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H J Andreyev

Publications and source records attributed to H J Andreyev.

17 recordsLinked to original sources
PubMed2001

Kirsten ras mutations in patients with colorectal cancer: the 'RASCAL II' study.

Researchers worldwide with information about the Kirsten ras (Ki-ras) tumour genotype and outcome of patients with colorectal cancer were invited to provide that data in a schematized format for inclusion in a collaborative database called RASCAL (The Kirsten ras in-colorectal-cancer collaborative group). Our results from 2721 such patients have been presented previously and for the first time in any common cancer, showed conclusively that different gene mutations have different impacts on outcome, even when the mutations occur at the same site on the genome. To explore the effect of Ki-ras mutations at different stages of colorectal cancer, more patients were recruited to the database, which was reanalysed when information on 4268 patients from 42 centres in 21 countries had been entered. After predetermined exclusion criteria were applied, data on 3439 patients were entered into a multivariate analysis. This found that of the 12 possible mutations on codons 12 and 13 of Kirsten ras, only one mutation on codon 12, glycine to valine, found in 8.6% of all patients, had a statistically significant impact on failure-free survival (P = 0.004, HR 1.3) and overall survival (P = 0.008, HR 1.29). This mutation appeared to have a greater impact on outcome in Dukes' C cancers (failure-free survival, P = 0.008, HR 1.5; overall survival P = 0.02, HR 1.45) than in Dukes' B tumours (failure-free survival, P = 0.46, HR 1.12; overall survival P = 0.36, HR 1.15). Ki-ras mutations may occur early in the development of pre-cancerous adenomas in the colon and rectum. However, this collaborative study suggests that not only is the presence of a codon 12 glycine to valine mutation important for cancer progression but also that it may predispose to more aggressive biological behaviour in patients with advanced colorectal cancer.

Adolescent↗
PubMed2001

Antisense treatment directed against mutated Ki-ras in human colorectal adenocarcinoma.

BACKGROUND: Kirsten ras (Ki-ras) mutations are common in gastrointestinal cancer and one codon 12 mutation, glycine to valine, is particularly aggressive in colorectal cancer. AIMS: To investigate if this valine point mutation could be targeted with antisense oligonucleotides and to determine the efficacy of any antisense/mRNA interaction. METHODS: Twenty nine antisense oligonucleotides were screened against target and control Ki-ras RNA in a cell free system and against target and control cell lines in culture. RESULTS: The activity and specificity of the oligonucleotides varied. Results for the individual oligonucleotides were consistent in a cell free model and in cell culture using two different uptake promoters. Only one oligonucleotide was specific in its cleavage of target Ki-ras mRNA in the cell free system and appeared specific in cell culture, although changes in Ki-ras mRNA and protein expression following a single treatment could not be detected. Experiments in the cell free system showed that the point mutation is relatively inaccessible to oligonucleotides. Other sites on the Ki-ras RNA molecule, away from the point mutation, can be targeted more effectively. CONCLUSIONS: Successful targeting of the clinically relevant Ki-ras point mutation with antisense oligonucleotides is difficult because of RNA structure at the mutated site and is inefficient compared with other sites on the Ki-ras mRNA.

Adenocarcinoma↗
PubMed2001

Inhibition of Kirsten-ras expression in human colorectal cancer using rationally selected Kirsten-ras antisense oligonucleotides.

