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Biomedical subjects

E Reed

Publications and source records attributed to E Reed.

At least 145 records · Page 8Linked to original sources
PubMed1994

Total body nitrogen in children with chronic renal failure and short stature.

OBJECTIVE: To directly assess the body protein content of children with chronic renal failure (CRF) and short stature. SETTING: A tertiary referral paediatric hospital. SUBJECTS: There were: (i) 17 patients (10 male, nine pre-pubertal; mean age 12.90 +/- 3.20 years) with CRF and height standard deviation (SD) score < -2.00, and (ii) 43 normal children (18 male, 27 pre-pubertal; mean age 10.34 +/- 3.34 years). INTERVENTIONS: CRF patients had the following measurements: anthropometry, total body nitrogen (TBN) by neutron capture analysis, 4 day weighed food record and serum albumin levels. Control subjects had TBN and anthropometric measurements only. RESULTS: Although older than the controls, the CRF patients had significantly lower TBN values (645 +/- 265 vs 930 +/- 365 g, P < 0.01). Mean values for TBN and TBN/height (percentages of expected) in the CRF patients were significantly reduced to 54% and 63% respectively, when predicted from age. However, their TBN predicted from height was 100% of expected. %TBN (predicted from age) correlated significantly with height SD score (r = 0.79), weight SD score (r = 0.87), upper arm muscle area percentile (r = 0.62) and serum albumin (r = 0.62). Mean oral energy and protein intakes were 65% and 172% of recommended dietary intake respectively. CONCLUSIONS: Children with CRF and short stature are significantly protein-depleted for age although not for height. Chronic energy deficiency may contribute to impaired protein deposition which, in turn, may be important in the pathogenesis of growth failure in CRF.

Adolescent↗
PubMed1994

Nutritional needs of trauma patients: challenges, barriers, and solutions.

Trauma patients require aggressive nutritional intervention to prevent the progressive and often rapid catabolic response associated with severe injury. This article presents an overview of the stress response as a foundation for further discussion regarding the challenges, barriers, and solutions associated with providing adequate nutritional support to the trauma patient. Current nutritional support strategies are presented for the practitioner to take to the bedside, in order to optimize the metabolic response to acute injury.

Critical Care↗
PubMed1993

Inhibition of DNA repair and sensitization of cisplatin in human ovarian carcinoma cells by interleukin-1 alpha.

Interleukin-1 alpha induced an increase in both the cellular accumulation of cis-diamminedichloroplatinum (II) (cisplatin) and DNA platination and significantly reduced the removal of platinum from DNA of human ovarian (NIH: OVCAR-3) carcinoma cells in culture. The combinations of IL-1 alpha and cisplatin were highly synergistic against these ovarian carcinoma cells and maximum levels of sensitization (15-20-fold) were observed during simultaneous exposure of cisplatin and IL-1 alpha. IL-1 alpha specific receptor antagonist decreased this synergy. These results strongly indicate that IL-1 alpha inhibits DNA repair, and this inhibition of DNA repair may explain, in part, a strong synergistic interaction between IL-1 alpha and cisplatin in NIH: OVCAR-3 cells.

Cell Line↗
PubMed1993

Platinum-DNA adduct in leukocyte DNA of a cohort of 49 patients with 24 different types of malignancies.

Using atomic absorbance spectrometry with Zeeman background correction, we measured platinum-DNA adduct levels in leukocyte DNA of 49 patients receiving therapy consisting of only carboplatin and cisplatin. Twenty-four histological types of malignancy were included in the cohort. Peripheral blood leukocytes were collected at defined times during the first two cycles of treatment. The relationship between adduct level and disease response was highly statistically significant during cycle 1 of therapy (two-sided P = 0.007 at day 2), but statistical significance was lost during cycle 2. On all days studied, median and mean adduct levels were consistently higher in responders as compared to nonresponders (summary two-sided P = 0.0004). These data suggest that the processes which protect cellular DNA may be common to malignant and nonmalignant rapidly dividing tissues of the same individual, regardless of the type of tumor that individual may harbor.

