PubMed Health⌕ Search

Biomedical subjects

David Cunningham

Publications and source records attributed to David Cunningham.

At least 19 recordsLinked to original sources
PubMed2026

The clinical relevance of regional lymph node microarchitecture in oesophageal cancer patients - Results from the UK MRC OE02 trial.

BACKGROUND: In oesophageal cancer (OeC) patients, neoadjuvant chemotherapy followed by surgery improves survival. Anti-tumour immune responses are mediated by lymph node (LN) microarchitecture. We investigated whether neoadjuvant chemotherapy and/or presence of tumour changes LN microarchitecture, and whether such changes are associated with survival. METHODS: Microarchitectural features (lymphocytes, germinal centres (GermC), histiocytes) were quantified morphometrically in 433 LNs from 333 OE02 trial patients (165 neoadjuvant chemotherapy+surgery (CS), 168 surgery alone (S)). Features were compared between tumour-negative (LNneg) and tumour-positive LN (LNpos) by treatment group. Associations with clinicopathological variables and overall survival (OS) were evaluated. RESULTS: LNneg GermC density was lower in CS patients than in S patients (median: 1% vs 2%; p = 0.0004). No other microarchitectural features differed by treatment group or LN status (LNneg vs LNpos). Low histiocyte content in LNneg and LNpos was associated with improved OS in S patients only (HR:0.67, 95%CI: 0.46-0.97, p = 0.03). Multivariable analysis confirmed the independent prognostic significance of LNneg histiocytes (HR:0.62, 95%CI: 0.42-0.9, p = 0.01). CONCLUSION: These findings suggest that LN microarchitecture may be a biomarker for treatment-related immune modulation and prognosis in patients with resectable OeC. These findings warrant independent validation and further investigation to determine whether LN microarchitectural features could inform personalised therapeutic strategies.

Humans↗
PubMed2007

Dominance of amyloid precursor protein sequence over host cell secretases in determining beta-amyloid profiles studies of interspecies variation and drug action by internally standardized immunoprecipitation/mass spectrometry.

beta-Amyloid peptides, tentatively regarded as the principal neurotoxins responsible for Alzheimer's Disease, make up a set of products that varies significantly among different biological systems. The full implications of this complexity and its variations have yet to be defined. In this work, Abeta peptide populations were extracted from animal brain tissue or cell-conditioned media, immunoprecipitated with specific antibodies, and analyzed by matrix-assisted laser desorption time-of-flight mass spectrometry. (15)N-Substituted Abeta internal standards were added to gauge variations in the profile of captured peptides. Results from a range of species, including guinea pig, dog, rabbit, and wild-type and transgenic mice, showed that the Abeta peptide population in each system was mainly determined by the species of origin of the amyloid precursor protein (APP) and not by the host tissue or cell line. The same method was used to gauge the effect on the Abeta peptide profile of an inhibitor of gamma-secretase, one of the two proteinases that excises Abeta peptides from the precursor protein with different effects on specific peptides. Overall, the results demonstrate that the species of origin of the APP substrate dictates the outcome of APP processing to a greater extent than the origin of the processing enzymes, an important consideration in rationalizing the properties of different model systems.

Alanine↗
PubMed2006

Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer.

BACKGROUND: A regimen of epirubicin, cisplatin, and infused fluorouracil (ECF) improves survival among patients with incurable locally advanced or metastatic gastric adenocarcinoma. We assessed whether the addition of a perioperative regimen of ECF to surgery improves outcomes among patients with potentially curable gastric cancer. METHODS: We randomly assigned patients with resectable adenocarcinoma of the stomach, esophagogastric junction, or lower esophagus to either perioperative chemotherapy and surgery (250 patients) or surgery alone (253 patients). Chemotherapy consisted of three preoperative and three postoperative cycles of intravenous epirubicin (50 mg per square meter of body-surface area) and cisplatin (60 mg per square meter) on day 1, and a continuous intravenous infusion of fluorouracil (200 mg per square meter per day) for 21 days. The primary end point was overall survival. RESULTS: ECF-related adverse effects were similar to those previously reported among patients with advanced gastric cancer. Rates of postoperative complications were similar in the perioperative-chemotherapy group and the surgery group (46 percent and 45 percent, respectively), as were the numbers of deaths within 30 days after surgery. The resected tumors were significantly smaller and less advanced in the perioperative-chemotherapy group. With a median follow-up of four years, 149 patients in the perioperative-chemotherapy group and 170 in the surgery group had died. As compared with the surgery group, the perioperative-chemotherapy group had a higher likelihood of overall survival (hazard ratio for death, 0.75; 95 percent confidence interval, 0.60 to 0.93; P=0.009; five-year survival rate, 36 percent vs. 23 percent) and of progression-free survival (hazard ratio for progression, 0.66; 95 percent confidence interval, 0.53 to 0.81; P<0.001). CONCLUSIONS: In patients with operable gastric or lower esophageal adenocarcinomas, a perioperative regimen of ECF decreased tumor size and stage and significantly improved progression-free and overall survival. (Current Controlled Trials number, ISRCTN93793971 [controlled-trials.com].).

