The economic impact of therapy on cancer patients.
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Clinical Trials as Topic↗
Biomedical subjects
W Lawrence
Publications and source records attributed to W Lawrence.
Diastolic compliance of hypertrophied ventricle is not acutely altered by pharmacologic agents influencing active processes.
OBJECTIVE: To test, by studying the acute effects of drugs that influence active processes, the hypothesis that in humans with marked ventricular hypertrophy, reduced chamber compliance is primarily caused by passive structural changes. DESIGN: An uncontrolled (before-after) study. SETTING: University Medical Center. PATIENTS: Fourteen patients with ventricular hypertrophy (19 +/- 4.5-mm diastolic-wall thickness) and normal resting systolic function were studied while they had invasive cardiac catheterization. INTERVENTION: Intravenous beta-blocker (esmolol) or calcium channel blocker (verapamil) or both. MEASUREMENTS: Left ventricular function was determined by pressure-volume relations. Volume was measured using conductance catheter, providing a continuous voltage signal proportional to chamber volume. Pressure was measured by micromanometer. Cardiac-specific assessment of change in chamber contractility and diastolic compliance due to each drug was determined. RESULTS: Both drugs lowered contractility by approximately 30% (P < 0.01). Esmolol slowed relaxation and reduced early peak filling rate, whereas verapamil delayed the time to peak filling (all P < 0.05). In contrast to the effects of both drugs on active contraction and early diastole, late-diastolic compliance was unaltered, and end-diastolic pressure-volume relations were almost identical. CONCLUSION: Neither beta-receptor nor calcium channel blockade acutely alters left ventricular compliance despite substantial active effects manifest in systole and early diastole. This supports the notion that chamber compliance is principally determined by passive structural elements in the heart rather than by active processes.
Adrenergic beta-Antagonists↗
Diminished contractile response to increased heart rate in intact human left ventricular hypertrophy. Systolic versus diastolic determinants.
BACKGROUND: Experimental studies indicate that in addition to diastolic dysfunction, hypertrophied myocardium can display depressed contractile responses, particularly at rapid heart rates, compounding reserve limitations. This study tests whether such abnormalities exist in intact human subjects at physiological paced rates and, if so, whether they are linked to simultaneous rate-dependent deterioration in diastolic function. METHODS AND RESULTS: Ten subjects with left ventricular hypertrophy (LVH) and 8 normal control subjects were studied. Most LVH patients presented with dyspnea and/or pulmonary edema and had concentric hypertrophy. Since rapid pacing simultaneously alters cardiac filling volumes and pressures, pressure-volume relation analysis was used to better define changes in contractile response. Patients were instrumented with a conductance catheter and micromanometer for pressure-volume data recording and a balloon occluder at the right atrial-inferior vena caval junction to vary filling and thus generate function relations. Data were obtained at baseline and at three atrial pacing rates (100, 120, 150 min-1). In addition, single-beat force-interval data were used to indirectly examine calcium cycling kinetics. LVH subjects demonstrated baseline diastolic abnormalities, including prolonged relaxation, elevated end-diastolic pressure, and reduced chamber compliance. However, systolic function was similar to that in control subjects. With rapid pacing, normal subjects displayed a positive contractile response, whereas this was markedly diminished in LVH subjects. With abrupt termination of pacing and return to slower sinus rhythm, LVH subjects displayed greater initial potentiation followed by a more rapid decline than control subjects, suggesting abnormalities of calcium handling. Despite contractile abnormalities, diastolic function did not further deteriorate with rapid pacing and thus did not appear to be tightly linked to the systolic changes. CONCLUSIONS: Pacing stress in intact human LVH can result in systolic impairment superimposed on preexisting but not worsened diastolic dysfunction. Abnormal calcium handling probably contributes prominently to this response.
Calcium↗
Mutagenesis of essential functional residues of rat androgen-binding protein/sex hormone-binding globulin.
