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Biomedical subjects

J H Scarffe

Publications and source records attributed to J H Scarffe.

At least 73 records · Page 4Linked to original sources
PubMed1990

Growth factor-assisted chemotherapy--the Manchester experience.

Stimulation of red cell production by erythropoietin and of granulocyte production by granulocyte colony-stimulating factor (G-CSF) and granulocyte macrophage-CSF (GM-CSF) has been demonstrated in several clinical studies. The first study to show that a human CSF could be used to shorten the period of neutropenia and reduce the risk of serious infection following intensive combination chemotherapy was carried out in Manchester using G-CSF. The period of neutropenia was significantly shortenened (by a median of 80%) and the neutrophil count levels were restored and above normal by 14 days after chemotherapy. In view of these results a further study was undertaken to examine the possibility of using intensive two weekly chemotherapy under cover of G-CSF. Treatment with Doxorubicin at doses of 75, 100, 125 and 150 mg/m2 was followed by infusion of G-CSF for 11 days. The neutrophil counts returned to normal within 12-14 days, allowing the delivery of up to three cycles of high dose chemotherapy at 14 day intervals. These studies demonstrated that intensive chemotherapy with dose-limiting myelodepression can be given with increased frequency under cover of G-CSF. Our studies using GM-CSF have also shown that administration by continuous i.v. infusion can reduce the period of life-threatening neutropenia following high dose Melphalan (120 mg/m2) without resort to autologous bone marrow transplantation (ABMT). In this study the period of granulocytopenia following Melphalan (less than 500 g x 10(9)/m2) was less than 15 days. This compares favourably with other series using high dose Melphalan followed by ABMT without CSF, where the duration of severe neutropenia was prolonged beyond three weeks. Although it appears that G-CSF and GM-CSF should be given either by continuous i.v. infusion or s.c. injection at doses between 3-10 micrograms/kg/day to obtain maximum biological effect, a great deal more work is required to determine optimum schedules and investigate the possibility of using more than one bioregulator.

Agranulocytosis↗
PubMed1990

Clinical studies with recombinant human granulocyte-macrophage colony-stimulating factor.

Recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) has been used in two clinical studies at the Christie Hospital in Manchester, United Kingdom. Short daily "bolus" injections (over 30 min) were associated with serious toxicity which included bone pain, pruritus and pericarditis. In contrast, continuous infusions did not cause any toxicity and produced significantly higher increments of the peripheral neutrophil counts. rhGM-CSF reduced the period of life-threatening neutropenia following high-dose i.v. melphalan (120 mg/m2). Also, rhGM-CSF shortened the duration of thrombocytopenia induced by this chemotherapy to less time than has been seen historically in conjunction with autologous bone marrow rescue.

Adult↗
PubMed1990

Double-blind placebo controlled study of vancomycin prophylaxis for central venous catheter insertion in cancer patients.

To assess whether vancomycin administration at the time of central venous catheter insertion would prevent catheter-related sepsis (CRS) in immunocompromised patients, 98 cancer patients were entered into a randomized placebo-controlled trial. Patients were stratified according to whether they were having therapy for acute leukaemia or undergoing bone-marrow transplantation (group A) or required chemotherapy for a solid tumour (group B). Eligible patients were randomized to receive either 500 mg vancomycin in 250 ml of 0.9% saline prior to catheter insertion followed by a further 500 mg infused via the established catheter, or the same regimen with 0.9% saline alone. In group A, there were 32 instances of CRS occurring in 20 of the 35 evaluable catheters (57%). Six catheters were removed because of CRS. No significant difference was found in the incidence of CRS between the two arms. Of the 37 evaluable catheters in group B, CRS occurred in 6 (16%), and none of the catheters required removal because of CRS. Again, no significant differences were found in the incidence of CRS between the patients given vancomycin or placebo. These findings indicate that the incidence of CRS is greater in patients who have more severe and prolonged immunosuppression and that vancomycin prophylaxis fails to reduce CRS in patients undergoing chemotherapy for malignant disease.

Adolescent↗
PubMed1990

Prognostic significance of osteopenia and immunoparesis at presentation in patients with solitary myeloma of bone.

