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D B Evans

Publications and source records attributed to D B Evans.

At least 19 recordsLinked to original sources
PubMed2006

Staging of pancreatic cancer with multidetector CT in the setting of preoperative chemoradiation therapy.

BACKGROUND: Preoperative chemoradiation can potentially improve outcomes in patients with pancreatic cancer. This study addresses its effect on staging pancreatic cancer with multidetector computed tomography (MDCT). METHODS: Fifty-five patients underwent a dual-phase MDCT pancreas protocol for proved pancreatic cancer. Of these, 16 patients underwent preoperative chemoradiation. Three radiologists independently reviewed images to assess for locally advanced disease, liver and peritoneal metastases on baseline studies of all 55 patients, and on follow-up preoperative studies for the 16 patients receiving preoperative therapy. Overall score for resectability was graded on a scale from 1 to 5 (1, definitely resectable; 5. definitely unresectable). Receiver operating characteristic curves and weighted (kappa statistics were determined. RESULTS: The areas under the receiver operating characteristic curves for readers 1, 2, and 3 were 0.98, 0.96, and 0.90, respectively. Weighted kappa values for reader 1 versus reader 2, reader 1 versus reader 3, and reader 2 versus reader 3 were 0.90, 0.57, and 0.54, respectively. Interpreting scores of 1 to 3 for resectability as resectable disease, the mean values for sensitivity, specificity, negative predictive value, positive predictive value, and accuracy were 0.92, 0.91, 0.74, 0.98, and 0.92 respectively. CONCLUSION: The negative predictive value for MDCT for identifying unresectable pancreatic cancer in the setting of preoperative therapy is comparable to that reported in the absence of neoadjuvant therapy.

Aged↗
PubMed2006

Intraductal papillary mucinous neoplasms of the pancreas.

The introduction of the exocrine pancreatic classification by the World Health Organization and improvements in pancreatic imaging have led to an improved understanding of intraductal papillary mucinous neoplasms (IPMNs) of the pancreas. As a result, IPMNs of the pancreas are increasingly being recognized as a separate disease entity. IPMNs are characterized by the cystic dilatation of the pancreatic duct and its branches, with papillary projections. There are three histological subtypes of IPMNs: main duct, branch duct, and mixed. The degree of atypia ranges from adenoma to frank invasive carcinoma. The lymph nodes are involved considerably less frequently than they are in pancreatic adenocarcinoma. Most patients are symptomatic at diagnosis and require a diagnostic workup similar to that for patients with pancreatic adenocarcinoma. Although some investigators continue to advocate total pancreatectomy, the evidence in support of this is decreasing. Partial pancreatectomy remains the treatment option. Intraoperative assessment of the resection surgical margins is an important component of surgical resection. Additionally, controversy also exists regarding the nature of the follow-up and the need for adjuvant chemoradiation therapy in the patient. Unlike ductal adenocarcinomas, IPMNs follow a relatively indolent course; the 5-year survival rate in patients with invasive IPMNs is 57%. A mural nodule and a main pancreatic duct diameter greater than 5 mm have been found to be predictors of malignancy.

Adenocarcinoma, Mucinous↗
PubMed2005

Overexpression of neuropilin-1 promotes constitutive MAPK signalling and chemoresistance in pancreatic cancer cells.