Testicular androgen-binding protein (ABP) and liver (plasma) sex hormone-binding globulin (SHBG) are extracellular carrier proteins that bind androgens with high affinity. Both proteins are encoded by the same gene and have the same primary amino acid sequence. Previous affinity labeling experiments to identify the steroid-binding site of ABP/SHBG led to ambiguous results, implicating various residues from 134 to near the C-terminus. To aid in elucidation of the essential functional residues of ABP/SHBG, we created mutant rat proteins by deletion and site-directed mutagenesis. The mutants were expressed in COS 7 green monkey kidney cells and analyzed for immunoreactive cellular and medium ABP and dihydrotestosterone (DHT) binding properties. Analysis of truncated ABP proteins revealed that removal of 26 or more residues from the C-terminus eliminates secretion and DHT-binding activity. Alteration of amino acid residues by site-directed mutagenesis from residue 54 to residue 333 resulted in elimination of DHT binding for 9 of 10 mutants and reduced DHT affinity for one altered protein (ABPGly54-57). Only one of the 10 mutant ABP proteins was secreted by the COS cells. This secreted mutant ABP (ABPArg139) exhibited no detectable DHT-binding activity. Thus, our data demonstrate that modifications of the ABP primary sequence throughout the molecule have a detrimental effect on steroid binding and secretion. These data, taken together with previous affinity labeling experiments, mutagenesis studies, and the conserved residues between rat and human ABP/SHBG, indicate that at least part of active site is located in residues 139-150, but most of the protein is required to maintain the conformation of the active site.(ABSTRACT TRUNCATED AT 250 WORDS)
Amino Acid Sequence↗
The effects of group housing on the research use of the laboratory rabbit.
This project evaluated the influence of group housing on common aspects of research use of female laboratory rabbits (Oryctolagus cuniculus). Eight rabbits housed individually in conventional cages were compared to a second group of 8 housed as a social group in a proportionately larger enclosure. The group housing method provided increased opportunities for exercise, social contact, and a more novel environment. As a function of housing style, the 2 experimental groups were compared on humoral and delayed hypersensitivity response, feed intake, growth rate, and selected physiological parameters that are considered to reflect stress in most species. Single and group housed rabbits did not significantly differ in physiological and immunological measurements, indicating that the practical research performance (immune response, stress level, growth rates etc.) of these rabbits was not significantly affected by group housing compared with the more traditional single housing. Analysis of group social behaviour indicated that the rabbits preferred small social groups, had preferences for microenvironments within the enclosure, and exhibited behaviours that are not possible when housed singly. Group housing appeared to be a successful method for enriching the environment of female rabbits and aspects of it should be considered in the approach to housing rabbits used in research.
Animals↗
The Commission on Cancer and the American Cancer Society: partners in cancer control.
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American Cancer Society↗
Modulation of cell cycle kinetics in human cancer with total parenteral nutrition.
Prior DNA flow cytometric data from the laboratory of the Division of Surgical Oncology, Massey Cancer Center, demonstrated an increase in the hyperdiploid compartment of tumor cells taken from patients with squamous cell carcinoma of the head and neck after a course of total parenteral nutrition (TPN). To assess a putative increase in the percentage of tumor cells actively synthesizing DNA in this system, the authors administered bromodeoxyuridine (BrdU) intravenously to ten patients before and after the administration of TPN. Cell suspensions prepared from biopsy specimens of normal oral mucosa and tumor tissue were analyzed with flow cytometric study. Before TPN administration, the mean percentage of tumor cells incorporating BrdU was 2.47 +/- 1.11%. After TPN administration, the percentage of S-phase cells increased significantly (P less than 0.05) to a mean of 4.52 +/- 2.67%. Before TPN was given, normal mucosa demonstrated a mean of 7.97 +/- 2.69% of cells incorporating BrdU. After TPN was given, a mean of 8.47 +/- 2.51% was seen (not significant [NS]). A potential strategy for the use of TPN to enhance tumor cell susceptibility to S-phase-specific chemotherapy is strongly suggested by these data.
Adult↗
Formal hepatic resection of colorectal liver metastases. Ploidy and prognosis.
Fifty consecutive patients who underwent 52 formal hepatic resections (excluding isolated wedge resections) for metastatic colorectal cancer were analyzed to determine whether DNA content was of prognostic significance. The Dukes' stages of the colorectal primaries were: A (10%), B (20%), C (40%), D (28%), and unknown in 2%. Four patients whose liver metastases were discovered at the time of resection of the primary bowel cancer underwent concomitant liver resection, and the remaining patients underwent delayed resections. The hepatic resections performed were right lobectomy (50%), extended right lobectomy (19%), left lobectomy (13%), left lateral segmentectomy (6%), left lobectomy and right wedge (6%), extended left lobectomy (4%), and right lobectomy and left wedge (2%). The overall morbidity rate was 29%. The in-hospital mortality rate was 9%. As of November 1991, 36 patients have recurred. The 5-year actuarial survival was 28%. Flow cytometry could be performed on 37 archival specimens, 15 of which were found to be diploid whereas 22 were aneuploid. All metastases from Dukes A colorectal primaries demonstrated a diploid DNA content. In addition, there was no difference in actuarial survival between diploid and aneuploid tumors. These data suggest that in selected patients, formal hepatic resection of colorectal liver metastases can be performed with an acceptable morbidity rate, mortality rate, and survival, but ploidy of the resected tumor is not of prognostic significance.
