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Biomedical subjects

N Thatcher

Publications and source records attributed to N Thatcher.

At least 163 records · Page 9Linked to original sources
PubMed1990

DNA analysis by flow cytometry in malignant pleural mesothelioma: relationship to histology and survival.

In a retrospective study of 70 patients with malignant pleural mesothelioma, 168 formalin-fixed, paraffin-embedded tumour specimens were examined for DNA content by flow cytometry. In 20 patients where two or more blocks of the same tumour were available, there was considerable agreement between ploidy status and S-phase percentage in the different specimens. There were no significant differences for survival for patients who had been exposed to asbestos and those in whom no exposure could be elicited, nor for aneuploid and diploid tumours. The S-phase content was examined for different areas of the same tumour and the percentages were largely in agreement. However, those patients who had tumours with an S-phase percentage greater than the median (6 per cent) had a significantly shorter survival than those with tumours of lower S-phase percentage. Differences in DNA content and other cell cycle parameters were not associated with the histological subtypes.

Aged↗
PubMed1990

The effect of route of administration and fractionation of dose on the metabolism of ifosfamide.

The measurement of urinary ifosfamide, isophosphoramide mustard, dechloroethyl ifosfamide and carboxyifosfamide using high-performance thin-layer chromatography with photographic densitometry (TLC-PD) is described. This technique was also used to demonstrate the large inter-individual variation in the ifosfamide metabolic profile of patients receiving the drug as single-agent therapy for non-small-cell lung cancer. In addition, oral administration was shown to result in higher levels of these metabolites in the urine. Fractionation of the ifosfamide dose over several days resulted in increasing levels of metabolites in the urine, consistent with auto-induction of ifosfamide metabolism.

Administration, Oral↗
PubMed1990

The stability of ifosfamide in aqueous solution and its suitability for continuous 7-day infusion by ambulatory pump.

Dose fractionation is known to reduce the toxicity of ifosfamide and also results in an increased production of alkylating metabolites. Administration by slow infusion using the convenience of ambulatory pumps is therefore of interest. We used HPLC to investigate the stability of ifosfamide in aqueous solution (either alone, solution A, or mixed with mesna, solution B) under various conditions over a 9-day period. At both ambient temperature in daylight and 27 degrees C in a dark environment, there was no evidence of ifosfamide decay in either solution. However, at 37 degrees C in a dark environment, a fall was detected in both solutions, which at 9 days amounted to a loss of 7% of the amount of ifosfamide present at time zero. At 70 degrees C, levels of ifosfamide in both solutions fell within 72 h to markedly lower levels than controls, thus confirming that the methods used were indicative of stability. We conclude that ifosfamide, either alone or mixed with mesna, is stable for 9 days at temperatures up to 27 degrees C; even at 37 degrees C, the measured loss is small. The continuous infusion of ifosfamide over 7 days by ambulatory pump is now a practical proposition.

Ambulatory Care↗
PubMed1990

Therapy for poor-risk patients with small-cell lung cancer using bolus ifosfamide and oral etoposide.

A total of 47 poor-risk small-cell lung cancer patients (elderly, poor performance status, recent myocardial infarction, or extensive-stage disease with biochemical abnormalities) were treated with a regimen of bolus ifosfamide at 1.5 g/m2 with equidose mesna as a 30-min infusion, followed by 100 mg oral etoposide daily for 8 days. Therapy was repeated every 3 weeks. The overall response rate was 60% (75% for limited-stage and 48% for extensive-stage disease), and the overall median survival was 7 months. Patients' performance status significantly improved with therapy (P less than 0.0001). Despite the poor-risk factors, the Manchester prognostic score was applied and verified. The median survival was 8 months for patients with a good prognosis, 6 months for those with an intermediate prognosis and 2.5 months for poor-prognosis patients (P = 0.0002). Therapy was well tolerated. The median WHO grade of haematological toxicity was 2 (range, 0-4). Only 10/226 (4%) courses were delayed due to leukopenia. Blood transfusions followed 18/226 (8%) courses. Intravenous antibiotics were given following 15/226 (7%) courses. No patient required platelet support. Poor-risk patients who have a good or intermediate Manchester prognostic score may benefit from this low-toxicity regimen.