Adenocarcinoma↗
PubMed2006

The role of probiotics in aquaculture.

The increase of productivity in aquaculture has been accompanied by ecological impacts including emergence of a large variety of pathogens and bacterial resistance. These impacts are in part due to the indiscriminate use of chemotherapeutic agents as a result of management practices in production cycles. This review provides a summary of the use of probiotics for prevention of bacterial diseases in aquaculture, with a critical evaluation of results obtained to date.

Animals↗
PubMed2006

Neoadjuvant capecitabine and oxaliplatin followed by synchronous chemoradiation and total mesorectal excision in magnetic resonance imaging-defined poor-risk rectal cancer.

PURPOSE: To evaluate neoadjuvant capecitabine/oxaliplatin before chemoradiotherapy (CRT) and total mesorectal excision (TME) in newly diagnosed patients with magnetic resonance imaging (MRI) -defined poor-risk rectal cancer. PATIENTS AND METHODS: MRI criteria for poor-risk rectal cancer were tumors within 1 mm of mesorectal fascia (ie, circumferential resection margin threatened), T3 tumors at or below levators, tumors extending > or = 5 mm into perirectal fat, T4 tumors, and T1-4N2 tumors. Patients received 12 weeks of neoadjuvant capecitabine/oxaliplatin followed by concomitant capecitabine and radiotherapy. TME was planned 6 weeks after CRT. Postoperatively, patients received another 12 weeks of capecitabine. RESULTS: Between November 2001 and August 2004, 77 eligible patients were recruited. After neoadjuvant capecitabine/oxaliplatin, the radiologic response rate was 88%. In addition, 86% of patients had symptomatic responses in a median of 32 days (ie, just over one cycle of capecitabine/oxaliplatin). After CRT, the tumor response rate was increased to 97%. Three patients remained inoperable. Sixty-seven patients proceeded to TME, and all but one patient had R0 resection. Pathologic complete response was observed in 16 patients (24%; 95% CI, 14% to 36%), and in an additional 32 patients (48%), only microscopic tumor foci were found on surgical specimens. Four deaths occurred during neoadjuvant capecitabine/oxaliplatin therapy as a result of pulmonary embolism, ischemic heart disease, sudden death with history of chest pain, and neutropenic colitis. CONCLUSION: Capecitabine/oxaliplatin before synchronous CRT and TME results in substantial tumor regression, rapid symptomatic response, and achievement of R0 resection.

Adult↗
PubMed2006

Chemotherapy for advanced pancreatic cancer.

Single-agent gemcitabine was established as standard treatment for advanced pancreatic cancer after a superior clinical benefit response was demonstrated in a randomized study comparing it to 5-fluorouracil (FU). Until recently, many subsequent randomized trials of newer, often gemcitabine-based combinations have not been able to show improved survival over gemcitabine. Combination gemcitabine and capecitabine is likely to become the preferred standard treatment, at least in the UK, on the basis of the positive interim results of the UK National Cancer Research Institute (NCRI) randomized study of chemotherapy with this combination. At present, there is no standard second-line treatment for patients who have become refractory to gemcitabine, although a recently reported study has suggested that oxaliplatin with FU and leucovorin is superior to best supportive care in these patients. This article will review and discuss the clinical trials of chemotherapy for this disease, including the more recent trials, which have included the novel targeted agents.

Antineoplastic Agents↗
PubMed2006

Sub-clinical dissemination of follicular lymphoma in normal sized lymph nodes may not be detected by radiologic staging: a case of disseminated follicular lymphoma detected in nodal clearance as part of therapy for cutaneous melanoma.

Patients with localized follicular lymphoma are potentially curable; however, the failure rate for local treatment suggests that a proportion of apparently localized disease is being under-staged. We report a case of incidentally diagnosed follicular lymphoma found in association with a stage II malignant melanoma, with immunohistochemical evidence of disseminated lymphoma in radiologically and clinically benign regional lymph nodes. This case provides some evidence to the cause of treatment failure in patients with clinically localized follicular lymphoma, and is a histologically proven example of the association between melanoma and lymphoma.

Aged↗
PubMed2006

Panitumumab.

