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Biomedical subjects

S R Bramhall

Publications and source records attributed to S R Bramhall.

36 records · Page 2Linked to original sources
PubMed2001

Marimastat as first-line therapy for patients with unresectable pancreatic cancer: a randomized trial.

PURPOSE: The prognosis for unresectable pancreatic cancer remains dismal (1-year survival rate, < 10%; 5-year survival rate, < 5%). Recent advances in conventional chemotherapy and novel molecular treatment strategies warrant investigation. This, the largest randomized study in pancreatic cancer performed to date, compares marimastat, the first of a new class of agents, with gemcitabine. PATIENTS AND METHODS: Four hundred fourteen patients with unresectable pancreatic cancer were randomized to receive marimastat 5, 10, or 25 mg bid or gemcitabine 1,000 mg/m2. The primary end point was survival. Progression-free survival, patient benefit, and safety were also assessed. RESULTS: There was no significant difference in survival between 5, 10, or 25 mg of marimastat and gemcitabine (P =.19). Median survival times were 111, 105, 125, and 167 days, respectively, and 1-year survival rates were 14%, 14%, 20%, and 19%, respectively. There was a significant difference in survival rates between patients treated with gemcitabine and marimastat 5 and 10 mg (P <.003). Both agents were well tolerated, although grade 3 or 4 toxicities were reported in 22% and 12% of the gemcitabine- and marimastat-treated patients, respectively. The major toxicity of marimastat was musculoskeletal (44% of marimastat patients, compared with 12% of gemcitabine patients; musculoskeletal toxicity was severe in only 8% of marimastat patients). CONCLUSION: The results of this study provide evidence of a dose response for marimastat in patients with advanced pancreatic cancer. The 1-year survival rate for patients receiving marimastat 25 mg was similar to that of patients receiving gemcitabine. In view of the manageable tolerability of marimastat and its ease of administration, further studies are warranted.

Adenocarcinoma↗
PubMed2001

Liver transplantation in the UK.

INTRODUCTION: This paper provides a review of the practice of liver transplantation with the main emphasis on UK practice and indications for transplantation. REFERRAL AND ASSESSMENT: This section reviews the process of referral and assessment of patients with liver disease with reference to UK practice. DONOR ORGANS: The practice of brainstem death and cadaveric organ donation is peculiar to individual countries and rates of donation and potential areas of improvement are addressed. OPERATIVE TECHNIQUE: The technical innovations that have led to liver transplantation becoming a semi-elective procedure are reviewed. Specific emphasis is made to the role of liver reduction and splitting and living related liver transplantation and how this impacts on UK practice are reviewed. The complications of liver transplan-tation are also reviewed with reference to our own unit. Immunosuppression:The evolution of immunosuppression and its impact on liver transplantation are reviewed with some reference to future protocols. RETRANSPLANTATION: The role of retransplantation is reviewed. OUTCOME AND SURVIVAL: The results of liver transplantation are reviewed with specific emphasis on our own experience. FUTURE: The future of liver transplantation is addressed.

Humans↗
PubMed2000

Novel non-operative treatment and treatment strategies in pancreatic cancer.

Patients with advanced pancreatic cancer have traditionally been treated with palliative care only. The last decade has seen significant improvements in the surgical treatment of this disease but until the late 1990s there was no effective non-surgical treatment for these tumours. The introduction of gemcitabine has given clinicians treating patients with pancreatic cancer a new option. The published randomised data of gemcitabine in patients with pancreatic cancer has shown both a small survival advantage and significant improvements in quality of life indicators in these patients. These data have stimulated a resurgence of interest in pancreatic tumours and several studies have been or are currently investigating novel treatments or treatment strategies. The explosion in the molecular knowledge of cancer has led to the development of several 'molecular designer drugs' that have been tested in pancreatic cancer. The furthest advanced of these is a matrix metalloproteinase (MMP) inhibitor called marimastat. The first randomised data using this new class of agents is increasing and suggests that marimastat may have a role in the future treatment of patients with pancreatic cancer. Other agents such as gastrimmune, are about to enter Phase III studies and several other molecular treatment strategies are progressing from the in vitro stage towards the clinical arena. Each of these treatments and treatment regimens are discussed along with their current progress.

