Biomedical subjects

Denis Smith

Publications and source records attributed to Denis Smith.

6 recordsLinked to original sources

PubMed2006

Feasibility of preoperative combined radiation therapy and chemotherapy with 5-fluorouracil and cisplatin in potentially resectable pancreatic adenocarcinoma: The French SFRO-FFCD 97-04 Phase II trial.

PURPOSE: More than 80% of patients who undergo a potentially curative resection for pancreatic cancer develop local or distant recurrence. Neoadjuvant chemoradiotherapy might offer potential benefits regarding local and systemic control and survival. This multi-institutional Phase II trial explored the feasibility of preoperative chemoradiation in this situation. METHODS AND MATERIALS: Treatment consisted of concurrent radiotherapy (50 Gy within 5 weeks), and chemotherapy with 5-fluorouracil (300 mg/m(2)/day, 5 days/week, 5 consecutive weeks) and cisplatin (20 mg/m(2)/day, Days 1-5 and 29-33), followed by surgical resection of the pancreatic tumor in patients without progression. RESULTS: A total of 41 patients were enrolled. Of these, 38 (93%) received > or =47 Gy; 30 patients (73%) received > or =75% of the prescribed doses of chemotherapy. Surgical resection was performed in 26 patients (63%). Because of local or metastatic progression, 5 patients (12%) did not undergo surgery and 10 underwent surgery without resection of the pancreatic tumor. Operative mortality was 2.8%. Among 40 evaluable patients, 27 were successfully treated (67.5%; 95% CI, 50.9-81.4%). CONCLUSIONS: Pancreatic cancer is chemo-radiosensitive. The proposed pre-operative scheme is feasible, does not prevent successful surgery, and must be tested on a Phase III setting. Yet, the large proportion of tumor progression during and after chemoradiation justifies the use of more efficient drugs such as Gemcitabine, and optimized radiotherapy including new techniques such as intensity-modulated radiation therapy.

Adenocarcinoma↗

PubMed2006

Subsequent resection of locally advanced pancreatic carcinoma after chemoradiotherapy.

OBJECTIVES: The aim of this study was to evaluate the possibility of subsequent resection of locally advanced pancreatic adenocarcinoma after chemotherapy and external-beam radiotherapy. PATIENTS AND METHODS: Between January 1996 and January 2001, 33 consecutive patients (18 males and 15 women, mean age 63 years) with locally advanced PA were treated with chemotherapy and concurrent external-beam radiotherapy. Radiotherapy delivered 45-50.4 Gy, in a classical manner (N=27) or on a split-course (N=6). Chemotherapy was made of 5FU by continuous infusion for all patients during 5 weeks and cisplatin at the 1st and 5th weeks (N=22). Tumor resectability was reassessed at the end of the chemoradiotherapy; surgical resection of tumour was attempted in patients whose tumor demonstrated reduction in size, and supplementary radiotherapy of 10 to 15 Gy was delivered to the others. RESULTS: Thirty-nine percent of patients experienced grade 3 acute toxicity. WHO criteria response to chemoradiotherapy four weeks after the end of treatment were: 4 partial responders (12%), 6 minor responders (18%), 14 stable disease (42%), 9 progression (28%). Ten patients underwent exploratory laparotomy, in one case vascular encasement did not allow for tumor resection, and in another patient, there was peritoneal carcinomatosis. In the 8 remaining patients, surgical (R0) resection was possible. In one patient histological examination showed fibrosis with no residual tumour. After a median follow-up period of 40 months, median survival was 16 months (66% and 37% of survival at 1 and 2 years respectively). In operated and non-operated patients, survival rates at 24 months were 73% and 12.5% respectively. At 1 year, 80% of the patients treated with radiochemotherapy developed recurrence, metastatic recurrence in 88%. Initial laparotomy, split course radiotherapy were poor outcome factors whereas chemotherapy appears to be a favorable outcome factor. CONCLUSION: Subsequent resection of locally advanced pancreatic adenocarcinoma is possible after chemoradiotherapy allowing for a prolonged survival in some patients.

Adenocarcinoma↗

PubMed2005

Predicting drug response and toxicity based on gene polymorphisms.

