Hearing loss in children and young adults receiving cisplatin with or without prior cranial irradiation.

One hundred seventy-seven children and young adults with various malignant neoplasms were prospectively tested for hearing loss after they had received cisplatin (n = 146), cranial irradiation (n = 18), or both (n = 13). Adequate renal function, no history of treatment with ototoxic drugs other than cisplatin, and availability for repeated audiometric testing were requirements for enrollment. Substantial hearing loss, defined as a hearing threshold of 50 dB or greater, was noted in only 11% of the cohort on tests conducted at the common speech frequencies (500 to 3,000 Hz).

Ribosomal proteins of Tetrahymena thermophila. Correlation of one- and two-dimensional electrophoretic migration patterns and characterization of additional small and large subunit proteins.

Further analysis of the protein complement of the cytoplasmic ribosome of the protozoon Tetrahymena thermophila has led to the identification and characterization of seven additional proteins, three in the small and four in the large subunit of this ribosome. Several of these proteins are poorly soluble or insoluble in the absence of high concentrations of urea and are not seen in the electrophoretic distribution patterns of ribosomal proteins in two-dimensional polyacrylamide gels unless 6 M urea is added to electrode buffers in contact with protein samples (first dimension) and first-dimension gels (second dimension). The migration patterns of the 40S and 60S subunits of the T.

Protein-RNA crosslinking in the subunits of the cytoplasmic ribosome of Tetrahymena thermophila.

Use of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide to introduce RNA-protein crosslinks in the 40S and 60S subunits of the cytoplasmic ribosome of Tetrahymena thermophila is described, and proteins linked covalently to 17S and 26S ribosomal RNAs are identified. RNA-protein crosslinking is accompanied by extensive dimerization and aggregation of ribosomal subunits probably due to formation of interparticle protein-protein crosslinks.

Clinical manifestations of ganglioneuroma.

Ganglioneuroma may occur spontaneously or after therapy for neuroblastoma. This lesion may be metastatic or unresectable in the primary site. The rarity of this situation and lack of understanding of the biology of this benign condition may lead to extensive, potentially life-threatening attempts at surgical resection or the futile use of chemotherapy or radiotherapy to try to cause regression or control growth.

Therapy for localized Ewing's sarcoma of bone.

Fifty-two previously untreated patients with localized Ewing's sarcoma of bone were treated with nonintensive chemotherapy in combination with surgery or radiation therapy (RT). RT was delivered to limited volumes in a dose dependent on the initial response to induction chemotherapy (30 to 35 Gy v 50 to 55 Gy). Fifty of the 52 patients achieved complete or partial responses with induction chemotherapy, with one nonresponding patient rendered free of tumor with surgery.

Clinical studies of ifosfamide/mesna at St Jude Children's Research Hospital, 1983-1988.

A phase-II study of ifosfamide with mesna, given intravenously daily for five days by bolus injection, has demonstrated the activity of ifosfamide against a spectrum of childhood malignant solid tumors. Ifosfamide presently is being investigated in alternative phase-I schedules, daily times three or every other day times three with the aim of delivering comparable amounts of ifosfamide without increasing toxicity--specifically, neurotoxicity. Additionally, response following ifosfamide treatment is being evaluated for previously untreated children with osteosarcoma and rhabdomyosarcoma after 6 weeks of treatment, and for previously untreated patients with Ewing's sarcoma after 9 weeks of treatment with ifosfamide/VP-16 (etoposide) given in combination.

Chemotherapeutic management of epidural neuroblastoma.

Nine children with neuroblastoma and spinal cord compression were managed initially with chemotherapy induction without laminectomy or radiotherapy. Of the nine children seven are neurologically normal, one has minimal residual deficits, and one remains paraplegic. The excellent results in these children, plus nine patients previously reported, emphasizes the validity of this approach in children with epidural extension of neuroblastoma.

Ifosfamide in pediatric malignant solid tumors.

Ifosfamide/mesna was given to 97 patients who had malignant solid tumors diagnosed before they were 21 years of age. Patients received 1.6 g/m2 ifosfamide daily x 5, given i.

Localized neuroblastoma treated by surgery: a Pediatric Oncology Group Study.

A prospective study was designed to evaluate the outcome of patients with localized resectable neuroblastoma without regional lymph node involvement when no therapy beyond surgical resection was administered. One hundred one patients observed for 3 to 60 months had a 2-year disease-free survival of 89% (SE = 5%). Of the nine patients experiencing relapse, only three have died.

Chest wall resection for Ewing's sarcoma of the rib: an unnecessary procedure.

Approximately 10% of all cases of Ewing's sarcoma arise from a rib. Conventional management has included chest wall resection (3 or more ribs) and radiation therapy. These forms of therapy have led to complications such as scoliosis and local deformity.

Clinical trial of etoposide (VP-16) in children with recurrent malignant solid tumors. A phase II study from the Pediatric Oncology Group.

Etoposide (VP-16), 150 mg/M2, given intravenously daily for 3 days every 3 weeks resulted in 3 complete responses and 6 partial responses in 154 patients with a spectrum of recurrent malignant solid tumors. There was evidence of disease control in an additional 37 patients (27 mixed responses and 10 stable disease). These responses occurred primarily in patients with Ewing's sarcoma, Hodgkin's disease, neuroblastoma and rhabdomyosarcoma.

