Biomedical subjects

D B Evans

Publications and source records attributed to D B Evans.

At least 37 records · Page 2Linked to original sources

PubMed2001

Improving adherence to malaria treatment for children: the use of pre-packed chloroquine tablets vs. chloroquine syrup.

Malaria is a major cause of morbidity and mortality among children under five in sub-Saharan Africa. Prompt diagnosis and adequate treatment of acute clinical episodes are essential to reduce morbidity and prevent complications and mortality. In many countries, chloroquine syrup is the mainstay of malaria treatment for children under five. Not only is syrup more expensive than tablets, adherence to the prescribed dose at home is a problem because mothers use wrongly sized measuring devices or have difficulty with the instructions. We investigated the impact of introducing pre-packed tablets for children on adherence to treatment and compared the total cost of the tablets with that of syrup. Children aged 0--5 years diagnosed with malaria at the clinic over a 6-week period received either pre-packed tablets or syrup by random assignment. The principal caregivers were interviewed at home on day 4 after attending the clinic. Of the 155 caregivers given pre-packed tablets, 91% (n=141) adhered to the recommended dosage, while only 42% (n=61) of 144 who were provided syrup did. Only 20% of caregivers who received syrup used an accurate 5 ml measure. The cost of treatment with tablets was about one-quarter that of syrup and 62% (n=96) of caregivers preferred tablets. Pre-packed chloroquine tablets are a viable alternative to syrup.

Antimalarials↗

PubMed2001

Characterization of the in vitro phosphorylation of human tau by tau protein kinase II (cdk5/p20) using mass spectrometry.

Hyperphosphorylated tau is an integral part of the neurofibrillary tangles that form within neuronal cell bodies, and tau protein kinase II is reported to play a role in the pathogenesis of Alzheimer's disease. Recently, we reported that tau protein kinase II (cdk5/p20)-phosphorylated human tau inhibits microtubule assembly, and tau protein kinase II (cdk5/p20) phosphorylation of microtubule-associated tau results in dissociation of phosphorylated tau from the microtubules and tubulin depolymerization. In the studies reported here, a combination of mass spectrometric techniques was used to study the phosphorylation of human recombinant tau by recombinant tau protein kinase II (cdk5/p20) in vitro. The extent of phosphorylation was determined by measuring the molecular mass of phosphorylated tau using mass spectrometry. Reaction of human recombinant tau with tau protein kinase II (cdk5/p20) resulted in the formation of two major species containing either five or six phosphate groups. The specific amino acid residues phosphorylated were determined by analyzing tryptic peptides by tandem mass spectrometry via either MALDI/TOF post-source decay or by electrospray tandem mass spectrometry. Based on these experiments, we conclude that tau protein kinase II (cdk5/p20) can phosphorylate human tau at Thr(181), Thr(205), Thr(212), Thr(217), Ser(396) and Ser(404).

Amino Acid Sequence↗

PubMed2001

Combining gemcitabine with radiation in pancreatic cancer: understanding important variables influencing the therapeutic index.

We compared and evaluated available laboratory and clinical data on the use of concurrent gemcitabine (Gemzar; Eli Lilly and Company, Indianapolis, IN) and radiation in pancreatic cancer to provide guidance for subsequent prospective research initiatives. Preclinical data suggest that the timing of administration of gemcitabine with respect to radiotherapy is important, but this issue has not yet been confirmed by clinical data. Phase I clinical data indicate that the amount of acute toxicity from the combination of gemcitabine and radiotherapy is strongly related to the dose and schedule of administration of gemcitabine, as well as to the radiation field size. There also appears to be an inverse linear relationship between the maximum tolerated gemcitabine dose and radiation dose. Also important, but less clear, is the infusion rate of gemcitabine as it relates to the systemic efficacy of the drug. The combination of additional agents with gemcitabine and radiation appears to be feasible. Finally, the addition of radioprotectors may enable chemotherapy dose escalation, but safe escalation of the radiotherapy dose with newer techniques has not been established. Semin Oncol 28 (suppl 10):25-33.

Antimetabolites, Antineoplastic↗

PubMed2001

Nonfunctioning islet cell carcinoma of the pancreas: survival results in a contemporary series of 163 patients.

