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Biomedical subjects

J L Palmer

Publications and source records attributed to J L Palmer.

At least 19 recordsLinked to original sources
PubMed2000

Comparison of the neurokinin-1 antagonist GR205171, alone and in combination with the 5-HT3 antagonist ondansetron, hyoscine and placebo in the prevention of motion-induced nausea in man.

AIMS: In man a neurokinin-1 (NK1) receptor antagonist has previously been shown to be ineffective in the prevention of motion-induced nausea. The antiemetic efficacy of NK1 receptor antagonists against chemotherapy-induced emesis is, however, enhanced when combined with a 5-HT3 receptor antagonist. Hence the efficacy of the NK1 antagonist GR205171 in combination with the 5-HT3 antagonist ondansetron (Zofrantrade mark) was assessed in motion-induced nausea. METHODS: GR205171 25 mg i.v., with and without concomitant administration of ondansetron 8 mg i.v., and hyoscine hydrobromide 0. 6 mg orally (positive control) were compared with placebo in a model of motion-induced nausea. The study was performed to a four-period, randomized, balanced, double-blind, crossover design in 16 healthy subjects. The end-point was the exposure to the motion stimulus required to produce moderate nausea in the subjects. RESULTS: The motion stimulus required to produce moderate nausea was significantly greater for the positive control than placebo (P < 0. 001). There was no significant difference between either GR205171 or GR205171 plus ondansetron and placebo (P = 0.648 and 0.342, respectively). CONCLUSIONS: The enhancement of NK1 receptor antagonist antiemetic activity through combination with a 5-HT3 receptor antagonist is not replicated in motion-induced nausea.

Adolescent↗
PubMed2000

Complementary/alternative medicine use in a comprehensive cancer center and the implications for oncology.

PURPOSE: Oncologists are aware that their patients use complementary/alternative medicine (CAM). As cancer incidence rates and survival time increase, use of CAM will likely increase. This study assessed the prevalence and predictors of CAM use in a comprehensive cancer center. SUBJECTS AND METHODS: Subjects were English-speaking cancer patients at least 18 years of age, attending one of eight outpatient clinics at The University of Texas M.D. Anderson Cancer Center, Houston, TX, between December 1997 and June 1998. After giving written informed consent, participants completed a self-administered questionnaire. Differences between CAM users and nonusers were assessed by chi(2) and univariate logistic regression analysis. A multivariate logistic regression model identified the simultaneous impact of demographic, clinical, and treatment variables on CAM use; P values were two-sided. RESULTS: Of the 453 participants (response rate, 51.4%), 99.3% had heard of CAM. Of those, 83.3% had used at least one CAM approach. Use was greatest for spiritual practices (80.5%), vitamins and herbs (62.6%), and movement and physical therapies (59.2%) and predicted (P <.001) by sex (female), younger age, indigent pay status, and surgery. After excluding spiritual practices and psychotherapy, 95.8% of participants were aware of CAM and 68.7% of those had used CAM. Use was predicted (P <.0001) by sex (female), education, and chemotherapy. CONCLUSION: In most categories, CAM use was common among outpatients. Given the number of patients combining vitamins and herbs with conventional treatments, the oncology community must improve patient-provider communication, offer reliable information to patients, and initiate research to determine possible drug-herb-vitamin interactions.

Cancer Care Facilities↗
PubMed1999

Therapeutic and prognostic implications of peripheral blood lymphopenia in patients with Hodgkin's disease.

Patients with Hodgkin's disease (HD) are known to have peripheral blood lymphopenia, but the prognostic significance of this observation and its implication on immune therapy remain controversial. We determined the peripheral blood lymphocyte (PBL) counts and their subsets of 238 newly diagnosed patients with HD referred to our institution, and the quantitative changes of B, T, and natural killer cells were correlated with the patients' clinical variables. The mean white blood cell count increased steadily with advancing disease stage. In contrast, the mean absolute PBL count and its CD4, CD8, and CD3-/CD56+/CD16+ subsets, after an initial increase in stage I, steadily decreased with advanced HD stages. The mean CD20 lymphocyte count decreased steadily with advancing stage without an initial increase. Prognostic factor analysis was determined in 196 patients adequately treated with modern therapies. Neither the absolute PBL count, nor CD4, CD8, or CD20 counts correlated with shorter disease free survival. In this study, the decline in total PBL count or in its subsets in HD patients did not correlate with shorter disease free survival. Because peripheral blood lymphopenia of HD correlated with advanced clinical stage but had no independent prognostic significance, we propose that this peripheral blood lymphopenia is likely to be due to lymphocyte trafficking and homing to the diseased nodes rather than due to an absolute quantitative deficiency. Thus, strategies to improve lymphocyte functions in HD patients should continue to be explored therapeutically.

