Tohru Tsuda

Analysis of N-myc amplification in relation to disease stage and histologic types in human neuroblastomas

Both untreated and treated primary neuroblastomas from 52 patients were analyzed to determine the correlation between the amplification of N‐myc oncogene and various prognostic factors. Amplification of N‐myc was observed in eight of 28 untreated cases and in 12 of 24 treated cases. As a whole, 12 of 18 tumors (67%) in Stage IV had N‐myc amplification, but there were fewer cases in the unadvanced disease stage, as reported previously by others. Furthermore, the authors detected N‐myc amplification in three of nine tumors in Stage IV‐S, although the amplification was less than 50 copies. Analysis of progression‐free survival at 24 months revealed that amplification of N‐myc was associated with the worst prognosis (P < 0.001). In the untreated group, no amplification of N‐myc was detected in any of two ganglioneuromas and four ganglioneuroblastomas, whereas amplification of N‐myc was observed in all two round‐cell and six of 20 rosette fibrillary neuroblastomas. On the other hand, the authors detected amplification of N‐myc in three of eight less differentiated ganglioneuroblastomas in the treated group and observed the worst prognosis in these three patients. The total percentage of the cases from both untreated and treated groups suggest that amplification of N‐myc may occur more frequently in undifferentiated types of neuroblastomas than in less malignant types. In conclusion, the amplification of N‐myc in neuroblastomas was closely associated with the worst prognosis, which was suggested by both disease stage and histologic characteristics.

N-myc oncogene amplification and prognostic factorsof neuroblastoma in children

The N-myc oncogene of 28 neuroblastic tumors obtained from 16 untreated and 12 pretreated children was clinically evaluated and compared with known prognostic factors. Significant amplification of the N-myc (more than ten copies) was observed in 0 of 2 tumors in stage I, 1 of 5 in stage II, 2 of 6 in stage III, 6 of 9 in stage IV, and 2 of 6 in stage IVS. In stages II, III, IV, and IVS, all 15 patients with low N-myc amplification (under ten copies) are alive without disease, while among 11 patients with the amplification, seven died with progressive disease and two have a recurrence (P less than .01). All tumors with N-myc amplification originated from the suprarenal region and the amplification appeared in 55% of those from that origin. The amplification also correlated with the age factor. These results suggest that the genomic amplification of N-myc seems to be correlated with known prognostic factors of neuroblastoma, and may be a reliable factor even in the case of preoperatively treated tumors.

Amplification of N-myc oncogene in stage II and IVS neuroblastomas may be a prognostic indicator

The amplification of N-myc oncogene is frequently observed in tumors of patients with advanced, poor prognostic stages of neuroblastoma (unfavorable stage group). However, there has been little documentation of the N-myc amplification in tumors of patients with stages II and IVS neuroblastoma (favorable stage group). In this communication, we present data on one patient in stage II and two in stage IVS. In these children, the primary tumors had an amplified N-myc and the clinical course was poor. In addition, from an analysis of the N-myc oncogene of 26 neuroblastomas, genomic amplification of more than three copies was observed in 4 of 11 (36%) in the favorable stage group, and in 9 of 15 (60%) in the unfavorable stage group. Death occurred only in those with an amplified N-myc, in both groups. The smaller copy number of N-myc amplification of stage IVS tumors as compared with those of stages III and IV, appeared to be characteristic. These findings suggest that N-myc amplification may be a reliable prognostic indicator even in the favorable stage group of neuroblastomas, and may be clinically useful as a guide for treating those with a poor prognosis in stages II and IVS.

