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K D Bagshawe

Publications and source records attributed to K D Bagshawe.

At least 19 recordsLinked to original sources
PubMed1992

Computer system for assisting with clinical interpretation of tumour marker data.

OBJECTIVE: To design and evaluate a computer advisory system for the treatment of gestational trophoblastic tumour. DESIGN: A comparison of clinicians' treatment decisions with those of the computer system. Two datasets were used: one to calibrate the system and one to independently evaluate it. SETTING: Department of medical oncology. PATIENTS: Computerised records of 290 patients with low risk gestational trophoblastic tumour for whom the advisory system could predict the adequacy of treatment. The calibration set comprised patients admitted during 1979-86(227) and the test set patients during 1986-89(63). MAIN OUTCOME MEASURES: The system's accuracy in predicting need to change treatment compared with clinicians' actions. The mean time faster that the system was in predicting the need to change treatment. RESULTS: On the calibration dataset the system was 94% (164/174) accurate in predicting patients whose treatment was adequate, recommending change when none occurred in only 10 (6%) patients. In patients whose treatment was changed the system recommended change earlier than clinicians in 39/53 cases (74%), with a mean time advantage of 14.9 (SE 2.02) days. On the test dataset the system had an accuracy of 91% (31/34) in predicting treatment adequacy and a false positive rate of 9% (3/34). The system recommended change earlier than clinicians in 22/29 cases (76%), with a mean time advantage of 12.5 (2.22) days. CONCLUSIONS: The computer advisory system could improve patient management by reducing the time spent receiving ineffective treatment. This has implications for both patient time and clinical costs.

Biomarkers, Tumor↗
PubMed1992

The cytotoxicity, DNA crosslinking ability and DNA sequence selectivity of the aniline mustards melphalan, chlorambucil and 4-[bis(2-chloroethyl)amino] benzoic acid.

Three aniline derivatives melphalan (L-PAM), chlorambucil (CHL) and 4-[bis(2-chloroethyl)amino] benzoic acid (BAM) have been compared on the basis of their in vitro cytotoxicities, DNA interstrand crosslinking ability and DNA sequence selectivity. Cytotoxicity was assessed in the human colonic adenocarcinoma LS174T and leukaemic K562 cell lines using the sulpho-rhodamine B and tetrazolium dye reduction assays. The order of cytotoxicities was L-PAM greater than CHL greater than BAM in both cell lines with K562 being less sensitive than LS174T. This was different from the order CHL greater than L-PAM greater than BAM which would be predicted from simple chemical reactivity or rate of hydrolysis, parameters which have been used previously as indicators of biological potency for aromatic nitrogen mustards. DNA interstrand crosslinking in cells as determined by alkaline elution showed a correlation with IC50 values. The ranking order of activity was further predicted by the ability of the agents to produce interstrand crosslinks in isolated DNA. The extent of guanine N-7 alkylation, assessed using a modified DNA sequencing technique, mirrored cytotoxicity and crosslinking ability, but at equivalent levels of alkylation there was no significant difference in DNA sequence selectivity. These data demonstrates that simple chemical reactivity or hydrolysis rate is not a good indicator of DNA reactivity or cytotoxicity for a number of aniline mustards, whereas DNA interstrand crosslinking ability either measured directly in cells or in isolated DNA, gives a good indication of biological activity.

4-Aminobenzoic Acid↗
PubMed1992

Gestational and nongestational trophoblastic tumors distinguished by DNA analysis.

In three patients in whom a diagnosis of gestational trophoblastic tumor was possible on the basis of pathology and elevated levels of serum human chorionic gonadotrophin, locus-specific minisatellite probes were used to identify restriction fragment length polymorphisms (RFLP) in DNA from the tumor, the patient, and her partner. On the basis of results from these studies, one tumor, originally diagnosed as a germ cell tumor, was reclassified as a gestational choriocarcinoma, whereas a second tumor, diagnosed as gestational choriocarcinoma, was shown to be of nongestational origin. In the third case, a diagnosis of gestational trophoblastic tumor was confirmed, but in this case the androgenetic origin of the tumor indicated that it was derived, not from the antecedent term pregnancy, but from a previous pregnancy with hydatidiform mole. This study clearly demonstrates the value of DNA analysis in the classification of tumors with trophoblastic differentiation.

