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Biomedical subjects

W B Carter

Publications and source records attributed to W B Carter.

At least 19 recordsLinked to original sources

Delivering adjuvant chemotherapy to women with early-stage breast carcinoma: current patterns of care.

BACKGROUND: Variations in practice patterns are markers for the quality of patient care in general medicine, but little is known about variation in care delivered to cancer patients. This study's purpose was to describe chemotherapy use, variations in chemotherapy delivery, and the incidence of complications in community practice settings. METHODS: Data describing adjuvant chemotherapy for patients with early-stage breast carcinoma (ESBC) were collected from an ongoing Oncology Practice Pattern Study at 13 large managed care, academic, and community practices (1111 patients). Data collection included information about diagnoses and adjuvant chemotherapy treatments, laboratory results, supportive care, complications, and treatment modifications. RESULTS: The median patient age was 50 years, and most patients had zero to three positive lymph nodes. Chemotherapy regimens consisting of cyclophosphamide, methotrexate, and 5-fluororacil (CMF) and of doxorubicin and cyclophosphamide (AC) accounted for 76% of the adjuvant therapies used. Overall, 30% of patients had delivered average relative dose intensities </= 85% of the referenced targets. Delivered summation dose intensities (SDIs) frequently were well below targeted SDIs. Neutropenia-related dose modifications occurred for 27.6% of patients and recurred with a 60.7% rate. AC was the regimen delivered with a dose intensity closest to the referenced target. However, patients who were treated with AC regimens and with regimens consisting of cyclophosphamide, doxorubicin, and 5-fluorouracil had significantly higher rates of chemotherapy-related complications compared with patients who were treated with CMF regimens in the most recent treatment years. CONCLUSIONS: Adjuvant chemotherapy for patients with ESBC frequently is not administered as referenced in off-protocol community settings. Variation in the delivered SDI raises concerns about potential treatment outcomes and warrants strategies to identify patients who are at risk for complications early in therapy.

Adult↗

HER2/neu over-expression induces endothelial cell retraction.

Over-expression of the HER2/neu (HER2) proto-oncogene in breast carcinoma imparts an enhanced metastatic potential. Metastasis requires escape of the tumor cell from the vasculature into subjacent tissue, a transmigration event across an endothelial cell (EC) monolayer. EC retraction has been reported to precede transmigration in several tumor metastatic models. Using intact human iliac vein EC monolayers, we tested the abilities of MCF-7 breast cancer cells and HER cells, a transfected MCF-7 line over-expressing HER2, to induce EC retraction. We further analyzed whether HER2 signaling influenced cancer cell-induced EC retraction. MCF-7 or HER cells were co-cultured onto mature EC monolayers. More HER than MCF-7 cells induced EC retraction (76 +/- 19% vs. 17 +/- 12%, p < 0.001) with resultant exposure of subendothelial matrix (6.80 +/- 2.86% vs. 0.85 +/- 0.39%, p < 0.001). Blockade of HER2 signaling using Herceptin nearly eliminated EC retraction (p < 0.01), while stimulation of HER2 using heregulin-beta1-augmented EC retraction (p < 0.05). Further, there was no difference between cell lines in either the number of cells adhered or the strength of adherence to EC under shear stress. These data suggest that HER2 signaling enhances metastasis in breast cancer cells by inducing EC retraction, a process that appears to precede endothelial transmigration.

Antibodies, Monoclonal↗

HER2 signaling--induced microvessel dismantling.

BACKGROUND: The human epidermal growth factor receptor 2 protein (HER2) signaling in breast cancer imparts a metastatic advantage to the cell, likely by regulating gene expression. The HER2 signaling up-regulates angiopoietin-2 (Ang-2), which disrupts endothelial cell (EC) adherens junctions. We postulated that HER2 signaling may facilitate angioinvasion by disrupting microvessel integrity. METHODS: Rat microvessels, embedded in collagen, were grown into capillary networks and cocultured with MCF-7 or HER2 overexpressing MCF-7 (HER) to test for microvessel breakdown. We quantitated this effect by determining the cumulative length of intact microvessels. Other experiments used Herceptin- or heregulin beta 1-pretreated MCF-7 cells to modulate HER2 signaling, or soluble Tie-2/Fc receptor fusion protein (sTie2) to sequester tumor-cell released Ang-2. RESULTS: The MCF-7 cells induced a time-dependent loss of microvessel integrity. At 12 hours, HER cells induced a 90% reduction in cumulative length (P <.05). Pretreatment with Herceptin reduced whereas heregulin beta 1 augmented microvessel dismantling (P <.01). Sequestration of Ang-2 significantly, though not dramatically, reduced the MCF-7 cell induction of microvessel dismantling (P <.01). CONCLUSIONS: We show that HER2 signaling in breast cancer cells leads to induction of microvessel dismantling, which may open a portal for angioinvasion. It appears that Ang-2 affects this mechanism, although other factors also function in microvessel dismantling.