Adult↗
Reduced left ventricular compliance in human mitral stenosis. Role of reversible internal constraint.
BACKGROUND: The mechanisms of depressed left ventricular (LV) pump performance in human mitral stenosis (MS) remain poorly understood, because reduced filling alone affects many hemodynamic measurements. Therefore, pressure-volume relations were examined in nine subjects with MS and compared with eight age-matched normal controls. METHODS AND RESULTS: Data were obtained by conductance catheter/micromanometer technique with transient inferior vena cava occlusion used to alter load and generate pressure-volume relations. In a subset of patients (n = 5), data were obtained both acutely and at 3 months (n = 4) after balloon valvuloplasty. MS patients had reduced cardiac output (3.3 +/- 0.9 versus 5.6 +/- 1.7 l/min) and end-diastolic volume (68.0 +/- 6.9 versus 115 +/- 31 ml) versus controls (p less than 0.001), with a mean transvalvular gradient of 14 +/- 6 mm Hg and estimated valve area of 0.6 +/- 0.2 cm2. Systolic function as assessed by the end-systolic pressure-volume relation was virtually the same in MS and control subjects. In contrast, end-diastolic pressure-volume relations in MS were consistently shifted leftward and had an increased slope (lower compliance) at matched pressure ranges (6.5 +/- 3.0 versus 2.2 +/- 0.53 ml/mm Hg at a mean diastolic pressure of 8 mm Hg, p less than 0.001). This change was not a result of reduced LV filling or probably of increased right heart loading. Valvuloplasty acutely returned chamber compliance to near normal, a change that was sustained at 3-month follow-up. Systolic function was little altered at this time. CONCLUSIONS: These data indicate an impairment of diastolic function in human MS that can be acutely reversed by balloon valvuloplasty. Lowered LV compliance probably results from a functional restriction caused by ventricular attachment to a thickened and immobile valve apparatus.
Cardiac Catheterization↗
The role of asparagine-linked oligosaccharides in the subunit structure, steroid binding, and secretion of androgen-binding protein.
Testicular androgen-binding protein (ABP) and liver sex hormone-binding globulin are encoded by the same gene. These proteins have the same primary amino acid sequences, but they differ in attached oligosaccharides; the differences are presumably due to cell-specific glycosylation mechanisms. To investigate the role of oligosaccharides in ABP/sex hormone-binding globulin subunit structure, secretion, and steroid binding, mutant rat ABP proteins were constructed that eliminated one or both of the two potential sites of asparagine (Asn)-linked glycosylation. Immunoblot analysis of wild type recombinant ABP yielded the typical heterogeneous banding pattern. Secreted ABP was composed of two protomers of M(r) 46,000 and M(r) 43,000, while cellular ABP yielded three mol wt species (M(r) 43,000, 41,000, and 39,000). Substitution of the Asn residue in either consensus sequence for Asn-linked glycosylation with an Ile residue resulted in increased mobility of the immunoreactive ABP species. These changes are consistent with the loss of an Asn-linked oligosaccharide. Substitution of both Asn residues yielded a single immunoreactive species in the medium and cell extracts that migrated as a M(r) 39,000 protein. These results demonstrate that the mol wt heterogeneity of ABP is due to differential Asn-linked glycosylation of both potential sites. All three mutant forms of ABP were secreted by the COS cells. However, the amount of immunoreactive ABP and [3H]5 alpha-dihydrotestosterone binding in the medium was lower than wild type (100%) in one of the single mutants (65%) and in the double mutant (29%). Unlike the glycosylation mutants, alteration of other residues, not involved in glycosylation, yielded cellular ABP and no detectable medium ABP.(ABSTRACT TRUNCATED AT 250 WORDS)
Androgen-Binding Protein↗
Advocacy. Necessary to achieve cancer control goals.
As resources become increasingly scarce, oncology professionals and consumers of oncology services are increasingly engaging in advocacy efforts to achieve goals in cancer control. Effective advocacy includes both legislative and direct educational efforts.
Aged↗
Prevalence of cryptosporidiosis in dogs and human beings in San Bernardino County, California.