Panitumumab, previously known as ABX-EGF, is the first fully human monoclonal antibody to be shown to be effective as a treatment for solid-tumor cancers. Its target is the epidermal growth factor receptor (EGFR), which when overactive may contribute to the development and progression of cancer and is expressed in several solid tumors, including colorectal cancer. In a recently reported phase III trial, patients with metastatic colorectal cancer who had failed previous treatment with oxaliplatin- and irinotecan-based therapy were randomized to receive single-agent panitumumab and best-supportive care, or best-supportive care alone. This trial demonstrated a significant improvement in progression-free survival with panitumumab treatment in these patients. A rash similar to that which occurs with the other anti-EGFR antibody, cetuximab, has been observed in up to 100% of patients treated with panitumumab in the various clinical trials. As with other EGFR antagonists, EGFR staining by immunohistochemistry has not been shown to be an effective method of selecting patients for treatment, whereas the severity of the rash appears to be predictive of outcome. Ongoing randomized trials are evaluating the use of panitumumab with combination treatment for the first-line treatment of metastatic colorectal cancer. This review summarizes the rationale for targeting the EGFR and the development of panitumumab in preclinical and early phase trials in several tumor types. Clinical trial results in colorectal cancer, in which the development of this agent is most advanced, will also be discussed, as will the rash associated with treatment.

Animals↗
PubMed2006

Potential of surface-coil MRI for staging of esophageal cancer.

OBJECTIVE: The aim of this pilot study was to assess the feasibility of external surface-coil MRI as a new method of imaging the esophagus and esophageal cancer. CONCLUSION: The results for the 10 patients investigated indicate that by using a high-resolution axial T2-weighted sequence (small field of view, thin section images), MRI provides detailed imaging of the anatomic layers of the esophageal wall and tumor. Three independent radiologists found good correlation in the morphologic appearance and extent of tumor between MRI and matched histology sections. This study illustrates the potential of the technique as an alternative form of local staging for esophageal cancer.

Adenocarcinoma↗
PubMed2006

Neoadjuvant treatment of unresectable liver metastases from colorectal cancer.

There has been increasing interest in the use of neoadjuvant treatment for downstaging and downsizing disease in patients with initially unresectable liver metastases from colorectal cancer with a view to potentially curative surgery. This has been increasingly feasible with the more active treatment combinations presently available based on oxaliplatin or irinotecan. This article reviews the evidence supporting the use of this treatment strategy and discusses the implications of advances in treatment in other metastatic disease settings for these patients and the issues of patient selection and prognostic factors.

Adenocarcinoma↗
PubMed2005

Description of the torcetrapib series of cholesteryl ester transfer protein inhibitors, including mechanism of action.

We have identified a series of potent cholesteryl ester transfer protein (CETP) inhibitors, one member of which, torcetrapib, is undergoing phase 3 clinical trials. In this report, we demonstrate that these inhibitors bind specifically to CETP with 1:1 stoichiometry and block both neutral lipid and phospholipid (PL) transfer activities. CETP preincubated with inhibitor subsequently bound both cholesteryl ester and PL normally; however, binding of triglyceride (TG) appeared partially reduced. Inhibition by torcetrapib could be reversed by titration with both native and synthetic lipid substrates, especially TG-rich substrates, and occurred to an equal extent after long or short preincubations. The reversal of TG transfer inhibition using substrates containing TG as the only neutral lipid was noncompetitive, suggesting that the effect on TG binding was indirect. Analysis of the CETP distribution in plasma demonstrated increased binding to HDL in the presence of inhibitor. Furthermore, the degree to which plasma CETP shifted from a free to an HDL-bound state was tightly correlated to the percentage inhibition of CE transfer activity. The finding by surface plasmon resonance that torcetrapib increases the affinity of CETP for HDL by approximately 5-fold likely represents a shift to a binding state that is nonpermissive for lipid transfer. In summary, these data are consistent with a mechanism whereby this series of inhibitors block all of the major lipid transfer functions of plasma CETP by inducing a nonproductive complex between the transfer protein and HDL.

Animals↗
PubMed2005

Site of relapse after chemotherapy alone for stage I and II Hodgkin's disease.

BACKGROUND: Short course chemotherapy followed by radiotherapy is a standard treatment for early Hodgkin's disease. There is yet no consensus regarding the appropriate radiotherapy portal following chemotherapy. A good guide to the adjuvant radiotherapy field is the site of relapse in patients treated with chemotherapy alone. PATIENTS AND METHODS: From 1980 to 1996, 61 patients with stage I and II supradiaphragmatic Hodgkin's disease were treated with chemotherapy alone at the Royal Marsden Hospital. We undertook a retrospective review and failure analysis to define the pattern of recurrence. RESULTS: After a median follow-up of 6.5 years, 24 patients had relapsed giving a 5-year relapse rate of 40%. The 5 and 10-year actuarial survival rates were 94 and 89%, respectively with cause-specific survival being 94% at 5 and 10 years. Two-thirds of the relapses were nodal and supradiaphragmatic. Twenty patients (83%) relapsed in the initially involved sites of disease and this was the sole site of recurrence in 11 (45%) of patients. In retrospect, it appeared that at least 12 recurrences could have been prevented by involved field radiotherapy. Review of detailed imaging data (available in 9 out of 11 patients with recurrences in initial sites of disease) showed that the relapses were always in the initially involved nodes. CONCLUSION: After chemotherapy alone in early stage HD most initial recurrences are nodal. Loco-regional recurrences are in the originally involved nodes. Based on limited data it appears that involved nodal RT is equivalent to involved field radiotherapy and may halve the risk of recurrence.

