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Biomedical subjects

N Thatcher

Publications and source records attributed to N Thatcher.

At least 19 recordsLinked to original sources
PubMed1992

Prevalence of the Rhesus-negative phenotype in Caucasian patients with small-cell lung cancer (SCLC).

We report that the Rhesus (Rh)-negative phenotype is more prevalent in patients with small-cell lung cancer (SCLC) than in the normal Caucasian population (SCLC: 25% Rh-negative vs. 15% expected, p less than 0.0001). This finding has been validated for a Central and a Northern European population (Switzerland and UK). In contrast, the Rh-negative phenotype is no more frequent in non-small-cell lung cancer patients or in heavy smokers with coronary heart disease than in the general population. There was a normal distribution of the ABO blood group phenotype in all patients studied. Whilst the significance of this observation is unclear, we hypothesize that a genetic predisposition to the development of SCLC may be linked to a hitherto unidentified gene on chromosome 1p near the Rh locus. Our observation may perhaps allow further progress to be made in understanding genetic mechanisms of SCLC carcinogenesis.

ABO Blood-Group System↗
PubMed1992

Haemopoietic cell kinetics in humans treated with rGM-CSF.

We have investigated the kinetics of myeloid cell proliferation in the marrow of patients with small-cell lung cancer and treated with 10 daily subcutaneous injections of granulocyte/macrophage colony-stimulating factor (GM-CSF). Bone marrow, obtained before and during treatment with the growth factor, was labelled in vitro with tritiated thymidine (3H-TdR). A 3rd bone-marrow sample was obtained 1 hr following an intravenous injection of 3H-TdR. Subsequent daily blood samples were also collected, and 3H-TdR labelling was assessed on these and the marrow preparations by autoradiography. GM-CSF treatment increased the peripheral granulocytic cells nearly 5-fold, but this included significant eosinophilia, so that the neutrophilic granulocytes increased only 3.3-fold. These cells were released from the marrow over a normal time scale, but their peripheral half-life was about 6 times longer than normal and they were probably functionally defective. Furthermore, significant numbers of immature cells were released from the marrow. Neutrophil production stimulated by GM-CSF was thus overestimated by measurement of the apparent peripheral granulocytosis. Increased labelling indices and grain counts in the proliferating granulocytic cells of the marrow indicate shortened cell-cycle times, and the excess granulocyte production appears to be the result of extra amplification divisions in the proliferative compartments.

Carcinoma, Small Cell↗
PubMed1992

In vivo depletion of O6-alkylguanine-DNA-alkyltransferase in lymphocytes and melanoma of patients treated with CB 10-277, a new DTIC analogue.

There is increasing evidence to suggest that alkylation of guanine residues in DNA at the O6 position is the critical cytotoxic event following treatment with dacarbazine (DTIC) and related drugs and that endogenous O6-alkylguanine-DNA alkyltransferase (ATase) gene expression may be a major factor in resistance to such agents. 1-p-Carboxyl-3,3-dimethylphenyltriazene (CB10-277) was recently selected for clinical evaluation as a DTIC analogue with improved solubility, stability and (possibly) metabolic activation. Serial ATase levels were measured in peripheral blood lymphocytes of nine patients and in biopsied melanoma samples of two patients undergoing treatment with 24-h continuous infusion of CB10-277 (12 g/m2). Wide individual variations in pre-treatment levels as well as in the post-treatment depletion of lymphocyte ATase were seen. Progressive depletion of lymphocyte ATase was seen during continuous infusion of CB10-277 in all patients. Complete suppression of lymphocyte ATase activity occurred in two patients whose pre-treatment ATase levels were low. Immediately following completion of the CB10-277 infusion, the median ATase activity was 17% of pre-treatment levels (range, 0-67%). At 24 h after the end of the infusion, no recovery of lymphocyte ATase activity was observed in six patients, but significant recovery to 50%, 100% and 102% of pre-treatment activity occurred in the other three. In three patients who returned for subsequent cycles of chemotherapy at 4 weeks after the first dose, pre-treatment ATase levels showed a 3- to 4-fold increase relative to the original pre-treatment values. A significant correlation was found between the extent of ATase depletion and the initial lymphocyte ATase levels (r = 0.725, P < 0.05). Haematological toxicity developed in two patients and was associated with low pre-treatment ATase activity. Depletion of tumour ATase activity was noted in these patients, with residual activity amounting to 8% and 11% of pre-treatment levels, respectively, in the biopsies melanoma tissues. These results indicate extensive metabolism of CB10-277 to a methylating agent capable of mediating alkylation of DNA and subsequent depletion of lymphocyte and tumour ATase levels and further indicate that the effects on lymphocytes may reflect effects on the target tumour.