Fecal specimens from 200 stray dogs impounded at the San Bernardino City and County animal shelters were screened for Cryptosporidium sp oocysts, using the auramine-rhodamine fluorescent staining procedure. The University of California, Los Angeles acid-fast stain was used for confirmation. Only 4 (2%) dogs were passing cryptosporidial oocysts. Likewise, stool specimens from 664 people were submitted to the San Bernardino County Department of Public Health Laboratory for routine parasitologic examination and were screened for Cryptosporidium sp. Cryptosporidial oocysts were detected in 20 human fecal specimens (3.01%). On the basis of these findings, it appears that the human and canine populations of San Bernardino County are at low risk for development of cryptosporidiosis at this time.
Age Factors↗
Some problems with clinical trials. James Ewing lecture.
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Clinical Trials as Topic↗
Diagnosis and management of sacrococcygeal chordoma.
Chordoma is a rare, slow-growing but locally aggressive malignant tumor derived from the primitive notochord and located along the axial skeleton. Between 1973 and 1991, of 15 patients with chordomas treated at the Medical College of Virginia, eight originated in the sacrococcygeal area. There was a median one year interval between the onset of symptoms and diagnosis (range of four months to six years) for this latter group. Two patients had undergone coccygectomies and one patient a lumbar discectomy prior to establishing the correct diagnosis of sacral chordoma. Seven patients underwent resection and one refused therapy. The four patients who had an initial wide radical resection had a longer disease-free survival than the three who underwent local excision. Three of four patients had metastatic disease at the time of death. Early diagnosis and aggressive initial surgical resection are necessary for long-term survival.
Adult↗
Evidence that antibodies eluted from rejected kidneys of HLA-identical transplants define a non-MHC alloantigen expressed on human kidneys.
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Autoantibodies↗
Partial cystectomy in the management of rhabdomyosarcoma of the bladder: a report from the Intergroup Rhabdomyosarcoma Study.
Among 154 children with primary vesical rhabdomyosarcoma entered in the IRS (1972 to 1986), tumor excision constituting a partial cystectomy was performed in 33. These procedures were performed in the following situations (1) as an initial operation for localized disease (22); (2) as a secondary procedure for localized disease following chemotherapy (CT) or CT/irradiation response (6); and (3) as an initial operation in the presence of disseminated abdominal disease (5). Partial cystectomy included full-thickness resection of 15% to 80% of the bladder wall. Ureters were reimplanted or revised in two patients. The 33 patients undergoing partial cystectomy were in the following clinical groups: I, total excision (10); II, gross excision with "microscopic residual" or positive nodes (8); III, subtotal excision (10); and IV, tumor dissemination (5). Patients in clinical groups I and II received vincristine and actinomycin-D (VA) or VA + cyclophosphamide (VAC) +/- adriamycin (ADR). Patients in groups III and IV received the same agents +/- cisplatin. Irradiation (2,000 to 5,000 cGy) was administered to 18 patients (55%) in groups II to IV. Six relapses occurred among 28 patients with localized disease, and one among five patients with dissemination; all resulting in progressive disease and/or death. Estimated 3-year survival following partial cystectomy (79%) is similar to that for all patients with primary bladder tumors (78%). In contrast with the total group, in which the majority of survivors have eventually required total cystectomy; 25 of 26 survivors of partial cystectomy have functional bladders from 146 to 686 weeks (median, 356 weeks) from study entry.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Treatment of biliary obstruction caused by metastatic cancer.
Over an 8-year period, among 41 patients with obstructive jaundice caused by metastases to the liver or lymph nodes adjacent to the porta hepatis, palliative biliary decompression was established surgically in 11, by percutaneous transhepatic biliary drainage (PTBD) in 25, and by both methods in 2. Three patients had no drainage procedure performed. Early mortality after drainage occurred in 6 of 38 patients, and the median survivals (actuarial) for the remaining 32 patients were 4.5 months for the surgical group (range 2 to 21 months) and 4 months for the PTBD group (range 2 to 14 months). Although there were trends toward more frequent hospital readmissions and episodes of cholangitis in the PTBD group, the only statistically significant difference was in the number of catheter manipulations required. We concluded that when patients develop obstructive jaundice as a manifestation of metastatic cancer, useful palliation can be achieved by either surgical or percutaneous decompression.
Adult↗
Soft tissue sarcomas.
Soft tissue sarcomas in infants and children differ from those in adults in clinical presentation, histology, and response to therapy. For rhabdomyosarcoma, the most common sarcoma in children, each primary site has special characteristics that affect both treatment programs and survival rates. Some results are so good, from the standpoint of survival data, that studies are now in progress to evaluate means of reducing treatment morbidity. Other ongoing studies focus on improved protocols for metastatic or recurrent rhabdomyosarcoma. Results thus far in the IRS trials have proven the value of cooperative clinical trials in the management of patients with this disease.
Adolescent↗