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Biomedical subjects

L Holden

Publications and source records attributed to L Holden.

At least 37 records · Page 2Linked to original sources
PubMed1997

Treatment of men with metastatic non-seminomatous germ cell tumours with cyclical POMB/ACE chemotherapy.

BACKGROUND: An alternating combination chemotherapy schedule for advanced nonseminomatous germ cell tumours (NSGCT) has been in use since 1977. PATIENTS AND METHODS: Three hundred thirty-nine men with metastatic NSGCT were treated with POMB/ACE (cisplatin, vincristine, methotrexate, bleomycin, actinomycin D, cyclophosphamide and etoposide), including 42 who had received previous chemotherapy or radiotherapy. Previously untreated patients were classified according to the International Germ Cell Cancer Collaborative Group (IGCCCG) model, and 31% were in the worst prognostic group. RESULTS: The median follow-up is eight years. The overall survival at five years is 82% (95% confidence interval (CI); 78%-85%). The survival of untreated patients exceeded that for previously treated patients (log-rank P = 0.04) and of testicular tumours exceeded that for primary extragonadal tumours (log-rank P < 0.0001). The survival of men with IGCCCG poor prognosis disease at three years is 75% (95% CI: 65%-84%) compared to 50% in the large cohort which was used to derive the model. There were five early treatment related deaths. In addition, five patients developed acute leukaemia, one developed a second primary lung adenocarcinoma, one man died of pulmonary fibrosis and three men died of cerebrovascular or cardiovascular disease. CONCLUSIONS: The POMB/ACE schedule has been employed in a large series of men with metastatic NSGCT over two decades. The fatal toxicity is equivalent to that described for simpler regimens. It yields equivalent response rates and survival in men with good prognosis disease and appears to achieve better survival in patients with poor prognosis disease.

Adolescent↗
PubMed1997

Gestational trophoblastic disease with liver metastases: the Charing Cross experience.

OBJECTIVE: To define management options for women presenting with gestational trophoblastic disease (GTD) which had already metastasised to the liver. DESIGN: Retrospective analysis of case records between 1958 and 1994. SETTING: A national referral centre for trophoblastic disease. RESULTS: The database containing 1676 treated patients was reviewed and 46 patients with hepatic metastases were identified (2.7%). The median age was 32 years (range 19-52 years). The antecedent pregnancy to the GTD was normal in 65% (30/46), and the time interval between the antecedent pregnancy and presentation was longer than one year in 50% (22/44). Lung metastases were present in 43 patients (93%) and brain deposits in 15 patients (33%). Forty-five patients (98%) were high risk by WHO criteria. The five-year overall survival was 27%. The five-year survival of the subgroup of patients having both hepatic and cerebral metastases was 10%. There was no significant survival difference between the different chemotherapy regimens used in the study period (pre-1979 CHAMOCA: methotrexate, actinomycin D, cyclophosphamide, doxorubicin, melphalan, hydroxyurea and vincristine; 1979 onwards EMA/CO-EP: etoposide, methotrexate, adriamycin-D/ cyclophosphamide, vincristine-etoposide and cis-platinum). Multivariate analysis revealed that a prognostic score > 12 was significant (Hazard ratio 5.4, 95% CI 0.7-41.9; P = 0.04). CONCLUSIONS: The outcome for women presenting with hepatic metastases from GTD is poor with an even worse prognosis if cerebral metastases are also present. Alternative therapeutic measures, such as high dose therapy or new drugs, should be explored in these women.

Adult↗
PubMed1997

EMA/CO for high-risk gestational trophoblastic tumors: results from a cohort of 272 patients.