Adolescent↗
PubMed1999

Heterogeneity in systemic availability of ondansetron and granisetron following oral administration.

This open-label, randomized, two-way crossover study compared the relative heterogeneity in systemic availability of oral ondansetron and granisetron. It was conducted in 10 healthy male and 10 healthy female subjects aged 18 to 50 years. Following an overnight fast, each subject received 8 mg ondansetron and 1 mg granisetron. Treatments were separated by 7 days. Blood samples for drug assay were collected over a period of 36 h and variability in pharmacokinetic parameter estimates were assessed following standardization by their respective means. Granisetron showed significantly more variability than ondansetron in the three primary endpoints of the area under the curve extrapolated to infinite time, the area under the curve to the last quantifiable time point, and maximal concentration (p =.0032,.0037, and.0042, respectively). In one subject, concentrations of granisetron were detectable but below the lower limit of quantitation at any time point. The impact this variability may have on therapeutic efficacy is not clear. An apparent bimodal distribution in granisetron AUC infinite, which appeared to be related to smoking was observed. Because granisetron has been reported to be metabolized primarily by the cytochrome P-450 (CYP) 3A isozyme family in humans, it is possible that cigarette smoke could be an inducer of CYP3A or that CYP1A2, also implicated in the metabolism of granisetron and known to be induced by smoking, is more important in the biotransformation of granisetron than previously thought.

Administration, Oral↗
PubMed1998

Bayesian optimal design in population models for haematologic data.

We introduce a population model to design optimal apheresis schedules to collect blood stem cells from cancer patients. Blood stem cells are collected prior to the patient undergoing high-dose chemoradiotherapy and are returned after this treatment to enable reconstitution of the white blood cell components. Maximizing the number of cells collected in as few apheresis as possible is desirable. We use a longitudinal data model with random effects to describe profiles of individual patients. A hierarchical prior model introduces common mean profiles for patients undergoing different treatments. We find the optimal apheresis schedule for a new patient by minimizing an expected loss over the posterior predictive distribution of the patient's predicted CD34 profile. We implement estimation of the model and solution of the optimal design problem by a simulation approach, which allows us to accommodate arbitrary shapes for the profiles and realistic loss functions that include relative penalties for the number of scheduled stem cell collections and for collecting fewer than a specified target quantity of total collected stem cells.

Antigens, CD34↗
PubMed1998

Hodgkin's disease: correlation of clinical characteristics with probabilities for negative lymphangiogram vs. negative laparotomy findings in patients with Stage I supradiaphragmatic presentations vs. those in patients with Stage II.

PURPOSE: At a time both when late complications and second malignancies have become a growing concern and when staging laparotomy has been largely abandoned and comparative studies for staging Hodgkin's disease by state of the art computed tomography (CT) vs. lymphangiography have revealed minimal differences in results for these procedures, our purpose for undertaking this study was twofold. Our initial reason was to determine and compare probabilities for negative abdominal findings for patients with Stage I presentations with those for patients with Stage II as determined by lymphangiography and subsequently by laparotomy for those patients who had negative lymphangiograms. Our second reason, being an extension of the first, was to create a resource that can be used in conjunction with other information for arriving at appropriate treatment decisions including giving either more or particularly less than standard institutional therapy and especially with respect to the abdomen. METHODS AND MATERIALS: Data on 714 patients with prelymphangiogram Stage I-II upper torso presentations of Hodgkin's disease were entered prospectively in our database between 1968 and 1987. Twenty-eight with lymphocyte predominant disease, who had both negative lymphangiogram and negative laparotomy findings and 17 with questionable diagnoses of lymphocyte-depleted or unclassified disease were excluded from subsequent analyses of 669 patients with nodular sclerosis (NS) and mixed cellularity (MC) diagnoses. RESULTS: Stage I: in final logistic models, negative lymphangiogram findings were associated strongly with a combination of no constitutional symptoms and nodular sclerosis histology, whereas negative laparotomy findings correlated strongly with a combination of no constitutional symptoms and female sex. Predicted probabilities depended on the ratios of favorable to unfavorable characteristics. Stage II: in final logistic models, negative lymphangiogram findings were associated strongly with a combination of no constitutional symptoms, nodular sclerosis histology, age <40 years, and <4 involved sites, whereas negative laparotomy findings correlated strongly with a combination of <4 involved sites and mediastinal disease. Predicted probabilities again depended on the ratios of favorable to unfavorable characteristics. CONCLUSION: This study demonstrated that probabilities for negative abdominal findings for patients with supradiaphragmatic presentations of NS and MC Hodgkin's disease depended on: 1) whether the disease presented as Stage I or as Stage II; 2) whether staging was limited to a lymphangiogram or whether it included a laparotomy; and 3) or whether the clinical features associated with the presenting stage and methods of staging were favorable or unfavorable.