Kirsten-ras is frequently mutated in colorectal cancers and may be an important therapeutic target, particularly because we have previously shown that acquisition of a mutation is associated with a poorer outcome. Understanding the role of Kirsten-ras and the consequences of inhibiting its activity or expression will contribute to our comprehension of colorectal cancer biology and may help to rationalize the choice of molecular targets suitable for therapeutic manipulation. Therefore we undertook a simple screen, incubating a library of oligonucleotides with Kirsten-ras mRNA and RNase H to identify an antisense oligonucleotide that effectively inhibited Kirsten-ras expression. We show for the first time in a human colon cancer cell line that inhibition of Kirsten-ras expression inhibits constitutive phosphorylation of Erk1/2, but not c-Akt, suggesting that in these cells constitutive phosphorylation of Erk 1/2 is dependent upon Kirsten-ras. Successful inhibition of Kirsten-ras had little effect on cell number or cell death and there was no evidence for accumulation of cells in any particular phase of the cell cycle. Kirsten-ras inhibition significantly reduced secretion of VEGF-A165 into the culture medium. Gene expression profiling by microarray detected altered expression of a number of genes. Of particular interest for future studies was the altered expression of genes encoding products involved in protein trafficking and the potential effects of these changes on cell adhesion. Our results suggest that, at least in this model, Kirsten-ras may contribute to malignancy predominantly through effects on angiogenesis, invasion, and metastasis, and that therapies directed at Kirsten-ras, including antisense approaches, may have particular utility through these mechanisms.

Adenocarcinoma↗
PubMed1998

Kirsten ras mutations in patients with colorectal cancer: the multicenter "RASCAL" study.

BACKGROUND: Kirsten ras (Ki-ras) gene mutations occur early in the progression of colorectal adenoma to carcinoma. The aim of this collaborative study was to clarify the association between Ki-ras mutations, patient outcome, and tumor characteristics by use of data from colorectal cancer patients worldwide. METHODS: Investigators who had published data on Ki-ras and colorectal cancer were invited to complete a questionnaire for each patient entered into a database. Two-sided statistical tests were used to analyze data. RESULTS: Patients (n = 2721) were recruited from 22 groups in 13 countries. Mutations of Ki-ras codon 12 (wild type = GGT = glycine) or codon 13 (wild type = GGC = glycine) were detected in 37.7% of the tumors; 80.8% (584 of 723) of all the specified mutations occurred in codon 12, and 78.1% (565 of 723) of all the specified mutations were at the second base of either codon. Mutations were not associated with sex, age, tumor site, or Dukes' stage. Mutation rates seen in patients with sporadic tumors were comparable to those observed in patients with a predisposing cause for their cancer. Poorly differentiated tumors were less frequently mutated (P = .002). Multivariate analysis suggested that the presence of a mutation increased risk of recurrence (P<.001) and death (P = .004). In particular, any mutation of guanine (G) to thymine (T) but not to adenine (A) or to cytosine (C) increased the risk of recurrence (P = .006) and death (P<.001). When individual, specific mutations were evaluated, only valine codon 12 was found to convey an independent, increased risk of recurrence (P = .007) and death (P = .004). CONCLUSIONS: Ki-ras mutations are associated with increased risk of relapse and death, but some mutations are more aggressive than others.

Adolescent↗
PubMed1998

Why do patients with weight loss have a worse outcome when undergoing chemotherapy for gastrointestinal malignancies?

The aim of this study was to examine whether weight loss at presentation, in patients who were to receive chemotherapy for gastrointestinal carcinomas, influences outcome and whether nutritional intervention would be worthwhile. This study was a retrospective review of prospectively gathered data. The outcomes of patients with or without weight loss and treated for locally advanced or metastatic tumours of the oesophagus, stomach, pancreas, colon or rectum were compared. In 1555 such consecutive patients treated over a 6-year period, weight loss at presentation was reported more commonly by men than women (51 versus 44%, P = 0.01). Although patients with weight loss received lower chemotherapy doses initially, they developed more frequent and more severe dose limiting toxicity--specifically plantar-palmar syndrome (P < 0.0001) and stomatitis (P < 0.0001)--than patients without weight loss. Consequently, patients with weight loss on average received 1 month (18%) less treatment (P < 0.0001). Weight loss correlated with shorter failure-free (P < 0.0001, hazard ratio = 1.25) and overall survival (P < 0.0001, hazard ratio = 1.63), decreased response (P = 0.006), quality of life (P < 0.0001) and performance status (P < 0.0001). Patients who stopped losing weight had better overall survival (P = 0.0004). Weight loss at presentation was an independent prognostic variable (hazard ratio = 1.43). The poorer outcome from treatment in patients with weight loss appears to occur because they receive significantly less chemotherapy and develop more toxicity rather than any specifically reduced tumour responsiveness to treatment. These findings provide a rationale for attempting randomised nutritional intervention studies in these patients.