Neuropilin-1 (NRP-1) is a novel co-receptor for vascular endothelial growth factor (VEGF). Neuropilin-1 is expressed in pancreatic cancer, but not in nonmalignant pancreatic tissue. We hypothesised that NRP-1 expression by pancreatic cancer cells contributes to the malignant phenotype. To determine the role of NRP-1 in pancreatic cancer, NRP-1 was stably transfected into the human pancreatic cancer cell line FG. Signal transduction was assessed by Western blot analysis. Susceptibility to anoikis (detachment induced apoptosis) was evaluated by colony formation after growth in suspension. Chemosensitivity to gemcitabine or 5-fluorouracil (5-FU) was assessed by MTT assay in pancreatic cancer cells following NRP-1 overexpression or siRNA-induced downregulation of NRP-1. Differential expression of apoptosis-related genes was determined by gene array and further evaluated by Western blot analysis. Neuropilin-1 overexpression increased constitutive mitogen activated protein kinase (MAPK) signalling, possibly via an autocrine loop. Neuropilin-1 overexpression in FG cells enhanced anoikis resistance and increased survival of cells by > 30% after exposure to clinically relevant levels of gemcitabine and 5-FU. In contrast, downregulation of NRP-1 expression in Panc-1 cells markedly increased chemosensitivity, inducing > 50% more cell death at clinically relevant concentrations of gemcitabine. Neuropilin-1 overexpression also increased expression of the antiapoptotic regulator, MCL-1. Neuropilin-1 overexpression in pancreatic cancer cell lines is associated with (a) increased constitutive MAPK signalling, (b) inhibition of anoikis, and (c) chemoresistance. Targeting NRP-1 in pancreatic cancer cells may downregulate survival signalling pathways and increase sensitivity to chemotherapy.

Antineoplastic Agents, Alkylating↗
PubMed2005

The validation of new aromatase monoclonal antibodies for immunohistochemistry--a correlation with biochemical activities in 46 cases of breast cancer.

Intratumoral aromatase is a therapeutic target for the treatment of post-menopausal estrogen-dependent breast cancers. Therefore, reliable methods should be developed for routine application for the detection of intratumoral aromatase. Immunohistochemistry (IHC) is considered one of the most suitable methods in this regard. A multi-centre collaborative group has been established to generate and validate new aromatase monoclonal antibodies. We have selected two monoclonal antibodies, #677 against native aromatase protein and F2 against formalin-fixed protein for this purpose. With these two monoclonal antibodies 43 cases of invasive ductal carcinoma, which had been previously assayed for aromatase activity by product isolation methodology, were immunostained in three laboratories in UK, USA and Japan and independently evaluated by three pathologists (H.S., T.A. and S.G.S.). Staining of malignant epithelium, adipose tissue, normal/benign and stromal compartments of the tumors were assessed by estimating the proportion of positive staining cells and the relative intensity of staining in this fashion. Immunoreactivity could be detected in each component of the tissue specimens but a significant positive correlation with biochemical activity was detected only in malignant epithelium stained with 677 not in other components with #677 and not in any of the components. Staining using F2 as a primary antibody did not produce a positive correlation in any components with aromatase activity. These results suggest that we now have a monoclonal antibody against aromatase (#677) which may be used to stain archival materials. A methodology and scoring system is recommended whereby staining significantly correlates with aromatase activity of the resected tissue specimens of breast cancer.

Antibodies, Monoclonal↗
PubMed2004

Surgical and endoscopic palliation for pancreatic cancer.

Patients with pancreatic cancer often present with locally advanced or metastatic disease and are deemed not to be candidates for a curative resection. Palliation in these patients focuses on relief of biliary obstruction, gastroduodenal obstruction and pain. Palliative treatment modalities include both surgical and nonsurgical approaches. Biliary obstruction is often initially treated with endoscopic biliary stenting. Two major types of biliary stents are used, plastic and metallic stents. Both of these provide similar initial relief of biliary obstruction, however, plastic stents have a greater propensity for occlusion and should primarily be used in patients with anticipated short survival duration. Metallic stents have a greater initial cost, but provide an overall cost-saving in patients with expected survival duration of over 6 months. Surgical palliation for biliary obstruction should be primarily considered in patients who fail endoscopic biliary decompression or who develop clinical evidence of gastroduodenal obstruction. In these patients, surgical palliation should consist of biliary decompression with a choledochojejunostomy when ever feasible, a gastroduodenal bypass and a chemical splanchnicectomy for pain relief. An initial prophylactic gastroenterostomy at the time of endoscopic biliary decompression is rarely indicated. The role of palliative pancreaticoduodenectomy remains controversial and to date there are no prospective randomized data to support its role in palliation of locally advanced pancreatic cancer. This review examines the available data from prospective trials for surgical and nonsurgical palliation of locally advanced and metastatic pancreatic cancer.

Choledochostomy↗
PubMed2003

Pancreatic leak after left pancreatectomy is reduced following main pancreatic duct ligation.