Adult↗
PubMed1992

Suitability of cisplatin solutions for 14-day continuous infusion by ambulatory pump.

The stability of cisplatin (DDP) solutions (1 and 1.6 mg/ml in saline-mannitol) in plastic infusion bags was studied for up to 14 days at 25 degrees C, 37 degrees C and 60 degrees C. Small changes in the solution were observed, but no evidence of any decomposition product was seen. Some precipitation of DDP was seen in the 1.6-mg/ml solution at the lower temperatures. Fluid loss from the bags was significant at the higher temperatures.

Chromatography, High Pressure Liquid↗
PubMed1992

Clinical applications of interleukin-2.

Interleukin-2 (IL-2) is a cytokine with potent immunomodulating properties which has shown considerable antitumour activity in preclinical models. In clinical trials, the effects of IL-2 given by various routes and schedules have been investigated. IL-2 has been administered either as single drug or in combination with other cytokines and immunomodulating agents, chemo therapeutic agents, or reinfusions of ex vivo activated autologous cytotoxic effector cells. The results of published clinical studies with IL-2 based immunotherapy are reviewed in this paper.

Clinical Trials as Topic↗
PubMed1992

Infection risk in patients with small cell lung cancer receiving intensive chemotherapy and recombinant human granulocyte-macrophage colony-stimulating factor.

The effect of recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) was assessed in 17 patients with small cell lung cancer. GM-CSF was initially given alone by subcutaneous injection for 10 days at 50-500 micrograms/m2 per day. There was a significant rise in neutrophils and eosinophils and to a lesser extent in monocytes at all dose levels. During the next phase, patients received chemotherapy (etoposide, ifosfamide and doxorubicin), and GM-CSF was given on alternate cycles, the patients acting as their own controls, so that the amelioration of chemotherapy could be assessed. Despite partial abrogation of the neutropenia associated with chemotherapy (P = 0.04), GM-CSF failed to reduce the frequency of febrile episodes in association with neutropenia, with six episodes occurring on GM-CSF and seven while patients were not receiving GM-CSF after a total of 66 cycles of chemotherapy. After GM-CSF, there was a reduction in polymorph phagocytic ability and chemotaxis in 6/12 and 9/11 patients, respectively. Timed blood counts after GM-CSF administration showed that peak leucocytosis occurred at 8-12 h and fell to two-thirds of this level at 24 h. Toxicity consisting of lethargy, myalgia and bone pain occurred at all dose levels but was manageable. 2 patients had thromboembolism. This study failed to demonstrate a reduction in the infection risk associated with moderately intensive chemotherapy for small cell lung cancer despite the partial abrogation of neutropenia.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1992

Predicting septic complications of chemotherapy: an analysis of 382 patients treated for small cell lung cancer without dose reduction after major sepsis.

The incidence and risk of septic complications in 382 patients treated for small cell lung cancer with combination chemotherapy at a single centre have been analysed. Full protocol doses were employed throughout with no dose reduction after episodes of severe or life-threatening sepsis (SLTS). 50 (13%) patients experienced 66 episodes of SLTS associated with 1978 cycles of chemotherapy (3.2% cycles affected). 20 (5.2%) patients died due to sepsis (SD) of whom only 4 had experienced SLTS with a previous cycle of treatment. The others died as a result of their first septic episode. A model comprising four variables, age (< or = 50 or > 50 years), Karnofsky performance status (KP < or = 50 or > 50), treatment (two- or three-drug regimen) and previous sepsis (SLTS or no SLTS with previous cycles) was found to satisfactorily describe the incidence of SLTS and SD in the study population and once validated in another patient groups this model should allow identification of high-risk individuals before treatment starts. If so, we propose that high-risk patients (age > 50 years, KP < or = 50, treatment with three-drug regimen) receive 50% of protocol doses in the first cycle of treatment with escalation to 75% and eventually 100% doses in subsequent cycles if sepsis does not supervene. Those with one or two risk factors present run a relatively low risk of SLTS or SD and we consider that full-dose chemotherapy should be used throughout in these individuals.

Age Factors↗
PubMed1992

Immunohistological examination of the inter- and intracellular distribution of O6-alkylguanine DNA-alkyltransferase in human liver and melanoma.