In a prospective study of 32 patients with solitary myeloma of bone treated between 1974 and 1984, the median survival was 117 months. Twenty of the patients developed multiple myeloma with a median time to dissemination of 46 months. A multivariate analysis of presenting prognostic factors identified osteopenia (P less than 0.000003) and immunoparesis (P less than 0.00002) as the only independent prognosticators of overall survival. The removal of patients with osteopenia or immunoparesis at presentation identified a group of patients with 80-90% chance of surviving 10 years. Patients with either of the risk factors have a median survival of 27 months similar to patients with multiple myeloma, and should be considered for early systemic treatment.

Adult↗
PubMed1990

Granulocyte-macrophage colony stimulating factor (GM-CSF) after high-dose melphalan in patients with advanced colon cancer.

Nine patients with progressive, metastatic disease from primary carcinoma of the colon were entered into a phase I/II study using continuous intravenous infusions of granulocyte-macrophage colony-stimulating factor (GM-CSF) and high dose melphalan (120 mg m-2). GM-CSF was given alone to six patients during the first part of the study to determine a dose that would produce a peripheral leucocyte count (WCC) greater than or equal to 50 X 10(9) 1(-1) and was initially given at 3 micrograms kg-1 day-1 and escalated to 10 micrograms kg-1 day-1 after 10 days. The infusion was discontinued when the WCC exceeded 50 X 10(9) 1(-1) and after a gap of one week, melphalan was given over 30 min. GM-CSF was recommenced 8 h later and was continued until the neutrophil count had exceeded 0.5 X 10(9) 1(-1) for greater than 1 week. One patient achieved a WCC greater than 50 X 10(9) 1(-1) with GM-CSF 3 micrograms kg-1 day-1, but the other five who entered this phase of the study required dose escalation to 10 micrograms kg-1. No toxicity attributed to GM-CSF was seen. After melphalan, the median times to severe neutropenia (less than 0.5 X 10(9) 1(-1] and thrombocytopenia (greater than 20 X 10(9) 1(-1] were 6 and 9 days respectively. The median durations of neutropenia and thrombocytopenia were 14 and 10 days respectively. All patients required intensive support with a median duration of inpatient stay of 24 days. There was one treatment related death due to renal failure. One complete and two partial remissions (33% response rate) were seen but these were of short duration (median of 10 weeks). This study demonstrates that GM-CSF given by continuous intravenous infusion produces significant increments of peripheral granulocyte counts at 3 and 10 micrograms kg-1 day-1 and is not associated with any toxicity. The duration of neutropenia and thrombocytopenia induced by high-dose melphalan appears to be reduced by the subsequent administration of GM-CSF to times which are at least as short as have been reported in historical series which have used autologous bone marrow rescue.

Adult↗
PubMed1990

Clinical studies of granulocyte colony stimulating factor (G-CSF).

Granulocyte colony stimulating factor (G-CSF) can safely stimulate the production of neutrophils in normal and neutropenic patients. Phase II studies have shown potential benefit when G-CSF is given after chemotherapy and bone marrow transplantation and in dose intensification studies. Studies in myelodysplasia, chronic neutropenia and AIDS all show great promise. Phase III studies are now in progress, which will help identify precisely the role of this exciting molecule.

Acquired Immunodeficiency Syndrome↗
PubMed1990

Clinical application of hematopoietic growth factors.

Although many questions remain about the clinical use of hemopoietic growth factors, it is remarkable how much information has been gained in such a short time. There is enormous interest in these agents among physicians from a variety of specialties--all providing new ideas for potential studies. As the supplies increase, many new trials can be opened. It is important to design these studies with due regard to the results of in vitro and in vivo preclinical experiments--preferably after discussion with experimental hematologists--or vital information will be missed. There can have been few more exciting developments in clinical medicine in the recent past than the availability of the hemopoietic growth factors and, hopefully, it will not be long before the preliminary trials are completed and these agents are accepted for routine use to the benefit of a large number of patients.

Animals↗
PubMed1989

Clinical trials with haemopoietic growth factors.

