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Biomedical subjects

David Cunningham

Publications and source records attributed to David Cunningham.

At least 55 records · Page 3Linked to original sources
PubMed2004

Survival after surgery or therapeutic catheterisation for congenital heart disease in children in the United Kingdom: analysis of the central cardiac audit database for 2000-1.

OBJECTIVES: To analyse simple national statistics and survival data collected in the central cardiac audit database after treatment for congenital heart disease and to provide long term comparative statistics for each contributing centre. DESIGN: Prospective, longitudinal, observational, national cohort survival study. SETTING: UK central cardiac audit database. MAIN OUTCOME MEASURES: Survival at 30 days and one year after treatment in the year April 2000-March 2001, assessed by using both volunteered life status and independently validated life status through the Office for National Statistics, using the patient's unique NHS number, or the general register offices of Scotland and Northern Ireland. Institutional results following a group of six benchmark operations and three benchmark catheterisation procedures. RESULTS: Since April 2000 data have been received from all 13 UK tertiary centres performing cardiac surgery or therapeutic cardiac catheterisation in children with congenital heart disease. Altogether 3666 surgical procedures and 1828 therapeutic catheterisations were performed. Central tracking of mortality identified 469 deaths, 194 occurring within 30 days and 275 later. Forty two of the 194 deaths within 30 days were detected by central tracking but not by volunteered data. For surgery overall, survival at 30 days was 94.9%, falling to 91.2% at one year; this effect was most marked for infants. For therapeutic catheterisation survival at 30 days was 99.1%, falling to 98.1% at one year. Survival of individual centres or individual operators did not differ from the national average after benchmark procedures. CONCLUSIONS: Independent data validation is essential for accurate survival analysis. One year survival gives a more realistic view of outcome than traditional perioperative mortality. Currently no detectable difference exists in survival between any of the 13 UK tertiary congenital heart disease centres, but confidence intervals for small centres are wide, limiting our power to detect underperformance from analysis of a single year's data. Appropriately resourced, focused national audit is capable of accurate data collection on which nationwide, long term quality control can be based.

Cardiac Catheterization↗
PubMed2004

Sixty-day all-cause mortality rates in patients treated for gastrointestinal cancers, in randomised trials, at the Royal Marsden Hospital.

The aim of this study was to determine the 60-day all-cause mortality rate, during chemotherapy, for patients with oesophagogastric, pancreatic, and colorectal cancer. We analysed 1720 patients that were treated within randomised trials. The minimum follow-up period was > 60 days. Sixty-day mortality and 95% Confidence Intervals (CI) were calculated from the Kaplan-Meier survival curves. Causes of death were classified as treatment-related, disease-related or vascular syndrome-induced deaths. Patients with oesophagogastric cancer that could not tolerate a cis-platinum-containing regimens were treated with infused 5-fluorouracil (5FU)+/-mitomycin-C (MMC). The 60-day mortality rate depends upon the site of the primary tumour and the disease status (adjuvant versus advanced). The rate of treatment- and vascular syndrome-induced deaths was </=1.8%. For patients with advanced disease, most of the early deaths were disease-related. In adjuvant colorectal cancer, one patient died within 60 days (myocardial infarction). This study provides a benchmark for assessing the safety of regimens used in these disease settings.

Adolescent↗
PubMed2004

MALT lymphoma of the foreskin.

Here we present the first described case of MALT lymphoma involving the foreskin. The patient presented with a lump proximal to the glans penis. It was treated with radical excision and histology revealed positive margins. No further therapy was given as this may have resulted in significant morbidity. The patient remains relapse free more than 2 years later. MALT lymphomas are the third most common non-Hodgkin lymphoma accounting for 8% of cases. They have been described at almost all extranodal sites but this case is the first involving the foreskin.

Adult↗
PubMed2004

Systemic treatment of gastric cancer.

