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1.  Sequelae and survivorship in patients treated with 131I-MIBG therapy 
British Journal of Cancer  2013;109(3):565-572.
Background:
131I-meta-iodobenzylguanidine (131I-MIBG) has been in therapeutic use since 1980s. Newer treatment modalities are emerging for neuroendocrine tumours (NETs) and chromaffin cell tumours (CCTs), but many of these do not yet have adequate long-term follow-up to determine their longer term efficacy and sequelae.
Methods:
Fifty-eight patients with metastatic NETs and CCTs who had received 131I-MIBG therapy between 2000 and 2011 were analysed. Survival and any long-term haematological or renal sequelae were investigated.
Results:
In the NET group, the overall median survival and median survival following the diagnosis of metastatic disease was 124 months. The median survival following the commencement of 131I-MIBG was 66 months. For the CCT group, median survival had not been reached. The 5-year survival from diagnosis and following the diagnosis of metastatic disease was 67% and 67.5% for NETs and CCTs, respectively. The 5-year survival following the commencement of 131I-MIBG therapy was 68%. Thirty-two patients had long-term haematological sequelae: 5 of these 32 patients developed haematological malignancies. Two patients developed a mild deterioration in renal function.
Conclusion:
Long follow up of 131I-MIBG therapy reveals a noteable rate of bone marrow toxicities and malignancy and long term review of all patients receiving radionuclide therapies is recommended.
doi:10.1038/bjc.2013.365
PMCID: PMC3738119  PMID: 23860527
131I-MIBG; neuroendocrine tumour; chromaffin cell tumour; survival; haematological malignancy
2.  CyberKnife radiosurgery for an intracardiac metastasis 
BMJ Case Reports  2011;2011:bcr0720103197.
doi:10.1136/bcr.07.2010.3197
PMCID: PMC3062820  PMID: 22707622
3.  Elevated expression of artemis in human fibroblast cells is associated with cellular radiosensitivity and increased apoptosis 
British Journal of Cancer  2012;107(9):1506-1513.
Background:
The objective of this study was to determine the molecular mechanisms responsible for cellular radiosensitivity in two human fibroblast cell lines 84BR and 175BR derived from two cancer patients.
Methods:
Clonogenic assays were performed following exposure to increasing doses of gamma radiation to confirm radiosensitivity. γ-H2AX foci assays were used to determine the efficiency of DNA double-strand break (DSB) repair in cells. Quantitative PCR (Q-PCR) established the expression levels of key DNA DSB repair genes. Imaging flow cytometry using annexin V-FITC was used to compare artemis expression and apoptosis in cells.
Results:
Clonogenic cellular hypersensitivity in the 84BR and 175BR cell lines was associated with a defect in DNA DSB repair measured by the γ-H2AX foci assay. The Q-PCR analysis and imaging flow cytometry revealed a two-fold overexpression of the artemis DNA repair gene, which was associated with an increased level of apoptosis in the cells before and after radiation exposure. Overexpression of normal artemis protein in a normal immortalised fibroblast cell line NB1-Tert resulted in increased radiosensitivity and apoptosis.
Conclusion:
We conclude that elevated expression of artemis is associated with higher levels of DNA DSB, radiosensitivity and elevated apoptosis in two radio-hypersensitive cell lines. These data reveal a potentially novel mechanism responsible for radiosensitivity and show that increased artemis expression in cells can result in either radiation resistance or enhanced sensitivity.
doi:10.1038/bjc.2012.443
PMCID: PMC3493778  PMID: 23093295
cellular radiosensitivity; defective DNA repair; artemis overexpression
4.  The developing role for intensity-modulated radiation therapy (IMRT) in the non-surgical treatment of brain metastases 
The British Journal of Radiology  2010;83(986):133-136.