PURPOSE: To evaluate the results of etoposide, methotrexate, and dactinomycin alternating with cyclophosphamide and vincristine (EMA/CO) chemotherapy in women with high-risk gestational trophoblastic tumors (GTT) and to document the middle- and long-term toxicity of the regimen. PATIENTS AND METHODS: A total of 272 consecutive women with high-risk GTT, including 121 previously treated patients, were treated with weekly EMA/CO. The median follow-up duration is 4.5 years (range, 1 to 16). RESULTS: The cumulative 5-year survival rate is 86.2% (95% confidence interval, 81.9% to 90.5%). No deaths from GTT have occurred later than 2 years after the end [corrected] of EMA/CO. In a multivariate model, adverse prognostic factors were the presence of liver metastases (P < .0001), interval from antecedent pregnancy (P < .0001), brain metastases (P = .0008), and term delivery of antecedent pregnancy (P = .045). There were 11 (4%) early deaths, while 213 patients (78%) achieved a complete remission. Forty-seven (17%) developed drug resistance to EMA/CO, of whom 33 (70%) were salvaged by further cisplatin-based chemotherapy and surgery. Two women developed acute myeloid leukemia, two cervical malignancy, and one gastric adenocarcinoma after EMA/CO. More than half (56%) of the women who had fertility-conserving surgery and who have been in remission at least 2 years have become pregnant since the completion of EMA/CO, with 112 live births, including three infants with congenital abnormalities. CONCLUSION: EMA/CO is an effective and well-tolerated regimen for high-risk GTT. More than half of the women will retain their fertility; however, there is a small but significant risk of second malignancy.

Adolescent↗
PubMed1996

Chemotherapy for ovarian germ cell tumours.

59 patients were treated for newly diagnosed metastatic ovarian germ cell tumours with POMB/ACE chemotherapy (which contains cisplatinum, vincristine, methotrexate, bleomycin, actinomycin D, cyclophosphamide and etoposide). The median follow-up was 7.7 years. The 3 year survival is 87.8% (95% confidence interval 76.9-93.9%) and no relapses occurred more than 3 years after treatment. 4 (7%) patients had primary drug resistance to POMB/ACE and 4 (7%) have relapsed. One patient in complete remission developed secondary acute myeloid leukaemia after receiving a total of 1.3 g/m2 etoposide. 6 of 12 (50%) patients referred at relapse were salvaged by POMB/ACE. 14 of 33 (42%) women (> 18 years old) have had successful pregnancies after fertility conserving surgery and chemotherapy with no congenital abnormalities reported. The POMB/ACE regimen is as efficacious as other published regimens for ovarian germ cell tumours (OGCT) and balances a low incidence of life-threatening toxicity with a high success rate.

Adolescent↗
PubMed1996

Combination but not single-agent methotrexate chemotherapy for gestational trophoblastic tumors increases the incidence of second tumors.

PURPOSE: No increase in second tumor incidence was found in a previous analysis of women treated with chemotherapy for gestational trophoblastic tumors (GTT). More patient years at risk enabled a further analysis of the risk of second tumors to be performed in the 1,377 women treated in this until up to 1990. PATIENTS AND METHODS: Health questionnaires were returned on 93.3% of patients who successfully completed chemotherapy and were living in the United Kingdom. The remainder were flagged for death or developing further cancers by the Office of Population Census and Surveys and by the Thames Cancer Registry. Incidence density analysis was performed based on 15,279 person-years of observation available. Standardized incidence ratio (SIR) was used to estimate the relative risk (RR) of second tumors associated with the treatment. To calculate the expected number, the actual incidence rates observed by the Thames Cancer Registry during the same calendar period of observation were used. RESULTS: An overall 50% excess of risk (RR = 1.5; 95% confidence interval [CI], 1.1 to 2.1; P < .011) was observed: there were 37 second tumors, when 24.5 were expected. For specific second tumors, the risk was significantly increased for myeloid leukemia (RR = 16.6; 95% CI, 5.4 to 38.9), colon (RR = 4.6; 95% CI, 1.5 to 10.7), and breast cancer when the survival exceeded 25 years (RR = 5.8; 95% CI, 1.2 to 16.9). The risk was not significantly increased among the 554 women receiving single-agent therapy (RR = 1.3; 95% CI, 0.6 to 2.1). Leukemias only developed in patients receiving etoposide plus other cytotoxic drugs. CONCLUSION: This study suggests that there is a slight increased risk of second tumors after sequential or combination chemotherapy for GTT. This has become apparent since the introduction of etoposide and longer follow-up.