Adult↗
PubMed1992

Doppler assessment of the uterine circulation and the clinical behaviour of gestational trophoblastic tumours requiring chemotherapy.

The haemodynamics of the uterine arteries and myometrium were assessed using Doppler ultrasound in forty consecutive patients requiring treatment for invasive mole and choriocarcinoma. The investigations were performed prior to the commencement of chemotherapy and the subjects followed prospectively. The Doppler waveforms from the uterine arteries were analysed using the pulsatility index. It was found that patients with a pulsatility index of 1.1 or less were significantly more likely to develop drug resistance than those with a higher value (P < 0.04). There was no significant association between the pulsatility index and metastatic disease or uterine bleeding. Five out of eight patients who developed drug resistance could have avoided initial inadequate treatment if the Doppler findings were included in the scoring system for selecting chemotherapy for these tumours. It can be concluded that assessment of the uterine arteries using the pulsatility index prior to the treatment of patients with invasive mole and choriocarcinoma is of help in predicting those who will develop drug resistance.

Arteries↗
PubMed1992

Choriocarcinoma. A model for tumour markers.

Human chorionic gonadotrophin (hCG) was the first major tumour marker to be identified and in gestational choriocarcinoma remains the closest we have to the ideal indicator of tumour activity. What is measured in assays for this substance is however a complex subject which has to be understood if misinterpretation of the data is to be avoided. It is also necessary to understand the pathology and natural history of the spectrum of hCG producing tumours. The distinction between luteinising hormone (LH) and hCG only became possible with the production of antisera predominantly directed at the beta subunit of hCG. Since then monoclonal antibodies directed at restricted epitopes have revealed that a range of hCG fragments contribute to what is measured. Within the spectrum of hCG producing lesions are those that are self-terminating whilst others are premalignant, malignant but responsive to chemotherapy, or refractory to all present agents. Awareness of this complexity is essential for interpretation of values. For patients with hydatidiform mole hCG measurements form the basis of identifying progressive lesions and thus constituting a still unique biochemical screening programme for cancer. Its roles in diagnosis, prognostication, monitoring the course of the disease and in follow-up for detection of recurrence are unique in many respects. Although hCG measurements provide information critical to the management of each of these lesions that information can only be properly understood through an understanding of the pathological entities involved and the pharmacokinetics of hCG metabolism and excretion.

Biomarkers, Tumor↗
PubMed1991

Comparison of ondansetron and ondansetron plus dexamethasone as antiemetic prophylaxis during cisplatin-containing chemotherapy.

Ondansetron, a serotonin antagonist, is effective in controlling the emesis associated with cancer chemotherapy; however, emesis in patients receiving high-dose cisplatin is poorly controlled by ondansetron alone. Dexamethasone is an effective antiemetic with no known interaction with serotonin receptors and was thus chosen for study in combination with ondansetron. 31 patients (30 male, 1 female; median age 28.5 years, range 18-49) receiving a 4-day course of a chemotherapy regimen containing cisplatin (100-120 mg/m2) for metastatic germ-cell tumours were entered in a randomised, double-blind, cross-over trial comparing oral ondansetron plus placebo with oral ondansetron plus dexamethasone as antiemetic prophylaxis. Ondansetron (8 mg every 8 h) was given to all patients for 8 days from the start of chemotherapy. Patients were given 8 mg of dexamethasone or placebo every 8 h starting 2 h before cisplatin (on day 4) and continuing for six doses (ie, for 2 days only). A second course of chemotherapy began 14 days after the start of the first, during which patients crossed over to the alternative antiemetic regimen. Results were available from 27 patients. In the 24-48 h after cisplatin 78% of patients taking ondansetron plus dexamethasone reported complete or major control of emesis compared with 30% of those taking ondansetron plus placebo (p = 0.001). Cross-over analysis showed a significant advantage for ondansetron plus dexamethasone in the control of nausea (p = 0.013) and emesis (p less than 0.001) over the 8-day study. 24 of 26 patients expressed a preference for the combination therapy (p less than 0.001). Ondansetron plus dexamethasone is effective antiemetic prophylaxis for high-dose cisplatin chemotherapy, has few side effects, and is active when given orally.

