Shingi Sasaki

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)

Esophageal tracheoplasty for congenital tracheal stenosis

Two infants with congenital long tracheal stenosis underwent operation by means of an esophageal tracheoplasty. The first patient had previously undergone tracheal reconstruction using the pericardium. Although ventilation improved somewhat following this procedure, the pericardial patch suddenly ruptured 12 days after the operation, requiring an immediate esophageal tracheoplasty. The esophageal portion of the reconstructed trachea epithelialized 1 month later, with the lumen maintaining its proper size. However, the patient died 3 months after the second tracheoplasty. The cause of death was thought to be due to complications arising from prolonged high-pressure use of mechanical ventilation. He had been on a respirator for 6 months before the first tracheoplasty. The second patient has been doing well with no recurring respiratory problems for 25 months now. Her reconstructed trachea has adapted with her growth. This technique should be considered along with other forms of treatment for tracheal reconstruction because it is relatively simple and pliable.

Evaluation of patients with advanced neuroblastoma surviving more than 5 years after initiation of an intensive Japanese protocol: A report from the study group of Japan for treatment of advanced neuroblastoma

In January 1985, a single protocol consisting of cyclophosphamide, vincristine, tetrahydropyranyl adriamycin, and cis-platinum for the treatment of advanced neuroblastoma was begun nationwide in Japan and was found to improve clinical results significantly in terms of 2- or 3-year survival rate. Between January 1985 and December 1988, 113 eligible patients (7 infants younger than 12 months of age with stage IVA disease and 106 patients aged 12 months or older with stage III or IV disease) were enrolled and followed up for 5 years or more after initiation of treatment, as of March 1994. In this study, the usefulness of the protocol for the treatment of advanced neuroblastoma was evaluated with survival rates in relation to age, tumor site, stage, and N-myc amplification for patients surviving more than 5 years after initiation of the protocol. Fifty of the 113 patients were alive 5 years or more after initiation of the treatment, 39 without any episodes of disease recurrence. Fourteen (70%) of 20 patients with stage III, 6 (50%) of 12 with stage IVB, and 24 (30%) of 81 with stage IVA disease were alive and disease-free 5 years after initiation of the protocol. Twenty (56%) of 36 patients without N-myc amplification were alive at 5 years after initiation of the protocol. Only one patient who was alive without evidence of the disease at 5 years had recurrence afterward.

A cellular uptake of cis-platinum-encapsulating liposome through endocytosis by human neuroblastoma cell

To explore the mechanisms involved in the efficient intracellular delivery of an antitumor agent, the uptake mechanism of cis-diamminedichloroplatinum (CDDP)-encapsulating liposome (phosphatidylcholine:phosphatidylserine:cholesterol = 6:2:3 in molar ratio) (CDDP-liposome) by the human neuroblastoma cell, IMR-32, was investigated. Dansylcadaverine, chloroquine and antimycin A suppressed the growth-inhibitory activity of CDDP-liposome mostly due to the interference of the energy-dependent internalization process. Colchicine and vinblastine also neutralized the DNA synthesis-inhibitory activity of CDDP-liposomes. Stimulation with CDDP-liposomes at low temperature (4 degrees C), which induces the disruption of microtubules under immunofluorescent visualization, markedly lowered the growth-inhibitory activity of CDDP-liposomes. These findings suggested that the action of CDDP-liposome was temperature-dependent and microtubules participated in the intracellular drug delivery. A23187 (0.4 ?M), further, promoted the action of CDDP-liposome, suggesting that an increase of intracellular Ca(2+) levels promotes the growth inhibitory activities of CDDP-liposomes. Taking the uptake-mechanisms and intracellular delivery processes of CDDP-liposomes into consideration, the use of CDDP-liposomes may present a promising tool for neuroblastoma chemotherapy.

Thirty years' experience of open-repair surgery for pectus excavatum: development of a metal-free procedure

OBJECTIVE Throughout the history of surgery for pectus excavatum (PE), the Nuss procedure and open repair have been performed with many modifications, with most of these procedures using a metal bar. However, the use of a metal bar has several drawbacks. Thus, we aimed to develop a procedure that did not require a metal bar. METHODS Through our experience of 426 pediatric cases that underwent various procedures for open repair of PE at Nagoya City University, we arrived at the current procedure that we describe herein. We have evaluated this procedure by review of clinical results and deformity indices (Hallers, steepness, excavation volume, and asymmetry index). RESULTS The latest and current procedure that supports the sternum with a bridge constructed by the 4th or 5th costal cartilages is associated with fewer complications, a lower re-operation rate, and striking improvement in the indices examined. CONCLUSIONS Our current open-repair procedure that does not require a metal bar is recommended for correction of deformities of PE in children.

