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P Ghaneh

Publications and source records attributed to P Ghaneh.

At least 37 records · Page 2Linked to original sources
PubMed2003

Adjuvant therapy in pancreatic cancer: historical and current perspectives.

The results from pancreatic ductal adenocarcinoma appear to be improving with increased resection rates and reduced postoperative mortality reported by specialist pancreatic cancer teams. Developments with medical oncological treatments have been difficult, however, due to the fundamentally aggressive biological nature of pancreatic cancer and its resistance to chemotherapy coupled with a relative dearth of randomised controlled trials. The European Study Group for Pancreatic Cancer (ESPAC)-1 trial recruited nearly 600 patients and is the largest trial in pancreatic cancer. The results demonstrated that the current best adjuvant treatment is chemotherapy using bolus 5-fluorouracil with folinic acid. The median survival of patients randomly assigned to chemoradiotherapy was 15.5 months and is comparable with many other studies, but the median survival in the chemotherapy arm was 19.7 months and is as good or superior to multimodality treatments including intra-operative radiotherapy, adjuvant chemoradiotherapy and neo-adjuvant therapies. The use of adjuvant 5-fluorouracil with folinic acid may be supplanted by gemcitabine but requires confirmation by ongoing clinical trials, notably ESPAC-3, which plans to recruit 990 patients from Europe, Canada and Australasia. Major trials such as ESPAC-1 and ESPAC-3 have set new standards for the development of adjuvant treatment and it is now clear that such treatment in this field has the potential to significantly improve both patient survival and quality of life after curative resection.

Carcinoma, Pancreatic Ductal↗
PubMed2003

Review article: chemotherapy for pancreatic cancer.

Pancreatic cancer is a common, highly lethal disease that is rising in incidence. Chemotherapy based on 5-fluorouracil (5-FU) has been shown to prolong survival in advanced pancreatic cancer. Gemcitabine improves major symptoms and survival outcomes compared with bolus 5-FU. Many novel small molecules are being widely and actively researched. These compounds are based on classical mechanisms of action as well as biological therapies targeting novel cellular survival pathways, and include fluoropyrimidines, nucleoside cytidine analogues, platinum analogues, topoisomerase-inhibitors, antimicrotubule agents, proteasome inhibitors, vitamin D analogues, arachidonic acid pathway inhibitors, histone deacytylator inhibitors, farnesyltransferase inhibitors and epidermal growth factor receptor therapies. Adjuvant chemotherapy has also demonstrated the best survival outcomes following resection compared to other adjuvant or neo-adjuvant strategies such as radiation-based treatments. These benefits are superimposed on the dramatic increase in resectability rates and reduction in post-operative mortality achieved by centralisation of treatment in high-volume speciality centres. Newer 'small-molecule' drugs as well as the latest 'large-molecule' biological agents hold considerable promise for the future. Real advances are anticipated over the next five years but are dependent on large randomised controlled trials for success.

Antimetabolites, Antineoplastic↗
PubMed2003

Surgery for midgut carcinoid.

Many clinicians prefer to avoid surgery in patients with carcinoid neoplasia, because of its slow growth and relatively favourable prognosis. Nevertheless, the commonest cause of death in patients with carcinoid is advanced metastatic disease, and both clinical and epidemiological data indicate that the more effectively the disease is ablated, the more long-lasting the benefit. Multidisciplinary management of patients with carcinoid must consider inherited risk, possible multiple carcinoids and/or synchronous non-carcinoid cancer, and the use of a range of investigations that also evaluate the 10% of patients with carcinoid syndrome with or without valvular heart disease. Although primary size is correlated with the presence of nodal with or without liver metastases, carcinoid tumours <1 cm in diameter may be metastatic at presentation, particularly those arising within the small intestine. In the jejunum and ileum, resection of all sizes of carcinoid with local and regional nodes is preferred, to prevent nodal dissemination causing mesenteric ischaemia with or without infarction. Resection of nodal metastases should be undertaken in those with persistent or recurrent nodal disease if possible. Appendiceal and right colonic carcinoids are most effectively treated by right hemicolectomy with local and regional nodal clearance, as for adenocarcinoma. However, for most appendiceal carcinoids which are <1 cm in diameter and non-invasive, appendicectomy alone is sufficient. For appendiceal carcinoids 1-2 cm in diameter, histopathological assessment helps to determine the need for hemicolectomy. Liver resection has been followed by prolonged 5 year survival in several series and is recommended in appropriate patients to attempt cure or to debulk metastatic disease. Liver transplantation has had only qualified success in highly selected patients without extra-hepatic disease in whom other therapies have failed.