18th Sir Hans Krebs lecture. Knowledge-based protein modelling and design.

A systematic technique for protein modelling that is applicable to the design of drugs, peptide vaccines and novel proteins is described. Our approach is knowledge-based, depending on the structures of homologous or analogous proteins and more generally on a relational data base of protein three-dimensional structures. The procedure simultaneously aligns the known tertiary structures, selects fragments from the structurally conserved regions on the basis of sequence homology, aligns these with the 'average structure' or 'framework', builds on the loops selected from homologous proteins or a wider database, substitutes sidechains and energy minimises the resultant model.

Brain tumors in the very young child. Postoperative chemotherapy in combined-modality treatment.

Twelve consecutively diagnosed children with brain tumors, ages 7 to 27 months, were treated by a combined-modality approach featuring aggressive surgical resection followed by chemotherapy and delayed irradiation. Patients received multiple clinical neurologic examinations and psychological evaluations, as well as diagnostic imaging studies, to monitor the efficacy of chemotherapy and toxic effects of therapy. Six of the eight children with residual tumor evident postoperatively on computed tomography scans had objective responses to chemotherapy.

Prediction of electrostatic effects of engineering of protein charges.

Accurate prediction of electrostatic effects on catalytic activity is an essential component of protein design. Site-directed mutagenesis of charged groups in subtilisin of Bacillus amyloliquefaciens has provided experimental measurements of electrostatic interactions which may be used to test such theoretical methods. The pKa of the histidine of the active site has been perturbed by +0.

Knowledge based modelling of homologous proteins, Part II: Rules for the conformations of substituted sidechains.

This paper describes a rapid, automated procedure which can be used for model building sidechains using (i) spatial information from sidechains in topologically equivalent positions as far as such a correlation is observed, and then (ii) most probable conformations of the sidechains in the respective secondary structure type. Analysis of topologically equivalent residues in the structurally conserved regions of a family of proteins implies that the spatial positions of the atoms in the sidechains rather than conformations should be considered when model building. Rules for the modelling of all 20 side-chains from each other in alpha-helical, beta-sheet and loop regions--a total of 1200--are established.

5S RNA-protein complexes released by EDTA treatment of 60S ribosomal subunits of Tetrahymena thermophila.

Treatment of large (60S) subunit of the cytoplasmic ribosome of the protozoa Tetrahymena thermophila with EDTA causes quantitative release of 5S rRNA associated with variable non quantitative amounts of one or more of 60S proteins L4, L15, L24, L31 and L41. The composition of the group of proteins released with 5S rRNA depends on both the molar ratio of EDTA and 60S subunits and the concentration of 60S subunits, in treatment mixtures.

Consistent N-myc copy number in simultaneous or consecutive neuroblastoma samples from sixty individual patients.

Amplification of the N-myc oncogene is detected in about 30% of untreated neuroblastomas. Amplification is associated with advanced stages of disease and rapid tumor progression. However, it was not known if the N-myc copy number was homogeneous in tumor tissue of an individual patient, or if it changed with time in vivo.

Metastatic Ewing's sarcoma: remission induction and survival.

Eighteen patients with previously untreated metastatic Ewing's sarcoma (ES) entered a protocol designed to evaluate the response rate to cyclophosphamide and doxorubicin induction therapy delivered before delayed surgery and delayed lower dose, limited-field radiation therapy, (RT), and maintenance chemotherapy. With chemotherapy and delayed surgery, 14 of 18 were rendered free of gross tumor. RT was delivered to the primary site of 11 of these responding patients, plus four of those not free of gross disease.

Clinical pharmacodynamics of continuous infusion teniposide: systemic exposure as a determinant of response in a phase I trial.

Teniposide (VM-26) is an effective anticancer drug usually administered as a short infusion in doses of 150 to 165 mg/m2. The objectives of the trial reported here were to evaluate clinical responses and assess pharmacokinetic parameters as a determinant of outcome when VM-26 was administered as a 72-hour continuous infusion (CI) with doses escalated from 300 to 750 mg/m2 per course. Twenty-eight patients with recurrent leukemia, lymphoma, or neuroblastoma received 53 courses of CI VM-26 and 16 had measurable responses.

Phase II trial of ifosfamide in children with malignant solid tumors.

Ifosfamide was given to 61 patients with malignant solid tumors diagnosed before the age of 21 years. In this phase II study, all patients received 1.6 g/m2/day X 5 iv over 15 minutes followed by mesna at a dose of 400 mg/m2 iv at 15 minutes and 4 and 6 hours after ifosfamide.

Long-term survival in patients with Ewing's sarcoma relapsing after completing therapy.

While the proportion of patients with Ewing's sarcoma attaining and maintaining long-term remission has markedly improved, a proportion of patients suffer relapse of the tumor. In our experience relapses may occur late in the course of the disease, approximately 20% of those at risk beyond 5 years having recurrence of tumor. Review of our data indicates that for patients relapsing after therapy has been discontinued, the probability of attaining second remission is high (0.

Development of a tissue culture model for gonococcal invasion.

Neisseria gonorrhoeae invasion of the human endometrial cell line HecIB was monitored by electron microscopy. Within six hours postinfection, the gonococci have attached to the surface of some HecIB cells and are embraced by microvilli. Gonococci subsequently enter the HecIB cells in membrane bound vesicles but by eight hours, gonococci can be seen free in the cytoplasm.