Animals↗
PubMed1999

Phase II trial of radical surgery for locally advanced pelvic neoplasia.

BACKGROUND: Reported operative mortality and survival rates following total pelvic exenteration (TPE) for recurrent pelvic neoplasia are now as good as those for many primary treatments. The currently accepted primary treatments for these tumours are, however, still either radiotherapy alone or radiotherapy and chemotherapy. The primary aim of this study was to evaluate the safety and tolerability of TPE and secondarily to ascertain survival after TPE. METHODS: This was a phase II study of 50 patients with locally advanced pelvic tumours who underwent TPE. RESULTS: Thirty-two patients (64 per cent) underwent TPE for recurrent carcinoma of the cervix, seven (14 per cent) for rectal cancer, three (6 per cent) for vulval carcinoma, three (6 per cent) for vaginal carcinoma, two (4 per cent) for prostate cancer and three (6 per cent) for other tumours. The 30-day mortality rate was 8 per cent with an in-hospital mortality rate of 16 per cent. The crude morbidity rate was 62 per cent, with 23 patients (46 per cent) having grade III or IV toxicity. A complete response was achieved in 63 per cent and a partial response in 37 per cent of patients. The overall median survival time was 86 weeks; it was 111 weeks in patients in whom a complete response was achieved. CONCLUSION: The survival and operative mortality rates that are now attainable with TPE are comparable to those achieved with chemoradiotherapy in advanced pelvic neoplasia. TPE should no longer be reserved for salvage therapy and should perhaps be compared with chemoradiotherapy as first-line treatment in a phase III randomized trial in patients with these tumours.

Adult↗
PubMed1998

Stromal degradation by the malignant epithelium in pancreatic cancer and the therapeutic potential of proteolytic inhibition.

off matrix metalloproteinases (MMPs) and the tissue inhibitors of the metalloproteinases (TIMPs) are described and reviewed. The role of the MMPs and their inhibitors in tumour invasion and metastasis is reviewed and the interaction between the extracellular matrix and these enzymes is discussed. The expression and activity of the MMPs and TIMPs in pancreatic cancer is reported with reference to the literature and the author's own work. The effect of MMP inhibitors (MMPIs) in vivo and the use of batimastat and marimastat (both; British Biotech Pharmaceuticals, Oxford, UK) in animal experiments are also described. Preliminary phase II and III clinical trial data of marimastat in advanced pancreatic cancer is reported.

Animals↗
PubMed1998

The use of molecular technology in the differentiation of pancreatic cancer and chronic pancreatitis.

CONCLUSION: It is concluded that currently there are limitations in the use of some of the proposed tests, whereas in the future, further progress in our understanding of the molecular biology of pancreatic disease and the development and application of existing techniques should have a greater impact on clinical practice. BACKGROUND: Fifteen to 20% of patients with pancreatic cancer present with a resectable mass in the head of the pancreas, but there is a subgroup of patients for whom it is difficult to reach the correct diagnosis. METHOD: This article addresses how molecular technology can be used to aid in the diagnosis of this group of patients. The clinical and scientific literature is reviewed by accessing papers through the Medline database. RESULTS: This article reviews the limitations of conventional imaging techniques and the limitations of fine needle aspiration cytology and cytological examination of pancreatic duct secretions. The molecular biology of both pancreatic cancer and chronic pancreatitis is then reviewed with emphasis on the common molecular defects seen in these diseases. The current use of molecular techniques in the examination of cytological and histological specimens, stool, blood, and pancreatic duct secretions and how this helps discriminate between benign and malignant lesions of the pancreas is addressed. Finally, the use of novel serum screening tests in groups at high risk of pancreatic cancer is discussed.

Chronic Disease↗
PubMed1997

Imbalance of expression of matrix metalloproteinases (MMPs) and tissue inhibitors of the matrix metalloproteinases (TIMPs) in human pancreatic carcinoma.

