of the Gastrointestinal Tract: Correlations with Molecular Structures

Profiles of concanavalin A (Con A) and lentil agglutinin (LCH) affinity immunoelectrophoresis were compared for serum alpha-fetoprotein (AFP) from patients with yolk sac tumors and carcinomas of the gastrointestinal tract, in order to find some correlations between peaks of AFP subfractions detectable by two different lectins, and to investigate whether or not it is possible to prove that the binding of AFP to LCH is weakened to some extent if a fucosylated sugar chain has, in addition, a bisect N-acetylglucosamine (GlcNAc) attached to the beta-linked mannose. The results obtained with our improved techniques tend to indicate that a Con A-reactive AFP subfraction (peak a) corresponds to an LCH strongly reactive AFP (peak A), while a Con A-nonreactive AFP (peak b) corresponds to an LCH weakly reactive AFP (peak B). the authors consider the present data sufficient to support the above explanation.

Clinical Significance of Gene Amplification Studied in Human Neuroblastoma Xenografts: Relationship with Tumor Growth Rate, Chemotherapeutic Sensitivities and Levels of Neuron-Specific Enolase

Tumor doubling time, sensitivity to chemotherapeutic agents and concentrations of neuron-specific enolase were studied in nine human neuroblastoma xenografts, in which amplifications of N-myc, clones 8 and G21 were known; N-myc was amplified in eight, clone 8 in five and clone G21 in four of these nine xenografts. Tumor doubling time was longest in one xenograft, TNB10, which lacks the amplification of either N-myc or clone 8 or G21, and shortest in TNB1 in which all three DNA sequences are amplified with a DNA rearrangement in clone 8. No correlations were found between genomic amplification of N-myc, clones 8 and G21 and effectiveness of five chemotherapeutic drugs tested, except for cis-platinum. cis-Platinum was found to be effective on all but the one xenograft, TNB10, with the longest tumor doubling time. Concentration of neuron-specific enolase in tumor extract was lowest in TNB1 and correlated with the length of the tumor doubling time.

Effects of newly introduced chemotherapeutic agents on a cytogenetically highly malignant neuroblastoma, xenotransplanted in nude mice

A human neuroblastoma xenograft, designated TNB9, was used in this experiment. This xenograft is known to have a homogeneously staining region (HSR) on chromosome 20 and to exhibit 60- to 100-fold amplification of clones 8, G21 and N-myc, and showed a rapid tumor weight doubling time of 5.9 days; it represents one of the most malignant strains of human neuroblastoma. The effects of nine different chemotherapeutic agents on this xenograft were studied according to the standard Battelle Columbus Laboratories protocol, and the in vivo chemotherapeutic sensitivity assessment disclosed that Mitomycin C, Ifosfamide, and Carboplatin were highly effective against it, while VP-16, NK-171, 5-Fluorouracil, and THP-Adriamycin were ineffective. Cytogenetic and molecular-cytogenetic analyses suggest that the present data may accurately predict the clinical results with these chemotherapeutic agents in treating patients in advanced stages, as did those from our previous studies. Inclusion of Mitomycin C, Ifosfamide, and/or Carboplatin into a new chemotherapeutic protocol may be recommended.

Completely covered cloacal exstrophy: recognition of a new clinical sub-entity

A case showing many of the typical visceral features of cloacal exstrophy is reported. The patient had fn imperforate anus, a cecal-cloacal fistula, dehiscence of the pubiic symphysis, and lumbosacral spina bifida with synsingomyelia, but the lower abdominal wall was intact without any visceral extroversion. The pertinent literature was reviewed, and it was found that this case corresponded to t typical case of “completely covered cloacal exstrophy.” Only six cases, including the present one, have so far been reported in the literature. From a clinical viewpoint, it apparently occupies an intermediate position in the wide spectrum of cloacal anomalies between “classical cloacal exstrophy” and “imperforate anus with recto-cloacal fistula,” but anatomatically and embryologically it is definitely a variant of cloacal exstrophy. In other words, it looks like an imperforate anus with recto-cloacal exstrophy, but should be treated as a variant of loacal exstrophy. The anatomy, classification, embryology, diagnosis, and management of this peculiar surgical condition are discussed, and recognition of this entity is urged.

Origin of human neuroblastoma cell lines TGW and TNB1

Analysis of DNA rearrangements and N-myc gene amplification was reported by H. Kato and associates in the July 1989 issue of this journal [I]. They used three human neuroblastoma cell lines, IMR-32, TGW and GOTO. TGW (also designated TOG [2]) was established as a cell line by one of us (M.S.) in May 1979 from a human neuroblastoma in nude mice. It originated from an autopsy specimen of a 23-monthold Japanese boy with disseminated neuroblastoma who died on April 28, 1977 [3]. The tumor in nude mice was later called ‘TNBl xenograft’ in our laboratories due to the rapid increase in number of human tumors in nude mice. In December 1983, this xenograft was given to another investigator in our group (N.K.) as in vivo material of human neuroblastoma, who also succeeded in culturing this material in vitro. Since then, the tumor in nude mice and the new cell line have both been referred to as TNB 1, and the name TNB 1 has appeared in several publications [4-91. Cytogenetic and some molecular cytogenetic characteristics of both the first and the second cell line were recently studied again. Representative karyotypes are: