Hugh Coakham - Academia.edu (original) (raw)
Papers by Hugh Coakham
British Journal of Cancer, 1993
A pilot study was undertaken to determine the feasibility of infusing 131I labelled monoclonal an... more A pilot study was undertaken to determine the feasibility of infusing 131I labelled monoclonal antibodies (MoAbs) into either the cavity remaining after resection of malignant glioma or into glioma cysts. Of the seven patients recruited into the study, two had cystic lesions and five resection cavities. Six of the seven were treated after relapse from primary therapy. All patients apart from one, were given a single injection of 131I conjugated to a MoAb (ERIC-1) recognising the human neural cell adhesion molecule (NCAM). One patient received a further injection of 1 I-MoAb after regrowth of their disease. Pharmacokinetic studies revealed that the MoAb remained predominantly in the tumour cavity with little leakage into the systemic compartment. This resulted in a high calculated dose of radiation being delivered to the tumour cells either lining or within close proximity to the cavity/cyst wall. In such a small study, it is not possible to determine accurately response rates, but individual patient responses were observed. This, along with the low toxicity noted, demonstrates the feasibility of using '311-MoAbs in this way. With "3'I, radiation dose is deposited in tissue to a depth of I mm from the source. The possibility of applying isotopes such as 9OYttrium which will irradiate tumour/tissue to a greater depth (6 mm) is discussed in context with the biology of glioma infiltration into normal brain parenchyma. Antibodies were screened for bacterial and pyrogen contamination. Other quality control studies undertaken included determination of free iodine in the preparation by
British Journal of Cancer, 1998
We have previously demonstrated a 33% response rate in patients with primitive neurectodermal tum... more We have previously demonstrated a 33% response rate in patients with primitive neurectodermal tumours after the direct injection of 1311-monoclonal antibodies (MAbs) into the cerebrospinal fluid (CSF). Dose-limiting toxicity is myelosuppression due to the passage of the radioimmunoconjugate from the CSF to the blood compartment. This occurs at doses of 2220 MBq of 131 I-MAb and above, although this is not seen in all patients studied and appears to be related to the degree of prior therapy received. Rather than attempting to improve the efficacy of this approach to the treatment of disseminated disease within the CSF compartment by dose escalation and haemopoietic rescue, we have explored the possibility of repeatedly administering the radioimmunoconjugate. Eight patients were recruited to the study, two of whom received two and six of whom received three injections of 1311-MAb. After repeated administration of '311-MAb pharmacokinetic data revealed that, with one exception, the radioimmunoconjugate cleared from the CSF compartment with similar kinetics, while its residence time in the blood decreased with each injection. This was due to the development of an anti-mouse Ig response in the blood. Clearance of 131I-MAb from the ventricular CSF appears to be independent of the presence of an anti-mouse Ig response in this compartment. The differential clearance of the radioimmunoconjugate from the ventricular CSF and from the blood results in a marked increase in the therapeutic index that can be achieved. Up to 5920 MBq of '311-MAb was administered as the third injection of radioimmunoconjugate and combined doses of up to 12 500 MBq were given without either haematological or neurological toxicity. These data illustrate that dose escalation and thus an increase in the dose rate delivered to tumour cells within the CSF is possible if ways are found to reduce the residence time of the radioimmunoconjugate in the blood compartment. Suggestions as to how this can best be achieved are reviewed in detail.
Journal of Neurology, Neurosurgery & Psychiatry, 1991
Acta Neuropathologica, 1988
Frozen samples from 23 low grade (grade I and II) astrocytomas were studied by means of a panel o... more Frozen samples from 23 low grade (grade I and II) astrocytomas were studied by means of a panel of monoclonal antibodies to macrophages, lymphocytes (and their subsets) and HLA-DR antigens. Macrophages were present in low to moderate numbers in 38%-86% of cases, the variance in figures depending on the antibody used. T lymphocytes, the majority of CD8 phenotype, were detected in low numbers in 78% of tumours. B lymphocytes were scanty in 22% (5/22) and totally absent in the remaining cases. HLA-DR antigen was expressed by tumour cells in 35% (6/17) of cases. These findings indicate that in some low grade astrocytomas there is a mononuclear cell infiltrate with macrophages and secondarily CD8+ lymphocytes playing the major role. The significance of these findings remains speculative at present.
