Biomedical subjects

M P Findlay

Publications and source records attributed to M P Findlay.

8 recordsLinked to original sources

PubMed1999

E-cadherin germline mutations define an inherited cancer syndrome dominated by diffuse gastric cancer.

To extend earlier observations of germline E-cadherin mutations in kindreds with an inherited susceptibility to diffuse gastric cancer, we searched for germline E-cadherin mutations in five further families affected predominantly by diffuse gastric cancer and one family with a history of diffuse gastric cancer and early-onset breast cancer. Heterozygous inactivating mutations were found in the E-cadherin gene in each of these families. No mutation hotspots were identified. These results demonstrate that germline mutation of the E-cadherin gene is a common cause of hereditary diffuse gastric cancer and suggest a role for these mutations in the incidence of breast cancer.

Adenocarcinoma↗

PubMed1997

Active surveillance after orchiectomy for nonseminomatous testicular germ cell tumors: late relapse may occur.

OBJECTIVES: To review the outcome of men with Stage I nonseminomatous germ cell tumors managed with a policy of active surveillance following orchiectomy. METHODS: The clinical records of all men with Stage I nonseminomatous germ cell tumors seen at Royal Prince Alfred Hospital, Australia between 1982 and 1995 were reviewed. Data were obtained concerning the histologic type of tumor, levels of serum tumor markers, relapse and subsequent treatment, and survival. RESULTS: Seventy-seven patients were entered into the active surveillance protocol between 1982 and 1995. With a minimum follow-up of 2 years, 27 (35%) have relapsed, with a median time to relapse of 5 months. Two late relapses occurred at 37 and 57 months after diagnosis. Relapses occurred most commonly in the retroperitoneal lymph nodes, with the lungs the second most common site. Following treatment with chemotherapy and surgery, all patients achieved complete remission, with 1 patient subsequently relapsing and ultimately dying of progressive tumor. One other patient died of acute myeloid leukemia, thought to be secondary to chemotherapy. Overall, 75 patients (97%) remain alive and free of disease. CONCLUSIONS: Active surveillance is a safe and effective approach to the management of Stage I nonseminomatous germ cell tumors. Although most relapses occur within the first 2 years, late relapses may occur.

Adolescent↗

PubMed1997

Lack of correlation between thymidylate synthase levels in primary colorectal tumours and subsequent response to chemotherapy.

The increasing interest in 5-fluorouracil (5-FU) modulation and the development of new antifolates has focused attention in recent studies on the expression of the target enzyme thymidylate synthase (TS) as a determinant of drug sensitivity and resistance. Resistance to TS-directed drugs has been shown to occur in vitro and in vivo with increased expression of the enzyme (determined by enzymatic assays as well as protein and gene expression assays). Several studies have evaluated the role of TS as a prognostic indicator of clinical response to chemotherapy containing TS-directed drugs. We have used a polyclonal antibody to recombinant human TS to establish a silver-enhanced immunogold staining method to localize TS in human tumours. Human tumour cell lines with acquired resistance to TS inhibitors owing to increased levels of TS were used to confirm the specificity of immunostaining. Stained sections were evaluated by image analysis. Immunostaining in tumour sections was greatly reduced (>80%) by preabsorption of the antiserum with recombinant TS. The method was used to determine the extent of TS immunostaining in 134 primary human colorectal tumours. The results were then compared with the clinical outcome and response to chemotherapy for the treatment of subsequent metastatic disease. A wide range (approximately 100-fold) of TS immunostaining was observed in these primary tumour sections. Normal mucosal tissue levels were 5-10 times lower than those observed in the adjacent tumour tissue. The values for TS immunostaining did not correlate with clinical endpoints, such as time from diagnosis to relapse, response to chemotherapy for disseminated disease, nor with Dukes' staging. This lack of correlation may be because this group of patients was selected on the basis of their need for palliative chemotherapy and did not include patients who were cured of their disease. Also, primary tumour TS expression may not give a good indication of the TS expression in metastatic lesions. The prognostic significance of TS protein expression in primary and metastatic lesions requires further evaluation.