Degradation of the extracellular matrix (ECM) is an essential step in tumour invasion and metastasis. The matrix metalloproteinases (MMPs) each have different substrate specificities within the ECM and are important in its degradation. MMP activity is dependent on the levels of activated MMP and tissue inhibitors of matrix metalloproteinases (TIMPs). The expression of MMPs and TIMPs in pancreatic carcinoma, normal pancreas, and pancreatic carcinoma cell lines has been determined by Northern analysis. The transcripts have been localized by in situ hybridization and the MMP2 protein by immunohistochemistry. Expression of MMP2, -7, and -11 was greater in pancreatic carcinoma than in normal pancreas (P < 0.01). MMP7 expression in normal pancreas and MMP7 and -11 expression in tumours was always seen the TIMP1 expression. TIMP2 was expressed in only half of the tumours and a previously undescribed transcript size is reported for TIMP2. MTMMP was expressed concurrently with MMP2 in 64 per cent of tumours, but concurrent MMP2 and TIMP2 expression occurred in only half. MMP2 mRNA was found more often in the tumour stroma than with the other MMPs or TIMPs (P < 0.02). It is concluded that while overexpression of MMP7 and -11 may be countered by TIMP1, the aggressive phenotype of pancreatic carcinoma may occur because of overexpression of MMP2, activated by MTMMP and associated with a reduced expression of TIMP2.

Blotting, Northern↗
PubMed1997

The matrix metalloproteinases and their inhibitors in pancreatic cancer. From molecular science to a clinical application.

The matrix metalloproteinases (MMPs) and their tissue-specific inhibitors (TIMPs) are described and their roles in tumor invasion and metastasis are reviewed. The expression and activity of the MMPs and TIMPs in pancreatic cancer is reported and illustrated with immunohistochemistry and in situ hybridization. The role of MMP inhibitors (MMPIs) is reviewed in vivo and the use of novel MMPIs, e.g., BB94 (Batimastat) and BB2516 (Marimastat); in animal experiments are also described. Finally, the preliminary results from a phase 2 trial of BB2516 (Marimastat) in pancreatic cancer are reported.

Gelatinases↗
PubMed1997

Adjuvant chemotherapy in pancreatic cancer.

There is increasing interest in the use of adjuvant treatment for pancreatic cancer since although postoperative mortality is much improved, median long-term survival is only on the order of 11-15 mo. Despite a proliferation of studies in advanced pancreatic cancer indicating a benefit for chemotherapy, there has only been one small randomized adjuvant trial. A combination of 5-fluorouracil, doxorubicin, and mitomycin-C demonstrated a significantly improved median survival (23 vs 11 mo in controls) but no significant improvement in 5-yr survival (4 vs 8%, respectively). At present there is insufficient evidence to support the routine use of adjuvant chemotherapy (even with radiotherapy) outside of controlled trials. What is required is large randomized trials of adjuvant chemotherapy. A further important question that needs addressing is the role of adjuvant radiotherapy (with concomitant chemotherapy) with or without sequential chemotherapy.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1997

Serum levels of insulin-like growth factors (IGF-I and IGF-II) and their binding protein (IGFBP-3) are not elevated in pancreatic cancer.

CONCLUSION: Serum levels of IGF-I, IGF-II, and IGFBP-3 are not elevated in pancreatic cancer and do not appear to have a significant role in glucose homeostasis in this group of patients. BACKGROUND: The insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) have been implicated recently in the pathogenesis of pancreatic cancer, and increased serum levels of IGF-I or IGF-II have been reported previously in a number of other gastrointestinal malignancies. METHODS: Serum levels of IGF-I, IGF-II, and IGFBP-3 were measured by RIA in 20 patients with pancreatic cancer and 20 age-matched healthy control subjects and correlated with serum glucose, C-peptide, and glucose tolerance. RESULTS: No significant difference was observed in serum levels of IGF-I (13 vs 17 nmol/L, respectively), IGF-II (0.67 vs 0.91 U/mL), or IGFBP-3 (2.3 vs 2.3 mg/L) between the two groups of patients. Twelve (60%) patients had impaired glucose tolerance, but no correlation was observed between the serum levels of the IGFs and glucose tolerance.