BACKGROUND: Although much is known about the long-term outcome of patients undergoing left (distal) pancreatectomy for malignancy, comparatively little is known about the optimal management strategy for the residual transected pancreatic parenchyma and the divided pancreatic duct. Clinicopathological and operative factors that may contribute to postoperative pancreatic leak were evaluated. METHODS: A retrospective review of the medical records of 126 patients who underwent left pancreatectomy between June 1990 and December 1999 at the University of Texas M. D. Anderson Cancer Center was performed. RESULTS: Indications for left pancreatectomy included pancreatic neoplasms (n = 42; 33.3 per cent), en bloc resection for management of retroperitoneal sarcoma (n = 21; 16.7 per cent), gastric adenocarcinoma (n = 14; 11.1 per cent), renal cell carcinoma (n = 11; 8.7 per cent) and other tumours or benign conditions (n = 38; 30.2 per cent). Pancreatic parenchymal closure was accomplished by a hand-sewn technique, mechanical stapling, or a combination of the two in 83, 20 and 15 patients respectively. No form of parenchymal closure was used in eight patients. Identification of the pancreatic duct and suture ligation was performed in 73 patients (57.9 per cent). Twenty-five patients (19.8 per cent) developed a pancreatic leak. For subgroups having duct ligation or no duct ligation, pancreatic leak rates were 9.6 per cent (seven of 73 patients) and 34.0 per cent (18 of 53 patients) respectively (P < 0.001). Multivariate analysis including clinicopathological and operative factors indicated that failure to ligate the pancreatic duct was the only feature associated with an increased risk for pancreatic leak (odds ratio 5.0 (95 per cent confidence interval 2.0 to 10.0); P = 0.001). CONCLUSION: Pancreatic leak remains a common complication after left pancreatectomy. The incidence of leak is reduced significantly when the pancreatic duct is identified and directly ligated during left pancreatectomy.

Adenocarcinoma↗
PubMed2003

An integrated view of aromatase and its inhibition.

Aromatase inhibition has become a major treatment strategy for postmenopausal women with oestrogen-dependent breast cancer. Its optimal application is, however, dependent upon (i) the accurate identification of cancers which are ultimately dependent upon the activity of the aromatase enzyme, (ii) the use of the best method/inhibitor by which to blockade aromatase activity. The single best predictor of response to aromatase inhibitors is the presence of tumour oestrogen receptors; receptor-negative cancers rarely respond whereas those with high levels seem particularly likely to benefit. However, there is a need for additional discriminatory markers. The use of microarray technology coupled with neoadjuvant therapy is likely to yield promising candidate genes. The finding that, amongst peripheral tissues, the tumour itself may have high activity has led to the suggestion that the tumour aromatase measurements may be predictive; however, in situ studies and the lack of robust assays for tumour aromatase suggest that tumour aromatase may not be an influential marker. Whilst drugs such as anastrozole, exemestane, formestane and letrozole are all effective and specific inhibitors of aromatase, they differ in structure, potency and mechanism of action. Thus, differential sensitivity of tissues/tumours and non-cross resistance mean inhibitors are not equivalent and individual agents may have differing roles according to the setting in which they will be used. Aromatase inhibitors have evolved as key endocrine agents in the treatment of breast cancer. They offer the promise of rational treatment management based on the accurate identification of individual cohorts of tumours responsive to specific drugs.

Aromatase↗
PubMed2003

Validation of new aromatase monoclonal antibodies for immunohistochemistry: progress report.

Intratumoral aromatase is a potential therapeutic target for the treatment of postmenopausal estrogen-dependent breast cancers. Therefore, reliable methods should be developed for routine application for the detection of intratumoral aromatase. A multi-center collaborative group has been established to generate and validate new aromatase monoclonal antibodies (MAbs). A recombinant GST-aromatase fusion protein was expressed in baculovirus and the purified protein was used for immunization of mice either as a native or formalin-fixed antigen. Hybridomas were generated using standard techniques and screened biochemically prior to immunohistochemistry (IHC) evaluation in human placenta, ovary and breast cancer tissues. Twenty-three MAbs selected by biochemical assays were further evaluated by IHC of paraffin-embedded tissue sections including normal ovary, and placenta, and a small series of 10 breast carcinomas. Of the 23 MAbs, 2 (clones 677 and F2) were determined to specifically stain cell types known to express aromatase in normal tissues. In breast carcinomas staining of malignant epithelium, adipose tissue, normal/benign and stromal compartments was detected. IHC was performed and independently evaluated by three pathologists (HS, TJA and SGS), each using the same evaluation criteria for staining intensity and proportion of immunopositive cells. With these two MAbs, interpathologist and intralaboratory variations were minimal in comparison with differences which could be detected between tissue specimens and antibodies.