Aged↗
PubMed1990

Ifosfamide, doxorubicin and etoposide in small cell lung cancer patients with poor prognosis.

61 patients with small cell lung cancer in a poor prognosis group were treated with chemotherapy and with thoracic radiotherapy if they had 'limited stage' disease. No prophylactic cranial irradiation was given. Chemotherapy comprised doxorubicin 50 mg/m2 and ifosfamide 5 g/m2 with mesna on day 1, and etoposide 120 mg/m2 intravenously on days 1 and 2 and 240 mg/m2 orally on day 3. Treatment was repeated every 3 weeks for a maximum of six courses and no dosage reductions were allowed. Complete response rate in limited stage patients was 55% and 16% in extensive stage patients. The partial responses were 38% and 66% respectively. Overall median survival was 10.5 months with 2-year survival of 14%. The corresponding values for limited stage disease were 13 months and 16% and for extensive stage disease 8 months and 13%. Despite the addition of doxorubicin at a somewhat higher dosage than usual in this type of regimen and a policy of no dose reduction, toxicity was generally mild. There was, however, a 19% relapse rate in complete responders in the brain, apparently as the sole site of disease.

Adult↗
PubMed1990

DNA analysis by flow cytometry in nonsmall cell lung cancer: relationship to epidermal growth factor receptor, histology, tumour stage and survival.

In a retrospective study, surgical specimens of 136 patients with nonsmall cell lung cancer, were investigated for DNA content by flow cytometry. Seventy per cent of all tumours were aneuploid. Aneuploidy was a statistically significant factor for shorter survival and was independent of tumour size, histology, grade of differentiation, regional lymph node involvement, age and sex (P less than 0.02). A high proliferation index (greater than 7.5%) was also a prognostically unfavourable factor and was observed significantly more often in tumours where the majority of cells expressed epidermal growth factor receptor.

Carcinoma, Non-Small-Cell Lung↗
PubMed1990

Recombinant interleukin-2 (rIL-2) with flavone acetic acid (FAA) in advanced malignant melanoma: immunological studies.

Natural killer (NK) cell activity and lymphokine activated killer (LAK) cell cytotoxicity were measured in patients receiving recombinant interleukin 2 (rIL-2) and flavone acetic acid (FAA) for treatment of progressing metastatic melanoma. NK activity was increased in 23 of 26 patients and LAK activity induced in 13 of 26 patients. However, levels of cytotoxicity in the present study were not significantly greater than a previous study using rIL-2 alone. LAK cell precursors demonstrated by in vitro incubation of pretreatment lymphocytes with IL-2 and subsequent cytotoxicity were no different in the patients compared to normal controls. Analysis of cell surface phenotypes failed to reveal any significant changes in the cell populations examined, including IL-2R and Leu 19. Although five patients had tumour response, one being complete, there was no correlation with the immunological parameters examined.

Adjuvants, Immunologic↗
PubMed1990

Recombinant interleukin-2 (rIL-2) with flavone acetic acid (FAA) in advanced malignant melanoma: a phase II study.

Recombinant interleukin 2 (rIL-2) and flavone acetic acid (FAA) were used to treat 34 patients with progressing metastatic melanoma. Five patients had solely non-visceral disease and the median number of organ sites involved was two. Five doses of rIL-2 were given, the first dose intrasplenically via a femoral artery catheter with a further dose 4 h later i.v. and the other doses i.v. on alternate days. The rIL-2 dose was 11 x 10(6) Cetus units m-2; the day before rIL-2, FAA (4.8 G m-2) was given as a 6 h i.v. infusion, in order to enhance further killer cell activity. A total of three courses at 21-day intervals was planned and 74 courses in all were given. Despite the high dose of rIL-2 and the potential overlapping toxicity affecting blood pressure with the addition of FAA, side-effects were generally mild. There were only five episodes of grade 4 toxicity: one of ventricular tachycardia and four other episodes of transient biochemical or haematological disturbance. Grade 3 hypotension or hypertension occurred on 22 courses but again was transient. No patient required intensive care facilities. Five patients had tumour response, one being complete. Responses occurred in pulmonary and hepatic metastases, but mainly in non-visceral sites. Eleven patients remain alive at 6-17 months and in five there is no relapse or progression of disease. Despite the impressive results in animal tumour models, the addition of FAA to rIL-2 in the present study has not markedly improved results over rIL-2 alone.