BACKGROUND: The natural history of nonfunctioning islet cell carcinoma of the pancreas is poorly defined. We therefore reviewed our institutional experience during a period of 12 years to define more clearly the natural history of this disease as a basis for individual therapeutic recommendations. METHODS: The records of all patients who had histologically or cytologically confirmed nonfunctioning islet cell carcinoma of the pancreas were retrospectively reviewed. Patients were grouped by extent of disease at diagnosis and by initial treatment. Survival distributions were estimated by Kaplan-Meier analysis. RESULTS: One hundred sixty-three patients with nonfunctioning islet cell carcinoma of the pancreas were identified. The overall median survival duration was 3.2 years. The median survival was 7.1 years in patients with localized disease who underwent a potentially curative resection and 5.2 years in those with locally advanced, unresectable, nonmetastatic disease (P = .04). Patients with metastatic disease that could not be resected had a median survival of 2.1 years. CONCLUSIONS: Patients with completely resected localized disease had a long median survival. Patients with nonmetastatic but unresectable locally advanced disease also had a surprisingly long median survival; major treatment-related morbidity may be hard to justify in this subgroup. The short median survival in patients with metastatic disease suggests that the frequent practice of observation in this patient subgroup needs to be reexamined and that continued investigation of regional and systemic therapies with novel agents is warranted.

Adult↗

PubMed2001

Evaluation and surgical resection of adrenal masses in patients with a history of extra-adrenal malignancy.

BACKGROUND: Adrenal abnormalities are often identified on imaging studies performed during the staging of patients presenting with a new malignancy or restaging of patients with a history of a malignancy. METHODS: We reviewed the records of patients who underwent surgical resection of an adrenal mass identified in the setting of previously or newly diagnosed extra-adrenal malignancy. RESULTS: Eighty-one patients with an adrenal mass and recently diagnosed malignancy (n = 24) or history of a malignancy (n = 57) underwent adrenalectomy. In 42 patients (52%) the adrenal mass was a metastasis. In 39 patients (48%) the adrenal mass was an additional primary adrenal tumor process: 19 pheochromocytomas, (14 syndrome-associated, 5 sporadic), 13 cortical adenomas, 3 adrenocortical carcinomas, 2 ganglioneuromas, and 2 cases of nodular hyperplasia. CONCLUSIONS: In this series nearly half of the patients with cancer and an adrenal mass had adrenal pathologic condition independent of their primary malignancy. Despite the presence of a newly diagnosed malignancy or history of malignancy, all patients with an adrenal mass should undergo a standard hormone evaluation to confirm that the mass is not a functional neoplasm. An assumption that the adrenal mass is metastatic disease will be wrong in up to 50% of such patients.

Adrenal Gland Neoplasms↗

PubMed2001

Optimal treatment strategy in patients with papillary thyroid cancer: a decision analysis.

BACKGROUND: The management of patients with papillary thyroid carcinoma (PTC) remains controversial. We used decision analysis to identify the optimal treatment strategy for patients with PTC, stratified by risk-group classification. METHODS: We designed a Markov model to compare thyroid lobectomy and total thyroidectomy (with adjuvant radioiodine therapy) in low- and high-risk patients with PTC. Morbidity, recurrence, and mortality estimates were obtained from the literature. Outcomes were quality-adjusted by using health state preferences. RESULTS: In low-risk patients, lobectomy and total thyroidectomy resulted in 31.7 and 32.9 quality-adjusted life years (QALYs). Total thyroidectomy was the optimal strategy as long as the relative risk of recurrence after lobectomy was greater than 1.3. Lobectomy became the preferred strategy if subjects were willing to give up 1.5 years of life to avoid thyroid hormone dependency and a remote risk of radioiodine-induced malignancy. In high-risk patients, lobectomy and total thyroidectomy resulted in 11.2 and 16.5 QALYs. Model results were robust to varying the permanent complication rates of initial or completion thyroidectomy, the efficacy of adjuvant radioiodine therapy, and the impact of complications and cancer recurrence on quality of life, irrespective of risk-group classification. CONCLUSIONS: Total thyroidectomy maximized quality-adjusted life expectancy in low- and high-risk patients with PTC.

Carcinoma, Papillary↗

PubMed2001

Measuring quality: from the system to the provider.