Carcinoid Tumor↗
PubMed2002

Complications of pancreatic cancer resection.

Pancreatic cancer is a common cause of cancer death in the developed world. Currently, resection is the only chance of long-term survival. The post-operative mortality in nonspecialist centres often exceeds 20% but is around 6% or less in specialist centres. The overall complication rate even in specialist centres is 18-54%. An analysis of eleven large series of pancreatic resections shows an incidence of common complications of 10.4% for fistula, 9.9% for delayed gastric emptying, 4.8% for bleeding, 4.8% for wound infection and 3.8% for intra-abdominal abscess. The median hospital stay is 13-18 days in different series. The re-operation rate varies from 4 to 9% with a mortality rate of 23 to 67%. Major complications are a significant factor in post-operative mortality, especially if they require re-operation. The use of octreotide or somatostatin to prevent complications is supported by several multicentre, double-blind, randomized controlled trials. The best way to improve outcome is to concentrate pancreatic cancer care in regional specialist centres.

Anastomosis, Surgical↗
PubMed2001

Adenovirus-mediated transfer of p53 and p16(INK4a) results in pancreatic cancer regression in vitro and in vivo.

Pancreatic cancer has a very poor prognosis. Current chemotherapy and radiotherapy regimens are only moderately successful. The tumour suppressor genes p53 and p16(INK4a)encode cell cycle regulatory proteins that are important candidates for gene replacement therapy. Over 80% of pancreatic adenocarcinoma cases lack detectable p16 protein while over 60% contain mutated p53 protein. We used replication-deficient recombinant adenoviruses to reintroduce wild-type p16 and p53 into pancreatic cancer cells in vitro and into subcutaneous pancreatic tumours in an animal model to determine the effect on tumour growth. Significant growth inhibition was observed in all five human pancreatic cell lines with these viruses (P < 0.002) compared with similar control viruses expressing either luciferase or beta-galactosidase. G1 arrest was observed in all cell lines 72 h after infection with Adp16. Infection with Adp53 caused significant levels of apoptosis (P < 0.004). Apoptosis was also observed to a lesser degree (P < 0.03) with the Adp16 vector. Subcutaneous pancreatic tumours, generated in nu-nu mice demonstrated significant growth suppression following injection of Adp53, Adp16 and a combination of both Adp53 and Adp16 (P < 0.0001). These results show that transfer of wild-type p53 and p16 produces significant growth suppression of pancreatic cancer in vitro and in vivo.

Adenoviridae↗
PubMed2001

Hepatic intra-arterial delivery of a retroviral vector expressing the cytosine deaminase gene, controlled by the CEA promoter and intraperitoneal treatment with 5-fluorocytosine suppresses growth of colorectal liver metastases.

Targeting of colorectal liver metastases by regional gene therapy was tested in a clinically relevant syngeneic model. First, the CEA-CD-113 retroviral vector containing the cytosine deaminase gene controlled by the CEA specific tumour cell promoter, was shown in vitro to convert 5-fluorocytosine to 5-fluorouracil, resulting in cancer cell killing with a large bystander effect. Second, 10 days after the establishment of liver metastases, retroviral vectors were delivered to the liver by hepatic artery injection. After 5-fluorocytosine administration for 7 days, most surface metastases disappeared and tumour volumes were suppressed up to 8.2-fold. The results support the development of this approach for patient treatment.

