Six months of maintenance chemotherapy after intensified treatment for acute lymphoblastic leukemia of childhood.

PURPOSE: We postulated that intensification of chemotherapy immediately after remission induction might reduce the leukemic cell burden sufficiently to allow an abbreviated period of antimetabolite therapy. PATIENTS AND METHODS: Three hundred forty-seven children (ages 1 to 15 years) with previously untreated acute lymphoblastic leukemia (ALL) were enrolled onto the Tokyo L92-13 study, which excluded patients with mature B-cell ALL and patients less than 1 year old. One hundred twenty-four patients were classified as standard risk, 122 as high risk, and 101 as extremely high risk, according to age, peripheral-blood leukocyte count, selected genetic abnormalities, and immunophenotype. All subjects received four drugs for remission induction, followed by a risk-directed multidrug intensification phase and therapy for presymptomatic leukemia in the CNS. Maintenance chemotherapy with oral mercaptopurine and methotrexate was administered for 6 months, with all treatment stopped by 1 year after diagnosis. RESULTS: The mean (+/- SD) event-free survival (EFS) and overall survival rates for all patients were 59.5% +/- 3.4% and 81.5% +/- 2.2%, respectively, at 5. 5 years after diagnosis. EFS rates by risk category were similar (60. 2% +/- 6.0% for standard risk, 57.7% +/- 5.6% for high risk, and 62. 5% +/- 5.7% for extremely high risk), whereas overall survival rates differed significantly (91.2% +/- 2.7%, 80.0% +/- 4.1%, and 72.1% +/- 4.5%, respectively, P <.0001 by the log-rank test). There were 107 relapses. Eighty-five (79.4%) of these 107 patients achieved second complete remissions, with subsequent EFS rates of 61.5% +/- 7. 9% (standard risk), 42.6% +/- 8.1% (high risk), and 9.6% +/- 6.4% (extremely high risk). Of the five risk factors analyzed, only the response to prednisolone monotherapy among extremely high-risk patients proved important. CONCLUSION: Early treatment intensification did not compensate for a truncated phase of maintenance chemotherapy in children with standard- or high-risk ALL. However, 6 months of antimetabolite treatment seemed adequate for extremely high-risk patients who were good responders to prednisolone and received intensified chemotherapy that included high-dose cytarabine early in the clinical course.

Establishment of a new human pre-B acute lymphoblastic leukemia cell line (KMO-90) with 1;19 translocation carrying p53 gene alterations.

A new human pre-B acute lymphoblastic leukemia cell line (KMO-90) was established from the bone marrow sample of a 12-year-old girl with acute lymphoblastic leukemia (ALL) carrying 1;19 chromosome translocation. KMO-90 cells expressed HLA-DR, CD10, CD19, and CD22 antigens. These cells had also cytoplasmic immunoglobulin lacking surface immunoglobulin, indicating that these had a pre-B phenotype. Chromosome analysis of this cell line showed 48, XX, +8, +19, t(1;19)(q23;p13). Southern blot analysis showed the same sized rearrangements of the E2A gene in KMO-90 cells as those in the original leukemic cells. By means of reverse transcriptase-polymerase chain reaction analysis, we detected E2A/PBX1 fusion transcripts in KMO-90 cells. KMO-90 is useful when studying the role of the 1;19 translocation in the etiology of pre-B ALL. Furthermore, we studied alterations of the p53 gene in this cell line by polymerase chain reaction, single-strand conformation polymorphism analysis. KMO-90 cells were identified to have a point mutation at codon 177 (CCC-->TCC) of the p53 gene, suggesting that alterations of the p53 gene may have an important role in the establishment of this cell line.

Suppression of H-ras-mediated transformation in NIH3T3 cells by a ras ribozyme.

Murine NIH3T3 cells were used to study the effect of ribozymes on H-ras-mediated transformation. Parental 3T3 cells were transfected with the activated H-ras gene. H-ras-transformed cells had altered morphology and increased colony formation in soft agar in contrast to untransfected 3T3 cells. A hammerhead ribozyme (site-specific ribonuclease) designed to cleave codon 12 (GUC) of the activated H-ras RNA was expressed in transformed cells. 3T3 clones expressing the ras ribozyme displayed decreased expression of activated H-ras RNA. The ras ribozyme reversed the transformed phenotype to resemble that of untransfected 3T3 cells. Furthermore, 3T3 cells containing the ras ribozyme were shown to suppress transformation when they were subsequently transfected with activated H-ras. Insertion of a mutant ribozyme largely devoid of cleaving capacity into H-ras-transformed cells resulted in smaller reductions in H-ras gene expression and colony formation in soft agar when compared with the ras ribozyme. Finally, the ras ribozyme alone did not perturb normal 3T3 cell growth. This study suggests the possible utility of anti-oncogene ribozymes as suppressors of tumor cell growth as well as inhibitors of cellular transformation.