Gastric cancer is one of the commonest cancers worldwide and is associated with a poor prognosis. Surgery remains the only potentially curative treatment, but is associated with a high rate of locoregional recurrence. Hence, there is ongoing debate regarding both the extent of lymph node dissection and the role of perioperative chemotherapy or chemoradiation for localized disease. Untreated metastatic gastric cancer is associated with a median survival of only 3-4 months, but this can be increased to 8-10 months, associated with improved quality of life, with combination chemotherapy. Currently, no standard combination chemotherapy regimen exists, although regimens utilizing both cisplatin and 5-fluorouracil, such as epirubicin/cisplatin/fluorouracil (ECF), are amongst the most active. Newer chemotherapeutic agents, including irinotecan, oxaliplatin and taxanes, show promising activity, and are currently being tested in phase III trials.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2004

Monoclonal antibodies against vascular endothelial growth factor and epidermal growth factor receptor in advanced colorectal cancers: present and future directions.

PURPOSE OF REVIEW: Targeted therapies are emerging as potentially important therapeutic interventions in the treatment of advanced colorectal cancer. There have been considerable developments in this field within the past few years, with some agents entering the clinic and others soon to follow. Monoclonal antibodies against important tumorigenic targets have been in development for over a decade. Recently, cetuximab and bevacizumab have generated significant interest and are the focus of this review. RECENT FINDINGS: Cetuximab, a monoclonal antibody against the epidermal growth factor receptor, and bevacizumab, a monoclonal antibody against vascular endothelial growth factor, have now been subject to rigorous assessment within several clinical studies, including a large randomized phase II study of cetuximab and a randomized phase III study of bevacizumab. The demonstration of efficacy and safety with these agents has led to the issue of licenses for cetuximab in Switzerland and bevacizumab in the United States. SUMMARY: These results have led to a rapid expansion of further studies to define the role of these antibodies and to aid their future integration with conventional approaches for the management of advanced colorectal cancer.

Antibodies, Monoclonal↗
PubMed2004

Phase III study of mitomycin-C with protracted venous infusion or circadian-timed infusion of 5-fluorouracil in advanced colorectal carcinoma.

The combination of protracted venous infusion (PVI) fluorouracil (5-FU) and mitomycin-C has previously been shown to be superior to PVI 5-FU alone in terms of response rate and failure-free survival. This study explores the effect of dose intensification by circadian timing of 5-FU in this combination on response, toxicity, and survival. Patients with advanced colorectal carcinoma were randomized to receive PVI 5-FU 300 mg/m2 daily or circadian-timed infusion (CTI) of 5-FU, beginning at 600 mg/m2 and subsequently reduced to 450 mg/m2, delivered as a flat-rate infusion from 10:15 PM to 9:45 AM. Both groups received mitomycin-C at a dose of 7 mg/m2 given every 6 weeks. From April 1996 to August 1998, 320 patients were randomized, including 263 with metastatic disease and 21 with circumferential margin involvement. The overall response rate for the PVI 5-FU group was 38%, compared with 30.3% for the CTI group (P = 0.176). There was no statistically significant difference in terms of failure-free survival (8.0 months vs. 9.9 months; P = 0.131) or overall survival (15.8 months vs. 16.3 months; P = 0.275) between the treatment groups. There were no differences in global quality of life. Grade 3/4 diarrhea occurred significantly more frequently with CTI 5-FU (6.5% vs. 19.8%; P < 0.001); a nonsignificant trend toward increased incidences of grade 3/4 infection and palmar plantar erythema were observed with CTI 5-FU. This study confirms the high response rate and overall survival figures for the combination of PVI 5-FU and mitomycin-C in colorectal cancer. However, dose intensification of 5-FU using a circadian-timed, flat-rate infusion did not lead to improved response or survival.

Adenocarcinoma↗
PubMed2004

Retrospective study of resection of pulmonary metastases in patients with advanced colorectal cancer: the development of a preoperative chemotherapy strategy.