Adenocarcinoma↗
PubMed1997

Bcl-2 expression and response to chemotherapy in colorectal adenocarcinomas.

In the last year, a number of studies have reported the expression of bcl-2 in colorectal adenocarcinomas. However, the influence of bcl-2 expression on response to chemotherapy and outcome in patients with advanced colorectal adenocarcinoma has not been reported. We analysed bcl-2 expression in 231 colorectal tumours from patients that were treated by surgery alone or with 5-fluorouracil-based chemotherapy. Of 231 tumours, 149 (64.5%) overexpressed bcl-2. Bcl-2 expression was associated with low plasma CEA levels (P=0.013) and inversely associated with poor differentiation (P=0.049). However, bcl-2 expression did not significantly influence failure-free or overall survival in surgically treated patients. In the group of patients receiving 5-fluorouracil-based chemotherapy bcl-2 expression did not influence response to chemotherapy; nor did it effect failure-free or overall survival.

Adenocarcinoma↗
PubMed1997

K-ras mutations in patients with early colorectal cancers.

BACKGROUND: Published data are contradictory about the importance of K-ras mutations in advanced tumours and are not available for early cancers. AIMS: To establish whether specific K-ras mutations are prognostic markers in early stage colorectal adenocarcinoma. METHODS: The presence of K-ras exon 1 mutations were correlated with tumour recurrence in two groups of patients: group 1 was a consecutive series of patients with resected colorectal adenocarcinoma at low risk of recurrence; group 2 were patients referred for chemotherapy after relapse of previously resected early stage tumours. K-ras mutations were detected by direct sequencing of whole tissue samples in all patients and in some, the leading edge and centre of the tumour were also microdissected out individually and sequenced. RESULTS: Mutations were present in 26 (26.5%) of 98 patients in group 1; 14 patients developed a recurrence, four (28.5%) of whom had a K-ras mutation. Seventy nine patients have not developed tumour recurrence, 22 (28%) of whom had a mutation (p = 0.84). K-ras mutations were present in five of 14 patients in group 2. Microdissection did not increase the number of mutations detected. CONCLUSIONS: Individual K-ras genotypes are distributed homogeneously throughout early stage colorectal adenocarcinomas, but detection of a mutation has no apparent prognostic value.

Adenocarcinoma↗
PubMed1996

Joint symptoms after restorative proctocolectomy in ulcerative colitis and familial polyposis coli.

We have determined the incidence and nature of joint symptoms in patients who had a restorative proctocolectomy and ileal reservoir for ulcerative colitis (UC) and familial adenomatous polyposis (FAP); we also have recorded the effect of drug treatment and surgery on these symptoms. One hundred seventy-three patients with UC and 25 patients with FAP who had undergone a restorative proctocolectomy answered a questionnaire about joint symptoms. These were present in 96 (55%) patients with UC and five (20%) with FAP. In the 69 patients with UC with joint symptoms before proctocolectomy, 31 (45%) reported improvement after colectomy. However, in 27 (28%) patients with UC and joint symptoms, and four of five patients with FAP with joint symptoms, these started after restorative proctocolectomy. A family history of joint symptoms did not predispose to the development of arthropathy in the patients with UC but may have in patients with FAP. Before colectomy, in most patients with colitis, azathioprine or sulfasalazine did not improve joint symptoms, but steroids were effective in 18 of 64 patients who had received them. Of 101 patients (43%) with joint symptoms in either disease, 43 had symptoms sever enough to interfere with daily activities. We conclude that joint symptoms are a major cause of morbidity in patients with UC. After restorative proctocolectomy they may develop de novo in patients with either UC or FAP.