Journal of …, 1995
STROBLASTOMA is a rare type of glial tumor, accounting for between 0.45% 17 and 2.8% 3 of gliomas... more STROBLASTOMA is a rare type of glial tumor, accounting for between 0.45% 17 and 2.8% 3 of gliomas in various series. Its first description in 1924 2 was supported by a series of 25 patients reported by Bailey and Bucy in 1930. 1 Since then, there has only been occasional reference to this tumor, although Bonnin and Rubinstein 4 published a pathological study of 23 cases. The existence of astroblastoma as a pure nosological entity has been questioned, 9,19 but most recent reports have concluded that it should be regarded as distinct from other types of astrocytic glioma. 4,5,16 It was distinguished from other gliomas in the most recent International Classification of Tumors of the Central Nervous System proposed by the World Health Organization. 10 Astroblastomas have a distinctive histological appearance characterized by a radiating arrangement of tumor cells with broad footplates forming perivascular pseudorosettes. 16 Although astroblastoma may occur in a patient of any age, it usually presents as a tumor in older children or young adults: its occurence in children of less than 5 years is most unusual. 8 We report, to the best of our knowledge, only the second case of congenital astroblastoma and perhaps the first in the English literature. Following radical but subtotal tumor resection, our patient received chemotherapy, radiation therapy being considered too hazardous for an infant. Evidence is presented for a possible response to chemotherapy, a benefit which has not previously been reported. The histological, ultrastructural, and immunohistochemical features of this tumor are also described. Case Report This male infant, weighing 2.5 kg (third percentile), was born at 39 weeks gestation to unrelated Caucasian parents following a normal pregnancy and delivery. At birth he appeared normal with a head circumference of 34.0 cm (25th percentile). Examination. He presented at 17 days of age with a 5-day history of vomiting, poor feeding, and irritability. On examinaton, there was obvious hydrocephalus with splayed cranial sutures, distended scalp veins, and a tense,
British Journal of Cancer, 1989
Although medulloblastoma and neuroblastoma share many common biological, histological and immunol... more Although medulloblastoma and neuroblastoma share many common biological, histological and immunological features, the frequency of N-myc amplification differs markedly between the two tumours. In this study, Southern blot analysis revealed that the N-myc gene was not amplified in any of the nine medulloblastoma samples analysed. In contrast, over-expression of the gene was found in six of 11 samples as determined
Acta Neurochirurgica, 1989
Cancer, 1994
Results. In Avon, 16 children with medulloblastoma presented in the period 19761984 and 2 in the... more Results. In Avon, 16 children with medulloblastoma presented in the period 19761984 and 2 in the period 19851991, representing a decrease in incidence from 9.6 per million per year to 1.7 per million per year. The incidence of medulloblastoma in the combined southwest ...
Cancer, 1995
Background. Medulloblastoma is one of the most common intracranial tumors in children. The percep... more Background. Medulloblastoma is one of the most common intracranial tumors in children. The perception that the incidence of this tumor has declined is reinforced by a decline in enrollment to international trials for the disease.
British Journal of Cancer, 1993
A pilot study was undertaken to determine the feasibility of infusing 131I labelled monoclonal an... more A pilot study was undertaken to determine the feasibility of infusing 131I labelled monoclonal antibodies (MoAbs) into either the cavity remaining after resection of malignant glioma or into glioma cysts. Of the seven patients recruited into the study, two had cystic lesions and five resection cavities. Six of the seven were treated after relapse from primary therapy. All patients apart from one, were given a single injection of 131I conjugated to a MoAb (ERIC-1) recognising the human neural cell adhesion molecule (NCAM). One patient received a further injection of 1 I-MoAb after regrowth of their disease. Pharmacokinetic studies revealed that the MoAb remained predominantly in the tumour cavity with little leakage into the systemic compartment. This resulted in a high calculated dose of radiation being delivered to the tumour cells either lining or within close proximity to the cavity/cyst wall. In such a small study, it is not possible to determine accurately response rates, but individual patient responses were observed. This, along with the low toxicity noted, demonstrates the feasibility of using '311-MoAbs in this way. With "3'I, radiation dose is deposited in tissue to a depth of I mm from the source. The possibility of applying isotopes such as 9OYttrium which will irradiate tumour/tissue to a greater depth (6 mm) is discussed in context with the biology of glioma infiltration into normal brain parenchyma. Antibodies were screened for bacterial and pyrogen contamination. Other quality control studies undertaken included determination of free iodine in the preparation by
British Journal of Cancer, 1998
We have previously demonstrated a 33% response rate in patients with primitive neurectodermal tum... more We have previously demonstrated a 33% response rate in patients with primitive neurectodermal tumours after the direct injection of 1311-monoclonal antibodies (MAbs) into the cerebrospinal fluid (CSF). Dose-limiting toxicity is myelosuppression due to the passage of the radioimmunoconjugate from the CSF to the blood compartment. This occurs at doses of 2220 MBq of 131 I-MAb and above, although this is not seen in all patients studied and appears to be related to the degree of prior therapy received. Rather than attempting to improve the efficacy of this approach to the treatment of disseminated disease within the CSF compartment by dose escalation and haemopoietic rescue, we have explored the possibility of repeatedly administering the radioimmunoconjugate. Eight patients were recruited to the study, two of whom received two and six of whom received three injections of 1311-MAb. After repeated administration of '311-MAb pharmacokinetic data revealed that, with one exception, the radioimmunoconjugate cleared from the CSF compartment with similar kinetics, while its residence time in the blood decreased with each injection. This was due to the development of an anti-mouse Ig response in the blood. Clearance of 131I-MAb from the ventricular CSF appears to be independent of the presence of an anti-mouse Ig response in this compartment. The differential clearance of the radioimmunoconjugate from the ventricular CSF and from the blood results in a marked increase in the therapeutic index that can be achieved. Up to 5920 MBq of '311-MAb was administered as the third injection of radioimmunoconjugate and combined doses of up to 12 500 MBq were given without either haematological or neurological toxicity. These data illustrate that dose escalation and thus an increase in the dose rate delivered to tumour cells within the CSF is possible if ways are found to reduce the residence time of the radioimmunoconjugate in the blood compartment. Suggestions as to how this can best be achieved are reviewed in detail.