Aged↗
PubMed1997

Outcome of surgery for chronic pancreatitis.

BACKGROUND: In patients with chronic pancreatitis, surgery is indicated for the management of intractable pain or for the treatment of complications. METHODS: Sixty-three consecutive patients (49 men and 14 women of median age 40 (range 20-72) years) who had undergone surgery over an 8-year interval for chronic pancreatitis were studied. The mortality and morbidity rates associated with surgery were assessed and quality of life was reviewed based on relief of symptoms, analgesic use, employment and long-term sequelae. RESULTS: Forty-four patients (70 per cent) had alcoholic chronic pancreatitis. In 60 patients the principal indication for surgery was intractable pain. Eighteen patients had a duodenum-preserving resection of the pancreatic head (Beger operation); the other surgical procedures were Whipple resection (15), left-sided resection (13), total pancreatectomy (seven), pseudocystjejunostomy (five), pancreaticojejunostomy (one) and bypass procedures (four). The median inpatient stay was 12 days; 23 patients had postoperative complications including one death (2 per cent). There was improved pain control (P < 0.001), a reduction in opiate analgesia use, increase in percentage weight gain (P < 0.01 at 2 years) and return to employment following surgery. Although there was an increase in diabetes mellitus and need for enzyme supplementation these were easily controlled. CONCLUSION: Surgery is an effective treatment in carefully selected patients with chronic pancreatitis but must be tailored to the pattern of disease in each individual.

Adult↗
PubMed1996

Expression of collagenase (MMP2), stromelysin (MMP3) and tissue inhibitor of the metalloproteinases (TIMP1) in pancreatic and ampullary disease.

It is now recognised that epithelial-stromal interactions are important in a wide range of disease processes including neoplasia and inflammation. Metalloproteinases are central to matrix degradation and remodelling, which are key events in tumour invasion and metastasis and may also be involved in tissue changes occurring in chronic inflammation. Immunohistochemistry was performed on sections from 50 patients with pancreatic cancer (n = 27), ampullary cancer (n = 12), low bile duct cancer (n = 3), neuroendocrine tumours (n = 3) and chronic pancreatitis (n = 5), using antibodies raised against collagenase (MMP2), stromelysin (MMP3) and tissue inhibitor of metalloproteinase (TIMP1) and developed using the avidin-biotin complex method. Abundance of MMP2, MMP3 and TIMP1 was greater in pancreatic and ampullary cancer than any other pathology and immunoreactivity in the malignant epithelial cells in pancreatic and ampullary cancer was greater than in the stromal tissues (in pancreatic cancer: MMP2 100% vs 37%, MMP3 93% vs 15%, TIMP1 93% vs 4%, P < 0.0001). There were strong correlations between the immunoreactivity of the two antibodies for MMP2 (P < 0.0001), between MMP2 and TIMP1 (P < 0.0001) and between MMP3 and TIMP1 (P < 0.0001). The immunoreactivity for TIMP1 in pancreatic and ampullary cancers with lymph node metastases was significantly less compared with those cases without lymph node metastases (P < 0.02) and there was an association between increased immunoreactivity for MMP2 and the degree of tumour differentiation (P < 0.01). The results implicate MMP2, MMP3 and TIMP1 in the invasive phenotype of pancreatic and ampullary cancer.

Ampulla of Vater↗
PubMed1996

Monitoring the introduction of laparoscopic cholecystectomy in a district general hospital.

