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J Neoptolemos

Publications and source records attributed to J Neoptolemos.

17 recordsLinked to original sources
PubMed2002

Novel cationic trypsinogen (PRSS1) N29T and R122C mutations cause autosomal dominant hereditary pancreatitis.

Hereditary pancreatitis (HP) is usually caused by mutations in the cationic trypsinogen (PRSS1) gene, especially R122H or N29I. We sequenced the PRSS1 gene in the proband of families without these common mutations. Novel R122C and N29T mutations were detected in independent families that segregated with the disease in an autosomal dominant fashion. The R122C mutation eliminates the arginine autolysis site as with R122H mutations. The N29T mutation may also enhance intrapancreatic trypsin activity as has been demonstrated in vitro. Identification of these new mutations requires special attention as commonly used detection methods may fail.

Adult↗
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↗
PubMed2000

Screening for early pancreatic ductal adenocarcinoma in hereditary pancreatitis.

Patients with hereditary pancreatitis have a 40% lifetime risk of developing pancreatic ductal adenocarcinoma. Existing methods of diagnosing pancreatic cancer such as tumor markers, endoscopy, and radiological imaging lack the sensitivity and specificity for early diagnosis, particularly in a background of chronic pancreatitis. Molecular based strategies offer new avenues of screening for pancreatic ductal adenocarcinoma in these high-risk patients, which may allow the development of highly sensitive and specific diagnostic tests for the early detection of cancer.

Adenocarcinoma↗
PubMed2000

SPINK1/PSTI polymorphisms act as disease modifiers in familial and idiopathic chronic pancreatitis.

BACKGROUND & AIMS: Gain-of-function trypsin mutations cause acute pancreatitis and chronic pancreatitis. Loss of trypsin inhibitor function may have similar effects. We investigated the prevalence of SPINK1 (PSTI) mutations in familial pancreatitis, idiopathic chronic pancreatitis, and controls. METHODS: Genetic-linkage studies were performed in 5 familial pancreatitis families. The entire SPINK1 gene was sequenced in 112 affected individuals and 95 control DNA samples, and exon 3 was sequenced in 95 additional controls. X-ray crystallography-based model building and statistical studies were performed. RESULTS: Significant linkage between pancreatitis and 5q31.1-2 was excluded. Novel SPINK1 mutations, one D50E mutation, one IVS3+125 C>A, and five IVS3+184 T>A intronic polymorphisms were identified. The N34S and P55S mutations were observed in 29 of 112 patients (25%) as N34S/N34S (n = 7), N34S/wt (n = 19), N34S/P55S (n = 2), and N34S/D50E (n = 1). Three hundred eighty control alleles revealed 3 N34S (0.77%), 2 P55S (0.53%), and no D50E mutations. Age of disease onset and severity were similar between homozygous and heterozygous patients. Structural modeling revealed several possible pathophysiologic mechanisms for the N34S mutation. CONCLUSIONS: SPINK1 mutations are common in the population (approximately 2%), but are clearly associated with pancreatitis. The mutation-associated risk is low. Modeling and familial clustering suggest that SPINK1 mutations are disease modifying, possibly by lowering the threshold for pancreatitis from other genetic or environmental factors, but by themselves do not cause disease.

Amino Acid Sequence↗
PubMed1999

Protein kinase C isoenzyme patterns characteristically modulated in early prostate cancer.