Animals↗
PubMed2001

Letrozole is more effective neoadjuvant endocrine therapy than tamoxifen for ErbB-1- and/or ErbB-2-positive, estrogen receptor-positive primary breast cancer: evidence from a phase III randomized trial.

PURPOSE: Expression of ErbB-1 and ErbB-2 (epidermal growth factor receptor and HER2/neu) in breast cancer may cause tamoxifen resistance, but not all studies concur. Additionally, the relationship between ErbB-1 and ErbB-2 expression and response to selective aromatase inhibitors is unknown. A neoadjuvant study for primary breast cancer that randomized treatment between letrozole and tamoxifen provided a context within which these issues could be addressed prospectively. PATIENTS AND METHODS: Postmenopausal patients with estrogen- and/or progesterone receptor-positive (ER+ and/or PgR+) primary breast cancer ineligible for breast-conserving surgery were randomly assigned to 4 months of neoadjuvant letrozole 2.5 mg daily or tamoxifen 20 mg daily in a double-blinded study. Immunohistochemistry (IHC) for ER and PgR was conducted on pretreatment biopsies and assessed by the Allred score. ErbB-1 and ErbB-2 IHC were assessed by intensity and completeness of membranous staining according to published criteria. RESULTS: For study biopsy-confirmed ER+ and/or PgR+ cases that received letrozole, 60% responded and 48% underwent successful breast-conserving surgery. The response to tamoxifen was inferior (41%, P =.004), and fewer patients underwent breast conservation (36%, P =.036). Differences in response rates between letrozole and tamoxifen were most marked for tumors that were positive for ErbB-1 and/or ErbB-2 and ER (88% v 21%, P =.0004). CONCLUSION: ER+, ErbB-1+, and/or ErbB-2+ primary breast cancer responded well to letrozole, but responses to tamoxifen were infrequent. This suggests that ErbB-1 and ErbB-2 signaling through ER is ligand-dependent and that the growth-promoting effects of these receptor tyrosine kinases on ER+ breast cancer can be inhibited by potent estrogen deprivation therapy.

Antineoplastic Agents↗
PubMed2001

Comparative efficiency of national health systems: cross national econometric analysis.

OBJECTIVE: To improve the evidence base for health policy by devising a method to measure and monitor the performance of health systems. DESIGN: Estimation of the relation between levels of population health and the inputs used to produce health. SETTING: 191 countries. MAIN OUTCOME MEASURE: Health system efficiency (performance). RESULTS: Estimated efficiency varied from nearly fully efficient to nearly fully inefficient. Countries with a history of civil conflict or high prevalence of HIV and AIDS were less efficient. Performance increased with health expenditure per capita. CONCLUSIONS: Increasing the resources for health systems is critical to improving health in poor countries, but important gains can be made in most countries by using existing resources more efficiently.

Delivery of Health Care↗
PubMed2001

Role of cysteine-291 and cysteine-322 in the polymerization of human tau into Alzheimer-like filaments.