Aged↗

PubMed1996

Measurement of plasma 5-fluorouracil by high-performance liquid chromatography with comparison of results to tissue drug levels observed using in vivo 19F magnetic resonance spectroscopy in patients on a protracted venous infusion with or without interferon-alpha.

PURPOSE: To measure plasma 5-fluorouracil (5-FU) levels using high-performance liquid chromatography (HPLC) and compare the findings to the tissue metabolism of 5-FU evaluated using 19F magnetic resonance spectroscopy (MRS), during a protracted venous infusion (PVI) with or without interferon-alpha. METHODS: Patients receiving PVI 5-FU (300 mg/m2/day) with or without interferon-alpha (5 x 10(6) units 3 times per week), had 2 weekly plasma 5-FU levels evaluated using reverse-phase ion-pairing HPLC. These samples were drawn just prior to the patient undergoing MRS using a 1.5T Siemens Magnetom whole body magnetic resonance system with a 16 cm surface coil placed over normal liver or metastatic tumour. Semi-quantitated MRS values were compared with the plasma 5-FU levels using linear regression analysis. Data were available from patients given interferon-alpha with PVI 5-FU from day 1 or at the point of 5-FU refractory disease. RESULTS: A total of 30 patients were studied. Plasma 5-FU concentrations while on a protracted venous infusion varied from <25 ng/ml (0.192 mu M) to 25,000 ng/ml (192 mu M). A high plasma 5-FU concentration was associated with an increase in patient toxicity. Patients given interferon-alpha with 5-FU had higher median plasma 5-FU levels higher than patients on 5-FU alone (6138 vs. 218 ng/ml; p = 0.03). There was no correlation between the plasma 5-FU concentration and tumour response. A comparison of the plasma 5-FU data to the MRS studies in normal liver revealed a positive correlation between plasma 5-FU and liver catabolite signal (r = 0.68; p = 0.016) but a negative correlation with the log plasma 5-FU concentration and 5-FU liver signal (r = -0.63; p = 0.022). The patients experiencing toxicity, in addition to having a higher plasma 5-FU concentration did not exhibit a liver 5-FU signal, while the reverse was true for those having no toxicity. CONCLUSIONS: Plasma 5-FU levels may show greater interpatient variation when given as a protracted venous infusion. Levels of 5-FU correlated with treatment toxicity but not with anti-tumour activity. The addition of interferon-alpha to 5-FU increases plasma 5-FU levels. MRS findings suggest patients with low plasma 5-FU levels have higher 5-FU levels in normal liver tissue than in those with higher plasma levels.

Antimetabolites, Antineoplastic↗

PubMed1994

In vivo monitoring of fluoropyrimidine metabolites: magnetic resonance spectroscopy in the evaluation of 5-fluorouracil.

Since 5-fluorouracil (5-FU) was synthesized in the late 1950s it has become an important component of many anticancer treatment regimens. The increasing volume of literature accumulating about this drug is evidence that the optimal administration schedule and its combination with modulators has yet to be determined. Much of the investigation of 5-FU, particularly in the clinical setting, has been in the development of administration schedules based on plasma pharmacokinetic data. Particularly with the development of modulators of 5-FU, investigators are looking more closely at its intracellular tissue pharmacology and metabolism. To study the tissue metabolism of 5-FU (and other drugs), patients often have to be willing to undergo invasive procedures, sometimes with significant discomfort, usually with little direct benefit to their management. The ability to conduct an investigation of the cellular effects of a drug in both tumor and normal tissue non-invasively will not only be more acceptable to patients, resulting in better compliance to protocols, but will give information about the in situ tissue which is not subject to the problems of invasive sampling techniques. Magnetic resonance spectroscopy is a non-invasive technique that has recently started to show potential in the area of investigating 5-FU metabolism and its impact on tumor and patient outcome. Further development of this method may ultimately have an impact on the investigation of any new anticancer agent.

