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R H Begent

Publications and source records attributed to R H Begent.

At least 73 records · Page 4Linked to original sources
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

Histamine but neither angiotensin nor vasopressin increases antibody uptake into xenograft colorectal liver metastases.

Although the majority of colorectal carcinomas express carcino-embryonic antigen (CEA), systemic anti-CEA antibody administration is an ineffective treatment for colorectal liver metastasis. A xenograft model of human colorectal carcinoma in the rat was used to determine anti-CEA antibody uptake into liver metastases. The influence of systemic (iliolumbar vein) or regional (gastroduodenal artery) delivery and effects of regional delivery of histamine, angiotensin II and vasopressin on anti-CEA antibody uptake by metastases were examined. Systemic antibody delivery achieved a median tumour:liver antibody uptake ratio of 1.60 (interquartile range (i.q.r.) 1.02-2.51). Regional delivery resulted in a similar median ratio of 1.61 (i.q.r. 1.22-2.46). Histamine and antibody delivered regionally produced a median tumour:liver ratio of 3.15 (i.q.r. 2.50-4.27), which was significantly greater than that obtained with systemic delivery (P = 0.004). Regional infusion of angiotensin resulted in a median (i.q.r.) ratio of 2.23 (1.58-2.49) and vasopressin in 2.15 (1.41-2.60), values that were not significantly different from those found with systemic or regional delivery alone. When both angiotensin and histamine were infused with antibody, the median tumour:liver ratio was 3.09 (i.q.r. 2.22-4.31), significantly greater than for systemic delivery (P = 0.01) but not significantly different from that obtained following the addition of histamine alone (P = 0.94). Histamine significantly increases antibody uptake in a model of liver metastasis and may improve the effectiveness of targeted immunotherapy in the treatment of colorectal liver metastasis.

Animals↗
PubMed1993

CD44 is associated with proliferation in normal and neoplastic human colorectal epithelial cells.

Flash-frozen biopsies obtained from surgical specimens of three adenomatous polyps and 22 colorectal adenocarcinomas (19 primary and three metastatic) were tested by immunohistochemistry for CD44 expression using F10-44-2 monoclonal antibody. CD44 positivity was correlated with proliferative status defined by Ki-67 monoclonal antibody reactivity. In normal colonic mucosa, CD44 was expressed in the proliferative zone of crypts. In tumours, CD44 expression was associated with proliferative areas irrespective of tumour stage or differentiation. Non-proliferating areas of the carcinomatous epithelium did not express CD44 although non-proliferating stromal lymphoid tissue did. There was no apparent association with tumour progression. F10-44-2-defined CD44 is consistently expressed during proliferation by normal colorectal epithelial cells and by both benign and malignant colorectal tumour cells.

Adenocarcinoma↗
PubMed1993

Comparative radioimmunotherapy using intact or F(ab')2 fragments of 131I anti-CEA antibody in a colonic xenograft model.

The therapeutic efficacy of intact and F(ab')2 fragments of a 131I anti-CEA antibody were compared in an established LS174T colonic xenograft model in nude mice. A single IV dose of either 0.5 mCi (18.5 MBq) intact or 1.0 mCi (37 MBq) F(ab')2 fragments significantly delayed tumour growth, and increased survival time to the same extent. Biodistribution studies showed that the more rapid clearance of the fragments from the circulation improved the tumour: normal tissue ratios found for the intact antibody, but reduced the duration and therefore absolute amount of radioantibody localisation (% injected dose/gram) at the tumour site. The tumours received a similar accumulated beta radiation dose, with 4,065 cGy from 0.5 mCi intact antibody and 4,500 cGy from 1.0 mCi F(ab')2 fragments. The dose rate to the tumour was initially higher for the fragments, but fell off more rapidly as clearance occurred. However, the rapid circulatory clearance resulted in a radiation dose of only 995 cGy to the blood, compared with 2,300 cGy for the intact antibody. This suggests that twice the radiation dose could be delivered to the tumour in the form of fragments for the same blood dose from the intact antibody. Fractionating the 1.0 mCi dose of F(ab')2 into three doses of 0.33 mCi (12.2 MBq), given on days 1, 3 and 5, significantly reduced the therapeutic effect of the treatment. The clinical relevance of these findings is discussed.

Adenocarcinoma↗
PubMed1993

Pellagra secondary to 5-fluorouracil.

The development of pellagra in a patient treated with 5-fluorouracil for malignant disease is reported. The aetiology of pellagra in this patient is discussed, and the reasons for possible under-diagnosis of pellagra in association with malignant disease considered. We report a patient who presented with the typical skin changes of pellagra. The rash, and an associated acute deterioration in cerebral function, were exacerbated by treatment with 5-fluorouracil. The importance of considering nicotinic-acid deficiency in patients with malignant disease has not been emphasized in the literature.

Aged↗
PubMed1992

Colorectal cancer.

Explore the source record for details and available documents.

Colorectal Neoplasms↗
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

Localization of CEA messenger RNA by in situ hybridization in normal colonic mucosa and colorectal adenocarcinomas.

Carcinoembryonic antigen (CEA) mRNA expression was studied in 14 cases of normal colorectal mucosa and colonic adenocarcinomas using in situ hybridization with a 32P-labelled cDNA probe to the unique 3'-untranslated region of CEA. This approach has the advantage that the target mRNA remains in the cell of origin, whereas there is considerable ambiguity in immunocytochemistry data for CEA because the protein is secreted. Furthermore, the specific cDNA probe overcomes potential problems of immunological cross-reactivity with other members of the CEA family. The results demonstrated that abundant, heterogeneously distributed CEA mRNA was present in colorectal adenocarcinomas, with the highest levels in cells lining glandular structures. Parallel immunohistochemistry with anti-CEA monoclonal antibody A5B7 showed that the regions of tumours with the highest levels of CEA mRNA also had the highest CEA protein levels, suggesting that the heterogeneous distribution reflects CEA expression rather than differential secretion of the protein. In the normal colonic mucosa, CEA mRNA expression was observed in surface epithelial cells and goblet cells of the upper crypts, with very low hybridization in the mid crypt and at the base. This crypt-surface distribution was identical to that observed for CEA protein. In situ hybridization therefore confirms that high levels of CEA mRNA are expressed in differentiated surface epithelial cells of the normal colon.

Adenocarcinoma↗
PubMed1992

Factors influencing variability of localisation of antibodies to carcinoembryonic antigen (CEA) in patients with colorectal carcinoma--implications for radioimmunotherapy.

Tumour localisation of anti-tumour antibodies varies greatly between patients. Factors which may be responsible for this have been investigated in 56 patients with colorectal carcinoma with a view to improving radioimmunotherapy. Thirty-seven to seventy-four MBq of 125-I labelled mouse monoclonal antibody to CEA, was given intravenously and tumour resected 70-480 h later. Percentage injected activity kg-1 (% inj.act kg-1) in tumour, was inversely correlated with the time interval between injection and operation (P = 0.004). To assess the influence of other parameters on localisation, patients were divided into two time groups according to time interval between injection and operation, 70-120 h (n = 33) and 144-480 h (n = 23). In neither group was there a significant correlation of % inj.act kg-1 with time. The % inj.act kg-1 in tumour showed a significant correlation with that in the blood for both groups (P = 0.005 and P = 0.01). There was no significant correlation for either time group between % inj.act kg-1 in tumour and serum CEA values, the per cent of tumour cells positive for CEA and vascularity. Tumour to blood ratios varied considerably (range 0.3-28.5:1) suggesting that factors other than time and persistence of activity in the blood contribute to efficient targeting. Tumour to blood ratios were inversely correlated with % inj.act kg-1 in blood for the 70-120 h group (P = 0.007), and were positively correlated with % inj.act kg-1 in tumour (P = 0.012). Autoradiography showed that antibody localised predominantly on tumour cells but was distributed heterogeneously, was not solely related to the expression of antigen and in some cases accumulated in necrotic more than viable areas of tumour. Penetration of antibody into malignant acinar structures was poor and CEA-positive cells closer to the blood supply were targeted to a greater extent than distant cells. Preoperative administration of radiolabelled antibody to CEA may be helpful in selecting patients with favourable localisation for radioimmunotherapy.