Abdomen↗
PubMed1998

Noninvasive diagnosis of oral neoplasia based on fluorescence spectroscopy and native tissue autofluorescence.

OBJECTIVE: To evaluate the clinical potential of fluorescence spectroscopy (a noninvasive technique for assessing the chemical and morphologic composition of tissue) for in vivo detection of oral cavity neoplasia. DESIGN: A fluorescence spectroscopy system recorded spectra from oral cavity sites in 8 healthy volunteers and in 15 patients with premalignant or malignant oral cavity lesions at 337-, 365-, and 410-nm excitation wavelengths in the emission range of 350 to 700 nm. Fluorescence peak intensities and spectral line shapes were compared and diagnostic algorithms were developed to distinguish normal sites from abnormal sites. SETTING: The head and neck cancer clinic at a tertiary referral center in Houston, Tex. RESULTS: Differences were found in spectra from normal, dysplastic, and malignant oral mucosa. The fluorescence intensity of normal mucosa was greater than that of abnormal areas. In addition, the ratio of red region (635-nm) to blue region (455-490-nm) intensities was greater in abnormal areas. Diagnostic discrimination was achieved when test site spectra were compared with spectra from a normal site in the same patient. One diagnostic algorithm based on spectra at 337 nm gave a sensitivity of 88% and a specificity of 100%. CONCLUSIONS: Consistent differences exist between the fluorescence spectra of abnormal and normal oral mucosa. Therefore, fluorescence spectroscopy has the potential to improve the noninvasive diagnosis of oral cavity neoplasia. Further studies will better define the role of this technique in the detection of premalignant and early oral cancer lesions.

Adult↗
PubMed1998

Population pharmacokinetics of ondansetron: a covariate analysis.

AIMS: To construct a population model to account for the variability in ondansetron pharmacokinetics and to evaluate methods for the efficient development of population models. METHODS: Population models were developed using 99 subjects consisting of paediatric patients, young, elderly and aged volunteers. A two compartment pharmacokinetic model with a zero order input was used to describe the pharmacokinetics of ondansetron. Three stepwise methods were proposed and used alongside a three step approach to develop population models with both rich and sparse data sets. The stepwise methods were based on obtaining empirical Bayes posterior estimates of pharmacokinetic parameters within a nonlinear mixed effect modelling (NONMEM) program. The parameters were then regressed against covariates in a stepwise procedure. Variance parameters were obtained by fitting the proposed population model to the data in one further NONMEM run. The population model was validated against a test data set of 54 subjects, including children, young and elderly patients and volunteers. RESULTS: The population model adequately described the differences in ondansetron pharmacokinetics between paediatric patients, young, elderly and aged volunteers. Different covariates were identified by the various methods. Weight was found to have a strong positive linear relationship with all four pharmacokinetic parameters. Clearance showed a weak negative relationship with age. Males were found to have a greater clearance than females after weight adjustment. CONCLUSIONS: The stepwise search procedures potentially are capable of considerably reducing the time required to develop population pharmacokinetic models. The model developed for ondansetron gave accurate predictions of both the concentration-time profile and variability in an independent data set.

Adolescent↗
PubMed1998

Elevated levels of biologically active soluble CD40 ligand in the serum of patients with chronic lymphocytic leukaemia.

