End of an era or not? That is the question--in response to Dr. J. M. Brown, IJROBP 32:883-885; 1995.
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Clinical Trials, Phase III as Topic↗
Biomedical subjects
D J Lee
Publications and source records attributed to D J Lee.
Results of an RTOG phase III trial (RTOG 85-27) comparing radiotherapy plus etanidazole with radiotherapy alone for locally advanced head and neck carcinomas.
PURPOSE: The objectives of this study were to determine the efficacy and toxicity of Etanidazole (ETA), a hypoxic cell sensitizer, when combined with conventional radiotherapy (RT) in the management of advanced head and neck carcinomas. METHODS AND MATERIALS: From March 1988 to September 1991, 521 patients who had Stage III or IV head and neck carcinomas were randomized to receive conventional RT alone (66 Gy in 33 fractions to 74 Gy in 37 fractions, 5 fractions per week) or RT+ETA (2.0 g/m2 thrice weekly for 17 doses), of whom 504 were eligible and analyzable. Treatment assignments were stratified before randomization according to the primary site (oral cavity + hypopharynx vs. supraglottic larynx + oropharynx + nasopharynx), T-stage (T1-3 vs. T4), and N-stage (N0-2 vs. N3). Pretreatment characteristics were balanced. In the RT-alone arm, 39% of patients had T3 and 34% had T4 disease, whereas in the RT+ETA arm, 42% of patients had T3 and 33% had T4 disease. Thirty-eight percent of the RT-alone patients and 37% of the RT+ETA patients had N3 disease. The median follow-up of surviving patients was 3.38 years, with a range between 0.96 and 5.63 years. RESULTS: One hundred and ninety-four of the 252 (77%) RT+ETA patients received at least 14 doses of the drug. Overall RT protocol compliance rate was 82% in the RT-alone arm and 86% in the RT+ETA arm. No Grade 3 or 4 central nervous system or peripheral neuropathy was observed in the RT+ETA arm. Eighteen percent of the patients developed Grade 1 and 5% developed Grade 2 peripheral neuropathy. Other drug related toxicities included nausea/vomiting (27%), low blood counts (15%), and allergy (9%). Most of these toxicities were Grade 1 and 2. The incidence of severe acute and late radiation effects were similar between the two arms. The 2-year actuarial local-regional control rate (LCR) was 40% for the RT-alone arm and 40% for the RT+ETA arm. Two-year actuarial survival was 41% for the RT-alone arm and 43% for the RT+ETA arm (p = 0.65). Multivariate analyses were performed to investigate the influence of covariates on treatment effects. A strong treatment interaction with N-stage was revealed: LCR (50% vs. 40% at 2 years), RT+ETA improved for patients with N0-2 disease but not for N3 patients (22% for RT+ETA and 40% for RT). Further analyses showed that RT+ETA was more advantageous in N0-1 patients, with a 2-year LCR of 55% for RT+ETA vs. 37% for RT only (p = 0.03). A similar phenomenon was observed when using survival as the end point. CONCLUSION: The results showed that adding Etanidazole to conventional RT produced no global benefit for patients who had advanced head and neck carcinomas. There was a suggested benefit for patients who had N0-1 disease, and that needs to be confirmed by another study.
Carcinoma, Squamous Cell↗
Chemoradiotherapy for organ preservation in oral and pharyngeal carcinoma.
OBJECTIVES: To use concurrent chemoradiotherapy as primary treatment for resectable head and neck squamous cell carcinoma to (1) demonstrate the feasibility of an organ preservation approach for nonlaryngeal sites; (2) evaluate the toxic reactions and response to a new combination of two platinum compounds; and (3) monitor the effect of therapy on oral and pharyngeal function. DESIGN: Case series, a prospective single-armed trial. SETTING: Tertiary referral center. PATIENTS: Twenty-two patients with head and neck squamous cell carcinoma of the oral cavity, oropharynx, and hypopharynx for whom surgery would significantly compromise function were entered in this trial. INTERVENTION: Standard fractionation external-beam radiation therapy (2 Gy/Fx; total, 70 Gy) was given during a 9-week period, including a 2-week break after 40 Gy, concurrently with eight weekly doses of carboplatin and three doses of cisplatin (100 mg/m2) at 3-week intervals. A biopsy was performed 12 weeks after the completion of chemoradiotherapy to assess clinical response. All patients presenting with nodes greater than 3 cm had planned neck dissection. MAIN OUTCOME MEASURES: Tumor response, toxic reactions, survival, and oral and pharyngeal function. RESULTS: Overall complete response was 86%. Estimated overall 2-year survival was 64%, and disease-specific survival was 71% (median follow-up time, 25 months). Five patients have died of disease and two of unrelated causes. Treatment was completed by all, with toxic reactions including myelosuppression, mucositis, and dysphagia. Half of the patients required gastrostomy. CONCLUSIONS: Concurrent chemoradiotherapy using two platinum analogues was tolerated with good local control and survival. Notable dysphagia was common. This study provides pilot data for randomized clinical trials to confirm the usefulness of chemoradiotherapy for nonlaryngeal organ preservation.