Angiopoietin-1↗

Parathyroid-produced angiopoietin-2 modulates angiogenic response.

BACKGROUND: Upon explant, parathyroid tissue (PTH) upregulates vascular endothelial growth factor (VEGF), a potent endothelial cell mitogen, yet PTH induces a more robust angiogenic response than VEGF alone. This implies that other angiogenic factors are also produced. We tested PTH for production and function of angiopoietin-2 (Ang-2), a protein known to modulate VEGF response. METHODS: With use of reverse transcriptase-polymerase chain reaction and SELDI (Surface Enhanced Laser Desorption/Ionization) (Ciphergen, Freemont, Calif) technology, we tested explanted PTH for Ang-2 production and determined the time sequence of Ang-2 upregulation. With use of an in vitro rat microvessel angiogenesis assay, we determined the angiogenic response to PTH-produced Ang-2. RESULTS: Ang-2 messenger RNA was induced within 1 hour of parathyroid explant, with a maximum level detectable at 24 hours. Ang-2 protein production was maximal at 24 hours, with elimination by 48 hours. Ang-2 supplemented gels appeared to prompt earlier angiogenic induction, whereas sequestration of Ang-2 with soluble Tie2 receptor appeared to delay angiogenic induction. Soluble Tie2 treatment did not significantly decrease cumulative microvessel length, and no significant increase in neovessel length was seen with Ang-2 supplemented gels. CONCLUSIONS: PTH upregulates Ang-2 upon explantation, with peak protein production by 24 hours. Ang-2 appears to functionally enhance initiation of PTH-induced angiogenesis, although the ultimate neovessel length appears to be dependent on other PTH-produced factors.

Angiopoietin-2↗

The impact of age on delivered dose intensity and hospitalizations for febrile neutropenia in patients with intermediate-grade non-Hodgkin's lymphoma receiving initial CHOP chemotherapy: a risk factor analysis.

The purpose of this historical case series study was to evaluate the association of age on delivered dose intensity of initial CHOP (cyclophosphamide/doxorubicin/ vincristine/prednisone) chemotherapy and the occurrence of hospitalizations for febrile neutropenia for patients with intermediate-grade non-Hodgkin's lymphoma (NHL). Findings are reported for 12 managed community and academic practices. Medical records of 930 NHL patients not enrolled on clinical trial protocols were reviewed. We reported on 577 of the study patients (62%) who received initial CHOP chemotherapy. Median age of the patients was 65.1 years. Older patients (age > or = 65 years) had more hospitalizations for febrile neutropenia (28% vs. 16%; P < 0.05) than younger patients (age, 18-64 years). In patients with advanced-stage NHL (stage III/IV), older patients received fewer cycles of CHOP (< 6 cycles, 35% vs. 22%; P < 0.05) than younger patients. Older patients were planned for lower average relative dose intensity (ARDI < or = 80%; P < 0.05) and had more heart disease and comorbid conditions (P < 0.05) than younger patients. Multiple logistic regression models showed that older patients were more likely to receive a lower dose intensity (ARDI < or = 80%; odds ratio = 2.46, 95% confidence interval [CI]: 1.62-3.72) during their first 3 cycles of therapy and to experience more hospitalizations for febrile neutropenia (odds ratio = 2.17, 95% CI: 1.43-3.30). We found the dose intensity of delivered CHOP chemotherapy for elderly patients to be less than standard CHOP therapy and the risk of hospitalizations for febrile neutropenia to be greater than in younger patients. Prospective clinical trials examining supportive care measures, such as colony-stimulating factor, for elderly NHL patients are recommended.

