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Biomedical subjects

C J Gallagher

Publications and source records attributed to C J Gallagher.

At least 19 recordsLinked to original sources
PubMed1997

Phase II study of paclitaxel in pretreated patients with locally advanced/metastatic cancer of the bladder and ureter.

Fourteen patients with previously treated, locally advanced/metastatic transitional cell carcinoma (TCC) of the bladder or ureter received paclitaxel at a dose of 200 mg m-2 administered as a 3-h infusion every 21 days. The activity of paclitaxel in this group of patients was modest. The response rates were one partial response (PR) (7%) and three stable disease (SD). There were two early deaths.

Adult↗
PubMed1996

The expression of gonadotropin-releasing hormone and its receptor in endometrial cancer, and its relevance as an autocrine growth factor.

The presence of a direct extra-pituitary action of gonadotropin-releasing hormone (GnRH) via specific receptors in endometrial cancer (EC) has been suggested as an explanation for the therapeutic effect of GnRH analogue (GnRHa) in recurrent disease. We have sought the expression of the GnRH peptide and functional GnRH receptor (GnRH-R) in human tissues and cell lines to investigate the possibility of an autocrine growth regulation mechanism. Using reverse transcription-PCR, differing GnRH mRNA transcripts were detected in two EC cell lines (Ishikawa and HEC-1A), a choriocarcinoma (JEG3) cell line, and tissues from endometrium and placenta. However, secretion of immunoreactive GnRH could be detected by RIA in only 1 of 10 EC tissues in primary culture, and in none of the cell lines. Low levels of GnRH-R mRNA expression were found in the same cells, which were only detectable by reverse transcription-PCR and Southern blotting of the PCR product. In radioligand binding assays using GnRHa goserelin, no pituitary-like, high-affinity GnRH binding sites could be found in either EC cell lines or tissues. Low affinity binding (Kd = 1.0 - 3.1 x 10(-7)M) was detected in three of eight (37%) EC tissues. Furthermore, receptor signal transduction measurements carried out in these cells showed no increases in either total inositol phosphate, cyclic AMP production, or cytosolic Ca2+ in response to either GnRH or GnRHa. Finally, no effect of either GnRH or GnRHa on the growth of EC cell lines was detected in vitro, under estrogen-free conditions, assessed by DNA content. Our data suggest that although there is a potential for autocrine activity for GnRH in EC as judged by the presence of mRNA for peptide and receptor, no functional receptor activity could be detected in vitro. Alternative mechanisms should be studied to explain the in vitro action of GnRHa.

Animals↗
PubMed1996

Long-term follow-up of gonadotrophin-releasing hormone analog treatment for recurrent endometrial cancer.

To test the antitumor effect of gonadotrophin-releasing hormone (GnRH) analogs, 32 consecutive patients with recurrent endometrial cancer that had progressed through conventional treatments were entered into an open observational trial of treatment with this class of compounds. Patients recruited had progressive, symptomatic, and measurable disease. Treatment was with monthly subcutaneous injections of GnRH analog. Measurements of gonadotrophins, sex hormones, and tumor dimensions were made together with repeat biopsy when possible to assess response to treatment. An objective response was seen in nine patients (28%, 95% CI 13-43%). Responses were seen within the first 2 months of treatment and included pelvic as well as distant sites of recurrence. Significantly greater response rates were seen in previously irradiated sites when compared with nonirradiated sites of recurrence (0.01 > P > 0.001). There was no significant difference between the response in patients with G3 lesions compared with patients with G1/G2 lesions (P > 0.5). Response did not correlate with previous progestogen exposure. No evidence of disease flare or drug toxicity was observed. GnRH analogs have a significant and durable antitumor effect in recurrent endometrial cancer which warrants further examination in comparison with progestogens.

Adult↗
PubMed1995

Accelerated cisplatin-based chemotherapy for advanced bladder cancer.