Five glycoprotein growth factors capable of stimulating the proliferation and differentiation of haemopoietic progenitor cells in vitro have been identified and sequenced over the past ten years. Recombinant DNA technology has recently enabled the production of sufficient amounts of these agents for preclinical testing. Erythropoietin (EPO), granulocyte-macrophage colony-stimulating factor (GM-CSF), and granulocyte colony-stimulating factor (G-CSF) have already entered clinical studies in humans. Interleukin-3 (IL-3) and macrophage colony-stimulating factor (M-CSF) should soon be available for use in humans. EPO corrects the anaemia of end stage renal failure, improving the quality of life for such patients and preventing the need for red cell transfusions. At high dose it increases platelet production in vitro and in vivo and may be of value in humans to prevent the thrombocytopaenia associated with chemotherapy. G-CSF and GM-CSF have been used in several clinical studies. Administration of both growth factors results in a leucocytosis, G-CSF predominantly increasing neutrophil production and GM-CSF increasing production of neutrophils, eosinophils and monocytes. The optimal administration of these agents is via continuous intravenous infusion or daily subcutaneous injections at doses of 3-10 micrograms/kg/24 h. GM-CSF has shown promising results in patients with AIDS and the myelodysplastic syndrome and both G-CSF and GM-CSF have reduced the duration of neutropaenia and incidence of infection associated with chemotherapy. These agents may allow an escalation of the dose-intensity of chemotherapy in the future and thereby, hopefully, increase the response rate and survival for patients with a variety of neoplasms. Several other potential roles for these haemopoietic growth factors are discussed.

Hematopoietic Cell Growth Factors↗
PubMed1989

Recombinant human granulocyte macrophage colony stimulating factor (rhGM-CSF) given as daily short infusions--a phase I dose-toxicity study.

Twenty patients with progressive metastatic solid tumours were entered into a study to evaluate the biological effects and toxicity of recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF). GM-CSF was given as half-hour intravenous infusions during two 10-day phases of daily treatments (separated by 10 days without GM-CSF) and over a final phase of 20 days of alternate day infusions. Doses were escalated in steps from 0.3 to 60 micrograms kg-1 day-1 between successive patient groups. Significant increases (P less than 0.005) of total leucocyte, neutrophil and eosinophil polymorph counts were seen over the periods of daily infusions (up to four-fold rises of total white count) at dose levels of 10 micrograms kg-1 and above. Counts produced at 30 micrograms kg-1 were significantly higher than at 10 micrograms kg-1 (P less than 0.025). Toxic side effects of GM-CSF included mild transient pyrexias, bone pain and pruritus. The maximum tolerated dose was 60 micrograms kg-1, which produced severe toxicity in 80% of patients. The toxicity at this dose included pericarditis and dyspnoea ascribed to a 'capillary-leak' syndrome. One patient receiving 60 micrograms kg-1 died as a result of a pulmonary embolus. Seven patients with previously rapidly progressive metastatic tumours experienced stabilisation of disease while receiving GM-CSF and one patient with a previously heavily pretreated metastatic soft tissue sarcoma underwent a greater than 50% reduction of tumour volume. Patients undergoing chemotherapy may benefit both from a reduction of the myelosuppressive effects of cytotoxic agents and from an antitumour effect if GM-CSF is incorporated into future regimens.

Colony-Stimulating Factors↗
PubMed1989

Randomized trial comparing ciprofloxacin plus netilmicin versus piperacillin plus netilmicin for empiric treatment of fever in neutropenic patients.

To assess the efficacy of ciprofloxacin in neutropenic patients, we conducted a randomized prospective trial comparing the combination of ciprofloxacin and netilmicin against piperacillin plus netilmicin as an empiric treatment of fever in cancer patients with neutropenia. Of 214 evaluable episodes, 115 and 99 were randomly assigned to the ciprofloxacin and the piperacillin arms, respectively. The overall response rates were very similar (59 and 62% for the ciprofloxacin and piperacillin arms, respectively). The response for the gram-positive bacteremias was almost identical (around 40%); this low response was due in part to an outbreak of infection by a multiply resistant strain of Staphylococcus epidermidis (for which the ciprofloxacin MIC was greater than or equal to 128 micrograms/ml) which occurred during the second half of the trial. Among gram-negative bacteremias, 9 of 11 infections (82%) responded to the ciprofloxacin combination compared with 3 of 7 (43%) that responded to the piperacillin combination (P = 0.23). The incidences of persistent, profound neutropenia were comparable in both treatments, but the susceptibility of the gram-negative organism to ciprofloxacin and netilmicin was significantly higher than was susceptibility to the other combination. Ciprofloxacin was well tolerated, and patients were able to convert from intravenous to oral therapy in 64 of 115 episodes.