Filamentous tau pathology is central to a large number of dementing disorders, including Alzheimer's disease in which polymerized tau is hyperphosphorylated. Previous studies on heparin-dependent tau polymerization, using recombinant tau isoforms lacking Cys-291, suggest that tau dimerization via Cys-322 is critical for initiation of assembly of soluble tau into filaments. We report heparin-dependent in vitro polymerization of human recombinant tau (1-383 isoform), containing both Cys-291 and Cys-322, into paired helical filaments as characterized by electron microscopy. Tau polymerization, under physiological tau concentrations in the presence of dithiothreitol (DTT), was followed by a Thioflavine S fluorescence assay. To understand the molecular basis for heparin-induced tau polymerization, we expressed and purified C291A, C322A, and C291A/C322A tau mutants. The DTT requirement for tau polymerization was abolished using either the C291A or C322A tau mutant and polymerization was not observed with the C291A/C322A tau double mutant. Analysis by sodium dodecyl sulfate gel electrophoresis showed that, unlike wild type tau, a significant amount of the C291A mutant and the C322A mutant is present as a disulfide bonded dimer. Taken together these results suggest that, in isoforms containing both Cys-291 and Cys-322, a dimeric tau with an intermolecular disulfide bond through either Cys-291 or Cys-322 is presumably acting as a seed for initiation of tau polymerization.

Alzheimer Disease↗
PubMed2001

Critical issues in the economic evaluation of interventions against communicable diseases.

Economic appraisal seeks to provide policy-makers with guidance about how scarce resources can be used to derive the greatest possible social benefit. Its use in the health sector has increased dramatically over the last decade although much of it has been focused on the problems of the more developed countries. The relatively sparse literature on communicable diseases has been dominated by interventions related to HIV/AIDS, hepatitis, malaria and tropical diseases. Reviews of this literature from the perspective of specific conditions such as Hepatitis B are already available, and recently the entire literature has been evaluated against the technical criteria for economic evaluations published in standard textbooks. Accordingly, this paper focuses on issues which would make economic appraisal more useful to policy-makers than it currently is. Given that few countries have the resources to undertake all the necessary analysis in their own settings, it is important that studies in one setting are undertaken in a way that allow generalisability to similar settings. Some of the most important challenges this poses for cost-effectiveness analysis (CEA) are identified. Firstly, incremental analysis is appropriate to local decision making when policy-makers are constrained to keep the current interventions and can consider only marginal improvements. However, it does not allow re-evaluation of existing interventions and is not transferable across settings. A version of Generalised CEA is proposed as an alternative. Secondly, data on costs and effectiveness are often not presented appropriately. The challenge for effectiveness is to adjust the evidence from efficacy studies to allow for different patient or population groups, and local variations in adherence, coverage, and infrastructure. For costs, it is important for studies to report the physical resources used in an intervention as well as unit prices. Thirdly, some long-term effects are still not well incorporated into CEA, especially those affecting child development and drug resistance. These questions are technically challenging and require more concerted efforts over the next few years. Finally, it is important for analysts to provide decision-makers with estimates of the resources that would be required to implement interventions claimed to be cost-effective. These improvements would better enable the evidence from economic analyses to enter the policy debate and be weighed against the other goals and objectives of the health system when allocating scarce resources.

Communicable Disease Control↗
PubMed2001

Stochastic league tables: communicating cost-effectiveness results to decision-makers.

The presentation of the results of uncertainty analysis in cost-effectiveness analysis (CEA) in the literature has been relatively academic with little attention paid to the question of how decision-makers should interpret the information particularly when confidence intervals overlap. This question is especially relevant to sectorial CEA providing information on the costs and effects of a wide range of interventions. This paper introduces stochastic league tables to inform decision-makers about the probability that a specific intervention would be included in the optimal mix of interventions for various levels of resource availability, taking into account the uncertainty surrounding costs and effectiveness. This information helps decision-makers decide on the relative attractiveness of different intervention mixes, and also on the implications for trading gains in efficiency for gains in other goals such as reducing health inequalities and increasing health system responsiveness.

Communication↗
PubMed2001

Adrenal cortical carcinoma.

Adrenal cortical carcinoma is a rare endocrine tumor for which complete surgical resection is the only potentially curative treatment. Accurate preoperative evaluation (biochemical and radiographic) of the patient who presents with an adrenal mass maximizes the opportunity for the patient to undergo a complete, margin-negative resection of the primary tumor, which is the most powerful prognostic variable for long-term survival. The response to chemotherapy or mitotane is modest in patients with advanced disease. Hopefully, an improved understanding of the molecular pathogenesis of this challenging tumor will lead to the development of more effective therapies in the future.

Adrenal Cortex↗
PubMed2001

Neoadjuvant chemoradiotherapy for adenocarcinoma of the pancreas: treatment variables and survival duration.