Adolescent↗
PubMed1995

Secondary tumours following etoposide containing therapy for germ cell cancer.

BACKGROUND: Reports have implied etoposide as the cause of secondary leukaemia in patients treated for germ cell cancer. PATIENTS AND METHODS: Between 1979 and 1992, 679 male patients with germ cell cancer received etoposide containing chemotherapy. RESULTS: Six of 679 patients developed acute myeloid leukaemia (relative risk 150; CI: 55-326). None of these patients had a primary mediastinal germ cell tumour and only 1 patient received previous radiotherapy. The median interval between the onset of cytotoxic treatment and the development of leukaemia was 27 months. The FAB M4 morphology was seen in 4 of 6 cases. CONCLUSION: The benefit of etoposide containing protocols outweigh the risk of leukaemia in patients with intermediate or high risk disease, however in patients with good risk disease non-etoposide containing protocols should be explored.

Acute Disease↗
PubMed1995

Serum anticholinergic activity in hospitalized older persons with delirium: a preliminary study.

OBJECTIVE: To evaluate the relationship between total serum anticholinergic activity (SAA) and the presence or absence of delirium in older hospitalized persons on general medical wards. DESIGN: Case-control study and within-subjects repeated-measures in recovered delirious patients. SETTING: Minneapolis Veterans Affairs Medical Center medical wards. PARTICIPANTS: Eleven male delirious patients (DSM-III-R criteria) aged 60 or older and 11 comparably aged male nondelirious controls. MEASUREMENTS: Radioreceptor bioassay of total SAA using tritiated quinuclidinyl benzilate (QNB) binding to muscarinic receptors. Results are expressed in terms of atropine equivalents (nM). MAIN RESULTS: Mean SAA was significantly elevated in the delirious group (mean +/- SD = 6.05 +/- 2.97 nM atropine equivalents) compared with the controls (3.38 +/- 2.49; t(20) = 2.28, P < .05). At study entry, mean SAA was significantly higher in delirious subjects whose symptoms eventually resolved completely (mean +/- SD = 7.77 +/- 2.37) compared with subjects whose delirious symptoms persisted (3.99 +/- 2.30; t(9) = 2.68, P < .05). All six patients in whom delirium resolved completely had a decrease in serum anticholinergic activity when measured during delirium (7.77 +/- 2.37) and after symptom resolution (3.92 +/- 2.61; t(5) = 3.29, P < .05). CONCLUSIONS: Our findings suggest that serum anticholinergic activity may play a role in delirium in medical inpatients. The relationships between SAA and delirium in medical patients and between total SAA and medication use warrant further study.

Aged↗
PubMed1994

The long-term outcome of patients who relapse after chemotherapy for non-seminomatous germ cell tumours.

OBJECTIVE: To examine the long-term survival of a group of patients with non-seminomatous germ cell tumours, who relapse after chemotherapy and are retreated with a cisplatin and etoposide-based regimen. PATIENTS AND METHODS: At the Charing Cross Hospital between 1979 and 1988 38 patients in relapse were seen. The median interval after primary therapy was 8 months. They were treated with an intensive cisplatin and etoposide-based regimen with cycles repeated at 7-10 day intervals, and with surgery in 22 patients. RESULTS: Forty-seven per cent of patients entered a second complete remission and 88% of these remain disease free. The overall survival was 46% with a median follow-up of more than 4.3 years. Surgery was performed in 14 of 18 patients who entered a second complete remission. Adverse risk factors before initial chemotherapy and the time to relapse did not predict outcome but patients with unresectable radiological masses after relapse therapy had a poor outcome despite normalization of serum tumour markers. The tumours of 68% of patients initially treated with cisplatin-based regimens and 62% of patients who also received etoposide remained responsive to conventional doses of these drugs at relapse. CONCLUSIONS: This study demonstrates that there is a group of patients with relapsed teratoma who can be cured without the need for very high dose chemotherapy and autologous bone marrow rescue.

Adolescent↗
PubMed1993

Correlation between clinical staging (FIGO) and prognostic groups with gestational trophoblastic disease.