Administration, Oral↗
PubMed1989

The use of bone marrow cells grown in long-term culture for autologous bone marrow transplantation in acute myeloid leukaemia: an update.

Eleven patients with acute myeloid leukaemia have been transplanted with autologous marrow grown in long-term bone marrow culture. In the high risk group (six patients who had all previously relapsed) the procedure induced a remission in two patients who were in florid relapse at the time of the transplant. Five patients were transplanted in first remission and they remain well and disease-free between 150 and 12 weeks after their autologous transplant.

Adolescent↗
PubMed1988

Maintenance chlorambucil after CVP in the management of advanced stage, low-grade histologic type non-Hodgkin's lymphoma. A randomized prospective study with an assessment of prognostic factors.

One hundred sixty-two patients with Stages III and IV non-Hodgkin's lymphoma of low-grade histologic type were treated with combination chemotherapy using cyclophosphamide, vincristine, and prednisolone (CVP) followed by radiotherapy to sites of previous bulk disease. The patients were randomized to receive either follow-up alone or "maintenance" chemotherapy with 2 years of intermittent chlorambucil. A complete remission was obtained in 56% of patients and the median survival was 64 months (median follow-up, 74 months). Multivariate analysis revealed stage (P less than 0.0001) and Karnofsky performance status (P = 0.021) to predict complete response (CR) and the achievement of a CR (P less than 0.0001), female sex (P = 0.008), the absence of bulk disease (P = 0.038) and low serum alkaline phosphatase (P = 0.002) to predict prolonged survival. The median relapse-free survival (RFS) of the complete responders was 41 months. A prolonged RFS was predicted by low stage (P = 0.014), low serum lactic dehydrogenase (LDH) (P = 0.045) levels, and by the administration of maintenance chlorambucil (P = 0.045). A prolonged survival of the complete responders was predicted by a low number of nodal sites of involvement with lymphoma at presentation (P = 0.022) and lack of liver involvement (P = 0.011). The administration of oral maintenance therapy with chlorambucil for a full 2 years was only possible in 38% of patients, mainly because of progression of disease and the induction of thrombocytopaenia, but despite this it prolonged the median RFS by 38 months and its use could be considered when future studies are being designed.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1988

A phase I and pharmacokinetic study of amphethinile.

Amphethinile is a new spindle poison with a novel structure that has shown activity in the L1210, ADJ/PC6 and Walker carcinoma rodent tumours. In addition the agent appeared to have an improved therapeutic ratio compared to existing spindle poisons and is well absorbed when administered orally. The starting dose for the phase I study was 40 mg m-2 (1/10th mouse LD10) and further patients were studied at 200, 400, 800 and 1200 mg m-2, dose escalation being based on pharmacological monitoring. Significant toxic effects were seen only at 800 and 1200 mg m-2. At these doses patients experienced nausea and vomiting, light headedness during the infusion and varying degrees of lethargy following therapy. Two of six patients at 800 mg m-2 developed severe pain in the tumour bearing area 1-2 h after treatment and one experienced colicky abdominal pain. At 1200 mg m-2 two patients died within 48 h of treatment from what appeared to be vascular causes. Following these episodes the trial was discontinued. Neutropenia and alopecia occurred in two patients, one at 800 and one at 1200 mg m-2. These patients achieved the highest drug exposure in terms of area under the concentration x time curve. It was not possible to achieve an AUC consistently high enough to produce cytotoxic effects due to the occurrence of dose limiting toxicities thus amphethinile cannot at present be recommended for phase II testing by the i.v. route. The dose escalation scheme based on pharmacological monitoring resulted in a considerable saving in the duration of the trial. Further evaluation of this methodology is recommended.

Adult↗
PubMed1988

In vitro and in vivo analysis of the effects of recombinant human granulocyte colony-stimulating factor in patients.