Expression of protein kinase C (PKC) isoenzymes -alpha, -beta, -delta, -epsilon, -gamma, -iota, -lambda, -mu, -theta, and -zeta, and of their common receptor for activated C-kinase (RACK)-1, was determined immunohistochemically using specific antibodies in formalin-fixed and paraffin-embedded specimens of early prostatic adenocarcinomas (n = 23) obtained at radical prostatectomy. Expression of each isoenzyme by malignant tissues was compared with nonneoplastic prostate tissues removed at radical cystectomy (n = 10). The most significant findings were decreased PKC-beta expression in early neoplasia when compared to benign epithelium (P < 0.0001), together with a reciprocal increase in expression of PKC-epsilon (P < 0.0001). Detectable levels of PKC-alpha and PKC-zeta were also significantly increased in the cancers (P = 0.045 and P = 0.015 respectively) but did not correlate with either PKC-beta or PKC-epsilon for individual cases. Alterations in the levels of the four PKC isoenzymes occurred specifically and consistently during the genesis and progression of human prostate cancer. PKC-delta, -gamma, and -theta were not expressed in the epithelium of either the benign prostates or the cancers. Levels of expression for PKC-A, -iota, -mu, and RACK-1 were not significantly different between the benign and malignant groups. Although changes in PKC isoenzyme expression may assist in explaining an altered balance between proliferation and apoptosis, it is likely that changes in activity or concentrations of these isoenzymes exert important modulating influences on particular pathways regulating cellular homeostasis. The findings of this study raise an exciting possibility of novel therapeutic intervention to regulate homeostatic mechanisms controlling proliferation and/or apoptosis, including expression of the p170 drug-resistance glycoprotein, intracellular Ca2+ concentrations, and enhanced cellular mobility resulting in the metastatic dissemination of human prostate cancer cells. Attenuation of PKC-beta expression is currently being assessed as a reliable objective adjunct to morphological appearance for the diagnosis of early progressive neoplasia in human prostatic tissues.

Disease Progression↗
PubMed1999

Cytokines and acute pancreatitis.

Cytokines have been shown to play a pivotal role in multiple organ dysfunction, a major cause of death in severe acute pancreatitis. Moreover, the two-hit hypothesis of the cytokine-induced systemic inflammatory response syndrome explains the variable individual response to severe acute pancreatitis and the impact of secondary events such as sepsis or therapeutic intervention. Many experimental anti-cytokine therapies have been administered following induction of experimental pancreatitis, and have proved to be therapeutic. Patients with severe pancreatitis present early because of pain. Clearly then a window for therapeutic intervention is available between onset of symptoms and peak pro-inflammatory cytokine expression. It is this fundamental observation that convinces many in the field that the treatment of AP will be one of the first clinical successes for novel drugs or therapy that seek to modulate the inflammatory response.

Acute Disease↗
PubMed1998

Review article: current treatment and optimal patient management in pancreatic cancer.

This review analyses the current state of knowledge and understanding concerning the optimum treatment and therapeutic management of patients who suffer from pancreatic cancer. It outlines recent advances in scientific understanding and assesses their potential future value to clinicians in confronting this disease. Despite a significant expansion in scientific knowledge relating to factors underlying the early development of pancreatic carcinoma, the clinician continues to be restricted to a severely limited therapeutic armoury for this disease. Local therapies (surgery and radiation) are inevitably of limited value in the face of a disease that is normally encountered at a stage where metastasis is already highly developed. Despite such limitations, however, surgery performed in specialist units may be of value for 10-20% of patients, with a 5-year survival rate in such units of between 10 and 24%. This may be improved even further by appropriate use of adjuvant treatment. The advanced stage of the disease when normally encountered emphasizes the potential value of systemic treatment in this therapeutic area. Unfortunately systemic treatment (chemotherapy) has been found to be ineffective to date in significantly extending survival, with a low rate and duration of remission being identified in most trials. The challenge for both the health service and the pharmaceutical industry is to harness recent and future developments in scientific knowledge to the practical benefit of clinicians. Where cure is possible it should be vigorously pursued; where it is not, in this field above all others, clinicians have a duty of care. To achieve this it is necessary to abandon the therapeutic nihilism that has characterized the attitudes of clinicians towards this disease in the past. It is time that such nihilism was replaced by a recognition of the challenges and the opportunities available to clinicians in enhancing the quantity and quality of life available to patients. The dictum of 'curing whenever possible but caring always' should be the future therapeutic philosophy used to guide clinicians in this important and rapidly changing therapeutic area.

Antineoplastic Agents↗
PubMed1998

Review article: current practice and future perspectives in detection and diagnosis of pancreatic cancer.