The toxicity and efficacy of accelerated cisplatin, vincristine and methotrexate was assessed in patients with advanced urothelial carcinoma. 30 consecutive patients were entered into a phase II trial and treated with cisplatin, vincristine and methotrexate given every 10 days (MOPq10) for four cycles, followed by two further cycles at 21 day intervals. Five complete responses and 14 partial responses were observed (overall response rate 63%; 95% confidence interval 45-78%). The median progression-free survival was 7.5 months (range 1.8-28) and the median overall survival 10.5 months (range 2.36). Toxicity was moderate with no treatment-related deaths. It is concluded that although the overall survival is still disappointing, the toxicity is less with the protocol than reported with methotrexate, vinblastine, doxorubicin and cisplatin (M-VAC) or escalated M-VAC (E-MVAC) and the time on treatment is shorter. MOPq10 provided palliative benefit to two-thirds of patients with advanced transitional cell carcinoma including those in their eighth decade.

Adult↗
PubMed1995

Castration-induced lymphocytosis in prostate cancer: possible evidence for gonad/thymus endocrine interaction in man.

Prompted by evidence from animal studies that castration produces lymphocytosis associated with thymic hyperplasia, this paper has reviewed serial lymphocyte levels in patients with prostate cancer undergoing hormone treatment. On day 7, 5 of 12 patients (58%) showed diminished circulating lymphocyte levels (compared to day 0) reflecting the surge of testosterone after treatment with LHRH analogues, while on day 28 a reversal had occurred and 13 of 17 (77%) had increased lymphocytes (compared to day 0). Possible relevance of these observations to defining a subgroup of patients with hormone-sensitive cancer who might benefit from immunotherapy is discussed.

Castration↗
PubMed1995

Intermittent endocrine therapy and its potential for chemoprevention of prostate cancer.

This chapter has reviewed the limitations of the use of chemotherapy in patients with hormone resistant prostate cancer. Although demonstrating that there is a small number of patients with very chemosensitive tumours, the age profile and intolerance to chemotherapy make it highly unlikely that this modality of treatment will be used more routinely despite the increasing evidence that the slow decline of prostate specific antigen with endocrine treatment can be used early to select patients who might respond to chemotherapy. Equally certain is that it will not be of use for chemoprevention of the early stages of this disease. Although some data suggest that tumours that respond rapidly and completely to endocrine therapy may benefit from the use of non-specific immunotherapy, there is no evidence that any form of vaccination therapy would be of value in preventing the disease in the main because all attempts to find evidence of a virus, particularly a human papillomavirus subtype, involved in its aetiology have proved negative. The discovery that standard endocrine therapy induces thymic regeneration and peripheral blood lymphocytosis, taken together with the demonstration that surgical trauma induced by a needle biopsy could accelerate tumour dissemination because of tumour activation by trauma induced release of tissue repair cytokines, has led to the proposal that short term endocrine treatment should be given to all prostate specific antigen positive patients prior to needle biopsy. New information on the slow kinetics of prostate cancer growth, with cancers detected by screening being found up to 20 years before clinical presentation and more than 80% of early tumours failing to double the prostate specific antigen level within 2 years, has led to proposals for a new strategy for endocrine chemoprevention of prostate cancer. This has in part been encouraged by greater confidence in the use of intermittent hormone therapy to treat patients with metastatic disease. These observations have led to the suggestion that it might be possible to prevent deaths by treating early cases detected from prostate specific antigen screening with short term (1-3 months) endocrine treatment every 5 to 10 years.

Androgen Antagonists↗
PubMed1994

Characterisation of the differential expression of marker antigens by normal and malignant endometrial epithelium.

In order to examine the production of marker proteins, a reproducible method has been established for culturing purified epithelial cells from normal and malignant endometrium. We have examined the differential expression of secretory proteins using immunohistochemistry in frozen tissue sections, immunocytochemistry in cell cultures derived from the same specimens and protein assays on the culture supernatants. Placental protein 14 (PP14) was produced by normal premenopausal epithelium but not by the post-menopausal or malignant endometrial epithelium. In contrast, placental alkaline phosphatase (PLAP) was produced by endometrial cancers and the endometrial adenocarcinoma-derived cell line Ishikawa, but not by the normal endometrial epithelium. Other markers such as CA-125, which was produced by both normal and malignant endometrium but not by the cell line, and human chorionic gonadotrophin (beta-hCG), which was produced by Ishikawa cells but not by any of the fresh tissues, were less cancer specific. Placental alkaline phosphatase is a direct product of endometrial cancers that can be readily assayed in serum using this two-site assay to test its clinical usefulness in monitoring patients at risk for endometrial cancer.