Carboplatin↗
PubMed1993

Contribution of direct and indirect recognition pathways to T cell alloreactivity.

T cells from an HLA-DR11/DR12 responder were stimulated in mixed lymphocyte culture with cells carrying the DR1 antigen. After priming, T cells proliferated in response to both DR1-positive-stimulating cells and a peptide derived from a polymorphic region of the HLA-DR beta 1*0101 chain presented by responder's antigen-presenting cells (APC). The dominant epitope recognized by the primed T cells corresponded to residue 21-42 and was presented by the responder's HLA-DR12 antigen. The DR1 peptide-reactive T cells express T cell receptor V beta 3. The results demonstrate that allopeptides derived from the processing and presentation of donor major histocompatibility complex molecules by host-derived APC trigger alloreactivity. The frequency of T cells engaged in the indirect pathway of allorecognition is about 100-fold lower than that of T cells participating in the direct recognition of native HLA-DR antigen. However, indirect allorecognition may play an important role in chronic allograft rejection, a phenomenon that is mediated by the activation of T helper cells and of alloantibody-producing B cells.

Alleles↗
PubMed1993

Older women as the focus for research and treatment of ovarian cancer. An overview for the National Institute on Aging, National Cancer Institute, and American Cancer Society Multidisciplinary Working Conference.

Ovarian cancer disproportionately affects women 65 years of age and older who are likely to have concomitant changes in physical ability, physiological functioning, and other chronic conditions associated with advancing age. The National Institute on Aging, National Cancer Institute, and the American Cancer Society cosponsored a multidisciplinary working conference, "Perspectives on Ovarian Cancer in Older-Aged Women: Current Knowledge and Recommendations for Research," at the National Institutes of Health on November 20-21, 1991 to confront the age-related aspects of ovarian cancer in epidemiology, etiology, clinical investigations, and patient management. Conference participants devoted attention to such special topics as drug resistance, dose intensity, patterns of care, and screening potential for ovarian cancer. After exploring these areas with existing data, the task was then to generate recommendations for research and practice. The scope of the conference and an introduction to the proceedings are presented in this paper.

Aged↗
PubMed1993

Age does not influence taxol dose intensity in recurrent carcinoma of the ovary.

BACKGROUND: In the treatment of advanced-stage ovarian cancer, it is common practice to treat elderly patients in a less aggressive fashion than young patients. This approach is based on the notion that age is associated with poor patient tolerance to aggressive chemotherapy. Relatively little data exist to support this contention. The most exciting new chemotherapy agent to be developed in the last 10 years is taxol, a diterpeniod derivative of the Northwestern yew Taxus brevifolia. METHODS: The ability to administer dose-intensive taxol to adult patients with recurrent ovarian cancer was assessed retrospectively, and the question was asked whether the administered dose intensity of taxol was unfavorably influenced by age. Forty-eight patients with recurrent ovarian carcinoma received taxol at an initial dose of 250 mg/m2 every 3 weeks. Age in this cohort ranged from 26 to 74 years, with a median of 55. Twenty-nine percent (14 of 48) of the patients treated were 61 years of age or greater. Criteria for administration of taxol included a creatinine clearance of > 45 ml/minute, minimal abnormalities in liver function tests, good performance status, and the absence of substantial comorbid disease. RESULTS: Elderly patients in this cohort (age > 60 years) did not differ from younger patients with respect to administered dose intensity, number of cycles of therapy administered, or the occurrence of serious or mild toxicities.

Adult↗
PubMed1993

Dose intensity analysis of high-dose carboplatin in refractory ovarian carcinoma relative to age.