Administration, Oral↗
PubMed1991

Cytoreductive surgery in disseminated non-seminomatous germ cell tumours of testis.

Between 1977 and 1988, 67 patients underwent surgical removal of residual metastatic deposits following an aggressive chemotherapy regimen (cisplatin, vincristine, methotrexate and bleomycin alternating with etoposide, actinomycin D and cyclophosphamide) for disseminated germ cell tumours of the testis (stage IIB or above). Ninety-one surgical procedures were performed. There were 63 (69 per cent) retroperitoneal lymph node dissections, 16 (18 per cent) thoracotomies, three (3 per cent) hepatic resections, three (3 per cent) craniotomies, five (5 per cent) delayed orchidectomies and one anterolateral decompression of the vertebral column. Nine (13 per cent) patients required a repeat retroperitoneal node dissection and one patient needed a repeat thoracotomy to remove recurrent metastatic deposits during the period of follow-up. Multivisceral resections and vascular reconstruction procedures were required in 20 (30 per cent) patients undergoing retroperitoneal node dissection. Fifty-five (82 per cent) patients remain in complete remission with a mean follow-up period of 49.6 months (range 2-121 months). Nine (13 per cent) patients died with metastatic disease between 2 months to 4 years after operation. There were three deaths in the perioperative period (4 per cent). The histology of the resected metastases revealed undifferentiated active tumour in 20 (30 per cent) patients, differentiated mature teratoma in 29 (43 per cent) patients and fibrosis/necrosis in 18 (27 per cent) patients. Twelve (60 per cent) patients with undifferentiated elements and 15 patients (60 per cent) with raised preoperative tumour markers (poor prognostic categories) are in complete remission. Cytoreductive surgery in patients with metastatic germ cell tumours offers the best chance of remission following chemotherapy even in poor prognostic group categories.

Adolescent↗
PubMed1991

Correlation of plasma methotrexate concentration with human chorionic gonadotropin and therapeutic response to low-dose methotrexate-citrovorum factor in low-medium-risk gestational trophoblastic tumors.

Seventeen patients with low- or medium-risk gestational trophoblastic tumors (GTT) and one patient with a placental-site trophoblastic tumor were treated according to an 8-day schedule of low-dose methotrexate (LDMTX) alternating with citrovorum factor (CF). Plasma concentrations of methotrexate (MTX) were correlated with serum human chorionic gonadotropin (hCG) levels and clinical response. After an intramuscular dose of 50 mg, plasma MTX levels rose rapidly, reached a peak concentration of 5.8 x 10(-6) M/liter at 1 hour and persisted above 10(-6) M/liter normally considered inhibitory for DNA synthesis, for approximately 7 1/2 hours. Rapid plasma clearance followed with plasma levels reaching 5-7 x 10(-8) M/liter at the time of CF administration. At 48 hours, plasma MTX levels continued to exceed 10(-8) M/liter--the break point for the appearance of clinical toxicity due to MTX. In six of sixteen, or 38%, an initial rise in hCG levels was observed. Five of the seventeen patients, or 29%, and the one patient with PSTT developed MTX resistance. The administered dose (approximately 30 mg/M2) and plasma pharmacokinetics did not differ significantly between the tumors that responded and became resistant to MTX. The authors conclude that MTX resistance in GTT occurs as a result of impaired cell membrane uptake, gene amplification of dihydrofolate reductase, or both.

Chorionic Gonadotropin↗
PubMed1991

Results with the EMA/CO (etoposide, methotrexate, actinomycin D, cyclophosphamide, vincristine) regimen in high risk gestational trophoblastic tumours, 1979 to 1989.