Animals↗
PubMed2001

(131)I-MIBG radionuclide therapy is safe and cost-effective in the control of symptoms of the carcinoid syndrome.

BACKGROUND: The standard treatment used to control the symptoms of carcinoid syndrome (CS) involves subcutaneous injections of the somatostatin analogue octreotide. This is expensive (US $8000--16,000 per year), and treatment may be for many years. The aim of this study was to evaluate the efficacy and cost-effectiveness of our experience over the last 5 years with 1-131-labelled metaiodobenzylguanidine (MIBG) radionuclide therapy in the palliation of patients with CS. METHODS: A consecutive series of 20 symptomatic patients (referred between 1994 and 1999) with CS were evaluated. Fifteen of them underwent(123)I-MIBG scanning. Of the 13 patients with significant tracer uptake in metastatic deposits compared to background, 12 underwent a course of therapeutic(131)I-MIBG (one patient refused). Symptoms, biochemical markers, CT scans, follow-up(123)I-MIBG scans, and the requirement for octreotide were used to assess outcome of treatment. Costs of(131)I-MIBG and octreotide treatments were compared. RESULTS: MIBG treatment was well tolerated in all with only transient side-effects. Ten patients showed a measurable clinical improvement. Seven had a complete clinical response. The mean duration of response was 15.4 months. Octreotide was not required or was reduced in eight patients. Treatment with(131)I-MIBG resulted in a saving of US $1000 per patient, with effective symptom control, when compared to octreotide. CONCLUSION: 1-131 MIBG therapy is a safe and cost-effective therapeutic option to successfully control symptoms in patients with carcinoid syndrome.

3-Iodobenzylguanidine↗
PubMed2001

Management of necrotizing pancreatitis.

Infection complicating pancreatic necrosis leads to persisting sepsis, multiple organ dysfunction syndrome and accounts for about half the deaths that occur following acute pancreatitis. Severe cases due to gallstones require urgent endoscopic sphincterotomy. Patients with pancreatic necrosis should be followed with serial contrast enhanced computed tomography (CE-CT) and if infection is suspected fine needle aspiration of the necrotic area for bacteriology (FNAB) should be undertaken. Treatment of sterile necrosis should initially be nonoperative. In the presence of infection necrosectomy is indicated. Although traditionally this has been by open surgery, minimally invasive procedures are a promising new alternative. There are many unresolved issues in the management of pancreatic necrosis. These include, the use of antibiotic prophylaxis, the precise indications for and frequency of repeat CE-CT and FNAB, and the role of enteral feeding.

Humans↗
PubMed2001

Adjuvant therapy in pancreatic cancer.

The outlook for patients with pancreatic cancer has been grim. There have been major advances in the surgical treatment of pancreatic cancer, leading to a dramatic reduction in post-operative mortality from the development of high volume specialized centres. This stimulated the study of adjuvant and neoadjuvant treatments in pancreatic cancer including chemoradiotherapy and chemotherapy. Initial protocols have been based on the original but rather small GITSG study first reported in 1985. There have been two large European trials totalling over 600 patients (EORTC and ESPAC-1) that do not support the use of chemoradiation as adjuvant therapy. A second major finding from the ESPAC-1 trial (541 patients randomized) was some but not conclusive evidence for a survival benefit associated with chemotherapy. A third major finding from the ESPAC-1 trial was that the quality of life was not affected by the use of adjuvant treatments compared to surgery alone. The ESPAC-3 trial aims to assess the definitive use of adjuvant chemotherapy in a randomized controlled trial of 990 patients.

Antineoplastic Agents↗
PubMed2000

K-ras oncogene subtype mutations are associated with survival but not expression of p53, p16(INK4A), p21(WAF-1), cyclin D1, erbB-2 and erbB-3 in resected pancreatic ductal adenocarcinoma.