Adult↗

Patterns of chemotherapy administration in patients with intermediate-grade non-Hodgkin's lymphoma.

Records from 653 patients treated between 1991 and 1998 in the Oncology Practice Patterns Study (OPPS) were analyzed to determine contemporary chemotherapy delivery patterns in patients with intermediate-grade non-Hodgkin's lymphoma (NHL). Of the 653 patient records reviewed, 90 (14%) omitted an anthracycline or mitoxantrone (Novantrone) from primary therapy. Among patients receiving CHOP (cyclophosphamide [Cytoxan, Neosar], doxorubicin HCl, vincristine [Oncovin], prednisone) or CNOP (cyclophosphamide, mitoxantrone, vincristine, prednisone), 134 (27%) of 492 received an average relative dose intensity of less than 80% of the literature-referenced dose, due either to an inadequate planned or delivered dose. Of 181 advanced-stage patients with responsive disease, 28 (15%) failed to receive at least six treatment cycles. Overall, 283 (43%) of 653 patients potentially received suboptimal chemotherapy due either to choice of regimen or chemotherapy delivered. Patient age > or = 65 years and cardiac comorbidity appeared to have the greatest influence on a physician's decision regarding chemotherapy administration. Among the 492 patients who received CHOP or CNOP, 235 (48%) experienced a delay or reduction in chemotherapy dose (usually neutropenia-related), 100 (20%) developed mucositis, and 116 (24%) were hospitalized for febrile neutropenia. Growth factor was administered to 261 patients (53%), and its primary prophylactic use was associated with a significant reduction in the incidence of hospitalizations for febrile neutropenia in all patient subgroups receiving appropriate chemotherapeutic dose intensity (P = .02). This assessment of chemotherapy delivery to patients with intermediate-grade NHL showed significant variation from current standards. Further analysis of factors influencing chemotherapy delivery might improve therapeutic outcomes.

Adolescent↗

Development of subscales from the symptoms/problems and effects of kidney disease scales of the kidney disease quality of life instrument.

BACKGROUND: The Kidney Disease Quality of Life Instrument (KDQOL) was developed to provide clinicians with a comprehensive assessment of the important domains of health-related quality of life (HRQOL) for patients with end-stage renal disease who are undergoing hemodialysis. OBJECTIVE: The purpose of this study was to develop subscales from the 55 items comprising the Symptoms/Problems and Effects of Kidney Disease scales of the KDQOL and to measure the internal consistency reliability of these subscales. METHODS: The 55 items from the Symptoms/Problems and Effects of Kidney Disease scales were arranged into substantively meaningful clusters using an affinity mapping procedure. The resulting subscales were assessed for internal consistency reliability using data from a sample of 165 individuals with kidney disease who had completed the KDQOL. RESULTS: Eleven multi-item subscales were identified: pain, psychological dependency, cognitive functioning, social functioning, dialysis-related symptoms, cardiopulmonary symptoms, sleep, energy, cramps, diet, and appetite. Four items (clotting or other problems with access site, high blood pressure, numbness in hands or feet, and blurred vision) were not included in any of these subscales. Internal consistency reliability estimates for the 11 subscales ranged from 0.66 to 0.92. These subscales correlated with the scales from the 36-Item Short-Form Health Survey as hypothesized (ie, corresponding pain, energy, and social functioning scales had the highest correlations). In addition, several subscales were significantly associated, as hypothesized, with other variables such as the number of disability days. CONCLUSIONS: The results of this study further support the reliability and validity of the KDQOL. The 11 subscales identified yield more detailed information on the HRQOL of patients with kidney disease and provide a basis for specific improvements in the quality of care delivered to these patients.

Adult↗

Parathyroid-induced angiogenesis is VEGF-dependent.