Journal of Neurology, Neurosurgery & Psychiatry, 1991
Acta Neuropathologica, 1988
Frozen samples from 23 low grade (grade I and II) astrocytomas were studied by means of a panel o... more Frozen samples from 23 low grade (grade I and II) astrocytomas were studied by means of a panel of monoclonal antibodies to macrophages, lymphocytes (and their subsets) and HLA-DR antigens. Macrophages were present in low to moderate numbers in 38%-86% of cases, the variance in figures depending on the antibody used. T lymphocytes, the majority of CD8 phenotype, were detected in low numbers in 78% of tumours. B lymphocytes were scanty in 22% (5/22) and totally absent in the remaining cases. HLA-DR antigen was expressed by tumour cells in 35% (6/17) of cases. These findings indicate that in some low grade astrocytomas there is a mononuclear cell infiltrate with macrophages and secondarily CD8+ lymphocytes playing the major role. The significance of these findings remains speculative at present.
Journal of …, 1995
STROBLASTOMA is a rare type of glial tumor, accounting for between 0.45% 17 and 2.8% 3 of gliomas... more STROBLASTOMA is a rare type of glial tumor, accounting for between 0.45% 17 and 2.8% 3 of gliomas in various series. Its first description in 1924 2 was supported by a series of 25 patients reported by Bailey and Bucy in 1930. 1 Since then, there has only been occasional reference to this tumor, although Bonnin and Rubinstein 4 published a pathological study of 23 cases. The existence of astroblastoma as a pure nosological entity has been questioned, 9,19 but most recent reports have concluded that it should be regarded as distinct from other types of astrocytic glioma. 4,5,16 It was distinguished from other gliomas in the most recent International Classification of Tumors of the Central Nervous System proposed by the World Health Organization. 10 Astroblastomas have a distinctive histological appearance characterized by a radiating arrangement of tumor cells with broad footplates forming perivascular pseudorosettes. 16 Although astroblastoma may occur in a patient of any age, it usually presents as a tumor in older children or young adults: its occurence in children of less than 5 years is most unusual. 8 We report, to the best of our knowledge, only the second case of congenital astroblastoma and perhaps the first in the English literature. Following radical but subtotal tumor resection, our patient received chemotherapy, radiation therapy being considered too hazardous for an infant. Evidence is presented for a possible response to chemotherapy, a benefit which has not previously been reported. The histological, ultrastructural, and immunohistochemical features of this tumor are also described. Case Report This male infant, weighing 2.5 kg (third percentile), was born at 39 weeks gestation to unrelated Caucasian parents following a normal pregnancy and delivery. At birth he appeared normal with a head circumference of 34.0 cm (25th percentile). Examination. He presented at 17 days of age with a 5-day history of vomiting, poor feeding, and irritability. On examinaton, there was obvious hydrocephalus with splayed cranial sutures, distended scalp veins, and a tense,
British Journal of Cancer, 1989
Although medulloblastoma and neuroblastoma share many common biological, histological and immunol... more Although medulloblastoma and neuroblastoma share many common biological, histological and immunological features, the frequency of N-myc amplification differs markedly between the two tumours. In this study, Southern blot analysis revealed that the N-myc gene was not amplified in any of the nine medulloblastoma samples analysed. In contrast, over-expression of the gene was found in six of 11 samples as determined
Acta Neurochirurgica, 1989
Cancer, 1994
Results. In Avon, 16 children with medulloblastoma presented in the period 19761984 and 2 in the... more Results. In Avon, 16 children with medulloblastoma presented in the period 19761984 and 2 in the period 19851991, representing a decrease in incidence from 9.6 per million per year to 1.7 per million per year. The incidence of medulloblastoma in the combined southwest ...
Cancer, 1995
Background. Medulloblastoma is one of the most common intracranial tumors in children. The percep... more Background. Medulloblastoma is one of the most common intracranial tumors in children. The perception that the incidence of this tumor has declined is reinforced by a decline in enrollment to international trials for the disease.