Whole brain radiotherapy (WBRT) is the standard non-surgical treatment for brain metastatic disease, but rarely eradicates bulky metastases from most common cancers. Recent literature has demonstrated the safety and efficacy of delivering very high focal doses of radiation (by radiosurgical techniques) to the gross tumour volume of bulky brain metastases, thereby obtaining more certain local control than is achieved by WBRT. In this paper we report a study of 11 patients with bulky brain metastases in whom an intensity-modulated radiation therapy (IMRT) facility has been used to concomitantly boost the gross tumour volume of bulky brain metastatic disease (to 40 Gy) during a standard 30 Gy in 10 fractions WBRT schedule. No acute or subacute morbidity was encountered, and good early control data were noted. We discuss the perceived advantages of such a technique.
doi:10.1259/bjr/28596848
PMCID: PMC3473526  PMID: 20019176
6.  Radiotherapy in benign orbital disease. II: Ophthalmic Graves' disease and orbital histiocytosis X. 
Ophthalmic Graves' disease and histiocytosis X involving the orbit are occasionally refractory to treatment, so that vision may be threatened. In these situations megavoltage external beam radiotherapy should be employed, and the indications for this treatment are discussed. A highly accurate technique is described, using precise planning with information obtained from high definition CT scans, a complete patient head shell for immobilisation, and modern megavoltage radiotherapy treatment machines. As a result the dose to the lens is minimised (to a maximum of 10% of the prescribed dose), and late morbidity will be small. Two cases are described to illustrate this procedure and the response to treatment.
Images
PMCID: PMC1041435  PMID: 3259894
7.  Radiotherapy in benign orbital disease. I: Complicated ocular angiomas. 
Radiotherapy has been successful in the management of complicated ocular and orbital angiomas, but late morbidity (particularly radiation induced cataract) has been a problem. With modern radiotherapy techniques it is possible to minimise the morbidity to other tissues. By means of a recently developed method of lens-sparing ocular radiotherapy (initially adopted for retinoblastoma therapy) two cases of diffuse ocular haemangioma complicated by retinal detachment have been treated, with evidence of regression.
Images
PMCID: PMC1041434  PMID: 3378026
8.  Remission of postmenopausal breast cancer during treatment with the luteinising hormone releasing hormone agonist ICI 118630. 
British Journal of Cancer  1986;54(6):903-909.
Ten previously untreated postmenopausal women with metastatic breast cancer, none of whom had received prior systemic therapy, were treated with the luteinising hormone releasing hormone (LHRH) analogue D-Ser(But)6, Azgly10-LHRH (ICI 118630). Two obtained an objective partial remission, one in bone metastases and one in lung metastases. One patient proved unassessable. Amongst the seven failures, incomplete pituitary gonadotrophin suppression over the relatively short treatment period with the daily injections was noted. The seven patients failing ICI 118630 received tamoxifen and two with high tumour oestrogen receptor values responded. LHRH analogues may provide a novel endocrine therapy for postmenopausal breast cancer although more data are needed. In this study, the monthly depot injection proved superior to daily injections with regard to gonadotrophin suppression, although it is not clear that this provides the mechanism of action.
Images
PMCID: PMC2001583  PMID: 2948537
10.  Globe conserving treatment of the only eye in bilateral retinoblastoma 
The British Journal of Ophthalmology  2003;87(11):1374-1380.
Aims: To quantify the rates of eye preservation and patient survival, local tumour relapse and recurrence, and development of new tumours in the remaining eye of children with bilateral retinoblastoma with one eye already enucleated. Also, in the same children, to describe the types of primary and secondary treatment procedures, and to define the anatomical outcome.
Methods: This is a retrospective observational case series report. The study participants consisted of 107 patients with bilateral retinoblastoma with one eye enucleated within 1 month of baseline examination and had their remaining eye treated conservatively. The main outcome measure were: primary treatment failures, new tumours, enucleation of the only eye, death, remission, and anatomical outcomes (retinal detachment, vitreous haemorrhage, and cataract).