Previous studies of molecular prognostic markers following resection for exocrine pancreatic cancer have produced conflicting results. Our aim was to undertake a comprehensive analysis of potentially useful molecular markers in a large, multicentre patient population and to compare these markers with standard pathological prognostic variables. Formalin-fixed, paraffin-embedded specimens of pancreatic ductal adenocarcinoma were analysed from 157 patients [100 men and 57 women with a median (range) age of 60 (33-77) years] who had undergone pancreatectomy. Immunohistochemistry was used to detect expression of p16(INK4), p53, p21(WAF1), cyclin D1, erbB-2 and erbB-3. Mutations in codons 12 and 13 of the K-ras oncogene were detected by SSCP and sequencing following DNA extraction and amplification by PCR. The median (range) survival post-resection was 12.5 (3-83) months. Abnormalities of p16(INK4), p53, p21(WAF1), cyclin D1, erbB-2 and erbB-3 expression were found in 87%, 41%, 75%, 72%, 33% and 57% of cases, respectively. There was no significant correlation between expression of any of these markers and patient survival. K-ras mutations were found in 73 (75%) of 97 cases with amplifiable DNA. The presence of K-ras mutation alone did not correlate with survival, but there were significant differences in survival according to the type of K-ras mutation (p = 0.0007). Reduced survival was found in patients with GaT, cGT and GcT K-ras mutations compared to GtT, aGT and GaC mutations. In conclusion, survival was associated with type of K-ras mutation but not expression of p16(INK4), p53, p21(WAF1), cyclin D1, erbB-2 and erbB-3.

Adult↗
PubMed2000

Gene therapy for pancreatic cancer--current and prospective strategies.

Pancreatic ductal adenocarcinoma is one of the most common causes of cancer death in the developed world. Long-term survival is currently only achieved through surgical resection. Most patients have locally advanced or metastatic disease at the time of diagnosis and are therefore not amenable to resection, whilst chemotherapy and radiotherapy are by and large ineffective. Gene therapy offers an alternative to current adjuvant strategies. With approximately two-thirds of all gene therapy trials worldwide directed at cancer, the gene therapy approaches that are currently being explored for pancreatic cancer are specifically examined. Gene delivery systems, genetic targets, and combined gene delivery with chemotherapy are discussed in the context of pancreatic cancer treatment.

Adenocarcinoma↗
PubMed2000

Adjuvant therapy for pancreatic cancer.

Pancreatic cancer was once considered to be a disease without hope. Advances in regionalisation of treatment in specialist units have resulted in a great improvement in resection outcome. Studies in advanced pancreatic cancer have indicated an advantage for chemotherapy. For 15 years only the GITSG had tested adjuvant therapy in a randomised controlled trial. This small study of only 43 patients suggested a survival benefit for post-operative chemoradiotherapy combined with follow-on chemotherapy. Recently two large trials of over 800 patients, one from the EORTC and the other from ESPAC, have shown no benefit from chemoradiotherapy alone. Results from a Norwegian and from ESPAC suggest that adjuvant chemotherapy (without chemoradiotherapy) prolongs survival. The major randomisation and recruitment centres for ESPAC include Berne, Switzerland, Verona, Italy and Liverpool, UK. The ESPAC-3 Trial plans to recruit 990 patients to definitively answer the chemotherapy question as adjuvant treatment for pancreatic cancer. The new millennium brings hope at last to the most challenging cancer of all--cancer of the pancreas.

Adenocarcinoma↗
PubMed1999

The matrix metalloproteinases and their inhibitors in the treatment of pancreatic cancer.

Matrix metalloproteinases (MMPs) are a family of zinc-containing proteolytic enzymes that break down extracellular matrix proteins (ECM) in physiological and pathological conditions. Disruption in the tight control of MMP metabolism occurs in cancer, resulting in excessive destruction of the ECM, neovascularization, tumor spread and metastases. Recent studies have shown that overexpression of MMPs is associated with poor prognosis. Several MMP inhibitors have been developed and preclinical trials have confirmed a reduction in tumor spread and metastases. Marimastat is a broad spectrum inhibitor, and recent published results shows the drug is well tolerated in patients with advanced cancer. Phase II studies which have used marimistat alone or in combination with other cytotoxic agents, have produced encouraging results with improved survival. Phase III trials are now underway for the use of marimastat in advanced pancreatic cancer and as an adjuvant therapy in patients following resection of pancreatic cancer.