Adjuvants, Immunologic↗
PubMed1990

Malignant pleural mesothelioma and epidermal growth factor receptor (EGF-R). Relationship of EGF-R with histology and survival using fixed paraffin embedded tissue and the F4, monoclonal antibody.

The expression of epidermal growth factor receptor (EGF-R) in 34 formalin fixed paraffin embedded specimens of malignant mesothelioma was examined using the F4 antibody. Eight samples of reactive pleura showed homogenous cytoplasmic staining with the antibody. EGF-R positive cells (greater than or equal to 5%) were found in 68% of the mesotheliomas examined. EGF-R positivity was more commonly seen in the epithelial histological subtype than in the sarcomatous or mixed subtypes. Patients with less than 5% of mesothelioma cells staining positive for EGF-R had a significantly shorter survival (median 299 days) compared with patients whose tumours had a greater number of cells positive for EGF-R (median 446 days) (P = 0.04). However, when the histological subgroup was also taken into consideration (epithelial type had a significantly longer survival than the sarcomatous or mixed) the survival difference in relation to EGF-R positivity was no longer significant (P = 0.08). EGF-R could not be used to distinguish between malignant and benign mesothelial tissue and was not an independent prognostic factor for survival.

Adult↗
PubMed1990

The effect of age on the pharmacokinetics of ifosfamide.

The effect of age on the pharmacokinetics of ifosfamide was studied in 20 patients with advanced non small cell lung cancer. A positive correlation was found between the elimination half-life of ifosfamide and age (r = 0.48, 0.05 less than P less than 0.01). This was due to an increase in volume of distribution with age (r = 0.66, 0.001 less than P less than 0.01). Total plasma clearance, renal clearance and non renal clearance did not change with age. Age did not affect the autoinduction of ifosfamide metabolism. Further studies are needed to demonstrate any adverse effects of ifosfamide in the elderly.

Adult↗
PubMed1990

Carboplatin in small cell lung cancer.

The high activity of carboplatin as a single agent in small cell lung cancer was first identified in 30 previously untreated patients who had a 60% response, which included a 10% complete remission (CR). In this and subsequent studies, carboplatin showed high activity without the nephrotoxicity and neurotoxicity associated with cisplatin. Gastrointestinal side effects and alopecia were also generally mild; the major toxicity was myelosuppression. Two important studies of carboplatin 300 mg/m2 and etoposide (300 to 400 mg/m2) in divided doses have reported objective responses of 85% (21% CR) and 65% (21% CR) in previously untreated patients. However, the median survival in the first study was only 9.5 months in both limited- and extensive-stage patients. In this study, 19% of patients had substantial dose reductions because of myelosuppression. The second study reported a better median survival of 15.3 months for limited-stage patients and 8.3 months for extensive-stage patients. These patients received a maximum of six courses of chemotherapy as opposed to four in the first study, and cranial irradiation in addition to mediastinal irradiation. There also appeared to be fewer dose reductions, ie, 11% for carboplatin. Another study using the combination of carboplatin and etoposide in extensive-stage patients only reported a 56% response rate, including 16% CR and a median survival of 8.1 months. The major toxicity in these three studies was myelosuppression, particularly leukopenia, but only three neutropenia-associated deaths occurred in a total of 180 patients. A recent study has reported the use of similar doses of carboplatin and etoposide in combination with ifosfamide 5 g/m2 (with mesna) and midcourse vincristine. Thoracic radiotherapy was given after six courses of chemotherapy in responding patients, but no cranial irradiation was used. In 42 patients, 30 of whom had limited-stage disease, the response rate was 78%, including a 57% CR rate. The median survival was 14 months, and the 2-year actual survival rate is 33%. These and other studies of carboplatin combinations (which are only preliminary) have described high response rates and possibly improved survival compared with less intensive therapy.(ABSTRACT TRUNCATED AT 400 WORDS)

Antineoplastic Agents↗
PubMed1990

Preliminary experience with quality of life evaluation in patients with lung cancer.