There has been recent concern regarding the widespread introduction of laparoscopic procedures without adequate training. We report a 2 year prospective series of 229 consecutive open and laparoscopic cholecystectomies, following the introduction of laparoscopic surgery at a district general hospital. All laparoscopic cholecystectomies were performed by surgeons without formal training in this procedure. The proportion of laparoscopic cholecystectomies rose from 27% in 1992 to 62% in 1993, with a conversion rate of 14%. An overall complication rate of 23% was recorded, 29% for open cholecystectomy and 16% for laparoscopic cholecystectomy. Procedure specific complication rates were 6% and 3% respectively. No major bile duct injuries occurred and the 30-day mortality was 0.9%. We conclude that laparoscopic cholecystectomy has been introduced as a safe procedure in this hospital, as compared to open cholecystectomy. It is recommended that new techniques should be introduced carefully and monitored by means of prospective audit.

Cholecystectomy, Laparoscopic↗
PubMed1995

Treatment and survival in 13,560 patients with pancreatic cancer, and incidence of the disease, in the West Midlands: an epidemiological study.

The trends in treatment and outcome of 13,560 patients with pancreatic cancer, and in incidence of the disease, in the West Midlands health region were determined between 1957 and 1986 using data from the West Midlands Region Cancer Registry. Patients were divided into those diagnosed in the first 20 years (1957-1976, n = 7888) and the most recent 10 years (1977-1986, n = 5672). The disease was more common in men and the incidence increased up to 1970 after which it levelled off. In the 1977-1986 period a lower proportion of patients had laparotomy alone (825 (14.5 per cent) versus 1552 (19.7 per cent)), a similar proportion had bypass surgery (2010 (35.4 per cent) versus 2760 (35.0 per cent)), while a greater proportion had supportive care (2710 (47.8 per cent) versus 3368 (42.7 per cent)) but the resection rates were the same (145 (2.6 per cent) versus 208 (2.6 per cent)). The 30-day mortality rates between the two periods improved for resection (40 (27.6 per cent) versus 94 (45.2 per cent)), bypass surgery (436 (21.7 percent) versus 691 (25.0 per cent)) and laparotomy (372 (45.1 per cent) versus 873 (56.3 per cent)). The 12-month survival rate for bypass did not significantly differ during the study (14.9 per cent versus 12.4 per cent) but there was a significant improvement in the 5-year survival for resection (9.7 per cent versus 2.6 per cent, P < 0.015). The resection rates were low and 30-day mortality rates for surgery were high compared with those of other published series.

Actuarial Analysis↗
PubMed1995

Advances in diagnosis and treatment of pancreatic cancer.

This review focuses on key advances in diagnosis and treatment of pancreatic cancer, with a particular emphasis on the expanding potential application of molecular techniques and the great strides made in evolving safe pancreatic resection. The epidemiology of pancreatic cancer is reviewed, and recent advances for potential screening are reported. Improvements in operative morbidity and mortality following pancreatic resection have led to calls for more radical surgery, and the results of conventional and extended radical surgery are compared. Recently combined multimodality adjuvant therapy has been used following "curative resection" for pancreatic cancer, and the current status concerning use of this treatment is addressed. Although there is insufficient evidence to recommend routine use of adjuvant therapy, there are sufficient encouraging data to advocate entering patients in large, adjuvant therapy trials. In addition to safe resectional surgery, advances in novel molecular therapy mean that the outlook for patients with pancreatic cancer should no longer be considered hopeless.

Chemotherapy, Adjuvant↗
PubMed1993

An improved method for oesophageal intubation.

The authors describe a method of inserting an Atkinson tube using a flexible upper gastrointestinal endoscope which does not require the use of X-ray screening. A retrospective review of 50 patients intubated by this technique has been undertaken and the results presented. Of the lesions, 40% were squamous cell carcinoma and 40% adenocarcinoma, with 84% being situated in the lower third of the oesophagus; 94% of patients only required one intubation. The two major complications of the procedure are tube displacement and oesophageal leak; a tube displacement rate of 13% was recorded, comparable with other series. Eleven patients (20.8%) were found to have an oesophageal leak, but this resulted in death in only three patients (6%). The reasons for these figures are explained. An operative mortality rate of 12% is comparable with series using other methods. The authors conclude that this method of intubation is as safe as Atkinson's original method but has the advantage that X-ray screening is not required.

Aged↗