Chronic lymphocytic leukaemia (CLL) is an indolent lymphoproliferative disorder manifested by low growth fraction and prolonged survival of the malignant cells. The mechanisms that enable CLL cells to live longer and to resist apoptosis remain unclear. Because the malignant CLL cells express CD40 and Fas receptors, which can transduce cell-survival and cell-death signals, we examined the role of CD40 in the growth regulation of CLL cells and its interaction with Fas-mediated and fludarabine-induced apoptosis in vitro. Primary CLL cells underwent spontaneous apoptosis in culture, which was enhanced by exogenous human Fas ligand (FasL) or fludarabine. Exogenous CD40L rescued CLL cells from spontaneous apoptosis in a dose-dependent manner, and caused CLL cells to resist apoptosis induced by FasL or fludarabine. Patients' autologous plasma rescued CLL cells from spontaneous apoptosis, an effect that could be reversed with anti-CD40 ligand (CD40L) antibodies. The levels of soluble CD40 ligand in the sera of 51 CLL patients and 55 healthy donors were determined by enzyme-linked immunosorbent assay. The mean soluble CD40L level in normal donors was 0.29 ng/ml compared to a mean value of 0.80 ng/ml in CLL patients (P < 0.001). CD40L up-regulated bcl-X(L) mRNA but not bcl-2 in CLL cells within 3-6 h in culture. Our results demonstrated that serum of patients with CLL contained elevated levels of biologically active soluble CD40L, and that CD40L can prolong survival of CLL cells and mediate their resistance to FasL and fludarabine in vitro.

Adult↗
PubMed1998

Hyper-CVAD and high-dose methotrexate/cytarabine followed by stem-cell transplantation: an active regimen for aggressive mantle-cell lymphoma.

PURPOSE: Diffuse and nodular forms of mantle-cell lymphoma (MCL) are consistently associated with poor prognosis. In an effort to improve the outcome, we adopted a treatment plan that consisted of four courses of fractionated cyclophosphamide (CY) 1,800 mg/m2 administered with doxorubicin (DOX), vincristine (VCR), and dexamethasone (Hyper-CVAD) that alternated with high-dose methotrexate (MTX) and cytarabine (Ara-C). After four courses, patients were consolidated with high-dose CY, total-body irradiation, and autologous or allogeneic blood or marrow stem-cell transplantation. PATIENTS AND METHODS: Forty-five patients were enrolled; 25 patients were previously untreated, 43 patients had Ann Arbor stage IV disease, and 42 patients had marrow involvement. Forty-one patients had diffuse histology, two patients had nodular, and two patients had blastic variants. RESULTS: Hyper-CVAD/MTX-Ara-C induced a response rate of 93.5% (complete response [CR], 38%; partial response [PR], 55.5%) after four cycles of pretransplantation induction chemotherapy. All patients who went on to undergo transplantation achieved CRs. For the 25 previously untreated patients, the overall survival (OS) and event-free survival (EFS) rates at 3 years were 92% (95% confidence interval [CI], 80 to 100) and 72% (95% CI, 45 to 98) compared with 25% (95% CI, 12 to 62; P = .005) and 17% (95% CI, 10 to 43; P = .007), respectively, for the previously treated patients. When compared with a historic control group who received a CY, DOX, VCR, and prednisone (CHOP)-like regimen, untreated patients in the study had a 3-year EFS rate of 72% versus 28% (P = .0001) and a better OS rate (92% v 56%; P = .05). Treatment-related death occurred in five patients: all were previously treated and two received allogeneic transplants. CONCLUSION: The Hyper-CVAD/MTX-Ara-C program followed by stem-cell transplantation is a promising new therapy for previously untreated patients with MCL.

Adult↗
PubMed1998

Coincident renal cell carcinoma and nonHodgkin's lymphoma: the M. D. Anderson experience and review of the literature.