Adenomatous Polyposis Coli↗
PubMed1995

Squamous oesophageal cancer can be downstaged using protracted venous infusion of 5-fluorouracil with epirubicin and cisplatin (ECF).

21 patients with squamous oesophageal carcinoma were treated with a new regimen designed in our unit and effective in treating gastric adenocarcinoma, consisting of continuous venous infusion of 5-fluorouracil for up to 24 weeks (200 mg/m2/day) with epirubicin (50 mg/m2) and cisplatin (60 mg/m2) every 3 weeks. 12 patients (57%) had an objective response. The median relapse free period was 7 months, median survival from start of chemotherapy 8.4 months, and median survival from diagnosis, 14 months. Symptomatic improvements were reported by 10/11 patients with pain (91%), 8/9 with anorexia (89%), 8/10 with reflux (80%) and 10/14 with dysphagia (71%). Grade 3 or 4 toxicity was reported by 11 patients: 5 had haematological toxicity, 3 vomiting, 2 infection and 1 diarrhoea. One patient developed peripheral neuropathy, 1 renal impairment and another peripheral vascular disease. Following chemotherapy, surgery was attempted in 5 patients. One remains well 3 years on, 2 had macroscopic clearance of tumour but died of postoperative complications. In 2, disease was irresectable. This regimen of moderate toxicity is effective at improving symptoms in the majority of patients. In some patients, tumours are briefly downstaged so that inoperable tumours may become operable.

Adult↗
PubMed1995

Phase II study of continuous infusion fluorouracil and interferon alfa-2b in the palliation of malignant neuroendocrine tumors.

PURPOSE AND METHODS: Twenty-four patients with rapidly progressive neuroendocrine tumors were treated with a new regimen of continuous infusion fluorouracil for 20 weeks (200 mg/m2/d) together with interferon alfa-2b (5 MU three times per week). Maintenance interferon alfa at the same dose was continued after the initial 20-week period. RESULTS: Of 15 patients with carcinoid tumors, seven (47%) had an objective response, with a median duration of 20.5 months (range, 8.5 to 41), and five (33%) had stabilization of disease for between 3.5 and 42 months. Improvement in symptoms was reported by 10 patients (67%). Three early deaths occurred, all in patients with advanced disease. Of nine patients with neuroendocrine tumors other than carcinoid, three (33%) had an objective response that lasted 2.5 to 24.5 months, and five had disease stabilization for between 2.5 and 16 months. CONCLUSION: These data, particularly in respect to carcinoid tumors, are encouraging, especially since serious complications from treatment were limited. This regimen is not generally toxic, is well tolerated, and offers useful palliation and symptom control in patients with disease that does not respond to simple pharmacologic manipulations.

Adult↗
PubMed1994

Association between Meckel's diverticulum and Crohn's disease: a retrospective review.

The operation notes and pathology records of 294 consecutive patients who had right hemicolectomy for Crohn's disease were reviewed. A Meckel's diverticulum was found in 17 (5.8%) of these patients, 2-3 times the expected rate in the general population. At least 50% of diverticula in the normal population contain heterotopic mucosa, but none was found in those diverticula that were examined from this group. The increased prevalence of Meckel's diverticulum in patients with Crohn's disease confirms previous anecdotal reports, but the cause for the increased frequency remains unexplained. The significance of this finding is discussed.

Adolescent↗
PubMed1994

Acid secretion from a Meckel's diverticulum: the unsuspected mimic of Crohn's disease?

The commonest causes of ulceration in the terminal ileum are Crohn's disease, infection, and neoplasia. Meckel's diverticulum is said to be found more commonly in patients with Crohn's disease than in the general population. We describe a patient who developed extensive terminal ileal ulceration caused by acid secretion from gastric mucosa within a Meckel's diverticulum, a condition that has not been recognized before. Our patient demonstrated a number of clinical features that would be consistent with Crohn's disease, and we wonder whether the rare condition of "Meckel's ileitis" is occasionally misdiagnosed as Crohn's disease in other patients.

Crohn Disease↗