Treatment of standard risk acute lymphoblastic leukemia in children with the Tokyo Children Cancer Study Group (TCCSG) L84-11 protocol in Japan.

During the period June 1984 through February 1989, 207 children, newly diagnosed with standard-risk acute lymphoblastic leukemia (ALL), were treated with the Tokyo Children Cancer Study Group L84-11 protocol. The patients were randomized into two regimen groups (S1 and S2). All patients received identical induction therapy with vincristine, prednisolone, and L-asparaginase. For central nervous system (CNS) prophylaxis, the patients in regimen S1 received cranial irradiation (18 Gy) and intrathecal chemotherapy starting at 5 weeks, while those in regimen S2 received this therapy starting at 24 weeks. Consolidation consisted of cyclic therapy with vincristine and dexamethasone, and then, after 128 weeks, with medium-dose methotrexate, CNS chemoprophylaxis, and dexamethasone. Regimen S2 employed early consolidation with three doses of medium-dose methotrexate and CNS chemoprophylaxis. The treatment duration was 3.5 years. Complete remission was achieved in 96.0% and 99.0% of the patients in regimens S1 and S2, respectively. Event-free survival (EFS) rates were 80.0 +/- 3.5% in total, 74.5 +/- 5.7% in regimen S1, and 85.1 +/- 5.7% in regimen S2 at a median follow-up of 42 months (< 85 months). There was no significant difference in the EFS between the two regimens. As compared with recently reported results of treatment for this disease, our protocol can yield similar EFS rates with mild toxicity.

Severe lightning pain after subarachnoid block in a patient with neuropathic pain of central origin: which drug is best to treat the pain?

OBJECTIVE: There have been many reports that spinal anesthesia induces severe lightning pain in the lower limbs of patients with phantom limb pain, tabes dorsalis, or causalgia. We report on a patient with neuropathic pain of central origin who showed newly developed severe lightning pain after therapeutic subarachnoid block (SAB). We performed SAB 16 times in this patient, and he complained of severe pain each time. We investigated which drug was best for treating such induced pain by administering various drugs to the patient. SETTING: The patient was hospitalized for treatment and observation. PATIENT: The patient was a 48-year-old man with neuropathic pain secondary to an incomplete spinal cord injury at the cervical segment. INTERVENTIONS: Various drugs were administered for relieving the newly developed severe pain, and the effectiveness of these agents was compared. RESULTS AND CONCLUSIONS: Intravenous thiopental, fentanyl, butorphanol, ketamine, midazolam, droperidol, and sevoflurane-oxygen anesthesia were quite effective. Intramuscular butorphanol was not effective. Intravenous physiologic saline and atropine sulfate as a placebo, intrathecal morphine hydrochloride, intravenous mexiletine, and lidocaine were ineffective. Intravenous thiopental (approximately 1 mg/kg) was thought to obtain the best pain relief because it stopped the pain quickly, the dose needed was subanesthetic, and there was no adverse effect.

Suppression of the human carcinoma phenotype by an antioncogene ribozyme.

A spectrum of oncogenes have been identified and are thought to be associated with the progression of neoplasia. These oncogenes include the following: growth factors/receptors, kinases, nuclear proteins (i.e., Fos/Jun), and tumor suppressor genes. Perturbation of one or more of these genes can transform normal cells into invasive/metastatic cancer cells. Understanding the role of these oncogenes for specific types of cancer may lead to a more rational basis for tissue-specific targets in cancer gene therapy.

Synthesis of 5-deoxy-5-fluoro and 5-deoxy-5,5-difluoro derivatives of kanamycin B and its analogs. Study on structure-toxicity relationships.

5-Deoxy-5-fluoro- (1), 5.3'-dideoxy-5-fluoro- (2), and 5,3',4'-trideoxy-5-fluoro-kanamycin B (3) have been prepared by treatment of 5-epihydroxyl precursors (prepared by the Mitsunobu reaction) with DAST as the key step. 5,3'-Dideoxy-5,5-difluoro- (26) and 5,3',4'-trideoxy-5,5-difluoro-kanamycin B (27) were also prepared by treatment of the corresponding 5-oxo derivatives with DAST. These 5-deoxy-5-fluoro and 5-deoxy-5,5-difluoro derivatives showed markedly decreased toxicity as compared with the parent compounds.