Pancreatic cancer is the tenth most prevalent malignancy and the fifth most common cause of cancer death in the developed world. Less than 10% of patients survive for more than 1 year following diagnosis and the 5-year survival rate (0.4%) is the lowest of any cancer. The poor prognosis associated with this diagnosis led in the past to therapeutic nihilism on the part of clinicians who were all too aware of the limitations of their available therapeutic strategies. Breaking this therapeutic impasse requires a significant expansion in the knowledge of clinicians concerning the pathogenesis and behaviour of pancreatic cancer. Recent advances in the scientific understanding of the aetiology of pancreatic cancer has facilitated progress towards the development of promising and innovative approaches to the early detection and diagnosis of pancreatic cancer. While acknowledging that pancreatic cancer will continue to present significant challenges to both scientists and clinicians in the foreseeable future, it is becoming increasingly clear that recent advances in our scientific knowledge base holds the potential to significantly improve prognosis for patients. The challenge facing both scientists and clinicians is how best to translate such promising scientific advances into survival and quality of life benefits to patients.

Biomarkers↗
PubMed1995

Phase I clinical and pharmacokinetic study of leucovorin and infusional hepatic arterial fluorouracil.

PURPOSE: A phase I and pharmacokinetic trial was performed between October 1993 and June 1994 to determine the maximum-tolerated dose of hepatic arterial infusion (HAI) of fluorouracil (5-FU) and intravenous (IV) leucovorin (folinic acid; FA) in patients with hepatic metastases from colorectal cancer. PATIENTS AND METHODS: Forty-three patients received 310 courses of HAI chemotherapy administered over 48 hours every 2 weeks. The regimen consisted of FA 200 mg/m2 by IV infusion over 2 hours, followed by a loading dose of 5-FU 400 mg/m2 by HAI over 15 minutes, followed by a 22-hour infusion of 5-FU at doses ranging from 0.8 to 1.84 g/m2, with identical chemotherapy on day 2. Pharmacokinetic studies were performed to determine peak and steady-state plasma concentrations (Css) of 5-FU. RESULTS: Severe diarrhea and cardiac and neurologic toxicity were dose-limiting at 1.84 g/m2. The recommended dose for the 22-hour component of the schedule was 1.6 g/m2 and was associated with tolerable toxicity. A Css of 2.2 +/- 0.8 mumol/L for 5-FU was achieved on the recommended schedule, which compares favorably with conventional IV 5-FU regimens. Among 30 patients assessable for response, there were four complete responses and seven partial responses, and 12 patients with stable disease and seven with progressive disease, reported after 3 months (ie, six cycles) of therapy. CONCLUSION: A regimen that combines 5-FU and FA has been identified for regional chemotherapy in patients with hepatic metastases from colorectal cancer. The systemic levels of 5-FU achieved are similar to the conventional IV de Gramont regimen using an identical schedule of 5-FU and FA, which implies that this chemotherapy has the best of both worlds, ie, a regional advantage in delivering high drug concentrations to the target organ with adequate systemic cover for extrahepatic micrometastases.

Adult↗
PubMed1994

Enteric alpha-1-antitrypsin loss and comparison with Okokit II and Haemoccult for the detection of colorectal cancer.

Faecal samples from patients with symptomatic colorectal cancer (n = 19) and from control subjects (n = 54) were analysed for alpha-1-antitrypsin (A1AT) and compared with Haemoccult and Okokit II. A1AT was also measured in paired samples of normal colonic mucosa and cancer tissue (n = 16) and in media from four human colorectal cell lines (COLO 320 DM, SW620, HT29, LS 174T). Faecal A1AT concentrations were greater than controls (P < 0.0001) and detected 12 (63%) patients with cancer compared to 10 (53%) by Okokit II and 7 (37%) by Haemoccult (P > 0.05). A1AT concentrations from colonic mucosa (median, range: 0.46, 0.17-0.79 mg/g wet wt) were greater (P = 0.01) than cancer tissue (0.29, 0.13-0.74 mg/g wt wt). Adjusting for albumin, A1AT concentrations from mucosa (12.0, 3.8-32.2 mg/g albumin) remained greater (P = 0.003) than for cancer tissue (5.9, 2.4-21.4 mg/g albumin). A1AT was not detected in any of the cell-line media. The most likely mechanisms for increased faecal A1AT concentrations, apart from increased blood loss, are increased cell turnover or leakage from epithelial tight junctions. The use of faecal A1AT measurement for the detection of colorectal cancer deserves further assessment.