Evaluating quality of life in patients receiving treatment for cancer has been an increasing concern, particularly when a cure may not be possible. Such measurements inform clinicians and investigators of the relative costs and benefits of palliative treatments, and are potentially important when there is little or no difference between drug regimens in terms of tumor response or survival. Where it is felt intuitively by oncologists that a particular mode or frequency of therapy may be superior to existing regimens, quality of life data may inform us differently, and there is a case to be made for incorporating such evaluations in clinical trials. In parallel to the experience of other groups, we have developed experience with certain scales, focusing on evaluations of lung cancer patients. This process enabled us to prospectively include and implement quality of life studies into our clinical trials.

Carcinoma, Non-Small-Cell Lung↗
PubMed1990

A clinicopathological study of the paraneoplastic neuromuscular syndromes associated with lung cancer.

The highest incidence of remote neuromuscular disorders in cancer has previously been reported in lung carcinoma. The clinical incidence of neuromuscular disorder was estimated and correlated with muscle histology and the histological type of lung tumour in 100 patients with lung carcinoma who were studied prospectively. Thirty-five patients had small cell carcinoma and 65 patients non-small cell lung cancer. Clinically, 33 patients had a polymyopathy, of whom 18 had a cachectic myopathy and 15 had a proximal myopathy (two patients had Lambert-Eaton myasthenic syndrome, one presented with dermatomyositis and one had evidence of ectopic ACTH production). Cachexia was more common in non-small cell cancer; proximal myopathy was more common in small cell cancer. Ninety-nine patients had abnormal muscle histology; 74 had type II atrophy, 12 had type I and II atrophy, one had type I atrophy and 12 had necrosis. The majority of patients were affected sub-clinically and the clinical entities of cachectic and proximal myopathy did not correspond to previous pathological classifications. Atrophy was not related to the duration of tumour symptoms, ageing, clinical type of myopathy or histological type of lung tumour, and was statistically different from that seen in controls. Qualitatively, the presence of weight loss, muscle wasting and metastatic disease were not factors in the development of atrophy. Similarly, necrosis was not related to the type of lung tumour, the presence of metastases, ageing, weight loss, muscle wasting, duration of tumour symptoms or the clinical form of myopathy. This study demonstrates that lung carcinoma has a direct effect on the motor unit, including atrophy, a necrobiotic myopathy and Lambert-Eaton myasthenic syndrome. Clinical assessment does not accurately assess the 'remote' neuromuscular effects of cancer on the motor unit.

Adult↗
PubMed1989

The effect of ifosfamide and its metabolites on intracellular glutathione levels in vitro and in vivo.

The effect of ifosfamide and its metabolites on intracellular levels of glutathione in P388 cells in vitro has been studied. It is demonstrated that glutathione depletion occurs only in the presence of 4-hydroperoxyifosfamide and chloroacetaldehyde. In contrast isophosphoramide mustard had no effect on glutathione levels in intact cells. The concentration of 4-hydroperoxyifosfamide required to reduce glutathione levels by 50% was approximately 1 mM and this represents a concentration far in excess of that achievable in patients receiving the drug. However the concentration of chloroacetaldehyde (approximately 100 microM) required to reduce intracellular levels of glutathione to a similar extent is attained in patients receiving ifosfamide. The glutathione levels in lymphocytes isolated from a patient undergoing an eight hour infusion of ifosfamide showed a marked decrease to about 30% of their original value. We conclude that ifosfamide causes glutathione depletion in vivo and the majority of this can be accounted for by the production of chloroacetaldehyde.

Acetaldehyde↗