BACKGROUND: Autotransplantation of parathyroid tissue after parathyroidectomy is successful at salvaging parathyroid function. The relatively high success of parathyroid transplantation is thought to be due, in part, to the ability of parathyroid tissue to induce angiogenesis and thus recruit a new vasculature. Vascular endothelial growth factor (VEGF) is a potent angiogenic factor produced by a number of tumors and hypoxic tissues. Using a 3-dimensional intact microvessel angiogenesis system, we evaluated the role of VEGF in the stimulation of angiogenesis by human parathyroid cells. METHODS: Freshly isolated rat microvessels embedded in a 3-dimensional collagen I matrix were treated with healthy 1-mm(3) fragments of human parathyroid tissue or isolated parathyroid cells. Other gels were supplemented with VEGF(165) or FLT-1 soluble receptor fusion protein to bind VEGF. After 11 days in culture, the gels were stained with Gs-1 lectin, a marker for rat endothelium, and linear growth of the microvessels was determined by using image analysis. Parathyroid production of VEGF was determined with reverse transcriptase-polymerase chain reaction. RESULTS: A significant increase in microvessel growth was seen in parathyroid coculture (8.4 +/- 1.0 mm) versus VEGF(165) supplemented gels (6.2 +/- 0.3 mm, P <.01). VEGF(165) significantly augmented parathyroid-stimulated angiogenesis (13.7 +/- 2.4 mm, P <.05 vs parathyroid alone). Using quantitative reverse transcriptase-polymerase chain reaction, we identified VEGF messenger RNA (mRNA) induction within 1 hour of parathyroid explant, with a 12-fold increase by 24 hours. Treatment of parathyroid cocultures with 0.2 microg/mL FLT-1 soluble receptor protein completely eliminated the parathyroid induction of angiogenesis. CONCLUSIONS: Parathyroid tissue expresses low levels of VEGF mRNA, which is significantly upregulated on explantation. Furthermore, the increased VEGF expression is essential to drive parathyroid-induced angiogenesis in our model. However, our data suggests that other parathyroid-produced factors are involved in mediating parathyroid-induced angiogenesis.

Adipose Tissue↗

HER2 regulatory control of angiopoietin-2 in breast cancer.

BACKGROUND: HER2 overexpression is a marker of aggressive breast cancer. Tumors that overexpress HER2 induce endothelial cell retraction and endothelial destabilization. Because angiopoietin-2 (Ang-2) also destabilizes microvessels, we postulated that HER2 signaling upregulates Ang-2 as a mechanism of angioinvasion. METHODS: We tested human breast cancers and breast cancer cell lines for coexpression of HER2 and Ang-2 with Northern blot, reverse transcriptase-polymerase chain reaction, and enzyme-linked immunosorbent assay. Further, we manipulated HER2 signaling with 100 ng/mL MAbHu HER2 (Herceptin; Genentech, San Francisco, Calif) and Heregulin beta1 (100 ng/mL; R&D Systems, Inc, Minneapolis, Minn) to test for HER2 regulation of Ang-2 production. RESULTS: Three of 4 breast cancer cell lines expressed HER2 protein and Ang-2 mRNA. HER cells, a stably transfected cell line that overexpresses HER2 6-fold, showed a 430% increase in Ang-2 mRNA compared to parental MCF-7 cells. Heregulin beta1 stimulation of HER2 signaling in MCF-7 cells increased Ang-2 by 20% (P <.05). HER2 signaling blockade with 100 ng/mL Herceptin reduced Ang-2 mRNA 90% (P <.001). Five of 11 cancers expressed both HER2 and Ang-2; 2 cancers expressed only Ang-2. CONCLUSIONS: We conclude that human breast cancers express Ang-2. HER2 signaling appears to regulate Ang-2 expression, although other signaling pathways may also regulate Ang-2. Ang-2 may be a therapeutic target in these cancers and may define which patients would benefit from Herceptin therapy.

Angiopoietin-2↗

Multiple ectopic parathyroid glands.

Parathyroid surgery to correct primary hyperparathyroidism is successful in 80 to 97 per cent of initial explorations. Failures are often linked to inability to locate ectopic parathyroid glands. Although ectopic parathyroid glands are relatively common (15%) multiple ectopic glands are rarely reported. We describe a case of multiple ectopic parathyroid glands and the intraoperative approach to their localization and review the anatomy and embryology of ectopic parathyroid glands. A 39-year-old woman presented with fatigue, lethargy, and depression. On biochemical evaluation she was noted to be hypercalcemic and hyperparathyroid. Preoperative parathyroid localization failed to identify abnormal parathyroid glands. At exploration three of four parathyroid glands, including an adenoma, were located in ectopic positions by a meticulous and systematic dissection. A careful exploration coupled with a thorough knowledge of parathyroid anatomy and embryology will produce successful surgical correction of primary hyperparathyroidism in greater than 95 per cent of patients even in the few patients with multiple ectopic parathyroid glands.