OBJECTIVE: To compare the Charing Cross Hospital scoring system with FIGO staging for gestational trophoblastic disease. DESIGN: A retrospective analysis of patients referred to Charing Cross during the period 1979-1989. SETTING: National referral centre. SUBJECTS: Two hundred and seven women with gestational trophoblastic disease presenting between 1979-1989. MAIN OUTCOME MEASURES: The women were classified according to the Charing Cross Hospital scoring system and FIGO clinical staging and the results of treatment compared. RESULTS: Of the 207 women studied, there were 102 low risk, 39 medium risk and 66 high risk according to the Charing Cross system and 26 stage 0, 83 stage 1, 23 stage 2, 51 stage 3 and 24 stage 4 according to the FIGO system. If the FIGO system had been used to determine therapy, 17 women would have been at risk of undertreatment and nine of overtreatment. The main prognostic factors contributing to a higher Charing Cross score and thus more intensive chemotherapy from the outset were: HCG > 10(5), interval from antecedent pregnancy > 12 months and term delivery. CONCLUSIONS: The Charing Cross scoring system incorporates factors predictive of the presence of drug resistant tumour and thus allows more appropriate use of chemotherapy from the start of treatment than is possible with the anatomically based FIGO staging. Moreover, the system is easy to apply relying only on history and clinical examination in addition to a reliable quantitative HCG assay.

Adult↗
PubMed1992

Haloperidol decanoate pharmacokinetics in red blood cells and plasma.

Red blood cell (RBC) and plasma concentrations of haloperidol (H) and reduced haloperidol (RH) were determined in nine patients (five men, four women) who had been receiving monthly injections of haloperidol decanoate (HD) for at least 3 months. A very sensitive high performance liquid chromatography method was used to measure H and RH, which could be detected at levels as low as 0.1 ng/ml. Blood samples for H and RH were drawn at the end of weeks 1, 2, 3, and 4 of a 4-week cycle. Monthly HD dosages ranged from 50 mg to 200 mg. At each time point RBC H did not differ significantly from plasma H. RBC RH and plasma RH did not change significantly over time and were consistently lower than RBC H and plasma H. However, RBC RH levels were higher than plasma RH levels. Also, the ratios of RBC RH/H were higher than were the ratios of plasma RH/H, which reflect an accumulation of RH intracellularly. HD dosage was highly correlated with both RBC H and plasma H, but RBC RH and plasma RH were not significantly related to dosage at any time point. Significant correlations were observed between HD dosage and prolactin concentration at week 1 and between prolactin concentration and RBC H and plasma H at weeks 1 and 4. Blood concentrations of H and RH and the corresponding standardized areas under the curve were not significantly related to smoking.

Adult↗
PubMed1992

Haloperidol and reduced haloperidol in saliva and blood.

A total of 18 outpatients (17 male, 1 female) ranging in age from 36-66 years old were on a constant dosage of haloperidol in equally divided doses at 9:00 a.m. and 9:00 p.m. for at least 1 month. DSM-III-R diagnoses included schizophrenia (N = 9), schizoaffective disorder (N = 3), bipolar disorder (N = 4), organic mental disorder (N = 1), and delusional disorder (N = 1). Blood samples for steady-state concentrations of plasma and red blood cell haloperidol (H) and reduced haloperidol (RH) were drawn at 9:00 a.m. (12 hr trough). The haloperidol dosage was held at 9:00 a.m. until samples of whole saliva and parotid saliva could be collected for flow rates and concentrations of H and RH. Haloperidol dosages ranged from 1 mg/day to 60 mg/day (mean 11 +/- 15). Correlation coefficients were calculated for saliva concentrations versus blood levels and for saliva secretion rates versus blood levels. The correlations between whole saliva measures and blood concentrations were all higher than the correlations between parotid saliva measures and blood concentrations. In one case the higher correlation reached statistical significance. There was only one case in which substitution of saliva secretion rate improved the correlation between measures with saliva concentration. Our findings suggest that saliva measures of H and RH are useful alternatives to plasma concentrations in monitoring maintenance haloperidol treatment.