PURPOSE: We recently observed nonHodgkin's lymphoma and renal cell carcinoma occurring simultaneously in several patients. We determine whether the incidence of co-occurrence of the 2 malignancies is greater than expected based on the incidence of each disease in the general population. MATERIALS AND METHODS: Patients diagnosed with simultaneous renal cell carcinoma and nonHodgkin's lymphoma were identified through the medical informatics data base at our cancer center. Charts of all patients were reviewed to collect detailed demographic information and confirm both diagnoses. United States population based cancer statistics (Surveillance, Epidemiology and End Results Program data) were used to arrive at the expected age adjusted incidence of co-occurrence of these diagnoses, and statistical analysis was performed to ascertain any differences between expected and observed incidences. RESULTS: We identified 41 cases with both diagnoses between 1954 and 1995, including 21 diagnosed after 1987. The latter group was used for statistical analysis. The observed rates of renal cell carcinoma developing in the nonHodgkin's lymphoma population (1.86) and nonHodgkin's lymphoma developing in the renal cell carcinoma population (2.67) were greater than expected and both reached statistical significance. CONCLUSIONS: There is a higher than expected incidence of co-occurrence of renal cell carcinoma and nonHodgkin's lymphoma. The cause remains speculative.

Carcinoma, Renal Cell↗
PubMed1998

p53 and RB expression predict progression in T1 bladder cancer.

The optimal clinical management of minimally invasive (stage T1) bladder cancer is controversial. T1 bladder cancers share characteristics of both noninvasive (Ta) papillary cancer and high stage, muscle-invasive bladder cancers. Patients with T1 bladder cancer have a higher risk of cancer progression and death than do patients with Ta bladder cancer. However, this risk is much lower than that of patients with high-stage bladder cancers. Methods of identifying T1 bladder cancer patients at greatest risk for progression may significantly improve clinical management. We retrospectively evaluated two tumor suppressor genes, p53 and RB, as potential prognostic markers for progression in a cohort of 45 patients with pT1 bladder cancer. Median follow-up for these individuals was greater than 3.5 years. Of this group, 58% had altered p53 expression based on positive p53 immunostaining. Three patterns for RB nuclear protein staining were observed: absent, heterogeneous (normal), and strongly homogeneous. Progression-free survival was similar for patients with loss of RB protein expression and those with apparent overexpression of RB protein. Therefore, both staining patterns were considered abnormal. Patients with normal expression of both proteins (i.e., p53 negative and RB heterogeneously positive) had an excellent outcome, with no patient showing disease progression, whereas patients with abnormal expression of either or both proteins had a significant increase in progression (P = 0.04 and P = 0.005, respectively). These data support the stratification of T1 bladder cancer patients based on p53 and RB nuclear protein status and suggest that patients with normal protein expression for both genes can be managed conservatively, whereas patients with alterations in one and particularly both genes require more aggressive treatment.

Cohort Studies↗
PubMed1997

Cytogenetic and molecular genetic analysis of a pediatric pleomorphic sarcoma reveals similarities to adult malignant fibrous histiocytoma.

Cytogenetic and molecular genetic studies were performed on a pleomorphic sarcoma removed from the left atrium of a 15-year-old girl. Histologic analysis was consistent with a storiform-pleomorphic malignant fibrous histiocytoma (MFH). Although MFH is the most common soft-tissue sarcoma of late adulthood. It is extremely rare in childhood and its existence in the pediatric population remains controversial. Cytogenetic analysis revealed several alterations previously associated with adult MFH, including abnormalities of chromosomal bands 11p11 and 19p13. Moreover, the tumor demonstrated homogeneously staining regions (HSR) and double minute chromosomes (dmin) suggestive of gene amplification. We therefore screened the case for amplification of genes localized to chromosomal bands 12q13-14, including the putative protooncogenes MDM2, CDK4, SAS, CHOP, and CLI, which are frequently amplified and overexpressed in adult MFH. Southern and Northern blot analysis confirmed the coamplification of MDM2, CDK4, SAS, and CHOP. To our knowledge, such coamplification studies of the 12q13-14 amplicon have not been previously detected in pediatric MFH. Our results provide cytogenetic and molecular genetic evidence that pediatric and adult MFH are histogenetically related entities.

Adolescent↗
PubMed1997

Allogeneic blood or marrow transplantation for chronic lymphocytic leukaemia: timing of transplantation and potential effect of fludarabine on acute graft-versus-host disease.