Adolescent↗
PubMed2005

Managing patients treated with bevacizumab combination therapy.

The anti-angiogenic agent bevacizumab (Avastin) has been rationally designed to target vascular endothelial growth factor (VEGF), a key mediator of tumor angiogenesis. Based on its limited roles in adults, VEGF inhibition using bevacizumab would be expected to have limited side effects. Furthermore, because its mechanism of action is different to that of standard chemotherapeutic agents, bevacizumab would not be expected to cause typical cytotoxic agent-related toxicity or to exacerbate the toxicity of concomitant chemotherapy. We have reviewed clinical trials published to date, primarily in metastatic colorectal cancer, and describe the safety profile of bevacizumab. The review focuses on hypertension, proteinuria, arterial thrombosis, effects on wound healing, bleeding and gastrointestinal (GI) perforation, which are the principal bevacizumab-related events seen in clinical trials. These events are for the most part mild to moderate in severity and clinically manageable (hypertension, proteinuria, minor bleeding) or occur uncommonly (wound healing complications, GI perforations and arterial thrombosis). The side-effect profile of bevacizumab makes it a suitable adjunct to standard chemotherapy in settings where efficacy has been demonstrated, and it is now approved for use in the USA, the European Union and other markets worldwide.

Angiogenesis Inhibitors↗
PubMed2005

The palatability of milk-based and non-milk-based nutritional supplements in gastrointestinal cancer and the effect of chemotherapy.

INTRODUCTION: Oral nutritional supplements may have a role in the management of weight loss in patients with cancer. Information on preference for different types of nutritional supplements and the influence of taste changes and chemotherapy is limited. AIMS AND METHODS: This study aimed, in patients with gastrointestinal (GI) cancer, to determine the short-term preference for commonly used nutritional supplements compared with controls, to examine whether preference is altered by chemotherapy and to assess the reproducibility of taste assessments conducted using a Visual Analogue Scale (VAS). Patients with GI cancer and controls were asked to rate the acceptability of three oral nutritional supplements on a VAS before starting chemotherapy and after 6 weeks of chemotherapy. Supplements were presented in a random order in sealed containers and subjects were blinded to the type of product. One supplement was repeated at random within each set (four cups) to assess the reproducibility of responses. RESULTS: Sixty patients and 63 controls were included in the study, 47 patients and 47 controls were available for follow-up. Before the start of chemotherapy, patients had a higher mean preference for Calshake (5.9 cm) than Ensure plus (5.1 cm) and Fortijuce (3.2 cm) (P=0.025 and P<0.001). Calshake was the most preferred supplement in the control group (mean 6.6 cm), with no significant differences in preferences between patients and controls. There were no changes in preference for patients after 6 weeks of chemotherapy. The results for the control group similarly showed no change after 6 weeks. No significant differences were found between scores assigned to the supplement repeated in the random order for any product at either timepoint. DISCUSSION: Patients with GI cancers prefer the taste of fresh milk-based supplements and short-term preferences are not changed by chemotherapy. Preferences are similar between patients with GI cancers and people without cancer. A VAS is a reliable tool to assess taste preference. Further studies are needed to assess the patient compliance over longer periods and the reasons for non-compliance with prescriptions for nutritional supplements.

Adult↗
PubMed2005

Adjuvant treatment for resectable pancreatic cancer.

There are relatively few randomized studies of adjuvant chemoradiotherapy and chemotherapy in patients with resected pancreatic adenocarcinoma. The European Study Group for Pancreatic Cancer 1 (ESPAC1) trial is the largest study of adjuvant treatment to date. The results of ESPAC1 are discussed in the context of other evidence from previous randomized studies, which have also been combined in a meta-analysis. Overall, the existing data show a clear benefit for postoperative adjuvant chemotherapy, which has not been demonstrated for adjuvant chemoradiotherapy. The subgroup of patients with resection margin positive disease did seem to benefit less from adjuvant chemotherapy, and showed a trend towards improved survival with chemoradiotherapy. Adjuvant chemoradiotherapy should be evaluated further in this latter group of patients. The optimal chemotherapy regimen for use as adjuvant treatment is the subject of ongoing trials. Other strategies which should be explored include neoadjuvant treatment and the incorporation of novel targeted agents into management.

Adenocarcinoma↗