Yoshio Zaizen

Surgical strategy for the treatment of pyriform sinus fistula

Pyriform sinus fistula recurs when a complete excision of the fistula has not been made. As a supportive technique for this radical operation, the authors performed an intraoperative endoscopic examination of the pyriform sinus for the cannulation or dye injection of the tract in four cases. In three cases, the sinuses were relatively long and ran outside the thyroid cartilage. The cannulation of the tract with a guide wire, in these cases, was useful for identifying the thin membranous tract. In one of these three cases sinus fistula recurred, but a complete excision of the tract was then performed by introducing a 10F Nelaton catheter over a guide wire, which allowed for easy handling of the remnant tract. In the remaining case, cannulation proved not to be useful because the tract was short and ran inside the thyroid cartilage. A short tract embedded within the inferior constrictor muscle could only be found through careful observation after repeated dye injections. The proper selection of the optimum supportive techniques as described above, are considered to be essential for performing a complete excision.

Different genomic and metabolic patterns between mass screening-positive and mass screening-negative later-presenting neuroblastomas

The mass screening of neuroblastoma has been undertaken in Japan by measuring urinary vanillylmandelic acid (VMA) and homovanillic acid (HVA) in all infants at the age of 6 months. This program may not only improve the prognosis but also provide important insights into the biology and evolution of human neuroblastoma. The authors studied and discuss the clinical significance of the N‐myc oncogene, catecholamine metabolism, and other tumor markers in 43 patients with neuroblastoma who underwent the urinary screening test at 6 months of age. Thirty patients were found by the screening, and 13 were negative at the screening but later had a tumor. In the former group, the tumors were mostly in early stages (Stage I, 12; Stage II, 11; Stage III, seven), no amplification of N‐myc was observed, and all patients are alive without disease. Although two patients whose urine at the screening showed elevated VMA and HVA levels and accidentally were not treated for 13 and 17 months, there was no change in the values of VMA and HVA during that time. However, in the latter group, the tumors were mostly in advanced stages (Stage I, one; Stage III, four; Stage IV, eight), and N‐myc amplification was observed in seven of 13. Only two of these 13 are alive without disease. The age at diagnosis of the screening‐negative group was 23 months compared with 8 months in the patients identified by screening, and the pattern of catecholamine metabolites in the screening‐negative group tended to be dopaminergic with a low VMA–HVA ratio, especially in cases with N‐myc amplification. These data suggest that the screening‐positive patients with neuroblastoma may have favorable characteristics, and the biology of these tumors may be different from that of screening‐negative later‐presenting tumors. They also suggest that there may be at least two distinct subsets of neuroblastoma. For the early detection of the poor prognostic neuroblastomas, the measurement of urinary dopamine with VMA and HVA at later ages, such as 1 to 2 years, should be considered.

The effect of perioperative exogenous growth hormone on wound bursting strength in normal and malnourished rats

Patients with significant malnutrition secondary to underlying disease may require major surgical intervention on an urgent basis. Nutritional restoration using enteral or intravenous alimentation requires a delay of 10 to 14 days and is frequently not practical. With the availability of human growth hormone (GH) produced by recombinant DNA technology, this study was undertaken to evaluate the effect of exogenous GH on wound tensile strength in a rat model. Fifty-four animals were divided into three groups: group I, normal nourished control; group II, malnourished; group III, malnourished, rat GH treated (1 mg GH administered 3 days preoperative and 5 days postoperative celiotomy). Wound tensile strength was measured at 6 days postoperatively. Wound strengths in malnourished rats were significantly less than in normal controls (P less than .001). With the administration of growth hormone in group III, wound strength was significantly improved when slightly improved over normally nourished controls (P less than .05). A dose response curve demonstrated progressive improvement in wound tensile strength from 0.01 mg/d to 1.0 mg/d. Thus growth hormone administration to malnourished animals significantly enhances wound strength. With the availability of recombinant produced human GH these observations may be clinically applicable.

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)

Mass screening for neuroblastoma: quo vadis? A 9-year experience from the Pediatric Oncology Study Group of the Kyushu area in Japan.

Since 1985, a nationwide program of mass screening for neuroblastoma has been available for 6-month-old infants throughout Japan. From 1985 to 1993, the authors studied 285 patients with neuroblastoma among their regional population of 15 million. There was an increase in the total number of patients per year in comparison to the previous 6-year period (1979 to 1984). However, no significant difference was noted in the number of patients older than 1 year or in the incidence of advanced-stage (stages III and IV) unscreened cases. The majority of neuroblastomas in the screened group showed favorable biological factors, even in the advanced stages. However, there was a small group with histologically and/or biologically unfavorable factors; five of 115 had amplified N-myc oncogene, four of 74 showed unfavorable Shimada histological findings, and three of 33 had an unfavorable DNA ploidy pattern. One case from this group with unfavorable factors died of the tumor. 3) Thirty-eight cases were negative at the time of mass screening, but later presented with neuroblastoma. Most of them were diagnosed between 1 and 3 years of age, and 30 of the 38 cases (78.9%) were advanced stage with unfavorable prognostic factors. Thus, the authors conclude that mass screening at 6 months can detect a selected population of infants with neuroblastoma; some of the tumors may represent subclinical masses destined for spontaneous regression. However, some tumors with unfavorable factors have been detected by mass screening before progression and/or dissemination. Infants in this group are considered to benefit most from early diagnosis and treatment.