The outcome of allogeneic haemopoietic transplants including the rate of immune complications for patients with chronic lymphocytic leukaemia (CLL) refractory to or relapsing after chemotherapy with fludarabine was analysed. Fifteen patients with advanced CLL who received allogeneic transplantation were prospectively analysed. All patients had previously received chemotherapy with fludarabine for 3-15 courses; 12 were refractory. The median number of circulating CD4+ and CD8+ lymphocytes at the time of transplant was 0.49 x 10(9)/l and 0.23 x 10(9)/l, respectively. One patient was transplanted from a one HLA-antigen mismatched unrelated donor. Three others received a one or two antigen mismatched graft and 11 had HLA-identical sibling donors. Patients received cyclosporine or tacrolimus in addition to methotrexate or methylprednisolone for prophylaxis of acute graft-versus-host disease (aGVHD). Fourteen patients engrafted; one patient had graft failure, but recovered after therapy with intravenous immunoglobulin. 13 (87%) achieved complete remission (CR). Nine (53%) remain alive and in CR with a median follow-up of 36 (range 3-60) months. None developed visceral graft-versus-host disease. These data compared favourably to published reports in other leukaemia patients and for patients with CLL who received a comparable immunosuppressive therapy but without prior fludarabine exposure. This data indicates that allogeneic haemopoietic transplantation can induce durable remission in patients with CLL refractory to fludarabine and that it is reasonable to delay transplantation until failure of fludarabine therapy. It also suggests that prior exposure to fludarabine may decrease the incidence of severe aGVHD, possibly through its immunosuppressive effects. Further studies are warranted to evaluate this observation.

Adult↗
PubMed1997

CD30 ligand in lymphoma patients with CD30+ tumors.

PURPOSE: CD30 ligand (CD30L), which is expressed on resting B and activated T lymphocytes, can induce cell death in several CD30+ cell lines. Patients with CD30+ tumors (Hodgkin's disease and Ki-1+ non-Hodgkin's lymphoma) frequently have elevated soluble CD30 (sCD30) levels in their serum, which correlates with a poor prognosis. The role of sCD30 in protecting tumor cells from CD30L-mediated cell death and the pattern of CD30L expression on human peripheral-blood lymphocytes (PBLs) of normal donors and patients with CD30+ tumors are investigated. MATERIALS AND METHODS: CD30L surface protein expression was determined by two-color flow cytometry on PBLs of patients with CD30+ tumors and normal individuals. CD30L levels were determined on subsets of PBLs before and after stimulation with phytohemagglutinin (PHA), anti-CD3 antibody, or CD40L. sCD30 was measured by enzyme-linked immunosorbent assay (ELISA). The apoptotic activity of membrane-bound CD30L was tested in a CD30+ cell line by the annexin V-binding method. RESULTS: Unstimulated T lymphocytes of normal donors and patients with lymphoma rarely expressed CD30L surface protein, but were able to express it after stimulation with PHA or anti-CD3 antibody. Resting B cells of patients with CD30+ tumors had lower levels of detectable surface CD30L compared with normal donors (mean, 55% and 80.6%, respectively; P = .0008). Patients with high levels of serum sCD30 had lower detectable levels of CD30L on their PBLs (R2 = .72, P = .0008) and exogenous sCD30 blocked membrane-bound CD30L-mediated apoptosis in a CD30+ cell line. CONCLUSION: In patients with CD30+ tumors, sCD30 can decrease the availability of CD30L on PBLs. Blocking the apoptosis-inducing activity of CD30L by its soluble receptor may explain how CD30+ tumors escape immunosurveillance and may be related to the reported poor prognosis of patients who have elevated sCD30 levels.

Adolescent↗
PubMed1997

Physiology of chemotherapy-induced emesis and antiemetic therapy. Predictive models for evaluation of new compounds.

The physiology of emesis has been studied for several hundred years, focusing on the different centres involved and the mechanics of expulsion. The vomiting centre receives inputs from various emetic detectors such as the gut, the vestibular labyrinths and the chemoreceptor trigger zone. Emesis is a common disabling effect in motion sickness, postoperative conditions and in radio- and chemotherapy. Our current understanding of the mechanisms has been provided mainly by the recent introduction of serotonin 5-HT3 receptor antagonists into therapeutic use. Nevertheless, despite the considerable advances made in the understanding of the different pathways involved in emesis, there are number of areas that still require experimental investigation. Different animal and human models are available to study the physiology of emesis and to evaluate the antiemetic activity of new compounds, but they need to be predictors of clinical situations.

Animals↗