Synthesis of 5-deoxy-5-epifluoro derivatives of arbekacin, amikacin, and 1-N-[(S)-4-amino-2-hydroxybutanoyl]tobramycin (study on structure--toxicity relationships).

As part of a study on fluorination--toxicity relationships for aminoglycoside antibiotics, 5,3'-dideoxy-5-epifluorokanamycin B (10), 5,3',4'-trideoxy-5-epifluorokanamycin B (11), 1-N-[(S)-4-amino-2-hydroxybutanoyl]-5-deoxy-5-epifluorotobramyc in (19), 5-deoxy-5-epifluoroarbekacin (20), and 5-deoxy-5-epifluoroamikacin (21) have been prepared. The acute toxicities of these three 5-deoxy-5-epifluoro compounds showed values almost identical or similar to those for arbekacin (ABK) and amikacin (15), making a sharp contrast with the toxicities of the corresponding 5-deoxy-5-fluoro derivatives. This fact is explained on the basis of basicity changes (retention for the 5-epifluoro derivatives and reduction for the 5-fluoro derivatives) at the H2N-3 groups of the fluorinated compounds compared to the parent compounds; this hypothesis was substantiated by the pKa values at the H3N(+)-1, 3 groups (determined by the shift changes depending on pD values at C-2 and C-4, 6 in their 13C NMR spectra) of 2,5-dideoxy-5-epifluorostreptamine (23) and 2,5-dideoxy-5-fluorostreptamine (24), chosen as model compounds, and 2-deoxystreptamine (DST).

Suppression of EJ cells tumorigenicity.

Ribozymes, site-specific ribonucleases, are a new vehicle for the manipulation of gene expression. A hammerhead ribozyme designed to cleave the GUC sequence in codon 12 of activated H-ras RNA was cloned into a plasmid (pH beta Apr-1) and transfected into EJ human bladder carcinoma cells. Expression of the ribozyme dramatically reduced H-ras gene expression and inhibited growth of EJ transformants in vitro. In vivo, the H-ras ribozyme suppressed EJ cell tumorigenicity in nude mice. In contrast, the insertion of a mutant ribozyme with no demonstrable cleavage capacity into EJ cells resulted in smaller reductions in H-ras gene expression and growth inhibition while also suppressing tumorigenicity in nude mice. The ribozyme's effect on tumorigenicity was stable, as the cells were cultured for up to five months in vitro prior to injection into nude mice. These studies define a role for anti-oncogenic ribozymes as a unique class of tumor suppressing agents.

Cystic duplication of the cecum lined by dermal type squamous epithelium.

This is a case report of a cystic duplication of the cecum in a 6-month-old female infant, which was lined by both columnar and squamous epithelium. This squamous epithelium did not resemble esophageal epithelium but dermal epithelium. The so-called split notochord theory can explain the possibility of the coexistence of ectoderm and entoderm components. However, the present case had no vertebral abnormalities.

A case of well-differentiated, fetal-type hepatoblastoma with very low serum alpha-fetoprotein.

Serum alpha-fetoprotein (AFP) is elevated in 96.6% of infants and children with hepatoblastoma and hepatocarcinoma. Serum AFP was of normal level in only one case of immature-type hepatoblastoma, and very low in only one case of fetal-type hepatoblastoma among 43 cases reviewed in 1986. Recently, a case of hepatoblastoma with very low serum AFP was encountered in the authors' surgical department. In October 1998, a 55-month-old girl was admitted. Her birth weight was 717 g. A large space-occupying lesion (SOL) located in the left lobe of the liver was seen by magnetic resonance imaging (MRI), and her serum AFP level was 322 ng/mL with a subfractionation pattern of the "benign liver disease" type based on reactivity with lens culnaris hemagglutinin and concanavalin A. The patient underwent successful left lobectomy, and histological examination showed that the tumor, weighing 268 g, was hepatoblastoma of the well-differentiated, fetal type. Immunohistochemistry findings for AFP were negative. A hepatic mass in infants and children with low serum AFP level indicates the presence of either well-differentiated or immature hepatoblastoma, or fibrolamellar hepatocellular carcinoma. Subfractionation of AFP may contribute to the differential diagnosis of these subtypes.

[Incidental renal cell carcinoma].