Considerable data are available to support the resection of hepatic metastases in patients with colorectal cancer, but there are relatively few studies on the role of pulmonary metastectomy. The small number of such studies is mainly noncontemporaneous and predates the use of preoperative neoadjuvant chemotherapy. A retrospective analysis of 31 patients with pulmonary metastases from colorectal cancer treated with surgery and perioperative chemotherapy between 1995 and 2003 was performed. Twenty patients (65%) proceeded directly to surgery and 5 of these received postoperative chemotherapy. Eleven patients (35%) received preoperative chemotherapy, which consisted of a fluoropyrimidine in combination with oxaliplatin or mitomycin-C, except for 1 patient who received single agent irinotecan. Nine of 11 patients (82%) had a partial response and 2 patients (18%) had stable disease. A total of 39 thoracic surgeries (6 bilateral and 1 incomplete) were performed. There were no postoperative deaths. Four of 20 patients (20%) who had initial surgery had postoperative complications, compared with 18% of the preoperative chemotherapy group. Overall 3- and 5-year survival rates after the first thoracic surgery were 65.2% (95% CI, 35.1%-83.9%) and 26.1% (95% CI, 4.3%-56.2%), respectively. Based on the limited data from this study, disease-free interval, number of pulmonary metastases, previous resection of hepatic metastases, prethoracotomy carcinoembryonic antigen levels, and preoperative chemotherapy were not found to be significant prognostic factors for survival. Therefore, surgical resection of lung metastases is associated with low morbidity and mortality and results in long-term survival for 20%-30% of patients. Moreover, preoperative chemotherapy produced a high response rate, with no patients experiencing disease progression before surgery.

Aged↗
PubMed2003

Left-sided CHILD syndrome caused by a nonsense mutation in the NSDHL gene.

Congenital hemidysplasia with ichthyosiform nevus and limb defects (CHILD) syndrome is a rare X-linked dominant malformation syndrome characterized by unilaterally distributed ichthyosiform nevi, often sharply delimited at the midline, and ipsilateral limb defects. At least two-thirds of cases demonstrate involvement of the right side. Mutations in an essential enzyme of cholesterol biosynthesis, NAD(P)H steroid dehydrogenase-like [NSDHL], have been reported in five unrelated patients with right-sided CHILD syndrome and in a sixth patient with bilaterally, symmetric nevi and mild skeletal anomalies, but not with CHILD syndrome as originally defined. Although all of the molecularly diagnosed cases with the CHILD phenotype to date have had right-sided disease, we report here a novel nonsense mutation (E151X) of NSDHL in an infant with left-sided CHILD syndrome. This result demonstrates that both right- and left-sided CHILD syndrome can be caused by mutations in the same gene.

3-Hydroxysteroid Dehydrogenases↗
PubMed2003

Molecular pharmacology of cancer therapy in human colorectal cancer by gene expression profiling.

Global gene expression profiling has potential for elucidating the complex cellular effects and mechanisms of action of novel targeted anticancer agents or existing chemotherapeutics for which the precise molecular mechanism of action may be unclear. In this study, decreased expression of genes required for RNA and protein synthesis, and for metabolism were detected in rectal cancer biopsies taken from patients during a 5-fluorouracil infusion. Our observations demonstrate that this approach is feasible and can detect responses that may have otherwise been missed by conventional methods. The results suggested new mechanism-based combination treatments for colorectal cancer and demonstrated that expression profiling could provide valuable information on the molecular pharmacology of established and novel drugs.

Adult↗
PubMed2003

X-ray crystallographic and kinetic studies of human sorbitol dehydrogenase.

Sorbitol dehydrogenase (hSDH) and aldose reductase form the polyol pathway that interconverts glucose and fructose. Redox changes from overproduction of the coenzyme NADH by SDH may play a role in diabetes-induced dysfunction in sensitive tissues, making SDH a therapeutic target for diabetic complications. We have purified and determined the crystal structures of human SDH alone, SDH with NAD(+), and SDH with NADH and an inhibitor that is competitive with fructose. hSDH is a tetramer of identical, catalytically active subunits. In the apo and NAD(+) complex, the catalytic zinc is coordinated by His69, Cys44, Glu70, and a water molecule. The inhibitor coordinates the zinc through an oxygen and a nitrogen atom with the concomitant dissociation of Glu70. The inhibitor forms hydrophobic interactions to NADH and likely sterically occludes substrate binding. The structure of the inhibitor complex provides a framework for developing more potent inhibitors of hSDH.

Binding Sites↗
PubMed2003

Matrix metalloproteinase inhibitors--an emphasis on gastrointestinal malignancies.