Adult↗
Slow release from a coated sphere with a slightly deformed coating.
Effects of a slight deformation of the coating film on the concentration distribution and the slow release characteristics of a coated drug particle is theoretically investigated in this work. A perturbation technique is employed for transformation of the deformed spherical problem into a series of concentric spherical problems with the degree of deformation considered as the perturbation parameter. In addition, the governing equations are solved analytically by further restricting the deformation shape function. Results in this study indicate that if the deformation is slight or only the average release rate is of interest, the effects of coating shape deformation are secondary. However, if the deformation is not so small and if the drug diffusivity in the film is low, the shape deformation could have a significant effect on the concentration profiles and/or the release rate from different parts of the particle surface.
Chemistry, Pharmaceutical↗
Psychosocial correlates of immune responsiveness and illness episodes in US Air Force Academy cadets undergoing basic cadet training.
This study examined psychosocial correlates of immune function and illness in 89 male first-year US Air Force Academy cadets. A psychosocial questionnaire was administered to cadets prior to their arrival at the academy and was readministered during cadet orientation and during the stressful environment of Basic Cadet Training (BCT). Immune responsiveness was analyzed by PHA-, PMA-, or anti-CD3-stimulated thymidine uptake in mononuclear leucocytes. Illness episodes were assessed via medical chart review and self-reported symptoms. There were significant increases in distress levels as cadets entered BCT. No psychosocial measure assessed prior to arrival at the academy predicted level of PHA-, PMA-, and anti-CD3-stimulated thymidine uptake or risk of illness. However, hostility levels reported during BCT predicted risk of illness in the four weeks following psychosocial assessment (odds ratio = 7.1; 95% confidence interval: 1.4-36.1). Elevated response to environmental stressors and lower well-being levels also predicted impending illness, but only in the cohort of cadets who had not contracted food poisoning prior to assessment during BCT (OR = 9.3, CI = 1.9-46.7; OR = 0.09, CI = 0.02-0.53). These results suggest that self-report measures of hostility, response to environmental stressors and well-being may be useful predictors of impending illness episodes in males encountering high stress environments.
Adaptation, Psychological↗
5' CpG island methylation is associated with transcriptional silencing of the tumour suppressor p16/CDKN2/MTS1 in human cancers.
Loss of heterozygosity on chromosome 9p21 is one of the most frequent genetic alterations identified in human cancer. The rate of point mutations of p16, a candidate suppressor gene of this area, is low in most primary tumours with allelic loss of 9p21. Monosomic cell lines with structurally unaltered p16 show methylation of the 5' CpG island of p16. This distinct methylation pattern was associated with a complete transcriptional block that was reversible upon treatment with 5-deoxyazacytidine. Moreover, de novo methylation of the 5' CpG island of p16 was also found in approximately 20% of different primary neoplasms, but not in normal tissues, potentially representing a common pathway of tumour suppressor gene inactivation in human cancers.
5-Methylcytosine↗
Detection of human cytomegalovirus mutations associated with ganciclovir resistance in cerebrospinal fluid of AIDS patients with central nervous system disease.