Animals↗

PubMed1993

The non-invasive monitoring of low dose, infusional 5-fluorouracil and its modulation by interferon-alpha using in vivo 19F magnetic resonance spectroscopy in patients with colorectal cancer: a pilot study.

BACKGROUND: 5-Fluorouracil (5-FU) is the most widely used cytotoxic drug in oncology and the only one useful in the management of colorectal cancer - a leading cause of cancer death worldwide. Recent studies of 5-FU have focused on increasing efficacy and reducing toxicity by varying the delivery schedule and combining it with modulators. With the development of whole body magnetic resonance systems it is now possible to examine the metabolism of 5-FU in vivo by exploiting the magnetic properties of the fluorine atom which is an integral component of the drug. PATIENTS AND METHODS: Magnetic Resonance Spectroscopy (MRS) was used to non-invasively monitor the metabolism of 5-FU in the liver metastases of colorectal cancer patients. The patients were treated with a continuous low dose intravenous infusion of 5-FU until the point of refractory disease, at which time interferon-alpha was added with the objective of modulating 5-FU activity. MRS was performed at specific phases of the treatment. RESULTS: Twenty-six patients were treated with 5-FU, 11 (42%) achieving partial response. Of the 15 given interferon when disease became refractory to 5-FU, 4 showed signs of further response. In patients observed by MRS during the first 8 weeks of 5-FU treatment, those with a visible 5-FU signal were likely to respond to treatment (p = 0.017). At the time of interferon-alpha addition, MRS showed that 7 patients developed new or increased 5-FU signals, and 4 patients showed a signal from the active metabolites of 5-FU. The patients who exhibited a new or increased 5-FU signal were more likely to show further response to interferon-alpha (p = 0.007). CONCLUSIONS: MRS is a powerful technique for monitoring intratumoural metabolism and modulation of 5-FU enabling prediction of tumour outcome. Direct metabolic information may facilitate the rapid development of optimal clinical schedules for 5-FU and its modulators, thus maximising antitumour effect and minimising toxicity to the patient. This technique may be applied to other areas of clinical medicine where knowledge of the tissue metabolism of a fluorinated drug is of interest.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1991

Retrospective review of chemotherapy for small cell lung cancer in the elderly: does the end justify the means?

Between 1978 and 1983, 72 patients aged 70 years or older (median 72, range 70-80) were treated for biopsy-proven, small cell lung cancer (SCLC). Intercurrent disorders were common, including ischaemic heart disease, peripheral vascular disease, chronic airflow limitation and second malignancies. 26 patients (36%) had limited extent of disease, and 46 (64%) had extensive disease. "Intensive" chemotherapy incorporating vincristine, cyclophosphamide and doxorubicin (OCA regimen) was administered to 32 patients [complete response (CR) + partial response (PR) = 84%]; less rigorous regimens (e.g. single agent chemotherapy, planned dose reductions, radiotherapy only) were used in 34 cases (CR + PR = 52%); and 6 received no active treatment. In the intensively treated group, there were 3 treatment-related deaths and 26 episodes of WHO grade 3-4 toxicity. In the less intensively treated group, there were no treatment-induced deaths and only 1 episode of severe toxicity. The overall median survival was 25 weeks (36 weeks for intensive treatment, 16 weeks with less intense treatment). For patients with limited disease only, the median survival in each group was 43 and 26 weeks, respectively. Intensive treatment for elderly patients with small cell lung cancer is associated with substantially increased toxicity and higher response rates than for gentle treatment, but without a major survival benefit.

Age Factors↗

PubMedDate not supplied

The case for a student honor code and beyond.

Preparing graduates to enter practice as responsible and accountable nurses is an essential goal of nursing programs. Faculty must be deliberate in their efforts to enhance personal and professional integrity and to facilitate the development of a value system that the graduates can incorporate into their professional practices. A student honor code within a school of nursing is one strategy that faculty can use to facilitate the development of these characteristics. A variety of resources, both human and printed, are available to guide the faculty.

Civil Rights↗