Gastrointestinal malignancies are the commonest sites of human cancer collectively. Improved understanding of tumour biology in the last few decades has allowed the identification of cellular pathways responsible for the autonomous growth and replication in cancer cells. There is considerable preclinical evidence implicating matrix metalloproteinases (MMPs) in cancer dissemination and tumour angiogenesis. Effective MMP inhibitors (MMPIs) may, therefore, hold an important key in the treatment of gastrointestinal cancers. MMPIs are cytostatic agents and traditional values of tumour regression may not be the best measures of treatment efficacy. Biological correlation studies are increasingly being incorporated into the early development of these agents, but many of these studies lack preclinical validation and are often chosen on availability rather than biological plausibility. Disappointing results with many MMPIs that have entered phase III testing so far would prompt for identification of reliable surrogate biomarkers and incorporation of functional imaging in the clinical development of matrix metalloproteinase inhibitors in gastrointestinal malignancies. In this review, the integral part in which MMPs are involved in cancer growth and metastases will be presented. This is then followed by a discussion of the challenges that clinicians are facing in assessing the efficacy of MMPIs and finally a review of the clinical studies of the synthetic MMPIs in development.

Gastrointestinal Neoplasms↗
PubMed2003

Gemcitabine, cisplatin and methylprednisolone chemotherapy (GEM-P) is an effective regimen in patients with poor prognostic primary progressive or multiply relapsed Hodgkin's and non-Hodgkin's lymphoma.

This study was designed to assess the efficacy and safety of gemcitabine, cisplatin and methylprednisolone (GEM-P) for patients with relapsed or refractory Hodgkin's disease (HD) and non-Hodgkin's lymphoma. Twenty-one patients were treated with gemcitabine (1000 mg/m2 d 1, 8 and 15), cisplatin (100 mg/m2 d 15) and methylprednisolone (1000 mg d 1-5) given every 28 d. Of these, 20 patients were evaluable for response. The median age was 38 years (range 17-64 years). Histological subtypes were: nodular sclerosing HD (n = 10), diffuse large B cell (n = 5), T cell-rich B cell (n = 2), follicular (n = 2), mantle cell (n = 1) and enteropathy-associated T-cell lymphoma (n = 1). The median remission duration prior to receiving GEM-P was only 42 d. The overall objective response rate was 80%[95% confidence interval (CI): 56-94%], including five complete and 11 partial responses. GEM-P induced responses in all histological subtypes, primary progressive disease and patients who had received a previous autograft. The only grade 3-4 toxicity was myelosuppression. However, no cases of febrile neutropenia or haemorrhage with thrombocytopenia were encountered. Median survival has not yet been reached and survival probability at 1 year was 60.8% (95% CI: 31.9-80.5%). In conclusion, GEM-P is a novel combination salvage therapy for poor-prognostic primary progressive or multiply relapsed lymphoma patients. It has clinically significant activity with a favourable toxicity profile.

Adolescent↗
PubMed2003

Overview of preoperative and postoperative therapy for colorectal cancer: the European and United States perspectives.

Surgery is the primary modality for cure in patients with localized colorectal cancer. However, despite potential curative surgery, the risk of recurrence is high. In colon cancer, the role of adjuvant chemotherapy with 5-fluorouracil (5-FU) and leucovorin (LV) is now established in stage III disease. The benefit of adjuvant treatment in stage II disease is likely to be small, and studies performed thus far have been generally underpowered to detect what might be a clinically significant effect on survival. Whereas bolus scheduling of 5-FU and LV is favored in North America, infusion of 5-FU/LV is preferred in Europe. Indeed, infused 5-FU/LV may be a safer partner with new drugs such as oxaliplatin and irinotecan. Oral fluoropyrimidines are attractive agents that might one day replace parenteral 5-FU. In rectal cancer, postoperative combined chemoradiation was recommended as standard practice in stages II and III disease. Despite a lack of randomized data demonstrating clinical benefit, preoperative chemoradiation has been increasingly used in patients with T3 disease in North America. However, preoperative radiation therapy is more frequently used in Europe. There are discrepancies in pathologic reporting of circumferential resection margin involvement and lymph node status between the United States and Europe. Standardized reporting with improved preoperative imaging would allow patients with truly early-stage disease to undergo more conservative management and be spared the morbidity and mortality of unnecessary adjuvant or neoadjuvant treatment.