The tissue and cellular distribution of the DNA repair protein O6-alkylguanine-DNA-alkyltransferase (ATase) is an important question in relation to the response of tumour and normal tissues to chemotherapeutic regimes employing alkylating agents such as methyltriazenes and nitrosoureas. In order to examine this issue by immunostaining, we have raised a rabbit antiserum to apparently pure recombinant human enzyme. The antiserum is highly specific and sensitive, detecting a band at 24 kDa on western blots of crude extracts of ATase-expressing human lymphoblastoid cells, liver and melanoma. Adjacent sections of acetone or formalin fixed normal human liver and subcutaneous malignant melanoma were reacted with preimmune serum or antiserum and an immunoperoxidase detection system with silver enhancement was used to locate binding of the primary antibody to the antigen. In sections reacted with preimmune serum or with antigen-preadsorbed antiserum, only faint cytoplasmic and little or no nuclear staining was seen. In contrast, using antiserum, the reaction in positively staining cells was very intense and predominantly nuclear. In the liver, there was interindividual variation in the cellular distribution of reaction with staining present in all discernable cell types in most samples but confined to the hepatocytes and bile duct epithelial cells in others. In the melanoma sections, all discernable cell types showed mainly nuclear staining: the intensity of staining varied between tissue samples and there was evidence of a range of intermediate staining intensities with some melanoma cells showing no detectable reaction.

Biopsy↗
PubMed1992

Novel approaches with ifosfamide in small cell lung cancer.

During the past 5 years, ifosfamide has been used increasingly in combination chemotherapy for small cell lung cancer (SCLC). The high activity and favorable toxicity spectrum (with the uroprotector mesna) will encourage further use. A policy of no dosage reduction is feasible in patients receiving combination chemotherapy with ifosfamide given as a 24-hour intravenous (IV) infusion, which is much more convenient than the more commonly used 4- to 5-day fractionated regimen. This policy has resulted in actual 2-year survivals of 22% to 33% among SCLC patients not intensively staged. The stability of ifosfamide and its high bioavailability have allowed its use in chronic, 7-day ambulatory IV infusions, with decreased toxicity and hospitalization. Recently, oral and subcutaneous administration also have been tried, again allowing outpatient treatment. The first studies with hemopoietic growth factor support, eg, granulocyte colony-stimulating factor, conducted with combination chemotherapy with ifosfamide-containing regimens in SCLC, demonstrated significant reduction in neutropenia, infections, and antibiotic use. It is clear that the dosage of ifosfamide can be intensified in the future. The broad versatility of the drug will allow interesting new studies, including those to be conducted with outpatients.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1991

O6-alkylguanine-DNA alkyltransferase depletion and regeneration in human peripheral lymphocytes following dacarbazine and fotemustine.

O6-Alkylguanine-DNA alkyltransferase (ATase) levels were measured in peripheral blood lymphocytes of 13 patients with advanced malignant melanoma treated with sequential dacarbazine (DTIC) and fotemustine. Wide interindividual variation in the pretreatment levels and in depletion and regeneration of ATase activity was noted. Depletion of ATase was seen within the first h after DTIC administration with values ranging from 44 to 92% of pretreatment levels. In 10 patients, progressive depletion of ATase activity occurred with nadir activity occurring at about 4 to 6 h with values ranging from 0 to 67% of pretreatment activity; at 18 h after DTIC infusion. ATase activity varied from 6 to 81%. No significant difference was seen between the rates of ATase depletion or regeneration between the two groups of patients receiving either 500 or 800 mg/m2 of DTIC with the same dose of fotemustine (100 mg/m2). In one patient, maximum depletion occurred within 1 h and no ATase activity was detectable over the next 18 h. In another patient, maximum depletion occurred at 2 h after DTIC followed by recovery of ATase activity to 71% at 18 h. In 2 patients who returned for subsequent cycles of chemotherapy, an increase in pretreatment ATase activity was seen. Overall, the extent of depletion of ATase following DTIC/fotemustine was directly proportional to the initial ATase level.

Adenosine Triphosphatases↗
PubMed1991

Recombinant human GM-CSF in small cell lung cancer: a phase I/II study.

Seventeen patients with small cell lung cancer were entered into a dose ranging phase I-II study using rhGM-CSF (Glaxo). In the phase I study patients received 50, 150, 300 or 500 micrograms/m2 GM-CSF for 10 days by daily subcutaneous injection. Full blood counts were performed thrice weekly. After 4 days off all therapy patients then received chemotherapy with doxorubicin 50 mg/m2 i.v. bolus, day 1, ifosfamide 5 g/m2 with mesna 5 g/m2 over 24 h by continuous infusion followed by mesna 3 g/m2, and etoposide 120 mg/m2 i.v. on days 1-3. A total of six courses of chemotherapy were given. In the phase II study patients received the same dose of GM-CSF as in the phase I. GM-CSF was given 24 h after the last dose of chemotherapy for 14 days. Full blood counts were checked thrice weekly and the incidence of infections noted. Patients were randomised to receive GM-CSF with either odd or even courses of chemotherapy. The leucocyte count rose from a mean of 8.7 to 21.6 x 10(9)/l at the 50 micrograms/m2 GM-CSF dosage and from 11.4 to 39.4 x 10(9)/l at the 500 micrograms/m2 dosage during the phase I study. Phase I toxicity was: bone pain in 65% of patients, rash in 47%, fever in 24%, lethargy in 12% and diarrhoea in 12%. In the phase II study the duration of neutropenia was less during the chemotherapy courses with GM-CSF (p = 0.04) but the number of infections was similar.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