Antibodies, Monoclonal↗
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↗
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

A phase-I study of repeated therapy with radiolabelled antibody to carcinoembryonic antigen using intermittent or continuous administration of cyclosporin A to suppress the immune response.

The anti-mouse antibody response was examined in patients receiving repeated i.v. therapy with radiolabelled mouse monoclonal antibody (MAb) to carcinoembryonic antigen (CEA): 131I anti-CEA was given approximately every 2 weeks with cyclosporin A, to suppress the anti-mouse antibody response. Two schedules of cyclosporin A--intermittent therapy for 6 days with each course of anti-CEA and continuous therapy--were compared. Suppression of the immune response in the intermittent high-dose (3 patients) and continuous low-dose groups (4 patients) was equivalent, but the latter regimen was less toxic. Repeated therapy led to the formation of small amounts of anti-mouse antibody, but provided that cyclosporin A was continued it did not prevent further therapy or lead to an increase in the rate of clearance of anti-CEA from blood. Without cyclosporin A no more than 2 courses of antibody therapy could be given. Patients received up to 4 doses of 131I anti-CEA. The nadir platelet count was related to the half-life of 131I anti-CEA in blood. Thrombocytopenia limited the amount of 131I anti-CEA that could be given and determined the interval between treatments. Effective suppression of the anti-antibody response is possible and this study has determined that myelosuppression is the principal obstacle to repeated therapy with radiolabelled antibody.

Adult↗
PubMed1991

The effect of radiosensitizers on radio-immunotherapy, using 131I-labelled anti-CEA antibodies in a human colonic xenograft model.

Anti-CEA antibodies were used for radio-immunotherapy in an established LS174T colonic xenograft in nude mice. A single IV dose of either 131I-PK4S (polyclonal) or -A5B7 (monoclonal) antibody produced tumour regression, and significantly delayed subsequent tumour growth. Administration of a clearing second antibody, 24 hr post 131I-PK4S and at 5 times the dose, significantly reduced the therapeutic effect of radio-antibody alone. Tumours of mice given non-specific antibody or unlabelled anti-CEA antibody grew like those of untreated controls. In an attempt to enhance therapy without increasing dose, radiosensitizers normally employed with external beam radiation were used in combination therapy. When the hypoxic cell radiosensitizer misonidazole was combined with 131I-A5B7, it significantly prolonged tumour-growth inhibition over radio-antibody alone. Conversely, the therapeutic effect of either radio-antibody was significantly reduced when used in combination with the halogenated pyrimidine radiosensitizer 5-iododeoxyuridine. Neither sensitizer alone affected tumour growth.

Animals↗
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

The value of radioimmunoguided surgery in first and second look laparotomy for colorectal cancer.

Radioimmunoguided surgery (RIGS) using an anti-CEA (A5B7) monoclonal antibody has been assessed in 52 patients (43 primary excisions and nine second look procedures) undergoing surgery for colorectal carcinoma. The antibody localized in 97.8 percent of primary tumours and in 88.8 percent of the principal tumor in second look procedures. Additional information concerning the extent of primary tumor was obtained in 11 of 43 patients (25.5 percent) undergoing excision of primary carcinoma and five of nine patients (55 percent) in the second look series. Incorrect information was obtained about the extent of the primary tumour in six patients (11.3 percent), whereas no incorrect information was obtained during second look procedures. RIGS correctly predicted the subsequent Dukes' staging in 77 percent of first look cases (sensitivity 65 percent, specificity 90 percent), although accurate identification of individual nodes was impossible. The technique influenced the surgical procedure performed in 2 of 43 cases (4.6 percent) in primary surgery and in three of nine patients undergoing second look laparotomy (33 percent). RIGS in primary colorectal carcinoma may provide additional information concerning extent of locally advanced tumors in particular and the principle that the subsequent surgery may be influenced has been established. The technique appears to have a greater role in second look procedures where it may help determine the extent of recurrent tumour. Larger follow-up series are required to define how the additional information provided by this technique may best be exploited.

Aged↗