Adult↗

Preoperative detection of sporadic parathyroid adenomas using technetium-99m-sestamibi: what role in clinical practice?

Preoperative localization of pathologic parathyroid glands remains controversial. Because experienced parathyroid surgeons can identify and cure parathyroid pathology in sporadic primary hyperparathyroidism in better than 95 per cent of first-time explorations, few consider preoperative localization studies cost effective in this population. However, the primary reason for failure at the initial exploration is the inability of the surgeon to identify an adenoma in a normal anatomical location. Recent reports have indicated that operative time can be reduced and initial success improved with preoperative localization of adenomas using the highly sensitive technetium-99m (Tc)-sestamibi scan. We evaluated 16 consecutive patients with sporadic primary hyperparathyroidism using a double-phase Tc-sestamibi scan with delayed images, hypothesizing that 90 per cent of adenomas would be accurately detected, and furthermore that a negative scan would predict multigland disease. Of the 16 scans, 13 showed a focal delayed washout of the tracer, constituting a positive scan. Eleven of 13 were true positive (85%), with two false positive scans (15%), both of which also had nodular thyroid disease. The three negative scans were indeed hyperplastic multigland disease, determined at exploration. The mean operative time for a bilateral exploration for the true positive cases was 109 minutes, compared to 148 minutes for a small cohort group without imaging (not significant). In conclusion, 85 per cent of adenomas can be successfully localized with the Tc-sestamibi delayed-image technique, and may decrease operative time. Additionally, a negative scan is a likely predictor of multigland disease, which allows for improved preoperative patient education and preparation for cryopreservation. These data suggest that preoperative Tc-sestamibi scanning may improve the success rate for the occasional parathyroid surgeon, and that an extended prospective trial is warranted.

Adenoma↗

Stimulation of angiogenesis by canine parathyroid tissue.

BACKGROUND: Autotransplanted parathyroid tissue is capable of inducing neovascularization in vivo, restoring calcium homeostasis with regulatory control. The mechanisms of parathyroid-induced neovascularization remain to be determined. Using an unique three-dimensional in vitro model, we tested the ability of parathyroid tissue to stimulate angiogenesis. METHODS: Healthy 1 mm3 fragments of normal canine parathyroid tissue were cocultured with freshly isolated microvessels that were embedded in a collagen I gel. After 7 days the gels were stained with Gs-1 lectin, a specific marker for rat endothelium. With image analysis the microvessel density (as the percentage of area) was determined. RESULTS: A significant increase in mean microvessel density (20.90% +/- 1.28 versus 16.51% +/- 1.66%) was seen with parathyroid coculture compared with control (n = 17, p < 0.05). There was no difference in microvessel density between controls and microvessels exposed to increasing concentrations of parathyroid hormone or calcium. The density of seeded microvessels influenced the effect of parathyroid stimulation of angiogenesis. The effect was apparent only at low seeding densities. CONCLUSIONS: We conclude that parathyroid tissue intrinsically stimulates angiogenesis in vitro by a secreted product, independent of calcium or parathyroid hormone.

Animals↗

Using the theory of reasoned action (TRA) to understand the decision to use condoms in an STD clinic population.

The theory of reasoned action (TRA) provides useful information when designing health education interventions. In this study, 703 heterosexual STD clinic clients responded to a TRA-based survey. With steady partners, social norms and attitudes toward condom use were significant predictors of intention for both men and women. The interaction of attitude and norm increased prediction for men (R = .64, p < 0.001) and women (R = .70, p < 0.001). With casual partners, attitude was a predictor for men and social norm was a predictor for women. Prior use of condoms increased prediction for men (R = .38, p < 0.001) and women (R = .47, p < 0.001). Findings suggest that, in addition to traditional TRA model variables, the relationship between sexual partners and the individual's prior experience with condom use should be incorporated into attempts to understand this complex, dyadic behavior. Examining specific outcome and normative beliefs also provides important information for intervention design.

Adult↗

Comparing the performance of health status measures for healthy older adults.