Genetic analysis of the cell binding domain region of the chicken fibronectin gene

We have determined the nucleotide sequence of the cell binding domain region of the chicken fibronectin gene and analyzed it evolutionaly. We present here the complete nucleotide sequence of 4.3 kb HindIII/EcoRI segment from the clone lambda FC23 of the chicken fibronectin gene. There were five exons in this segment. When we lined up the amino acid of exons 28, 29 and 31, three alignments, known as the Type III repeat, appeared. Tetrapeptide, -RGDS-, called the cell binding domain, existed in the second repeat, coding exon 30. It was presumed that the Type III repeats were composed of two exons in the chicken gene, the same as in the rat and humans. We found repeatedly appearing amino-acid sequences such as -TIT- (three arrays in these Type III repeats) but also found one of the amino acids substituted in the tripeptide in these Type III repeats (seven arrays). We analyzed these repeats from the point of view of evolution. We used three of the nucleotide sequences (12-18 bp) coding such -TIT- repeats as a unit length for comparing the various homologies after dividing the coding region into 56 segments. The mutual homology of the divided segments to each one of three showed 53% on average. On the other hand, the mutual nucleotide homology of the Type III repeat was 44%. This suggested that the Type III repeat may have been developed by frequent duplication of small gene units.

Differences of L-myc polymorphic patterns of neuroblastoma in patients under 1 year versus older ages: a preliminary report.

The age of the patient at the onset of symptoms or at diagnosis is generally accepted as one of the most important prognostic factors of neuroblastomas (NBs). Children less than 1 year of age have a better survival rate than older patients, but the reason for this is unknown. Forty-eight unselected NB patients were divided into two groups: less than 1 year (younger NB patient) and over 1 year (older NB patient) of age at diagnosis. Two of 12 younger NB patients and 18 of 36 older NB patients had N-myc amplification in their tumors. To elucidate further the possible genetic difference between younger and older NB patients, studies of restriction fragment length polymorphism (RFLP) of the L-myc gene was carried out in these two groups. The L-myc locus showed 2-allele polymorphism, allele L(10 kb) and S (6.6 kb), after digestion with EcoRI. Patients homozygous for L-band have been reported as individuals having less metastatic potential in some cancers. The allele frequencies of L and S in neuroblastomas of younger NB patients were 0.50 and 0.50, while those of older NB patients were 0.35 and 0.65, respectively. Although we did not determine L-myc RFLP in normal tissue of individual patients, we expect that the distribution of allele L and S is partly affected by possible allelic loss involving the L-myc region. However, the L-myc RFLP patterns in younger NB patients were the same as those of normal individuals and significantly differed from those of older NB patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Reassembly of the Photosynthetic Water-Oxidizing Complex on the Thylakoid Membranes

The manganese cluster catalyzing the photosynthetic water-oxidation is ligated to the PS2 reaction center proteins, the D1 and D2 proteins (1). Under illumination, vigorous photoreactions occur on the PS2 reaction center, resulting in photodamage and the subsequent repair of the PS2 proteins, particularly the D1 protein (2, 3). Thus, the manganese cluster may be disassembled and (re-)assembled on the thylakoids, in concern with recycling of the PS2 reaction centers. However, it remains open where and how the Mn cluster is assembled in vivo.

Comparison of the Effects of Different Schedules of rG-CSF Administration after Chemotherapy in Patients with Lung Cancer.

rG-CSFは, 白血球数最低値を底上げし, 白血球数減少期間の短縮が期待される薬剤として, 肺癌化学療法での併用が定着しつつある. しかし, どの時点からの投与開始が最適であるかの検討は十分にされていない. 今回我々は, 3つの化学療法レジメン (3日間) で, 投与開始時期により4群 (A群: rG-CSF非投与, B群: 白血球数2000/mm3以下からの開始, C群: day2からの開始, D群: day5からの開始) に分け, r G-CSFを2μg/kg皮下注して, 各群の白血球数最低値と白血球減少期間を比較した. この結果, D群は全例で白血球数最低値が2000/mm3以上になり, A群と比べ有意に最低値が底上げされた. またB, C群は同一症例で同一レジメンの比較で白血球数減少期間の短縮傾向を認めた. この結果から, 今回行った化学療法レジメンでは白血球数最低値を確実に底上げする目的ならば, day5からの投与開始が最も有用と思われた.