The literature on quality has often focused on process indicators. In this paper we outline a framework for describing and measuring the quality of health systems in terms of a set of desirable outcomes. We illustrate how it can be measured using data collected from a recent evaluation of health system performance conducted by the World Health Organization (WHO). We then explore the extent to which this framework can be used to measure quality for all components of the system; for example, regions, districts, hospitals, and providers. There are advantages and disadvantages to defining quality in terms of outcomes rather than process indicators. The advantage is that it focuses the attention of policy makers on whether systems are achieving the desired goals. In fact, without the ability to measure outcomes it is not possible to be sure that process changes actually improve attainment of socially desired goals. The disadvantage is that measuring outcomes at all levels of the system poses some problems particularly related to the sample sizes necessary to measure outcomes. WHO is exploring this, initially in relation to hospitals. The paper discusses two major challenges. The first is the question of attribution, deciding what part of the outcome is due to the component of the system under discussion. The second is the question of timing, including all the effects of current health actions now and in the future.

Delivery of Health Care↗

PubMed2001

Effect of preoperative biliary decompression on pancreaticoduodenectomy-associated morbidity in 300 consecutive patients.

OBJECTIVE: To examine the relationship between preoperative biliary drainage and the morbidity and mortality associated with pancreaticoduodenectomy. SUMMARY BACKGROUND DATA: Recent reports have suggested that preoperative biliary drainage increases the perioperative morbidity and mortality rates of pancreaticoduodenectomy. METHODS: Peri-operative morbidity and mortality were evaluated in 300 consecutive patients who underwent pancreaticoduodenectomy. Univariate and multivariate logistic regression analyses were done to evaluate the relationship between preoperative biliary decompression and the following end points: any complication, any major complication, infectious complications, intraabdominal abscess, pancreaticojejunal anastomotic leak, wound infection, and postoperative death. RESULTS: Preoperative prosthetic biliary drainage was performed in 172 patients (57%) (stent group), 35 patients (12%) underwent surgical biliary bypass performed during prereferral laparotomy, and the remaining 93 patients (31%) (no-stent group) did not undergo any form of preoperative biliary decompression. The overall surgical death rate was 1% (four patients); the number of deaths was too small for multivariate analysis. By multivariate logistic regression, no differences were found between the stent and no-stent groups in the incidence of all complications, major complications, infectious complications, intraabdominal abscess, or pancreaticojejunal anastomotic leak. Wound infections were more common in the stent group than the no-stent group. CONCLUSIONS: Preoperative biliary decompression increases the risk for postoperative wound infections after pancreaticoduodenectomy. However, there was no increase in the risk of major postoperative complications or death associated with preoperative stent placement. Patients with extrahepatic biliary obstruction do not necessarily require immediate laparotomy to undergo pancreaticoduodenectomy with acceptable morbidity and mortality rates; such patients can be treated by endoscopic biliary drainage without concern for increased major complications and death associated with subsequent pancreaticoduodenectomy.

Adolescent↗

PubMed2001

Toxicity and efficacy of concurrent gemcitabine and radiotherapy for locally advanced pancreatic cancer.

BACKGROUND: Gemcitabine and radiotherapy are a potent combination. A clinical assessment of the therapeutic ratio for locally advanced pancreatic cancer patients has not yet been reported. AIM OF STUDY: To assess the toxicity, survival, and pattern of failure of locally advanced pancreatic cancer patients treated with concurrent gemcitabine-based chemoradiation. Patients and Methods. Between the dates of December 1996 and August 2000 51 patients with locally advanced unresectable adenocarcinoma of the pancreas were treated with concurrent gemcitabine and radiotherapy at MDACC. Patients received 250-500 mg/m2 of gemcitabine weekly x7 over 30 min and 30-33 Gy in 10-11 fractions over two weeks to the primary tumor and regional lymphatics. Severe toxicity was defined as admission > 5 d, mucosal ulceration, > 3 dose deletions of gemcitabine or toxicity resulting in surgical intervention or that resulted in death. RESULTS: The median survival was 11 mo. Overall, 37 of 51 patients had objective evidence of local progression. The actuarial rate of local progression rate at 9 mo was 70%. The 9-mo distant metastasis rate was 52%. Tumors > or = 10 cm2 had worse local control, distant control, and overall survival. Six patients underwent pancreaticoduodenectomy after therapy. After review of the imaging, only four of these patients had minimal arterial involvement, one was incorrectly staged, and one had initial inflammatory change on CT that resolved. Twelve of 51 (24%) patients suffered severe acute toxicity, and 17 of 51 (33%) patients were admitted for supportive care. CONCLUSION: Concurrent gemcitabine and radiotherapy can be a very difficult combination to administer safely. Our results do not suggest a prolongation of median survival for patients with localized pancreatic cancer treated with this therapy. It is possible that gemcitabine-based chemoradiation contributes to the margin-negative resectability of a small number of patients with minimal arterial involvement, but this benefit is obscured by the frequent toxicity encountered in most patients. Locally advanced pancreatic cancer patients should continue to be enrolled on prospective studies investigating novel combinations of cytotoxic and/or biologic agents with concurrent radiotherapy.