BACKGROUND: Cisplatin and carboplatin are essential to management of advanced-stage epithelial ovarian carcinoma. No published data exist regarding carboplatin dose intensity importance in ovarian cancer, nor are there data for the effect of age on the ability to deliver dose-intensive carboplatin. METHODS: Retrospective dose intensity analyses were performed for 93 patients with advanced-stage refractory ovarian carcinoma, who received single-agent, high-dose carboplatin chemotherapy (800 mg/m2/35 days of 160 mg/m2/week). These patients had been treated on one of three high-dose carboplatin studies conducted in the Medicine Branch of the National Cancer Institute during the 1980s. Eligibility criteria required age greater than or equal to 18 years, good end organ function, and good performance status. RESULTS: Patients 60 years of age or older comprised 33% of the cohort and patients 70 years of age or older comprised 8% of the cohort. Administered dose intensity of carboplatin did not differ among age groups. Patients of age < or = 39 years received a dose intensity of 136 +/- 28 mg/m2/week, those of age 40-59 years received 129 +/- 33, those of age > or = 60 years received 134 +/- 24, and those of age > or = 70 years received 129 +/- 19. Further, the administered carboplatin dose intensity did not differ among clinical response groups. Dose intensity in complete responders was 138 +/- 18 mg/m2/week; in partial responders, 121 +/- 29; and in nonresponders, 134 +/- 30. The age distribution of responders matched the age distribution of the cohort. CONCLUSIONS: These data demonstrate that elderly patients with good end organ function and good performance status tolerate the same level of dose-intensive platinum therapy as younger patients. Age alone should not be a determinant for carboplatin dose modification in the treatment of ovarian carcinoma.

Adult↗
PubMed1993

Ormaplatin sensitivity/resistance in human ovarian cancer cells made resistant to cisplatin.

The human ovarian cancer cell lines A2780 and A2780/CP70 were studied to investigate the cellular basis for their relative sensitivities to tetrachloro(DL-trans)-1,2-diamminecyclohexaneplatinum(IV) (ormaplatin). Cells were exposed to ormaplatin for 1 h in all experiments. As assessed by colony formation assays, the A2780/CP70 cell line [50% inhibitory dose (IC50) = 3.6 microM] was 9.5-fold more resistant to ormaplatin than the A2780 cell line [IC50 = 0.38 microM]. For cisplatin, the IC50 doses were 40 and 3 microM, respectively. Both cell lines were treated with ormaplatin at doses ranging from 0.10 to 40 microM, for the purpose of studying drug accumulation and efflux, and DNA adduct formation and repair. When these cell lines were treated at their respective IC50 doses, drug accumulation was greater in the resistant cells. When treated at equal microM doses, the sensitive cells formed 8-fold more DNA adduct than the resistant cells. When cells were treated with ormaplatin so as to achieve equivalent levels of platinum-DNA modification, sensitive cells removed 53% of the platinum-DNA damage in the first 6 h after drug exposure, compared to 68% in the resistant cells. We conclude that in human ovarian cancer cells made resistant to cisplatin, there is moderate cross-resistance to ormaplatin. This cross-resistance is not explained by differences in drug accumulation but is associated with reduced platinum-DNA adduct formation, which may be attributable in part to cytosolic inactivation of drug.

Cisplatin↗
PubMed1993

Nephrotoxicity and hydration management for cisplatin, carboplatin, and ormaplatin.

Renal toxicity is a prominent component of the toxicity profile of platinum-based chemotherapy. Kidney damage, once dose limiting for cisplatin, occurs in some patients who receive carboplatin and may occur with the third-generation platinum analog ormaplatin. Herein, we review what is known about the pathophysiology of therapy-induced renal toxicity for each of these agents and what is known about appropriate maneuvers to circumvent this toxicity. For cisplatin, hydration is always indicated and mannitol may be useful in selected settings. Furosemide is probably not generally useful. For carboplatin, hydration is important for patients with impaired renal function and for patients receiving high doses of drug (> or = 800 mg/m2). For ormplatin, renal toxicity appears not be prominent when hydration is administered in a fashion similar to cisplatin hydration. Detailed suggestions regarding the protection of kidney function when using these compounds are presented.

Animals↗
PubMed1993

Incapacitating autonomic neuropathy precipitated by taxol.