Aged↗
PubMed1993

Detection of colorectal cancer by faecal alpha 1-antitrypsin.

Alpha 1-antitrypsin was measured in 5-day faecal collections from patients with colorectal cancer or adenomatous polyps and a symptomatic control group. Collections were homogenized and lyophilized prior to measurement of alpha 1-antitrypsin by radial immuno-diffusion. Colorectal cancer dry weight concentrations were significantly higher than the symptomatic control results, with 57% having results greater than 95% normal values of this control group. There was no significant difference between adenomatous polyp dry weight concentrations and symptomatic control results. Wet weight concentrations were calculated from wet/dry ratios. Colorectal cancer wet weight concentrations were significantly higher than symptomatic control results with 48% having results greater than 95% normal values of this control group. Alpha 1-antitrypsin was also measured in non-lyophilized samples from an asymptomatic control group (n = 39). Colorectal cancer wet weight concentrations were significantly higher than asymptomatic control results, with 62% having results greater than 95% normal values of this control group. Faecal alpha 1-antitrypsin measurement deserves further assessment for use in detecting colorectal cancer.

Adenoma↗
PubMed1991

Abnormalities of the p53 tumour suppressor gene in human pancreatic cancer.

The tumour suppressor gene p53 has been found to be mutated or inactivated at high frequency in several common human tumours. We have examined a series of exocrine pancreatic carcinomas for over-expression of mutant forms of p53 by immunohistochemistry with a panel of specific antibodies. We found immunodetectable p53 in 13 of 22 (60%) frozen pancreatic cancers and seven of 13 pancreatic cell lines. One of the antibodies, CM1, recognises p53 in formalin-fixed, paraffin-embedded archival material and using this reagent we found immunodetectable p53 in 28 of 124 (23%) pancreatic cancers. We have successfully demonstrated the presence of point mutations by direct sequencing of genomic DNA extracted from archival tissue showing CM1 immunoreactivity. We conclude that p53 activation is an important event in human pancreatic tumorigenesis and that the CM1 antibody can detect a proportion of cases of overexpression of mutant p53 in archival pathological material.

Antibodies, Monoclonal↗
PubMed1983

The effect of intralipid on human lymphocyte and monocyte function.

Peripheral blood lymphocyte function (PHA) was unaffected by Intralipid in patients receiving lipid as part of a parenteral nutrition regime, and in volunteers receiving a small intravenous bolus. However monocyte function (chemotaxis) was significantly impaired by Intralipid in both groups. Three measures of monocyte function confirmed depression following in vitro exposure to Intralipid. Electronmicrographs of circulating monocytes and autoradiographs of cells exposed to 14C-Intralipid in vitro suggested that this detrimental effect on monocytes may follow phagocytosis of lipid particles. These findings suggest that caution should be exercised with the use of Intralipid in patients at particular risk of sepsis.

Journal Article↗
PubMedDate not supplied

The effects of intralipid and heparin on human monocyte and lymphocyte function.

A group of patients were studied during the infusion of Intralipid as part of a parenteral nutrition regimen. Peripheral blood lymphocyte function was unaffected, but monocyte function (chemotaxis) was significantly depressed. A group of healthy volunteers received an intravenous bolus of 20% Intralipid. Blood was taken before and 15 min afterward for immunological studies, and the same changes were seen following Intralipid. Prior subcutaneous injection of 5000 U of heparin did not affect either immunological parameter, but completely prevented the changes in monocyte function caused by Intralipid. Electronmicrographs of monocytes from volunteers after injection of Intralipid, and autoradiographs of cells incubated with 14C-Intralipid in vitro, showed phagocytosis of fat particles by monocytes. These data suggest that Intralipid can have potentially serious side effects on the immune system, and that they may be alleviated by the use of subcutaneous heparin.

Autoradiography↗