OBJECTIVE: To assess the efficacy, toxicity and survival in patients with high risk GTT treated with the EMA/CO regimen (etoposide, methotrexate, actinomycin D, cyclophosphamide, vincristine/oncovine). DESIGN: Open non-randomized study of 148 consecutive patients referred to the Charing Cross Hospital between 1979 and 1989. SETTING: Trophoblastic disease centre in a London teaching hospital. SUBJECTS: 148 consecutive patients with high risk GTT were treated with the EMA/CO regimen. 76 patients had received no prior chemotherapy and 72 had received prior chemotherapy. MAIN OUTCOME MEASURES: Survival, causes of treatment failure and toxicity were analysed. RESULTS: Of 76 patients who had received no prior chemotherapy, 62 (82%) are in remission; an overall survival of 85% for the 148 patients. Ten of the 76 patients without prior chemotherapy died from extensive disease within 3 weeks of starting chemotherapy. The complete and partial response rates to EMA/CO chemotherapy were 80% and 18% respectively. The addition of cisplatin salvaged 9 of 11 (82%) who developed drug resistance and did not require surgery. Salvage surgery alone resulted in 7 of 8 (87%) having complete remissions. Relapse after EMA/CO chemotherapy is uncommon (5.4%) but survival is still relatively good with further chemotherapy and/or surgery with 6 (75%) of 8 patients obtaining a further sustained remission. Complications from EMA/CO chemotherapy are acceptable with myelosuppression being dose-limiting. Late sequelae are uncommon: menstruation usually returns with a few months, and no fetal abnormalities have been recorded in subsequent pregnancies. One patient developed what we presume to be a therapy-induced acute myeloid leukaemia. CONCLUSION: At present EMA/CO chemotherapy is our treatment of choice for patients with high risk GTT. Its toxicity is predictable and reversible. In patients developing drug resistance, salvage surgery is important. Future developments may include further dose intensification with the addition of haemopoietic growth factors, earlier diagnosis and the separation of gestational from non-gestational trophoblastic tumours.

Adult↗
PubMed1991

Comparison of half-lives and cytotoxicity of N-chloroethyl-4-amino and N-mesyloxyethyl-benzoyl compounds, products of prodrugs in antibody-directed enzyme prodrug therapy (ADEPT).

The synthesis of two novel drugs, 4-[bis[2-(mesyloxy)ethyl]amino]benzoic acid (7) and 4-[(2-chloroethyl)[2-(mesyloxy)ethyl]amino]benzoic acid (8) is described here. They are the active drugs of two prodrugs (9 and 10) designed for use as anti-cancer agents. The prodrugs (9, 10 and 11) were made as a series of compounds which are bifunctional alkylating agents in which the activating effect of the ionized carboxyl function is masked through an amide bond to a glutamic acid residue. These relatively inactive prodrugs were designed to be activated to their corresponding alkylating agent active drugs (7, 8 and 12 respectively) at a tumour site by prior administration of a monoclonal antibody conjugated to a bacterial enzyme. This system is called antibody-directed enzyme prodrug therapy (ADEPT). The chemical half-lives of the prodrugs and their active drugs were measured in order to determine their relative reactivities. The half-lives ranged from 21 to 324 min for the active drugs and from 42 to 1158 min for the prodrugs. The viability of two different tumour cell lines was monitored with each active drug and prodrug. The IC50 values varied from 65 to 625 microM for the active drugs: no IC50 values could be obtained for the prodrugs, using a rapid incubation procedure. Each in vitro technique demonstrated the ability of the glutamic acid moiety to deactivate the drugs, forming effective prodrugs.

Antibodies, Monoclonal↗
PubMed1990

A phase I/II study of the 5-HT3 antagonist GR38032F in the anti-emetic prophylaxis of patients receiving high-dose cisplatin chemotherapy.