Chemotherapy, Adjuvant↗
PubMed2003

Impact of 5-fluorouracil rechallenge on subsequent response and survival in advanced colorectal cancer: pooled analysis from three consecutive randomized controlled trials.

The aim of this analysis is to evaluate the effect of 5-fluorouracil (5-FU) rechallenge on subsequent response and survival in patients with advanced colorectal cancer (CRC). Between April 1992 and August 1998, 613 patients were enrolled into 3 consecutive prospective randomized controlled trials assessing first-line infused 5-FU in patients with advanced CRC. All patients had a planned maximum treatment period of 6 months. Those with responding or stable disease at the end of 6 months were observed off treatment. On subsequent disease progression, patients were retreated with 5-FU alone (5-FU group) or 5-FU plus mitomycin C (MMC group). Ninety-three patients have been retreated (5-FU group, n = 71; MMC group, n = 22). The median age was 60 years (range, 38-79 years), and the median time to rechallenge was 11.7 months (5-FU group, 11.7 months; MMC group, 11.4 months). Seventeen percent of patients had an objective response to rechallenge (5-FU group, 13%; MMC group, 27%). The median survival was 14.8 months (5-FU group, 15.2 months; MMC group, 10.5 months; log-rank test, P = 0.23) and the median failure-free survival was 5.4 months (5-FU group, 5.6 months; MMC group, 3.7 months; log-rank test, P = 0.06). On multivariate analysis, a prolonged treatment-free interval of > 12 months (hazard ratio [HR], 0.57; 95% CI, 0.35-0.94; P = 0.027) and good performance status of 0/1 (HR, 0.38; 95% CI, 0.22-0.68; P = 0.001) were associated with better overall survival. In conclusion, a proportion of patients who experienced a prolonged period of tumor control with first-line infused 5-FU therapy and had a planned treatment interruption, retained 5-FU sensitivity and had prolonged survival with 5-FU rechallenge.

Adult↗
PubMed2003

Thymidylate synthase expression in advanced colorectal cancer predicts for response to raltitrexed.

PURPOSE: The purpose of this research was to evaluate the predictive value of expression of thymidylate synthase (TS) and other genes for response to raltitrexed (RTX). EXPERIMENTAL DESIGN: Twenty-five patients with metastatic colorectal cancer received RTX 3 mg/m(2) 3-weekly. Pretreatment tumor biopsies were analyzed for TS, dihydropyrimidine dehydrogenase (DPD), thymidine phosphorylase (TP), folylpolyglutamate synthetase, and reduced folate carrier mRNA expression by real-time reverse transcription-PCR. TS protein expression was evaluated by immunohistochemistry using a polyclonal TS antibody. RESULTS: Twenty patients were evaluable for response and gene expression. Six of 20 (30%) achieved a partial response. Median TS/beta-actin was 5.7 x 10(3) (range, 2.2-42 x 10(3)). Median TS/beta-actin was 3.7 x 10(3) in responding patients and 6.1 x 10(3) in nonresponders (P = 0.048). Five of 6 patients with TS/beta-actin </=4.1 x 10(3) and 1 of 14 with higher values responded (P = 0.002). Overall survival was 21.7 months in patients with TS/beta-actin </=4.1 x 10(3) and 5.7 months in patients with higher values (P = 0.013). No correlations were seen between expression of TP, DPD, reduced folate carrier, or folylpolyglutamate synthetase mRNA and response or survival. Weak TS staining was seen in 10 of 21 tumors evaluable for immunohistochemistry, including 5 responders All 4 of the patients with both weak staining and TS/beta-actin </=4.1 x 10(3) responded. CONCLUSIONS: High TS mRNA expression predicts nonresponse to RTX. By contrast with 5-fluorouracil, high levels of TP and DPD mRNA are not associated with RTX resistance. Limited genomic fingerprinting could optimize single-agent therapy, allowing combinations to be reserved for high TS-expressing patients or for treatment failures, with potential reductions in toxicity and cost.

Antimetabolites, Antineoplastic↗