Taxol is one of the more significant advances in cancer chemotherapy in the last 10-15 years with a 30-50% response rate in both breast and ovarian cancers. The toxicity profile of taxol is still evolving as changes in the dosing and scheduling of the drug are instituted. We herein present the first evidence of taxol-induced quantifiable, objective autonomic neuropathy in two patients, one with and one without diabetes. The patients did not have symptoms of autonomic dysfunction prior to taxol therapy. Both developed severe orthostatic hypotension following completion of 24-hr infusional taxol at 170-250 mg/m2 and both improved markedly on fludrocortisone. Other possible etiologies of orthostatic hypotension were ruled out. Noninvasive autonomic tests performed on the first patient included tilt test, Valsalva ratio, heart rate variation with respiration, and change in diastolic blood pressure with hand grip; all were markedly abnormal. Noninvasive autonomic tests should be considered as part of the evaluation of patients on taxol who develop generalized weakness and orthostasis.

Aged↗
PubMed1993

Steady-state plasma concentrations and effects of taxol for a 250 mg/m2 dose in combination with granulocyte-colony stimulating factor in patients with ovarian cancer.

Taxol, a natural product initially isolated from the stem bark of the western yew Taxus brevifolia, is undergoing phase II and III evaluation due to its reported activity against a variety of tumors. Previous studies have described correlations between plasma concentrations and toxicity when taxol is given (a) at lower doses, (b) for shorter infusion times, and (c) without granulocyte-colony-stimulating factor. Because the 24-h infusion schedule is most commonly used in current clinical trials, we attempted to correlate steady-state plasma concentrations of taxol achieved with a 24-h continuous i.v. infusion with toxicities and responses. Plasma samples from 48 refractory ovarian cancer patients were obtained 1-2 h prior to the end of the first taxol infusion. Taxol concentrations were measured by high-performance liquid chromatography (HPLC). Interpatient variation of taxol plasma concentrations was small (mean +/- SD, 0.85 +/- 0.21 microM. Total taxol body clearance was 256 +/- 72 ml min-1 m-2 (mean +/- SD). Taxol plasma protein binding was 88.4% +/- 1.3% (mean +/- SD, n = 9). Grade 3-4 hematologic toxicity, mainly leukopenia, occurred in 92% of the patients. The leukopenia was transient and did not warrant a reduction in the dose of taxol. Grade 3-4 nonhematologic toxicity occurred in 8% of the patients. No severe hypersensitivity reaction or grade 3-4 neurotoxicity was observed. Correlations of plasma concentrations and toxicities were not feasible due to the high frequency of hematologic effects and the low frequency of nonhematologic toxicity. The low degree of interpatient variation in plasma concentrations hindered the development of correlations with response.

Blood Proteins↗
PubMed1993

Anti-idiotypic antibodies specific for HLA in heart and kidney allograft recipients.

Chronic rejection is the major threat to both heart and renal allograft survival. We have explored the possibility that some patients with anti-donor HLA antibodies (Ab1) develop specific anti-idiotypic antibodies (Ab2) which suppress the production of Ab1, and subsequently, the progression of chronic rejection. Analysis of Ab2 in sera obtained from Ab1 producers showed that 22% of heart and 18% of kidney recipients produced Ab2. The 4- and 5-year actuarial graft survivals in Ab2 producers were 100% and 83%, respectively, compared to 57% in patients who formed Ab1 but not Ab2 (p < 0.004). Patients carrying the DR2 alleles, DRB1*1501, *1502 or *1601 were at a lower risk of producing anti-donor HLA antibodies.

Alleles↗
PubMed1993

Expression of excision repair genes in non-malignant bone marrow from cancer patients.