A phase II study of ifosfamide and a2b-interferon in advanced non-small-cell lung cancer.

A total of 45 patients with advanced non-small-cell lung cancer were treated with a combination of 1.5 g/m2 ifosfamide given on days 1-5 every 3 weeks for four courses with 3 million IU a2b-interferon (Intron A) given s.c. three times a week for 12 weeks. Nine objective responses were seen, including two complete responses (CRs) and seven partial responses (PRs). Haematological and non-haematological toxicities were generally mild and did not necessitate discontinuation of therapy.

Adult↗
PubMed1991

A randomised study of intravenous bolus versus continuous infusion of ifosfamide and doxorubicin with oral etoposide for small-cell lung cancer.

159 "poor risk" patients with previously untreated small cell lung cancer were entered into a randomised study of intravenous bolus versus continuous infusion chemotherapy with doxorubicin on weeks 1, 3, 5 and ifosfamide with mesna on weeks 2, 4, 6. Oral etoposide was given on days 1-5, 15-19, and 29-33. There was no difference in response rate or survival. However, patients treated with continuous infusion therapy had significantly less haematological toxicity (P = 0.0007), and less nausea and vomiting (P = 0.03).

Administration, Oral↗
PubMed1991

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↗
PubMed1991

Ifosfamide and mitomycin in combination for the treatment of patients with progressive advanced non-small cell lung cancer.

42 patients with progressive and advanced non-small cell lung cancer received chemotherapy comprising ifosfamide 1.5 g/m2, mesna 1.5 g/m2 and mitomycin 1.2 mg/m2 daily for 5 days. Only those patients with symptoms and progressive disease were selected for treatment. Partial response was achieved in 10/42 patients (23.8%) and stable disease in 25/42 (59.5%). The Karnofsky performance status (KP) improved in 10/42 patients (23.8%) and a subjective respiratory symptom score improved in 12 patients (28.6%). In addition 27 patients (64.3%) had stabilisation of both the KP and respiratory score following chemotherapy. These results indicate that the ifosfamide and mitomycin combination is active in non-small cell lung cancer in this selected group of patients with antitumour and symptom control activity.

Adenocarcinoma↗
PubMed1991

Phase II study with mitomycin, ifosfamide and carboplatin in inoperable non-small cell lung cancer.

In a phase II study of non-small cell lung cancer a new chemotherapy combination of mitomycin 6 mg/m2 intravenously on day 1, carboplatin 400 mg/m2 intravenously on day 1 and ifosfamide with mesna 5 g/m2 intravenously over 24 hours on day 1 was evaluated. A maximum of four chemotherapy cycles was given at intervals of 4 weeks to 34 patients with progressive, inoperable disease. 1 complete and 10 partial remissions were documented, the overall response rate being 32.4%. In a further 13 patients (38.2%) the previously progressing tumours remained stable for at least 6 weeks. The median time to progression for responding patients was 184 days. The median survival time for the whole group has not yet been reached at 293 days. A considerable but easily manageable myelosuppression was the principal toxicity despite a "no dose reduction" policy. Indeed, the dose intensity of the chemotherapy actually given was extremely close (97%) to that intended on protocol. In conclusion, the regimen is active in patients with advanced non-small cell lung cancer but requires regular haematological monitoring to prevent morbidity resulting from myelotoxicity.

Aged↗
PubMed1991

Viridans streptococcal bacteraemia in patients with haematological and solid malignancies.

Thirty-three episodes of septicaemia caused by viridans streptococci are reported in 32 adults under treatment for malignant diseases. The underlying diseases were acute leukaemia (17), lymphoma (4), myeloma (1), small cell carcinoma of the bronchus (6), carcinoma of the breast (2) and carcinoma of the stomach (2). Important predisposing factors included severe neutropenia and oral mucositis due to intensive chemotherapeutic regimens. There was a poor response to standard empirical antibiotics and a mortality of 12%. A role for prophylactic penicillin in high risk groups is suggested.

Adolescent↗