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Biomedical subjects

R H Begent

Publications and source records attributed to R H Begent.

At least 91 records · Page 5Linked to original sources
PubMed1991

Weekly etoposide, methotrexate and actinomycin D, alternating with cyclophosphamide plus vincristine (EMA/CO): a phase II study in advanced gastric carcinoma.

A total of 27 patients with measurable/evaluable metastatic or locally advanced gastric carcinoma were given combination chemotherapy comprising etoposide, methotrexate, actinomycin D, cyclophosphamide and vincristine (EMA/CO). Ten achieved partial remission, giving a response rate of 37% (95% CI; 21.7%-66.3%), 12 attained stable disease, whereas five had disease progression despite treatment. Drug toxicity was moderate to severe. Five of those who achieved partial remission underwent an attempt to resect residual disease which was successful in only three patients.

Adenocarcinoma↗
PubMed1991

Optimum management of pineal germ cell tumours.

Non-seminomatous pineal region germ cell tumours have a poor prognosis when treated with radiation alone but little is known of the results of treatment with modern chemotherapy. Between 1983 and 1990 five pineal region germ cell tumours presented to the Charing Cross Hospital, London. All five patients received the EpPlt/OMB chemotherapy schedule with escalated dose systemic methotrexate and intra-CSF methotrexate. Two patients had had prior radiotherapy. Four patients (80%) remain well and disease-free 6 months--5 years after completing therapy. Chemotherapy is an effective modality for the treatment of pineal germ cell tumours and should be used when non-seminomatous elements are present or when the placement of ventriculo-peritoneal shunt in the presence of malignant cells in the CSF presents a risk of dissemination.

Adolescent↗
PubMed1991

Histamine, leukotriene C4 and interleukin-2 increase antibody uptake into a human carcinoma xenograft model.

Systemically administered radiolabelled anti-tumour antibody is ineffective in treating the majority of patients with liver metastasis from colorectal carcinoma. We have assessed whether agents which increase capillary permeability can increase tumour uptake of antibody isotope conjugate. We developed a xenograft model of colorectal carcinoma using an antibody directed against carcinoembryonic antigen (CEA). Tumours were grown subcutaneously in the hind limbs of athymic rats to derive their circulation from the femoral artery. Cannulae were placed in the common iliac artery and iliolumbar vein. Antibody was delivered systemically, regionally and regionally with histamine, leukotriene C4 and interleukin-2. Regionally administered anti-CEA antibody resulted in a significantly greater (P = 0.004) tumour to normal tissue ratio (1.66, s.d. = 0.68) compared to systematically administered antibody (1.25, s.d. = 0.73). The addition of vasoactive drugs produced an approximately 3-fold increase with an increase to a mean tumour:liver ratio of 3.24 (s.d. = 1.39) for histamine (P less than 0.001 compared to systemic delivery), 3.21 (s.d. = 1.13, P less than 0.001) for leukotriene C4 and 3.80 (s.d. = 1.53, P less than 0.001) for interleukin-2. The addition of histamine significantly (P = 0.004) increased the mean tumour to liver ratio (1.73, s.d. = 0.44) of non-specific antibody uptake compared with either systemic (1.12, s.d. = 0.24) or regional delivery (1.25, s.d. = 0.54) of non-specific antibody alone. Increasing tumour capillary permeability can produce a significant clinically useful increase in tumour uptake of antibody-isotope conjugate.

Animals↗
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↗
PubMed1990

In situ and slot hybridization analysis of RNA in colorectal tumours and normal colon shows distinct distributions of mitochondrial sequences.

cDNA clones of mRNAs with an abnormal abundance in familial adenomatous polyposis were used to examine the levels and distribution of the mRNAs in tissues from 15 patients with colorectal cancer. Of 12 cloned sequences studied by slot hybridization, one was substantially reduced in tumours compared with normal tissue. Sequence analysis showed this to code for IgA. In situ hybridization was consistent with slot hybridization and immunohistochemistry. Two mitochondrially encoded sequences had distinct distributions detected by in situ hybridization but did not have detectable quantitative differences in whole tumour or mucosa extracts.

Adenocarcinoma↗
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

Accurate quantification of 131I distribution by gamma camera imaging.

The development of targeted therapy requires that the concentration of the therapeutic agent can be estimated in target and normal tissues. Single photon emission tomography (SPET), with and without scatter correction, and planar imaging using 131I have been compared to develop a method for investigation of targeted therapy. Compton scatter was investigated using line spread functions in air and water, these data were used to set a second peak, adjacent to the photopeak, for scatter correction. The system was calibrated with an eliptical phantom containing sources in background activity of various intensities. Scatter corrected reconstructions gave accurate estimates of activity in the sources regardless of background activity. For planar scanning and SPET without scatter correction there was an overestimate of activity in the source of 290% and 40% respectively. The validity of this method was confirmed in patients by comparing activity in the cardiac ventricles measured by SPET with scatter correction with that in a simultaneous blood sample. A coefficient of correlation of 0.955 was achieved with 25 data points. SPET with scatter correction was compared with planar imaging in measuring activity in the liver and spleen of patients receiving 75 mCi 131I-antibody to CEA intravenously. Planar imaging gave significantly higher values than SPET for the spleen (t = 5.4, P less than 0.001 by the paired t-test) but no significant difference for the liver. SPET with scatter correction forms a basis for an improved technique of quantifying the targeting efficiency.

Humans↗
PubMed1990

Quantitative distribution of 131I-labelled monoclonal antibodies administered by the intra-ventricular route.

In a preliminary study in one patient [111In]DTPA was injected into the lateral ventricle and at the same time [99mT]DTPA into the lumbar sac. The 111In distributed freely throughout the CSF but the concentration of 99mTc in the ventricles remained consistently low. In the second phase of the study three patients with tumours confined to the neuraxis were treated with 20-50 mCi 131I-labelled monoclonal antibodies administered into the lateral ventricle via Ommaya reservoirs. Quantitative distribution of radio-labelled antibody was assessed at intervals up to 8 days post injection. In each case there was rapid distribution to all parts of the neuraxis with 38-68% of total CNS counts remaining in the head and 13-39% in each of the upper and lower half spine areas. The t1/2 for total CNS counts were 31.5, 19.8 and 15.5 h. There was no clear evidence of tumour localization and no neurological toxicity. These patients demonstrate that radiolabelled monoclonal antibodies can be given safely via Ommaya reservoirs and that in order to obtain optimal distribution throughout the CSF this should be the preferred method of administration. Further trials in patients with minimal disease are warranted.

Adult↗
PubMed1990

Antibody targeted therapy in cancer: comparison of murine and clinical studies.

Antibody targeted therapy can be effective in animal models of cancer. Treatment has been less successful in man, though some responses are reported. Understanding the distribution of antibody in man and animals shows how toxicity may be minimized and patients selected for therapy on the basis of efficient antibody localization in the tumour.

Animals↗
PubMed1990

Comparison of anti-fetal colonic microvillus and anti-CEA antibodies in peroperative radioimmunolocalisation of colorectal cancer.

Local recurrence of colorectal cancer may result from failure to assess accurately the extent of tumour at operation. It has been suggested that peroperative radioimmunolocalisation may improve this assessment. The degree to which this is possible has been studied using a hand-held gamma detecting probe and comparing two 125I-labelled monoclonal antibodies to colorectal tumours. The antibodies were to fetal colonic microvillus membrane (FM1D10) and to carcinoembryonic antigen (A5B7). Sixty-nine per cent (9/13) of the FM1D10 and 98% (43/44) of A5B7 labelled tumours took up significant amounts of antibody with a tumour to normal colon ratio of more than 1.5:1. The uptake was significantly better for A5B7 with a median tumour to normal colon ratio of 3.3 (1.1-13.8) compared to 1.85 (0.75-7.7) for FM1D10 (P less than 0.001). The tumour: colon ratio of both antibodies was independent of the serum CEA, Dukes' stage or the degree of histological differentiation. There was a linear correlation for tumour to normal colon ratios between the gamma detecting probe and the same tissue examined in a conventional well counter (correlation coefficient r = 0.78, P less than 0.001). Colorectal tumours demonstrate a rapid and reliable uptake of anti-CEA monoclonal antibody A5B7. This antibody can be detected with a peroperative gamma detecting probe and has the potential to improve the surgeon's appreciation of the extent of tumour and therefore may influence the surgery performed. Detailed clinical studies are now being carried out.

Adult↗
PubMed1990

Preliminary observations on the microdistribution of labelled antibodies in human colonic adenocarcinoma xenografts: relevance to microdosimetry.