The sequencing of the human genome has allowed the identification of thousands of gene polymorphisms, most often single nucleotide polymorphims (SNP), which may play an important role in the expression level and activity of the corresponding proteins. When these polymorphisms occur at the level of drug metabolising enzymes or transporters, the disposition of the drug may be altered and, consequently, its efficacy may be compromised or its toxicity enhanced. Polymorphisms can also occur at the level of proteins directly involved in drug action, either when the protein is the target of the drug or when the protein is involved in the repair of drug-induced lesions. There again, these polymorphisms may lead to alterations in drug efficacy and/or toxicity. The identification of functional polymorphisms in patients undergoing chemotherapy may help the clinician prescribe the optimal drug combination or schedule and predict with more accuracy the response to these prescriptions. We have recorded in this review the polymorphisms that have been identified up till now in genes involved in anticancer drug activity. Some of them appear especially important in predicting drug toxicity and should be determined in routine before drug administration; this is the case of the most common variations of thiopurine methyltransferase for 6-mercaptopurine and of dihydropyrimidine dehydrogenase for fluorouracil. Other appear determinant for drug response, such as the common SNPs found in glutathione S-transferase P1 or xereoderma pigmentosum group D enzyme for the activity of oxaliplatin. However, confusion factors may exist between the role of gene polymorphisms in cancer risk or overall prognosis and their role in drug response.

Cytochrome P-450 Enzyme System↗

PubMed2005

Towards an organization with a memory: exploring the organizational generation of adverse events in health care.

The role of organizational factors in the generation of adverse events, and the manner in which such factors can also inhibit an organization's abilities to learn, have become important agenda items within health care. The government report 'An organization with a memory' highlighted many of the problems facing health care and suggested changes that need to be made if the sector is to learn effective lessons and prevent adverse events from occurring. This paper seeks to examine some of these organizational factors in more detail and suggests issues that managers need to consider as part of their wider strategies for the prevention and management of risk. The paper sets out five core elements that are held to be importance in shaping the manner in which the potential for risk is incubated within organizations. Although the paper focuses its attention on health care, the points made have validity across the public sector and into private sector organizations.

Delivery of Health Care↗

PubMed2004

Impact of microscopic hepatic lymph node involvement on survival after resection of colorectal liver metastasis.

BACKGROUND: Macroscopic hepatic lymph node involvement is usually a contraindication to hepatic resection. Only a few studies have investigated the impact of hepatic lymph node involvement on survival. The aim of this retrospective study was to assess microscopic hepatic lymph node involvement in resectable colorectal liver metastasis and outcomes in patients with such involvement. STUDY DESIGN: From January 1985 to December 2000, 156 patients underwent curative liver resection in association with systematic hepatic lymph node dissection for colorectal liver metastasis. A first analysis was performed to assess the association between hepatic lymph node metastasis and patients' characteristics. A second analysis assessed survival after resection of liver colorectal metastasis by using the Kaplan-Meier method. RESULTS: Twenty-three of the 156 patients (15%) had microscopically involved hepatic lymph nodes. No predictive factor of lymph node metastasis was identified. Multivariate analysis showed that lymph node metastasis, preoperative carcinoembryonic antigen level, number of metastases, and morbidity were factors influencing survival. The 3- and 5-year survival rates of patients with lymph node metastasis were 27% and 5%, respectively, compared with 56% and 43% without lymph node metastasis (p = 0.0001). CONCLUSIONS: During resection of liver colorectal metastasis, microscopic lymph node involvement occurred in 15% of the patients and was associated with a poor 5-year survival. Hepatic lymph node dissection should be performed systematically to select high-risk patients.

Colorectal Neoplasms↗

PubMedDate not supplied

Value of microsatellite instability typing in detecting hereditary non-polyposis colorectal cancer. A prospective multicentric study by the Association Aquitaine Gastro.

AIM OF THE STUDY: To detect hereditary non-polyposis colorectal cancer (HNPCC) patients with a strategy combining clinical selection (patient age at onset of cancer less than 50 years or family history of HNPCC tumors) and microsatellite instability typing plus immunohistochemistry, leading to mismatch repair (MMR) germline mutation analysis. METHODS: Tumors were screened for microsatellite instability (MSI) and for hmlh1 and hmsh2 immunohistochemical expression. Germline mutation analysis was performed to search for MLH1 and MSH2 mutations in patients with MSI-High and MSI-Low tumors. RESULTS: 197 adenocarcinomas were studied: 164 patients were< or =50 years old, 33 were older than 50 years but had a family history of HNPCC tumors. Fifty tumors (25.4%) were MSI-High, 10 were MSI-Low (5.1%), and 130 were MS-Stable (66%). MSI typing was inconclusive in 7 (3.5%). Immunohistochemistry screening was performed on 165 tumors: sensitivity was 63.6%, specificity was 99%. Germline mutation analysis was performed in 33/60 MSI-High or Low tumors: 23 mutations were noted (70% of the tested patients). CONCLUSION: This proposed strategy of determining microsatellite instability in young colorectal cancer patients or in patients with a family history of HNPCC tumors led to an increased frequency in the detection of MMR germline mutations.

Adenocarcinoma↗