Adult↗
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↗
PubMed1988

Single agent etoposide in gestational trophoblastic tumours. Experience at Charing Cross Hospital 1978-1987.

Two hundred and two patients with gestational trophoblastic tumours (GTT) were treated using single agent etoposide. Patients were divided into low, medium and high risk groups using a prognostic index. Initial chemotherapy commenced with etoposide in 101 patients and 94 were accessible. Partial response (PR), defined by a log fall in serum human chorionic gonadotrophin (hCG) concentration within 1 week, occurred in 63 patients (67%) and was more common among low (5/8; 63%) and medium risk (47/64; 73%) than high risk patients (11/22; 50%) although these differences were not significant (P greater than 0.05). No patient showed a sustained rise in hCG level after etoposide and 91 (97%) showed some decrease. Ninety-one (97%) of these patients remain alive and well with median follow-up of 63 months but 29 (31%) required more intensive combination therapy. Of three deaths, two were due to progressive disease and drug resistance. Among 101 patients who had received previous chemotherapy when etoposide was first administered, response to etoposide was accessible in 39. Of these, PR occurred in 18 (46%) and only one patient progressed after etoposide. With a median follow-up of 35 months, survival in this group is 92% (36/39). All deaths were due to progressive disease and drug resistance. Single agent etoposide is very active in GTT but should be used in combination chemotherapy for patients presenting with adverse prognostic factors.

Adult↗
PubMed1987

Treatment of patients with poor prognosis anaplastic germ cell tumours (AGCT) of the testis and other sites.

Between 1977 and 1986, 170 male patients with anaplastic germ cell tumours (AGCT) completed chemotherapy with POMB/ACE (platinum, vincristine (oncovin), methotrexate, bleomycin, actinomycin D, cyclophosphamide and etoposide). By increasing the number of courses of POMB in 1979 we have been able to compensate for adverse prognostic factors. Since then each patient has received a minimum of three courses of POMB and 139 patients have completed therapy with an overall survival of 89%, and for those patients who had not received prior radiotherapy the survival is 92%. By increasing the number of courses of POMB, the initial serum concentrations of human chorionic gonadotrophin (hCG greater than 50,000 IU/I) and/or alpha-fetoprotein (AFP greater than 500 kU/l) have ceased to be poor prognostic variables. Neither stage at presentation nor the volume of metastatic disease is a major adverse prognostic variable using this chemotherapy.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1986

Current optimum management of anaplastic germ cell tumours of the testis and other sites.

Between 1977 and 1985, 149 male patients with anaplastic germ cell tumours (AGCT) completed chemotherapy with POMB/ACE (platinum, vincristine (oncovine), methotrexate, bleomycin, actinomycin D, cyclophosphamide and etoposide). By increasing the number of courses of POMB in 1979, we have been able to compensate for adverse prognostic factors. Since then each patient has received at least three courses of POMB and 118 patients have completed therapy. The overall survival rate since 1979 is 89% and for the 100 patients who had not received prior radiotherapy it is 92%. We established that an initial serum concentration of human chorionic gonadotrophin (HCG greater than 50,000 iu/l) and/or alphafetoprotein (AFP greater than 500 ku/l) indicated a poor prognosis. Between 1977 and 1979 the survival rate in 12 patients in this category was only 45%. After increasing the number of courses of POMB, the survival rate rose to 89% in 31 patients. However, patients who had received prior radiotherapy and who presented with high tumour markers (HCG greater than 50,000 iu/l and/or AFP greater than 500 ku/l) continue to have a poor survival rate (20% in five patients). With this chemotherapy, 14 of 16 patients (88%) presenting with liver metastases and 6 of 7 patients (86%) presenting with brain metastases are in complete remission. Neither the stage at presentation nor the volume of metastatic disease was a major adverse prognostic variable. We believe that POMB/ACE chemotherapy, followed by surgery in selected cases, is currently the best treatment for patients with AGCT.

Antineoplastic Combined Chemotherapy Protocols↗