The role of cellular motility in the invasion of human neuroblastoma cells with or without N-myc amplification and expression

BACKGROUND/PURPOSE Patients who have neuroblastomas with N-myc amplification that are extremely invasive and result in distant metastases tend to have a very poor prognosis. The authors reported previously that N-mycamplification and expression might be closely related to the invasiveness of human neuroblastoma cells. However, the role of cellular motility has not yet been clarified in the invasion of neuroblastoma cells. The aim of this study was, therefore, to elucidate the role of cellular motility in the invasion of neuroblastoma cells. METHODS Six human neuroblastoma cell lines were used for an invasion assay in vitro using polycarbonate filters coated with basement membrane Matrigel. The amplification and expression of N-myc oncogene was examined by Southern and Northern blotting, respectively. The cellular motility was quantified by computerized image analysis on the morphology of cultured cells. RESULTS IMR-32, GOTO, and DZ, all of which had N-myc amplification, showed a high degree of invasiveness and a high cellular motility, whereas NB-69 and SK-N-SH without N-myc amplification showed an extremely low degree of invasiveness and cellular motility. ST without N-myc amplification, which was established from an aggressive tumor, showed an exceptionally high degree of motility and invasiveness. A transcriptional reduction of the N-myc gene by retinoic acid (RA) decreased the motility, which thus resulted in a marked decline of invasiveness in IMR-32 and GOTO. CONCLUSION The cellular motility correlated with the invasive capacity of human neuroblastoma cells, which thus indicated that cellular motility may play an important role in invasion.

Patterns of destruction of mouse neuroblastoma cells by extracellular hydrogen peroxide formed by 6-hydroxydopamine and ascorbate

SummaryThe patterns of the cytolytic effects of 6-hydroxydopamine (6-OHDA), with/without ascorbate, on C-1300 and three other cloned mouse neuroblastoma cell lines (N1E-115, NS-20, N-18) were studied in vitro. The sensitivity to 6-OHDA differed and the three cloned cell lines were more sensitive than the wild type C-1300 cell line. Ascorbate synergistically potentiated the cytolytic effect of 6-OHDA to all four cell lines. The 6-OHDA cytotoxicity was eliminated by the addition of exogenous catalase but not by addition of other oxygen free radical scavengers, thereby suggesting that the hydrogen peroxide formed might influence the cells, extracellularly. In addition, the critical time for tumor cell lysis was the first 60 min of the reaction. The cytotoxicity induced by the unmasked cyclophosphamide, 4-hydroperoxycyclophosphamide, was synergistically enhanced in the presence of a nontoxic concentration of 6-OHDA and ascorbate. These data suggest that reactive oxygen intermediates may prove to be a good tool for destroying neuroblastoma cells.

The effect of N-myc amplification and expression on invasiveness of neuroblastoma cells

Most neuroblastomas with N-myc amplification, a sign of extremely poor prognosis, are extensively invasive to surrounding tissues. Therefore, we investigated the relationship between N-myc amplification and invasiveness of neuroblastoma cells, using an in-vitro assay system. Five human neuroblastoma cell lines were used for this study. IMR-32, GOTO, and DZ, all of which had N-myc amplification, showed a highly invasive capacity. In contrast, SK-N-SH without N-myc amplification showed extremely low invasiveness. ST unexpectedly showed high invasiveness in spite of the lack of N-myc amplification. Treatment of GOTO with 10(-5) mol/L all-trans-retinoic acid (RA) for 72 hours markedly decreased both N-myc expression and invasiveness. Treatment of GOTO with 2 mmol/L dibutyryl cyclic AMP (dbcAMP) for 72 hours caused a slight decrease of N-myc expression and invasiveness. These results indicate that N-myc amplification and expression might be closely related to the invasiveness of human neuroblastoma cells.

Retinoic acid induces insulin-like growth factor II expression in a neuroblastoma cell line

Insulin-like growth factor II (IGF-II) is implicated in the development of the vertebrate neural circuitry, and increases neurite growth in vitro and in vivo. We examined the relationship of IGF-II expression to the in vitro differentiation induced by retinoic acid (RA). We find that RA stimulates an increase in IGF-II messenger RNA (mRNA) in the SK-N-SH (SH) neuroblastoma cell line. An increase of IGF-II mRNA is detected within 12 h of treatment and precedes morphological differentiation. A RA dose response test indicates that an increase in IGF-II mRNA occurs within 2 days in SH cells treated with doses of RA from 1 x 10(-8) to 1 x 10(-5) M. We suggest that IGF-II expression may be regulated either directly or indirectly by RA in vitro and may lead to neuroblastoma differentiation.

How to deal with advanced cases of neuroblastoma detected by mass screening: A report from the pediatric oncology study group of the Kyushu area of Japan☆

Since 1985, a nationwide program of mass screening (MS) for neuroblastoma has been underway for 6-month-old infants throughout Japan. As a result, the number of patients with stage I or II disease has obviously increased, and this has resulted in overall improvement of the prognosis for neuroblastoma. Some cases detected by MS were already in an advanced stage and have also had a good prognosis. In such cases, no definitive treatment protocol has been developed. Therefore, the authors investigated (1) the clinical and biological features of the advanced neuroblastoma cases detected by MS and (2) the best way to deal with such cases. The authors analyzed 94 cases of advanced-stage neuroblastoma registered in the Kyushu area (population, 15 million) between 1985 and 1990. Eighteen cases (16 stage III, 2 stage IV) were found by MS, and the others (23 stage III, 53 stage IV) were diagnosed clinically. The following results were obtained: (1) No N-myc amplifications were observed in cases detected by MS, whereas 16 of the 45 examined patients in the non-MS group had high amplifications of N-myc. (2) With regard to Shimadas classification, DNA content, and S-100 protein positivity, most of the advanced tumors found by MS showed characteristics indicating a good prognosis. (3) The 5-year survival rate for the non-MS group is less than 25%, whereas all of the patients whose tumors were detected by MS are alive, even after undergoing mild chemotherapy.(ABSTRACT TRUNCATED AT 250 WORDS)