The patterns of expression of 3 human DNA-repair genes (ERCC1, ERCC2, ERCC6) were assessed in 52 bone-marrow specimens obtained from cancer patients prepared for autologous bone-marrow transplantation. Marrow was collected prior to the initiation of treatment in patients with sarcoma or testicular cancer; marrow was collected after initial cytoreductive therapy for patients with non-Hodgkin's lymphoma, Hodgkin's disease, and other tumors. Slot-blot analysis of marrow RNA showed a bimodal pattern of ERCC1, ERCC2 and ERCC6 gene expression with relative expression values ranging more than 200-fold. This pattern was seen in all patient groups and appeared to be independent of whether or not patients had received prior chemotherapy. In all patient groups, when expression was low for ERCC1, expression was also low for ERCC2 and ERCC6, suggesting that expression of these genes may be coordinated within an individual although they are located on two different chromosomes. Southern blot analyses of Pst I digests of DNA from 6 bone-marrow samples indicate no differences in ERCC1 gene copy number between high expressors and low expressors. There is absence of restriction fragment length polymorphism for ERCC1 suggesting that the different levels of expression in high and low expressors were not due to major deletions or rearrangements of the ERCC1 gene. We conclude that expression of these ERCC genes may vary widely between individuals, and that within an individual, their expression may be linked and coordinated by a common regulatory mechanism.

Bone Marrow↗
PubMed1993

Cisplatin sensitivity/resistance in UV repair-deficient Chinese hamster ovary cells of complementation groups 1 and 3.

We assessed the possible role of the human repair genes, ERCC1 and ERCC3, in resistance to cisplatin-induced cytotoxicity. The UV repair-deficient Chinese hamster ovary (CHO) 43:3B [designated ERCC1(-)] cell line and its paired subline 83-J5, which is stably transfected with the human DNA excision repair gene ERCC1 [designated ERCC1(+)], were used in this study. UV repair-deficient CHO 27-1 cells [designated ERCC3(-)] and its paired subline designated 'ERCC3(+)', which is stably transfected with the human DNA excision repair gene ERCC3, were also used. In each pair of cell lines, we assessed cisplatin cytotoxicity, cellular drug accumulation and platinum-DNA adduct repair after 1 h drug exposures. Drug accumulation and DNA repair were assessed by atomic absorption spectrometry with Zeeman background correction. ERCC1(+) cells (IC50 = 4.0 microM) were 5-fold more resistant to cisplatin than ERCC1(-) cells (IC50 = 0.75 microM). ERCC1(+) cells repaired 25% of DNA lesions in cellular DNA within a 6 h time period following an IC50 drug exposure and repaired 48% over 24 h. No DNA repair was observed in ERCC1(-) cells during the same time periods. Both cell lines showed similar patterns of drug accumulation. For ERCC3(-) cells (IC50 = 54 microM) and ERCC3(+) cells (IC50 = 49 microM), the profiles of cisplatin sensitivity and cellular drug accumulation were similar. When treated with 50 microM cisplatin, these cells showed similar patterns of drug accumulation, and were equally efficient at forming and repairing lesions in cellular DNA. These data show that in UV repair-deficient CHO cells, ERCC1 confers resistance to cisplatin and confers the ability to remove platinum from cellular DNA. In contrast, ERCC3 does not influence cisplatin drug sensitivity or adduct repair capability. This suggests that ERCC1 may be a determinant of cisplatin resistance, whereas ERCC3 is probably not.

Animals↗
PubMed1993

The absence of cumulative bone marrow toxicity in patients with recurrent adenocarcinoma of the ovary receiving dose-intense taxol and granulocyte colony stimulating factor.

Forty-eight patients with recurrent adenocarcinoma of the ovary were treated with taxol and granulocyte colony stimulating factor (G-CSF), with a target taxol dose intensity of 250 mg/m2 every 3 weeks (83.3 mg/m2/week). We have assessed the patterns of granulocyte and platelet toxicity seen in this cohort. Individual patients received up to nine cycles of therapy. Criteria for entry onto protocol included good end organ function, good performance status and the absence of substantial co-morbid disease. Mean taxol dose intensity was 79.0 mg/m2/week for the whole cohort and did not diminish with increased duration of therapy. Granulocytopenia and thrombocytopenia were well controlled, with the average duration of platelet and neutropenic nadirs being less than 1 day for all cycles. There was no evidence of cumulative toxicity for granulocytes nor platelets, for up to eight cycles of therapy. We conclude that taxol, when given with G-CSF support, can be safely administered in a dose-intense fashion for multiple cycles of therapy, without cumulative bone marrow toxicity.

Adenocarcinoma↗