We reviewed the cases of incidental renal cell carcinoma that had been treated at the Kitasato University Hospital between July, 1971 and December, 1989. Forty one of the 170 (24.1%) cases were found without any direct signs of renal cell carcinoma. The patients were between 30 and 78 years old (mean 55.0 years) and consisted of 29 males and 12 females. Fifteen cases were detected at the general health check-up and the remaining 26 during the postoperative follow-up for other malignant tumors or other diseases. Twenty three cases were identified by ultrasonography followed by computed tomography (CT) and excretory pyelography in 4 cases each. Especially, the number of patients incidentally found by ultrasonography had increased in the recent 8 years. Urinalysis did not show any microhematuria in 31 of the 37 cases (83.7%), and no tumor mass could be detected by excretory pyelography in 3 cases. We believe that ultrasonography may be valuable as a screening modality for early detection of renal cell carcinoma and should be used as a screening method at the routine health check-up.

[Primary carcinoid tumor of the testis with metastasis to the upper vertebrae. Report of a case].

A case of primary carcinoid tumor of the right testis with metastases to the cervical and thoracic vertebrae and epidural is reported. A 53-year-old man was first recognized as being with dysthesia of the left arm and shoulder in April 1986. In June, 1987, he was admitted to the Neurology service, complaining of sudden occurrence of abasia. Myelography and computerized tomography demonstrated an epidural mass and several high density areas in the vertebral bodies of Th1 and Th2. The patient underwent laminectomy from C7 to Th2. At operation, the neurosurgeons noticed a tumor mass in the right scrotum and requested our consultation. Thus right high orchiectomy was performed. Pathological examination including Grimerius' and Fontana-Masson's stain revealed carcinoid tumor of the right testis associated with metastases to the spinal column. Postoperatively, tumor maker studies revealed elevation of blood 5-hydroxytryptophan and marked increase of urinary 5-hydroxy-indoleacetic acid excretion. They showed remarkable decreases after a course of PVB chemotherapy. The patient has been under our observation as an out-patient for the past 27 months with metastases. This is the first case of primary carcinoid tumor of the testis with metastases so far reported in the domestic literature.

[Linear polarized light irradiation around the stellate ganglion area increases skin temperature and blood flow].

We evaluated the effect of linear polarized light irradiation with a SUPER LIZER around the stellate ganglion area on skin temperature and blood flow in healthy adult volunteers. We carried out two experiments (study I and study II). In study I, we investigated one-sided irradiation around the stellate ganglion area or posterior neck on the skin temperature of the bilateral nasus externi and earlobes. In study II, we investigated one-sided irradiation around the stellate ganglion area or posterior neck on the skin temperatures of both hands and skin blood flow on the irradiated side. In study I, irradiation around the stellate ganglion area increased skin temperature on the irradiated sides of the nasus externi (wings of the nose), and in study II, skin temperature and blood flow were increased on the irradiated side of the hands. These results suggest that linear polarized light irradiation with a SUPER LIZER around the stellate ganglion area would be useful and beneficial in clinical therapy.

[A case of atopic dermatitis treated with stellate ganglion block--the change of serum IgE and blood eosinophil levels].

Stellate ganglion block (SGB) therapy was tried on a patient with severe adult type atopic dermatitis. SGB was performed 102 times in total and clinical symptoms improved gradually. Serum IgE and blood eosinophil levels, which correlate with disease severity, increased gradually following repeated SGB. After a series of SGB was stopped, clinical symptoms became worse and serum IgE and blood eosinophil levels increased again. We conclude that although SGB is presumably one of the effective therapies for severe adult type atopic dermatitis, it might be difficult to improve atopic constitution entirely because the patient was not cured completely following repeated SGB.

[Changes in dementia rating scale scores of elderly patients with femoral neck fracture during perioperative period].

We evaluated changes in dementia rating scale scores in the revised version of Hasegawa's dementia scale (HDS-R), and rated dementia, 2 days before and 7 days after surgery in the elderly patients with femoral neck fracture. The 50 patients examined ranged in age from 70 years to 101 years. A perfect score in the HDS-R is 30 points, and a score below 20 points strongly suggests dementia. The results were as follows. In septuagenarian and octogenarian patients, the scale score was higher after surgery than the value before the surgery. Although the preoperative and postoperative scores of the patients who had been under epidural anesthesia were not significantly different, the score of patients who had been under general anesthesia was higher in the postoperative period than in the preoperative period. In octogenarian patients, there was a negative correlation between "postoperative score minus preoperative score" and "the number of the days from suffering fracture to surgery". These results showed that general anesthesia is more advantageous than epidural anesthesia from the viewpoint of the intellectual faculty in septuagenarian and octogenarian patients with femoral neck fracture, and it is within the bounds of possibility that the intellectual faculty may decline if an octogenarian patient is operated after a long delay from the occurrence of fracture. To prevent this decline, patients must be operated on as soon as possible.