Adenocarcinoma↗

PubMed2001

Phase I study of concomitant gemcitabine and IMRT for patients with unresectable adenocarcinoma of the pancreatic head.

PURPOSE: We hypothesized that dynamic intensity-modulated radiotherapy (IMRT) would protect normal tissues enough to allow the escalation of either the gemcitabine or radiotherapy dose in unresectable pancreatic cancer patients. METHODS AND MATERIALS: The trial was designed to build on a previous phase I trial that determined the maximum tolerated dose (MTD) of gemcitabine (350 mg/m2) with concurrent radiotherapy (30 Gy/10 fractions). Only patients with unresectable disease based on established criteria were eligible. The plan was to alternate escalating the radiation dose by 3 Gy and the gemcitabine dose by 50 mg/m2. The starting dose of gemcitabine was 350 mg/m2 and 33 Gy/11 fractions of IMRT to the regional lymphatics and primary disease. The NCI Common Toxicity Criteria were used for dose-limiting toxicity (DLT). RESULTS: All three patients in the first cohort treated suffered DLT. Therefore, a second cohort of patients received a lower gemcitabine dose (250 mg/m2). Both patients treated at this dose level experienced DLT. The DLTs were all due to myelosuppression and upper gastrointestinal toxicity. All patients required a gemcitabine dose reduction. Also, four patients required hospital admission for supportive care, while the fifth died of an unrelated cause shortly after completing therapy. The trial was then closed due to excessive toxicity. CONCLUSION: Hypofractionated dynamic IMRT to the primary site and regional lymphatics did not permit escalation of either the radiation or gemcitabine dose. Dynamic IMRT requires further investigation before it can be applied to toxic combinations of chemotherapy and radiation in the upper abdomen.

Adenocarcinoma↗

PubMed2001

Impact of prepackaging antimalarial drugs on cost to patients and compliance with treatment.

OBJECTIVE: To examine the extent to which district health teams could reduce the burden of malaria, a continuing major cause of mortality and morbidity, in a situation where severe resource constraints existed and integrated care was provided. METHODS: Antimalarial drugs were prepackaged into unit doses in an attempt to improve compliance with full courses of chemotherapy. FINDINGS: Compliance improved by approximately 20% in both adults and children. There were 50% reductions in cost to patients, waiting time at dispensaries and drug wastage at facilities. The intervention, which tended to improve both case and drug management at facilities, was well accepted by health staff and did not involve them in additional working time. CONCLUSION: The prepackaging of antimalarials at the district level offers the prospect of improved compliance and a reduction in the spread of resistance.

Acetaminophen↗

PubMed2001

Neoadjuvant strategies for pancreatic cancer.

Recent prospective and retrospective data suggest that the use of multimodality therapy combining pancreaticoduodenectomy with postoperative adjuvant chemotherapy (fluorouracil) and external-beam radiation therapy maximizes local tumor control and improves the length of survival in pancreatic cancer patients, compared with surgery alone. Since postoperative chemoradiation is often delayed in these patients due to the morbidity and prolonged recovery time associated with surgery, investigators are assessing the efficacy of administering chemoradiation before pancreaticoduodenectomy in patients with potentially resectable pancreatic adenocarcinoma. When given prior to surgery, chemoradiation is not delayed and patients found to have disease progression after chemoradiation are not subjected to an unnecessary laparotomy.

Adenocarcinoma↗

PubMed2001

Phase I trial of gemcitabine combined with radiation for the treatment of locally advanced pancreatic adenocarcinoma.