A total of 24 patients who were receiving combination chemotherapy (POMB) including cisplatin at a dose of 100-120 mg/m2 were treated with the 5HT3 antagonist GR38032F (GR) as an anti-emetic prophylaxis. GR was given as a 15-min loading infusion followed by a 24-h infusion at three escalating dose levels of 1, 2 and 4 mg/h. In the first 24 h after commencing treatment, six patients had complete control of nausea and vomiting (CR), two had 1-2 emetic episodes (MR) and five had 3-5 emetic episodes (mR). The major response rate (CR + MR) was thus 35%. Eight responding patients (CR or MR) went on to receive oral GR at 8 or 12 mg t.i.d. for 5 days. In this group there was one CR, one MR, two mRs and four failures (F). There was no evidence of an improved therapeutic effect with increasing dose in either the infusion or the oral section of the study, although numbers were limited in the latter part of the trial. Toxicity was mild, with low-grade headache affecting 25% of patients being the most frequent side effect. Pharmacokinetic data was obtained in six patients at each dose level. There was a progressive rise in clearance with increasing dose, indicating that the kinetics are non-linear. However, there was no evidence of an association between high plasma levels and therapeutic efficacy. GR38032F is well tolerated and has promising single-agent activity in preventing vomiting induced by high-dose cisplatin.

Adult↗
PubMed1990

Respiratory failure due to choriocarcinoma: a study of 103 dyspneic patients.

Treatment of choriocarcinoma is mostly successful but there is still appreciable mortality from early respiratory failure. A series of 135 patients with choriocarcinoma presenting with dyspnea between 1960 and 1988 was studied to find prognostic factors for early respiratory death and to identify how mortality may be further reduced. Mortality with respect to early respiratory death (ERD) was 11% and was significantly associated with WHO prognostic score, chest X-ray appearance, central cyanosis, tachycardia, anemia, and clinical evidence of pulmonary hypertension. Indicators on chest X ray of high risk of ERD were the presence of more than 10 opacities, extensive opacification of lung fields, size of metastases, and hazy background obscuring the vascular pattern. Intensity of initial treatment was not correlated with this outcome. A set of criteria has been derived which will predict ERD with 100% sensitivity and 38% positive predictive value. These are opacification of lung fields on chest X ray of more than 50%, OR initial plasma hCG level greater than 10(5) when there is anemia and a history of chest pain. Patients presenting with choriocarcinoma and dyspnea who fulfill these criteria should be considered for extracorporeal perfusion techniques. As respiratory failure in this condition is characterized by hypoxemia and right-to-left shunting, extracorporeal perfusion should be effective. Ventilation should be avoided as no patient survived mechanical ventilation.

Adult↗
PubMed1990

Frequency of serum tumour marker monitoring in patients with non-seminomatous germ cell tumours.

In patients relapsing on surveillance following orchidectomy for stage 1 non-seminomatous germ cell tumours, it is essential that treatment is initiated before they develop advanced disease with a poor prognosis. Patients who start chemotherapy with levels of human chorionic gonadotrophin (HCG) greater than 1,000 i.u. l-1 and/or alpha-fetoprotein (AFP) level greater than 500 ku l-1 have been shown to have a worse prognosis than patients with lower marker levels. We studied 64 patients between 1968 and 1987 with rising serial tumour markers. The potential time in which markers could rise to poor prognostic levels was calculated assuming an exponential rate of increase. Adverse levels were predicted in one patient (1.6%) within 7 days, in two patients (3.1%) within 14 days, in eight patients (12.5%) within 4 weeks and in 16 patients (25%) within 6 weeks. This suggests that, initially, weekly marker estimations should be performed on stage 1 surveillance patients. The extra cost to a specialist follow-up laboratory of weekly as opposed to the usual monthly marker measurements will be less than 33,600 pounds for every 400 patients on surveillance. One extra patient is likely to be cured for this sum.

Biomarkers, Tumor↗
PubMed1979

A microprocessor-controlled assay for the estimation of human placental lactogen.

A radioimmunoassay for human placental lactogen (HPL) is described using the KEMTEK 3000, which is a modular radioimmunoassay apparatus controlled by a microprocessor. Operation of the KEMTEK 3000 is largely automatic and it requires minimal intervention from the operator. It is capable of 300 reactions per hour so that a large number of estimations can readily be performed. HPL was assayed by a double antibody method on serum samples from pregnant women and patients with trophoblastic tumours.

Antigens↗