To examine the involvement of ganciclovir-resistant strains in the development of central nervous system (CNS) disease caused by human cytomegalovirus (HCMV), 14 AIDS patients with CNS disease caused by HCMV were studied for the presence of HCMV strains with UL97 gene mutations associated with ganciclovir resistance by using amplification and direct sequencing of HCMV DNA in cerebrospinal fluid (CSF). The CSF of all seven patients who had not received ganciclovir prior to the development of CNS disease and four patients who had been receiving the drug for 3 to 8 months contained wild-type UL97 sequences. The CSF of three patients who had received ganciclovir for 12 to 30 months contained HCMV strains with nucleotide changes leading to single-amino-acid substitutions within conserved UL97 sites implicated in nucleotide binding (position 460) and substrate recognition (position 591). Patients containing mutant and wild-type strains revealed a similar spectrum of clinical and histopathologic manifestations. These findings indicate that CNS disease in AIDS patients receiving prolonged ganciclovir therapy can be caused by ganciclovir-resistant HCMV strains. Direct genotypic analysis of HCMV DNA within CSF should help to identify ganciclovir-resistant virus and to guide anti-HCMV therapy.
AIDS-Related Opportunistic Infections↗
Detection of rye chromosome 2R using the polymerase chain reaction and sequence-specific DNA primers.
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Base Sequence↗
Mutations in human cytomegalovirus UL97 gene confer clinical resistance to ganciclovir and can be detected directly in patient plasma.
Specific mutations in the UL97 region of human cytomegalovirus (HCMV) have been found to confer resistance to laboratory-adapted strains subjected to ganciclovir selection. In this study, mutations in the UL97 region of HCMV isolates obtained from patients receiving ganciclovir therapy were examined to determine whether they would confer ganciclovir resistance, and if these mutations could be detected directly in the plasma of AIDS patients with progressive HCMV disease despite ganciclovir treatment. A single nucleotide change within a conserved region of UL97 was found in five resistant isolates, resulting in an amino acid substitution in residue 595: from leucine to phenylalanine in one, and from leucine to serine in four resistant isolates. A sixth resistant isolate demonstrated a single nucleotide change, leading to a threonine to isoleucine substitution in residue 659. The role of the 595 amino acid substitution in conferring ganciclovir resistance was confirmed by marker transfer experiments. In further studies, direct sequencing of HCMV DNA present in plasma obtained from persons with resistant viruses revealed the identical amino acid substitutions in plasma as those present in the cultured viruses. These findings indicate that clinical resistance to ganciclovir can result from specific point mutations in the UL97 gene, and that the emergence of the resistant genotype can be detected directly in patient plasma.
Acquired Immunodeficiency Syndrome↗
Microsatellite alterations as clonal markers for the detection of human cancer.
Microsatellite instability has been reported to be an important feature of tumors from hereditary nonpolyposis colorectal carcinoma (HNPCC) patients. The recent discovery of genetic instability in small cell lung carcinoma, a neoplasm not associated with HNPCC, led us to investigate the possible presence of microsatellite alterations in other tumor types. We examined 52 microsatellite repeat sequences in the DNA of normal and tumor pairs from 100 head and neck, bladder, and lung cancer patients by the polymerase chain reaction. Although alterations were rare in dinucleotide repeats, larger (tri- or tetranucleotide) repeats were found to be more prone to expansion or deletion. We screened 100 tumors with a panel of nine tri- and tetranucleotide repeat markers and identified 26 (26%) that displayed alterations in at least one locus. This observation prompted us to examine the possibility of using microsatellite alterations as markers to detect clonal tumor-derived cell populations in pathologic samples. The identical microsatellite alterations detected in the primary tumors were successfully identified in corresponding urine, sputum, and surgical margins from affected patients. This study demonstrates that appropriately selected microsatellite loci are commonly altered in many cancers and can serve as clonal markers for their detection.
Base Sequence↗
Salvage of a kidney graft in a patient with advanced carcinoma of the cervix by reimplantation of the graft from the pelvis to the upper abdomen in preparation for radiation therapy.
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Abdomen↗
Rates of p16 (MTS1) mutations in primary tumors with 9p loss.
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Carrier Proteins↗
Detection of rye chromosome 2R using the polymerase chain reaction and sequence-specific DNA primers.
Sequences derived from a rye gamma secalin gene were used as primers in polymerase chain reactions using DNA obtained from a series of wheat and triticale genetic stocks. A 473-bp fragment, the predicted size based on the distance between the selected primers, was found only in rye, triticales, and wheat lines carrying rye chromosome 2RS. Use of triticale lines with various wheat chromosome substitutions confirmed the chromosomal origin of the rye-specific marker. The presence of the 473-bp PCR product was always associated with the production of 75K secalins in grain samples. Thus, the primer sequences, and the clone of origin (pSC503), were both derived from the SEC-2 locus of rye chromosome 2RS.