Gemcitabine has modest activity in the treatment of advanced pancreatic cancer and is a potent radiosensitizer. We conducted a Phase I trial to determine the maximum tolerated dose of weekly gemcitabine delivered concurrently with radiation therapy for the treatment of locally advanced adenocarcinoma of the pancreatic head and to assess the treatment-related toxic effects associated with such a regimen. Eighteen patients with pathologically proven, locally advanced adenocarcinoma of the pancreatic head were enrolled in this study. Patients received seven weekly doses of gemcitabine with 3000 cGy of external beam radiation therapy delivered during the first 2 weeks of therapy. Six patients received gemcitabine at 350 mg/m(2)/week, nine at 400 mg/m(2)/week, and three at 500 mg/m(2)/week. Grade 3-4 hematological toxicity was observed in over half the patients treated. Nonhematological toxicities were significant and included fatigue, anorexia, nausea, vomiting, and dehydration. Forty-four % of the patients required admission to the hospital for management of nausea/vomiting and dehydration. The risk of hospitalization appeared to be dose-related; all of the three patients treated at 500 mg/m(2)/week required hospital admission during treatment. Seventeen patients were evaluated for response, and eight patients (47%) had evidence of a local anticancer effect. Four of these eight patients (24%) had a partial response to therapy. The median survival for the entire group was 6 months. The 1-year survival rate for patients with an objective response to therapy was 66%. The clinical responses observed in this group of patients suggest gemcitabine is a clinically relevant radiosensitizer in patients with pancreatic adenocarcinoma. However, the toxic effects are significant, suggesting that until dose and scheduling issues are explored further, concomitant administration of gemcitabine and radiation therapy should still be considered investigational.

Adenocarcinoma↗

PubMed2000

Tau phosphorylation at serine 396 and serine 404 by human recombinant tau protein kinase II inhibits tau's ability to promote microtubule assembly.

In Alzheimer's disease, hyperphosphorylated tau is an integral part of the neurofibrillary tangles that form within neuronal cell bodies and fails to promote microtubule assembly. Dysregulation of the brain-specific tau protein kinase II is reported to play an important role in the pathogenesis of Alzheimer's disease (Patrick, G. N., Zukerberg, L., Nikolic, M., De La Monte, S., Dikkes, P., and Tsai, L.-H. (1999) Nature 402, 615-622). We report here that in vitro phosphorylation of human tau by human recombinant tau protein kinase II severely inhibits the ability of tau to promote microtubule assembly as monitored by tubulin polymerization. The ultrastructure of tau-mediated polymerized tubulin was visualized by electron microscopy and compared with phosphorylated tau. Consistent with the observed slower kinetics of tubulin polymerization, phosphorylated tau is compromised in its ability to generate microtubules. Moreover, we show that phosphorylation of microtubule-associated tau results in tau's dissociation from the microtubules and tubulin depolymerization. Mutational studies with human tau indicate that phosphorylation by tau protein kinase II at serine 396 and serine 404 is primarily responsible for the functional loss of tau-mediated tubulin polymerization. These in vitro results suggest a possible role for tau protein kinase II-mediated tau phosphorylation in initiating the destabilization of microtubules.

Amino Acid Substitution↗

PubMed2000

The N-terminal domains of cyclin-dependent kinase inhibitory proteins block the phosphorylation of cdk2/Cyclin E by the CDK-activating kinase.

It has been suggested that binding of p27 and p21 kinase inhibitory proteins (KIPs) to cyclin-dependent kinases (cdks) render them inaccessible to cdk-activating kinase (CAK), presumably by steric hindrance by the C-terminal residues. However, this common mechanism of inhibition is inconsistent with the known structural divergence in the p27 and p21 C-terminal domains. Therefore, we studied the direct binding of N-terminal minimal domain of p27 (amino acids 28-81) to cdk2/cyclin E. An unlabeled p27 minimal domain, mutated in the N-terminal LFG motif, was unable to compete with a labeled minimal domain for binding to cdk2/cyclin E. The p27 and its minimal domain inhibited CAK-mediated phosphorylation of cdk2/cyclin E. This inhibitory effect was significantly diminished with p27 minimal domain mutated in the LFG motif. A synthetic peptide, ACRRLFGPVDSE, from the N-terminal residues 17-28 of p21, was also a potent inhibitor of CAK-mediated cdk2/cyclin E phosphorylation. Taken together, these results show that anchoring of p27 or p21 KIPs to cyclin E via the N-terminal LFG-containing motif can block CAK access to its cdk2/cyclin E substrate.