OBJECTIVES: The specific goals of the study were to compare three health status measures among older adults for their correlations with similar scales and to examine whether extreme (positive) health states might lead to measurement problems. We also report on practical administration and response problems among older adults. DESIGN: Eligible and randomly selected health plan enrollees aged 65 and older were sent a baseline survey about their health. A random sample of persons who returned this survey was recruited to participate in the comparative study. Additional questionnaires were completed by mail and telephone interviews. Measures were repeated at a 1-year follow-up mailing. SETTING: This study was conducted at Group Health Co-operative (GHC) of Puget Sound, a large prepaid health maintenance organization. PARTICIPANTS: Subjects were 200 of the 283 older adults selected (68.2% response). Mean age was 72.5 years. MEASUREMENTS: The primary measures were the Sickness Impact Profile (SIP), the Quality of Well-being Scale (QWB), and three scales of the Medical Outcomes Study Short-Form 36 (SF-36). Also included were a stress scale, the Positive Affect Scale, and the Chronic Disease Score (CDS) computed from the automated pharmacy data. RESULTS: SIP scores showed a very strong skew toward low (good health) scores with a mean of 3.4% (+/- SD 4.4). The QWB scores ranged from .50 to .90 (mean .73 +/- .09). For the MOS SF-36 scales, scores of 100 (good health) were common for both of the physical health scales but not for general health. Analyses showed the SIP, QWB, and MOS SF-36 scales were moderately to strongly correlated with similar measurement scales and with the independent measure of chronic disease and psychosocial health. Scales repeated at 1 year were highly correlated: intraclass correlation coefficients between baseline and 1 year ranged from an r = .51 to .73. CONCLUSIONS: Our results suggest that the SIP is not a useful tool for rating healthy, community-dwelling older adults. Two MOS SF-36 measures used in this study showed some tendency for "ceiling" measurement effects. The QWB demonstrated an acceptable distribution of scale scores; however, it is the most complex of the three measures to administer. Among the broad range of older adults, no one tool appears to apply to every situation.

Aged↗

Barriers to screening: the theory of reasoned action applied to mammography use in a military beneficiary population.

BACKGROUND: Mammography practices of women eligible for military health care are not known. METHODS: A questionnaire was mailed to a stratified sample of 500 military beneficiary women. The hypothesis was that this group would not differ from the general population in regular mammography use (31%) and that the theory of reasoned action (TRA) is significantly associated with intent to obtain a mammogram. RESULTS: Only 12.8% of these women had regular mammography according to current recommendations. High participation is associated with breast cancer risk factors, income, education, perceived risk of breast cancer, and a doctor's recommendation. The expanded model of the TRA regression is significantly associated with intent. CONCLUSIONS: Regular use of mammography among military beneficiaries is lower than rates in the non-military population. Providers need to stress regular use and address scheduling problems and patient beliefs about mammography. The TRA is a useful model for screening behavior.

Adult↗

Development of the kidney disease quality of life (KDQOL) instrument.

This paper describes the Kidney Disease Quality of Life (KDQOL) Instrument (dialysis version), a self-report measure that includes a 36-item health survey as the generic core, supplemented with multi-item scales targeted at particular concerns of individuals with kidney disease and on dialysis (symptom/problems, effects of kidney disease on daily life, burden of kidney disease, cognitive function, work status, sexual function, quality of social interaction, sleep). Also included were multi-item measures of social support, dialysis staff encouragement and patient satisfaction, and a single-item overall rating of health. The KDQOL was administered to 165 individuals with kidney disease (52% female; 48% male; 47% White; 27% African-American; 11% Hispanic; 8% Asian; 4% Native American; and 3% other ethnicities), sampled from nine different outpatient dialysis centres located in Southern California, the Northwest, and the Midwest. The average age of the sample was 53 years (range from 22 to 87), and 10% were 75 years or older. Internal consistency reliability estimates for the 19 multi-item scales exceeded 0.75 for every measure except one. The mean scores for individuals in this sample on the 36-item health scales were lower than the general population by one-quarter (emotional well-being) to a full standard deviation (physical function, role limitations due to physical health, general health), but similar to scores for dialysis patients in other studies. Correlations of the KDQOL scales with number of hospital days in the last 6 months were statistically significant (p < 0.05) for 14 of the 19 scales and number of medications currently being taken for nine of the scales. Results of this study provide support for the reliability and validity of the KDQOL.

Adult↗