Animals↗
PubMed1999

Exocrine pancreatic function following pancreatectomy.

Pancreatic exocrine insufficiency can follow major pancreatic resection and result in the malabsorption of fat, causing symptoms of steatorrhea, abdominal pain and weight loss. The extent of malabsorption will depend on the original disease process and the type and extent of surgical resection. The steatorrhea can be severe and difficult to control, and patients may require high doses of pancreatic enzyme supplements. There have been few studies that have looked at the treatment of steatorrhea postpancreatectomy, and very few randomized studies. Results of the latter have demonstrated that after treatment with oral pancreatic supplements over a third of postpancreatectomy patients still have significant levels of steatorrhea. These results show that even using the best available agents the complete elimination of steatorrhea following major pancreatic resection is not possible at the present time. This indicates a need for further effective therapies.

Animals↗
PubMed1999

Adjuvant therapy for pancreatic cancer.

Pancreatic cancer is a major cause of cancer death; and despite advances in the standards of surgery and supportive care, the median and long-term survival rates have not shown similar dramatic improvements. Techniques such as radical surgery alone cannot guarantee a cure. Previous work with conventional chemotherapy and radiotherapy in patients with advanced pancreatic cancer has indicated a role for adjuvant therapy for patients with resectable tumors. The main modalities that have been assessed are based on the Gastrointestinal Tumour Study Group (GITSG) results using 5-fluorouracil chemotherapy, external beam radiation therapy (EBRT), or both. Alternative approaches such as neoadjuvant therapy have been used, which may increase the number of patients suitable for resection; and regional therapy techniques have been used to increase the therapeutic potential by concentrating agents to the tumor bed. The results of single or combination therapy do show some improvement in survival but have been limited in most cases to retrospective nonrandomized series of patients. Therefore the results must be assessed as such. There are several large randomized trials that will deliver definitive answers in the near future as to whether conventional adjuvant therapy is effective. New approaches using novel agents for advanced disease are currently being assessed, and they may eventually identify the most appropriate and effective agents to use for pancreatic cancer in the adjuvant setting.

Antimetabolites, Antineoplastic↗
PubMed1999

Pancreatic exocrine insufficiency following pancreatic resection.

Major pancreatic resection can cause pancreatic enzyme insufficiency with fat malabsorption, resulting in symptoms of abdominal pain, steatorrhoea and weight loss which can be extremely debilitating. The most important factors influencing subsequent development of steatorrhoea are the extent and type of surgical resection and the underlying disease process. The resultant steatorrhoea can be marked and difficult to control. There have been relatively few randomised controlled studies which have addressed this particular problem in patients who have had pancreatectomy. The use of effective doses of pancreatic enzyme supplements is essential in those patients who are symptomatic. When stabilised on therapeutically effective doses of pancreatic enzyme supplements, however, over 30% of patients still have evidence of significant levels of steatorrhoea. These results emphasise that the complete eradication of steatorrhoea is still not feasible at the present time, even using the best currently available agents, highlighting the need for further effective therapies.

Abdominal Pain↗
PubMed1999

The potential for gene therapy in pancreatic cancer.

Pancreatic cancer is highly aggressive and is a leading cause of cancer death in the Western world. Currently, there is no effective treatment for this disease; resection is only available to a small fraction of patients and has a marginal effect on overall survival rates. Chemotherapy and radiation also have very limited effects on patient survival. There is clearly a need for new approaches to treatment of such an aggressive disease. Gene therapy is of potential use in the treatment of cancer, and all currently available strategies are discussed with relevance to pancreatic cancer. A key to such strategy is specific delivery and selective gene expression in target cells. Current approaches include replacement of tumor suppressor genes, the use of antisense (AS) oligonucleotides, gene-directed enzyme prodrug therapy (GDEPT), and immunotherapy. The scene is now set for the next phase of development in clinical trials.

Antisense Elements (Genetics)↗