Inhibition by neuroblastoma growth inhibitory factor of ascites-type neuroblastoma cell growth in coculture with normal glioblasts

A new ascites type neuroblastoma clone (NAs-1), which is characteristic both in anchorage-independent growth and catecholaminergic functions, attached on the monolayer culture of glioblasts and was subjected to morphological differentiation including the extrusion of neuronal processes. Other conventional neuroblastoma cells (Neuro2a, NS-20Y, and N1E-115) as well as NAs-1 in cocultured with normal glioblasts underwent a decrease in cell growth rates and DNA synthesis under the effect of the neuroblastoma growth inhibitory factor (NGIF) produced by glioblasts. After their NGIF production had been reduced by u.v. irradiation, glioblasts lost the growth-inhibitory and differentiation-promoting effects in coculture with NAs-1. The supplement of NGIF into u.v.-treated glioblasts restored the dose-dependent growth inhibition of NAs-1. The addition of nerve growth factor into the coculture system brought about neither the marked effect on growth inhibition of NAs-1 nor the morphological differentiation. The results imply a direct function of NGIF on the paracrine regulation of neuroblastoma cell growth in the coculture with normal glioblasts.

In vitro and in vivo growth characteristics of a new ascites-type neuroblastoma cell from mouse C1300 neuroblastoma.

A clonal ascited type cell, NAs-1, was obtained in culture from a mouse neuroblastoma C1300. The cells were adapted to anchorage-independently grow in the flask by the in vitro-in vivo alternate passage technique, and retained the ability of growing and producing ascites fluid when intraperitoneally injected into mice. Although the majority of growing cells in culture medium showed a small and round cell shape without any neuronal process, occasionally non-specific attachment onto the flask surface was observed, but devoid of the extrusion of processes. Karyotype analysis showed a homogeneous chromosome number, 40, with a marker chromosome [t(13:16)] and a minichromosome. Catecholamines, norepinephrine and dopamine, were found in the cell extracts and the contents of dopamine was particularly high as shown in another catecholaminergic neuroblastoma cell, N1E-115. Neuron specific enolase (?-subunit) was also detected. The treatment of the cells by dibutyryl cyclic AMP, prostaglandin E(1), or BL191 (phosphodiesterase inhibitor) induced the biochemical differentiation in terms of catecholamine and cyclic AMP contents, but failed to promote typical morphological differentiations including the extension of process or the significant promotion of adherence onto the flask surface.

Enhancement of Both Intracellular Uptake and Antitumor Action of Cisplatinum on Human Neuroblastoma Cells by Encapsulation in Liposomes

Phospholipid vesicles (phosphatidylcholine: phosphatidylserine: cholesterol=6:2:3 in molar ratio) with a small unilamellar structure were used as drug carriers for introducing cis‐diamminedichloroplatinum (CDDP) into human neuroblastoma cells, IMR‐32, GOTO, Nagai, and TGW. DNA synthesis of IMR‐32 cells among the human neuroblastoma cell lines was inhibited most strongly by CDDP‐liposomes. CDDP‐liposomes dose‐dependently inhibited the DNA synthesis of IMR‐32 in a similar fashion to that observed with free CDDP, but the drug concentration required to induce 50% inhibition of DNA synthesis for CDDP‐liposomes (IC50: 0.7 μg CDDP/ml) was 1/3 of the IC50 for free CDDP (2.0 μg CDDP/ml). In support of the marked growth‐inhibitory action of CDDP‐liposomes, the intracellular incorporation rate of CDDP‐liposomes was 3‐fold higher when liposomes were used as carriers than when free CDDP was directly applied. CDDP‐liposomes showed a stronger growth inhibition on IMR‐32 cells at a high cell density than at a low density in culture. CDDP‐liposomes were rapidly incorporated by IMR‐32 cells within 5 min, resulting in the inhibition of DNA synthesis to 40% of the control. Swiss albino mouse 3T3 cells were less inhibited by CDDP‐liposomes than by free CDDP, suggesting that encapsulation of CDDP in liposomes decreases cytotoxicity to normal cells.

Development of a tracheal stapling device

OBJECTIVE Recent years have witnessed a multitude of technical advances regarding gastrointestinal and vascular anastomosis. However, difficulties still hamper tracheal and bronchial anastomosis. We have therefore developed a novel set of instruments and performed end-to-end anastomosis of the transected canine cervical trachea to establish the operative procedures. METHODS A novel set of instruments was developed for tracheal anastomosis including two pairs of forceps for grasping the free tracheal ends, a metal connecting device, and clamping forceps for staple insertion. Briefly, the operative procedure involves fixation of forceps circumferentially to hold the cut trachea. End-to-end anastomosis is completed by joining the forceps with a clamp and stapling the tracheal ends everted outward. End-to-end anastomosis of the cervical trachea was performed on 23 dogs. Animals were monitored on a daily basis, and bronchofiberscopy was performed periodically. Deaths from all causes were evaluated by immediate necropsy. Sixteen dogs were sequentially sacrificed at 1, 2, 3 and at 6 months after surgery. RESULTS In our dog model, stenosis at the anastomosis of the cervical trachea was found as a complication in 8 of 23 cases. Tracheal rupture occurred in a further 3 cases, slight granulation in another 4, and the remaining 8 showed no complication. Histological findings of anastomotic healing were similar to those reported for hand suture.