Animals↗

PubMed2000

Relative contributions of technetium Tc 99m sestamibi scintigraphy, intraoperative gamma probe detection, and the rapid parathyroid hormone assay to the surgical management of hyperparathyroidism.

HYPOTHESIS: Technetium Tc 99m sestamibi scintigraphy, intraoperative gamma probe detection, and the rapid parathyroid hormone assay have been used to permit a directed operation in patients with hyperparathyroidism. We hypothesized that the coordinated use of these techniques might be particularly useful in patients who require a second operation for hyperparathyroidism. DESIGN: Retrospective analysis was performed to determine the specific contribution of these technologies to the surgical management of patients with hyperparathyroidism who underwent evaluation by at least 2 of these techniques between April 1996 and October 1999. SETTING: Patients were evaluated and treated by an endocrine tumor surgery group within a tertiary care referral center. PATIENTS: Coordinated application of 99mTc-sestamibi scintigraphy, intraoperative gamma probe detection, and/or the rapid parathyroid hormone assay was performed in 32 patients. RESULTS: Twenty-eight of 32 patients had primary hyperparathyroidism, 3 had multiple endocrine neoplasia type 1, and 1 had secondary hyperparathyroidism. The surgical procedure was an initial cervical exploration in 19 and a second operative procedure in 13. Parathyroidectomy was successful in all patients. A directed anatomic operation was performed in 24 patients, including 11 patients who underwent second operative procedures and 9 patients who underwent minimally invasive procedures under local anesthesia. A directed operation was facilitated by sestamibi scan in 22 of 24 patients, intraoperative gamma probe detection in 5 of 23 patients, and the rapid parathyroid hormone assay in 15 of 15 patients. CONCLUSIONS: Coordinated application of 99mTc-sestamibi scintigraphy, intraoperative gamma probe detection, and the rapid parathyroid hormone assay allows for successful directed reoperative parathyroidectomy; a minimally invasive procedure may be performed in selected patients.

Adenoma↗

PubMed2000

ATP site-directed competitive and irreversible inhibitors of protein kinases.

Several tyrosine and serine/threonine protein kinases have emerged in the last few years as attractive targets in the search for new therapeutic agents being applicable in many different disease indications. Initially, inhibition of these protein kinases by ATP site-directed inhibitors was considered less prone to success, but medicinal chemists from both academia and industry have been able to impart potency and selectivity to a limited number of scaffolds by modulating and fine-tuning the interactions of the modified template with the ATP binding site of the selected kinase. The chemical templates that have been used in the synthesis of ATP site-directed protein kinase inhibitors are reviewed with emphasis on the kinase inhibitors that have entered or are about to enter clinical trials. Examples have been selected to illustrate how structure-based design approaches and new methods to increase compound diversity have had an impact on this area of research.

Adenosine Triphosphate↗

PubMed2000

Development of WHO guidelines on generalized cost-effectiveness analysis.

The growing use of cost-effectiveness analysis (CEA) to evaluate specific interventions is dominated by studies of prospective new interventions compared with current practice. This type of analysis does not explicitly take a sectoral perspective in which the costs and effectiveness of all possible interventions are compared, in order to select the mix that maximizes health for a given set of resource constraints. WHO guidelines on generalized CEA propose the application of CEA to a wide range of interventions to provide general information on the relative costs and health benefits of different interventions in the absence of various highly local decision constraints. This general approach will contribute to judgements on whether interventions are highly cost-effective, highly cost-ineffective, or something in between. Generalized CEAs require the evaluation of a set of interventions with respect to the counterfactual of the null set of the related interventions, i.e. the natural history of disease. Such general perceptions of relative cost-effectiveness, which do not pertain to any specific decision-maker, can be a useful reference point for evaluating the directions for enhancing allocative efficiency in a variety of settings. The proposed framework allows the identification of current allocative inefficiencies as well as opportunities presented by new interventions.

Cost-Benefit Analysis↗