Adenocarcinoma↗
PubMed1994

Protracted oral etoposide in epithelial ovarian cancer: a phase II study in patients with relapsed or platinum-resistant disease.

This phase II study evaluates the efficacy and toxicity of a prolonged schedule of oral etoposide in patients with measurable advanced ovarian cancer resistant to, or relapsed following, platinum-based chemotherapy. Forty-seven patients participated, 20 of whom had received more than one prior treatment. Seventy-seven per cent had evidence of disease progression during or within 6 months of the previous chemotherapy. Initially, oral etoposide, 50 mg b.d. (regardless of patient size), was given for 14 days on a 21-day cycle. However, after encountering toxicity, the schedule was modified to 7 days' treatment escalating to 10 then 14 days if well tolerated. Among 41 assessable patients there were two complete and eight partial objective responses (24% response rate; 95% confidence interval 12-41%). Nine further patients (22%) had stable disease, four with a sustained fall of > 50% in CA-125. Median duration of response or stable disease was 35 weeks (range 21-49). Overall median survival was 41 weeks from study entry (range 2 to 96+ weeks). Toxicity for most patients was mild, but sporadic severe myelotoxicity occurred, with two treatment-related deaths. Risk factors for severe toxicity were: performance status 3; hepatic impairment; renal impairment. We conclude that oral etoposide has activity in platinum-resistant ovarian cancer and that it is a useful palliative therapy. It has significant toxicity which may be avoided by appropriate patient selection and an escalating-duration schedule.

Administration, Oral↗
PubMed1993

Combination chemotherapy for intermediate and high grade non-Hodgkin's lymphoma.

One hundred and eighteen consecutive adults with newly diagnosed intermediate and high-grade non-Hodgkin's lymphoma were treated with chemotherapy comprising Doxorubicin, Cyclophosphamide, Vincristine and Prednisolone with mid-cycle Methotrexate (MTX) and leucovorin rescue ('CHOP-M'). Intrathecal MTX was given with each treatment cycle as central nervous system (CNS) prophylaxis. 'Clinical remission' was achieved in 70/110 evaluable patients (64%), complete remission: 45/110, (41%), good partial remission: 25/110 (23%). Twenty two patients (19%) died prior to completion of therapy, 18 patients had persistent disease. Hyponatremia (< 137 mmol l-1), advanced age and hypoalbuminaemia (< 32 g l-1) correlated adversely with achievement of CR (P = 0.0007, 0.0005 and 0.04 respectively). With a minimum follow up of 41 years, 47 of the seventy patients (67%) in whom clinical remission was achieved remain well, 19 have developed recurrent disease, resulting in an actuarial projected remission duration of 70% at 8 years. Four died in CR. There has been only one isolated CNS recurrence. On univariate analysis, hypoalbuminaemia, hyponatremia and beta 2 microglobulin (> 3) correlated with unfavourable outcome in terms of duration of remission (P = 0.0009, 0.007 and 0.04 respectively). On multivariate analysis, only the serum sodium (0.002) and advanced age (0.01) were predictive for remission duration. Fifty patients (45%) are alive, the overall actuarial projected survival is thus 42% at 8 years. On univariate analysis, age, hypoalbuminaemia, hyponatraemia, liver involvement and the presence of B symptoms correlated unfavourably with survival. On multivariate analysis, hypoalbuminaemia, advanced age, hyponatraemia, male gender (aged > 50) and diffuse large cell or large cell, immunoblastic histology (Working Formulation) had an adverse effect (P = 0.003, < 0.0001, < 0.0001, 0.002, and 0.03). It was further possible, using cut-off points of 32 g l-1 and 136 mmol l-1 for albumin and sodium respectively to define prognostic categories for patients who differed significantly in terms of survival.

Adolescent↗
PubMed1992

Phase I study comparing continuous infusion of recombinant interleukin-2 by subcutaneous or intravenous administration.