Autoradiography with 125I-labelled antibodies 17-1-A and 11-285-14 (anti-carcinoembryonic antigen) injected singly or together into nude mice carrying two distinct human colorectal cancer xenografts delineates marked changes in distribution and retention of isotope over 72 h, which are relevant to microdosimetry. The antibodies localise independently at low concentrations. Slow accumulation and retention predominantly in membranes of glands and necrotic areas suggest that therapy will succeed best with isotopes whose range, half-life and/or mode of delivery can exploit optimally the greater selectivity of the late retention.

Adenocarcinoma↗
PubMed1990

Preliminary Doppler studies on the uterine artery and myometrium in trophoblastic tumours requiring chemotherapy.

The uterine circulation in 38 patients with invasive mole or choriocarcinoma were investigated using Doppler ultrasound. Twenty-six non-pregnant and 23 pregnant volunteers were assessed in a similar fashion to act as control groups. The pulsatility indices were significantly lower in the patients with trophoblastic disease when compared with the non-pregnant and pregnant groups (Student's t-test; P less than 0.001 and P less than 0.02 respectively). The uterine circulation in persistent trophoblastic diseases shows a characteristic Doppler profile suggesting the presence of large low resistance blood vessels. This may be useful in the initial assessment of these tumours before cytotoxic chemotherapy.

Adult↗
PubMed1990

Ultrasonic morphology of the uterus and ovaries after treatment of invasive mole and gestational choriocarcinoma.

Ultrasound imaging of the uterus and ovaries was performed on 41 patients after completion of apparently successful cytotoxic chemotherapy for invasive mole and choriocarcinoma. Uterine volume was calculated and the echopattern of the uterus and ovaries assessed. Forty-nine per cent of subjects had an abnormal uterine appearance and 20% had ovarian theca-lutein cysts. Two patients relapsed on follow-up but no predictive ultrasonic features could be established on uterine or ovarian morphology after chemotherapy.

Antineoplastic Agents↗
PubMed1989

Identification of a human ribosomal protein mRNA with increased expression in colorectal tumours.

A human ribosomal protein cDNA was selected from a normal colon cDNA library on the basis of overexpression in familial adenomatous polyposis. Nucleotide sequence analysis was used to identify this cDNA as corresponding to the human equivalent of the rat ribosomal protein L31 (HL31). We have quantified the expression of HL31 mRNA in colorectal tumours and found overexpression in 23 out of 23 cases. Our results indicate that HL31 is associated with a malfunction of normal growth regulatory mechanisms in these tumours, and suggest a role for HL31 in proliferation and neoplasia.

Adenocarcinoma↗
PubMed1989

The effect of second antibody clearance on the distribution and dosimetry of radiolabelled anti-CEA antibody in a human colonic tumor xenograft model.

Radioimmunotherapy in humans is limited by toxicity to normal tissues, caused by circulating radio-antibody. Second antibody directed against the first (anti-tumor) antibody accelerates clearance of first antibody from normal tissues, and may thus improve the therapeutic ratio. The effect of second antibody both on anti-tumor antibody distribution and on tumor and normal tissue radiation doses, has been investigated in nude mice bearing colonic tumor xenografts. Second antibody, given either 6 or 24 hr after the first, rapidly cleared circulating activity and reduced the calculated radiation dose to all tissues except the spleen, where it rose by 11 and 43% respectively. The dose received by the blood fell by 87% and 71%, while that to the tumor was reduced by 81% and 58%, after 6 or 24 hr second antibody. Administration of second antibody therefore improved the tumor to blood ratios. Tumor identification by gamma camera was greatly facilitated by the use of second antibody, and required no background subtraction. Results obtained from this system demonstrate the utility of second antibody in protecting normal tissues from prolonged circulating radioactivity during radioimmunotherapy.

Adenocarcinoma, Mucinous↗
PubMed1989

Treatment of small cell lung cancer by eight weeks chemotherapy.

Eighty-two patients with small cell lung cancer (SCLC), 32 with limited disease, were treated with alternating chemotherapy. Eight courses were administered at weekly intervals, and responding patients received radiotherapy to sites of bulk disease. Overall response rate was 76.8%. Overall median survival was 265 days, 408 days in patients with limited disease. The median symptom free period after chemotherapy was completed was 123 days. These results are comparable with those in reports of chemotherapy of longer duration and warrant the further investigation of short duration treatment in this disease.

Adult↗