Twelve patients with small cell lung cancer were treated with recombinant human granulocyte colony-stimulating factor, rhG-CSF, given by continuous infusion at doses ranging from 1 to 40 micrograms kg-1 day-1. Patients received the rhG-CSF before the start of intensive chemotherapy and after alternate cycles of chemotherapy. Several in vitro assays were performed using peripheral blood neutrophils and marrow progenitor cells collected from patients prior to and after infusion of the growth factor. Peripheral blood neutrophils were tested for mobility and phagocytic activity. In addition, in vitro clonogenic assays of marrow haemopoietic progenitor cells and analysis of bone marrow trephines and aspirates were carried out. We found that rhG-CSF in vivo has at least two main effects: (a) an early fall in peripheral neutrophils, within the first hour, followed by a rapid influx of mature neutrophils into the circulatory pool; (b) stimulation of proliferation and differentiation of neutrophil precursors in the bone marrow. Neutrophils released into the circulation were normal in tests of their mobility and phagocytic activity.

Antineoplastic Agents↗
PubMed1988

Phase I/II study of recombinant human granulocyte colony-stimulating factor in patients receiving intensive chemotherapy for small cell lung cancer.

Twelve patients with advanced small cell carcinoma of the bronchus were treated by continuous infusion of recombinant human granulocyte colony-stimulating factor (rh G-CSF) at the following dose levels: 1 microgram, 5 micrograms, 10 micrograms, 20 micrograms and 40 micrograms/kg/day for 5 days. No toxicities resulted from the treatment and in all 12 patients the number of peripheral neutrophils increased rapidly to a maximum of 100 x 10(9)/l in one patient at 10 micrograms/kg/day. The neutrophils were shown to be functionally normal in tests of their mobility and bactericidal activity. During the Phase II part of the patients were treated using a combination of i.v. Adriamycin, Ifosfamide and Etoposide. The chemotherapy was repeated every 3 weeks. rh G-CSF was given to each patient for 14 days on alternate cycles of chemotherapy and reduced the period of absolute neutropenia considerably (median of 80%), with a return to normal, or above normal, neutrophil counts within 2 weeks after day 1 of chemotherapy. Ten severe infective episodes were observed during the 20 cycles of chemotherapy which did not include rh G-CSF, while only one infective episode occurred in 20 courses when treated with rh G-CSF. These results demonstrate the utility of rh G-CSF in restoring functional neutrophils to patients undergoing intensive chemotherapy.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1988

Phase I study of recombinant DNA granulocyte macrophage colony stimulating factor.

In this Phase I study of rh GM-CSF three patients have been entered at each of the following dose levels--0.3, 1, 3, 10 and 30 micrograms/kg/day. The mean total white cell count (x 10(9)/l) over the first ten days of rh GM-CSF rose from 11 to 14 at 3 micrograms/kg, 8 to 23 at 10 micrograms/kg and 7 to 27 at 30 micrograms/kg. Side effects included transient pyrexias after the first two infusions of rh GM-CSF and bone pains which were severe and required analgesia in two patients receiving 30 micrograms/kg and one receiving 10 micrograms/kg. No neutralizing antibodies to rh GM-CSF have been detected in the six patients tested to date. Patients are now being studied at 60 micrograms/kg/day.

Colony-Stimulating Factors↗
PubMed1987

Interferon alfa-2b/melphalan/prednisone in previously untreated patients with multiple myeloma: a phase I-II trial.

Interferon alfa-2b (Intron A; Schering Plough) has been shown to be active in advanced previously treated multiple myeloma (MM). Recent in vitro evidence has suggested synergy between cytotoxic agents and interferon alfa-2b. This phase I-II protocol was initiated to study interferon alfa-2b in combination with melphalan and prednisone. Groups of five patients received interferon alfa-2b twice-weekly for two weeks at dose levels of 0.5, 1.0, 2.0, 5.0 and 10.0 X 10(6) IU/m2. During week 2, melphalan (9 mg/m2) and prednisone (40 mg/m2) were administered concurrently with interferon alfa-2b followed by a rest period during nadir myelosuppression, the cycles being repeated every 28 days. Thirty patients were entered of whom 21 were Stage III, 3 Stage II and 6 Stage I. Median nadir WBC/mm3 and platelets/mm3 at the various dose levels are given in the table. Serious adverse reactions while on study included myocardial infarction, renal failure and leukopenia-related sepsis. Early response information is available. Twenty-six patients are evaluable for response. Seven have had progressive disease and 19 (69%) a partial response, the median duration was 11+ months. Interferon alfa-2b does not appear to antagonize melphalan/prednisone effectiveness and may be additive or synergistic. Full evaluation of this combination will be undertaken in randomized controlled trials which are now underway.

Acute Kidney Injury↗