BACKGROUND: For patients with potentially resectable pancreatic cancer, the poor outcome associated with resection alone and the survival advantage demonstrated for combined-modality therapy have stimulated interest in preoperative chemoradiotherapy. The goal of this study was to analyze the effects of different preoperative chemoradiotherapy schedules, intraoperative radiation therapy, patient factors. and histopathologic variables on survival duration and patterns of treatment failure in patients who underwent pancreaticoduodenectomy for adenocarcinoma of the pancreatic head. METHODS: Data on 132 consecutive patients who received preoperative chemoradiation followed by pancreaticoduodenectomy for adenocarcinoma of the pancreatic head between June 1990 and June 1999 were retrieved from a prospective pancreatic tumor database. Patients received either 45.0 or 50.4 Gy radiation at 1.8 Gy per fraction in 28 fractions or 30.0 Gy at 3.0 Gy per fraction in 10 fractions with concomitant infusional chemotherapy (5-fluorouracil, paclitaxel, or gemcitabine). If restaging studies demonstrated no evidence of disease progression, patients underwent pancreaticoduodenectomy. All patients were evaluated with serial postoperative computed tomography scans to document first sites of tumor recurrence. RESULTS: The overall median survival from the time of tissue diagnosis was 21 months (range 19-26, 95%CI). At last follow-up, 41 patients (31%) were alive with no clinical or radiographic evidence of disease. The survival duration was superior for women (P = .04) and for patients with no evidence of lymph node metastasis (P = .03). There was no difference in survival duration associated with patient age, dose of preoperative radiation therapy, the delivery of intraoperative radiotherapy, tumor grade, tumor size, retroperitoneal margin status, or the histologic grade of chemoradiation treatment effect. CONCLUSION: This analysis supports prior studies which suggest that the survival duration of patients with potentially resectable pancreatic cancer is maximized by the combination of chemoradiation and pancreaticoduodenectomy. Furthermore, there was no difference in survival duration between patients who received the less toxic rapid-fractionation chemoradiotherapy schedule (30 Gy, 2 weeks) and those who received standard-fractionation chemoradiotherapy (50.4 Gy, 5.5 weeks). Short-course rapid-fractionation preoperative chemoradiotherapy combined with pancreaticoduodenectomy, when performed on accurately staged patients, maximizes survival duration and is associated with a low incidence of local tumor recurrence.

Adenocarcinoma↗
PubMed2001

Preoperative chemoradiation therapy for pancreatic cancer.

The authors present a critique of a fellow surgeon's version of multimodality therapy for patients with adenocarcinoma of the pancreas. Citing follow-up studies, the authors prescribe adjustments in therapeutic specifics to foster a more efficient approach to patients that results in lower toxicity and shorter treatment periods.

Adenocarcinoma↗
PubMed2001

Laparoscopy in the staging of pancreatic cancer.

BACKGROUND: Over the past decade, laparoscopy has emerged as a popular method of detecting extrapancreatic metastatic disease in patients presumed to have localized pancreatic cancer. METHODS AND RESULTS: The English language literature on laparoscopic staging of pancreatic cancer was reviewed. Interpretation of this literature on staging laparoscopy is difficult because (1) there has been inconsistent use of high-quality computed tomography (CT) in prospective studies, (2) many studies have included patients with locally advanced disease, and (3) the R0/R1/R2 resection rates among patients staged by laparoscopy have not been reported, making it impossible to correlate laparoscopic findings with the R0 resection rate. Laparoscopy may prevent unnecessary laparotomy in a proportion of CT-staged patients presumed to have resectable pancreatic cancer. However, routine laparoscopy is performed on patients judged to have resectable disease by high-quality CT, this fraction of patients is between 4 and 13 per cent. CONCLUSION: When state-of-the-art CT is available, the routine use of staging laparoscopy may not be easily justified from the data in the recent literature. Selective use of laparoscopy may be more appropriate and will probably be a more cost-effective staging approach. Criteria are presented for the selective use of laparoscopy in the staging of patients with localized pancreatic cancer.

Cost-Benefit Analysis↗