Base Sequence↗
Reduced growth hormone response to L-dopa and pyridostigmine in obesity.
The purpose of this study was to evaluate growth hormone (GH) secretion and clarify the factors influencing GH secretion in obesity. Nine obese subjects and eight controls were recruited. We compared the GH response to L-dopa with or without pyridostigmine pretreatment in obese and control subjects. Plasma glucose, insulin, insulin-like growth factor I (IGF-I) and free fatty acid (FFA) were also measured. Growth hormone responses and GH area under the response curve (AUC) to L-dopa were significantly lower in obese subjects than those in controls. Pyridostigmine significantly enhanced the GH response to L-dopa in both obese and control subjects. However, enhanced GH responses in obese subjects were attenuated biologically and lower than those in controls with L-dopa only. Plasma levels of insulin insulin and FFA were significantly higher in obese subjects than those in controls. Body mass index had a positive correlation with the levels of insulin and FFA. However, GH AUC had an inverse correlation with insulin and FFA in obese subjects and controls. Stepwise multiple regression analysis showed a highly significant effect of FFA on GH AUC, but no independent influence of other factors on GH AUC. The reduced GH secretion found in this study suggests an increase in somatostatinergic tone and a diminished release of GHRH from the hypothalamus in obesity. However, other factors including hyperinsulinemia and increased plasma FFA may play an important additional role in the secretory dysfunction of GH in obesity.
Adult↗
Musculoskeletal manifestations of human immunodeficiency virus infection: review of imaging characteristics.
As the AIDS epidemic progresses, more and more cases of musculoskeletal involvement have been seen and reported. Although HIV infection does not typically involve the musculoskeletal system, a number of abnormalities have been detected. The radiographic manifestations of AIDS in the musculoskeletal system are discussed in this article.
Acquired Immunodeficiency Syndrome↗
Pregnancy-induced hypertension and early neonatal death: a case-control study.
Literature on the association between pregnancy-induced hypertension and early neonatal death is limited. The present case-control study consisted of 342 early neonatal deaths and 523 frequency-matched controls. After controlling for other factors such as infant sex, gravidity, maternal age, threatened abortion, and maternal anemia, moderate to severe pregnancy-induced hypertension was associated with an increased risk of early neonatal death with apparent dose-effect gradients (odds ratio = 1.8 for moderate and 2.2 for severe). The biologic plausibility of pregnancy-induced hypertension as a cause of neonatal mortality is discussed.
Abortion, Threatened↗
Physicians' ratings of health in middle and old age: a cautionary note.
Physicians' global assessments traditionally have been considered to be relatively objective estimates of older people's health against which self-ratings of health and other self-reported measures are compared. Using data on middle-aged and older Mexican Americans from the Hispanic Health and Nutrition Examination Survey, it is suggested that the subjective component of physicians' assessments can create problems with validity, especially when a small number of physicians perform the assessments, as was the case in this study. It is recommended that researchers should not always assume that physicians' assessments represent an objective "gold standard" for validating self-reported measures of health.
Acculturation↗
Clinical experience with an endobronchial implant.
PURPOSE: To report clinical experience with an implantable capsule for treating endobronchial carcinoma by means of bronchoscopic insertion and retrieval. MATERIALS AND METHODS: The capsule consists of a plastic cylinder containing high-activity iodine-125 seeds and four restraining legs. Twelve patients with recurrent (n = 11) or inoperable carcinoma (n = 1) received a median dose of 4,500 (range, 2,633-6,299) cGy at a 1-cm radius from the center of the implant. RESULTS: No acute toxicities were observed. Five patients had complete regression of the endobronchial tumor, evidenced at bronchoscopy 2 months after therapy, and four patients had partial regression. Three patients failed to return for bronchoscopy. Symptomatic relief was achieved in eight of 10 patients with dyspnea, four of nine with cough, and two of three with hemoptysis. The median survival of the 12 patients was 6 months. The actuarial 1-year survival rate was 25%. CONCLUSION: This capsule is safe and efficacious in treating recurrent or inoperable carcinoma of the lung.
Aged↗