22 cancer patients entered a randomised phase Ib trial comparing the effects of low-dose recombinant interleukin-2 (300 micrograms/m2, approximately equivalent to 6.4 x 10(6) cetus units or 38 x 10(6) U per day) given continuously by intravenous or subcutaneous infusion. At 48 h after two 5-day courses, median lymphocyte levels (x 10(9)/l) were 6.0 (387% increase) in the subcutaneous arm (n = 9) and 5.9 (369% increase) in the intravenous arm (n = 8). Liver and renal toxicity were similar in the two groups. One minor response lasting 4 months occurred in 12 renal cancer/melanoma patients receiving subcutaneous treatment and one durable complete remission continuing at 30 months and one minor response lasting 10 months occurred in 6 renal cancer/melanoma patients receiving intravenous treatment.

Adult↗
PubMed1992

Pilot study to evaluate impact of a policy of adjuvant chemotherapy for high risk stage 1 malignant teratoma on overall relapse rate of stage 1 cancer patients.

A total of 41 patients with stage 1 malignant teratoma of the testis treated from January 1986 to June 1990 was entered into a pilot study of 2 courses of adjuvant cisplatin-based combination chemotherapy. Of the patients 22 had a high or intermediate risk of relapse according to the Medical Research Council (United Kingdom) prognostic factor analysis and surveillance was instituted for 19 patients with a low relapse risk. The overall relapse rate in this group of patients (median followup 2 years) was 9.7% (5% in the adjuvant group and 16% in the surveillance group), which was significantly better than the 35% rate in the historical series treated by surveillance from 1980 to 1985 and equaled or was possibly better than that reported from adjuvant retroperitoneal lymph node dissection. Justification for consideration of 1 course of adjuvant treatment for such cases is reviewed, and the need for examination of such an approach in a neoadjuvant setting with either lymph node dissection or surveillance is examined.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1991

A new treatment for endometrial cancer with gonadotrophin releasing-hormone analogue.

OBJECTIVE: To test the antitumour effect of gonadotrophin releasing-hormone (GnRH) analogues in women with recurrent endometrial cancer. DESIGN: An open phase II observational trial of GnRH analogues. Serial measurements of gonadotrophins, sex hormones and tumour dimensions were made together with repeat biopsy when possible to assess the response to treatment. SETTING: The outpatient clinics of the Department of Medical Oncology at The Royal London, Royal Marsden and St Bartholomew's hospitals. SUBJECTS: 17 patients with endometrial cancer which had recurred after surgery, radiotherapy and progesterone treatment and was symptomatic, progressive and assessable for response. INTERVENTION: Monthly subcutaneous injection of GnRH analogue. MAIN OUTCOME MEASURES: Reduction in serum gonadotrophins and reduction in tumour dimensions. RESULTS: Six out of 17 patients (35%, 95% CI 12.6-58%) achieved a complete or partial remission which continues for a median of 20 months with no adverse effects. CONCLUSION: GnRH analogues have a significant antitumour effect in recurrent endometrial cancer which warrants further examination in comparison with progestogens.

Adenocarcinoma↗
PubMed1990

Increased whole blood viscosity during coronary artery bypass surgery. Studies to evaluate the effects of soluble fibrin and poloxamer 188.

This study was designed to test the hypothesis that soluble fibrin complexes resulting from the trauma of surgery could produce elevated blood viscosity, to characterize the soluble fibrin polymers, and to evaluate in vitro the effect of a new hemorheologic agent, poloxamer 188, on viscosity in these abnormal situations. Ten patients undergoing aortocoronary bypass surgery were studied before and at various times after surgery. By 6 h after surgery, the mean hematocrit decreased by 23%, fibrinogen decreased 48%, and erythrocyte sedimentation rate decreased 33%, whole blood viscosity at a low shear rate rose on average of 69% and soluble fibrin rose 118%. Over the 6-day observation period, the concentrations of soluble fibrin paralleled the changes in viscosity, whereas the concentrations of fibrinogen varied nearly inversely with viscosity. The effects of various forms of fibrinogen and fibrin were tested by additions to normal blood. Soluble fibrin polymers, but not fibrin monomers, increased blood viscosity two to three fold. Poloxamer 188 reduced the viscosity of all patient samples to the normal range. These data support the hypothesis that increased whole blood viscosity at low shear rates is caused by hydrophobic adhesion of fibrin polymers to red cells and that poloxamer 188 normalizes viscosity by effectively disrupting the weak hydrophobic bonds.

Biopolymers↗