[Changes in hearing features according to days from onset of sudden deafness].

We analyzed 746 patients with idiopathic sudden hearing loss who visited our clinic within 16 days after the onset. Patients were divided into 10 groups according to the number of days between the initial visit and the onset. Initial hearing levels, audiometric types and hearing recoveries were investigated in these groups to estimate the natural history of sudden deafness. The results were as follows: 1) There were no significant differences among the 10 groups regarding the averaged five-frequency hearing levels of initial audiograms. 2) Regarding the audiometric types of the initial audiograms, flat and upward slope types were frequently seen in the groups who visited us within 6 days. In contrast, the population of down slope types gradually increased in the groups presenting after 7 days. In the ultimate audiograms, flat and down slope types were frequently seen in all groups. 3) There were significant differences among the 10 groups regarding the averaged five-frequency improvement (one-way analysis of variance, p < 0.01). After 9 days, hearing recovery became less likely.

[Cholesteatoma in children--sex differences].

It has been reported that cholesteatoma is more aggressive in children than in adults and that it affects boys more often than girls. We found particularly prominent sex differences in the clinical characteristics and behavior of cholesteatoma in children, by comparing them with those of acute otitis media (AOM), otitis media with effusion (OME) and adult cholesteatoma. We retrospectively analyzed the clinical records of children diagnosed as having cholesteatoma by comparing their courses with those of AOM, OME, chronic otitis media, microtia and congenital malformation of the ossicles. The boy-dominant tendency were observed in OMA, OME, pediatric cholesteatoma, microtia and congenital malformation of the ossicles. Cholesteatoma has a tendency to fill the middle ear cleft in boys, in whom the most extensive cholesteatomas were observed. If OMA, OME, and cholesteatoma in children are considered to be a series of inflammatory middle ear diseases, a common factor must be involved in the boy-dominant tendency for this series of inflammatory middle ear diseases. We have proposed six factors contributing to sex differences in pediatric cholesteatoma. Among these, immunological, environmental and congenital factors were thought to be responsible for the sex differences.

[Idiopathic bilateral sensorineural hearing loss: clinical study of cases with rapidly progressed deafness].

In a series of 127 patients with idiopathic bilateral sensorineural hearing loss (IBSH) at the Hearing Clinic in the Department of Otolaryngology, Kitasato University Hospital, 20 cases showed rapid progression of hearing impairment. These patients had been treated with the same therapeutic regimen used in sudden deafness (S.D.). Improvement of hearing loss after treatment was generally less effective in the cases with rapidly progressed IBSH than in the cases with S.D. However, hearing improvement was achieved in some cases with rapidly progressed IBSH when the treatment had started in the early stages after the onset of rapidly progressive hearing loss. The mode of fluctuating hearing loss in the cases with rapidly progressed deafness was assumed to be similar to that in the group of all cases with IBSH.

[The effect of aging on observation in hearing in the same individuals over a 5 year period].

The purpose of this study was to investigate the process of changes in hearing of pure tones with aging. Among individuals who had undergone thorough medical examination for the purpose of annual health-checks, 293 males (586 ears) whose hearing level had been examined for five years or more were enrolled in this study. Cases having conductive deafness or known sensori-neural deafness were excluded. Since the most typical change with aging is observed at 8 kHz, the investigation was carried out only on hearing at 8 kHz. Hearing level increasingly declined with advancing age. Hearing distribution for young subjects showed a peak in the normal hearing level range. This peak decreased with aging, and another peak appeared at 50 dB. Investigation of differences in hearing in the individuals over the five years showed that most subjects had a hearing level difference of 0 dB up to 54 years of age. From 55 years old onward, however, the difference was 5 dB. This indicates that gradual deterioration of hearing level with aging occurs most frequently. On the other hand, in some subjects, deafness progressed faster. Thirty-four and a half percent of the subjects had deteriorations of 20 dB or more in a single year during the entire observation period. A deterioration of 20 dB or more was noted in 4% of the young and 8% of the elderly. Such rapid progression of deafness was believed to be involved in formation of the 50 dB peak in the hearing distribution.