Results: The median age at diagnosis was 8.4 (range 0.2–44, SD 10.1) months with a median ophthalmic follow up of 44.3 (8.1–114, SD 10.1) months. In 22 of the 107 patients (21%) the treated eye was in Reese Ellsworth groups I or II and in the remaining 85 (79%) in groups III–V at diagnosis. The primary treatment was cryotherapy in 14% (15/107) of eyes, radioactive plaque brachytherapy in 3.7% (4/107), and chemotherapy in 10% (11/107). It was lens sparing radiotherapy in 37% (40/107), whole eye radiotherapy in 29% (31/107), combined radiotherapy and chemotherapy in 2.8% (3/107), chemothermotherapy in 0.9% (1/107), and combined focal therapy in 1.8% (2/107). The primary treatment failed to achieve local tumour control during the follow up period in 37% (40/107) of eyes. In 17 eyes failure was due to inadequate control of the presenting tumour, in 16 to development of a new tumour, and in eight eyes to a combination of both. 35 (88%) of the 40 failures were managed by secondary conservative treatment and the remaining five were treated by enucleation of the only eye. There were eight (7.4%) deaths and the 3 year survival rate was 93% (100/108). Anatomical results included vitreous haemorrhage in four cases, tractional retinal detachment also in four cases, and 24 children required cataract surgery.
Conclusions: Aggressive conservative treatment achieved a good rate of globe salvage without impairing survival.
PMCID: PMC1771893  PMID: 14609838
globe conservation; bilateral retinoblastoma; children
11.  External beam radiotherapy for retinoblastoma: I. Whole eye technique. 
A retrospective analysis has been performed of the results of external beam radiotherapy for retinoblastoma using a whole eye technique. Local tumour control has been assessed in a consecutive series of 175 eyes in 142 children all of whom received external beam radiotherapy as the primary treatment for retinoblastoma. Follow up ranged from 2 to 17 years (median 9 years). Tumour control rates have been analysed with respect to the Reese Ellsworth classification and the series includes eyes in groups I to V. Focal salvage therapy was given for persistent, recurrent, or new tumours after radiotherapy. Following whole eye radiotherapy alone, the overall ocular cure rate was 57%, though with salvage therapy 80% of eyes could be preserved.
PMCID: PMC505038  PMID: 7696227
12.  External beam radiotherapy for retinoblastoma: II. Lens sparing technique. 
A retrospective analysis is presented of the results of external beam radiotherapy for retinoblastoma utilising an accurate lens sparing technique. Local tumour control has been assessed in a consecutive series of 67 eyes in 53 children all of whom received external beam radiotherapy as the primary treatment of retinoblastoma. Follow up ranged from 12 to 82 months (median 35 months) with 76% of the children followed for more than 2 years. Tumour control rates have been analysed with respect to the Reese-Ellsworth classification. The role of adjuvant and salvage focal therapy is emphasised. Following lens sparing radiotherapy with prior adjuvant treatment of anterior tumours, where appropriate, the overall ocular cure rate was 72%. With salvage therapy of persistent, recurrent, or new tumours, 93% of eyes could be preserved in this series which includes mainly eyes classified in Reese-Ellsworth groups I-III. These results compare favourably with those of whole eye external beam radiotherapy for comparable tumours, and with those of lens and anterior segment sparing using other techniques. They were achieved without the ocular morbidity associated with whole eye external beam radiotherapy.
Images
PMCID: PMC505039  PMID: 7696228
13.  Relationship of regression pattern to recurrence in retinoblastoma. 
A retrospective analysis has been conducted of regression patterns following treatment of retinoblastoma by external beam irradiation. There were 180 tumours in 105 eyes of 83 patients. Type I regression was found to be the commonest pattern and occurred in 50% of cases. Initial tumour size was found to be the only statistically significant determinant of regression pattern (p < 0.01). Thirteen tumours (7%) recurred within a median interval to recurrence of 12 months. All recurrences occurred within 40 months of completion of treatment and none occurred after age 4 years. No tumour less than 6 mm in diameter recurred. Although 10 out of 13 recurrences were of Type I, Cox model regression analysis showed initial tumour size to be the only independent predictor of recurrence (p < 0.01).
Images
PMCID: PMC504414  PMID: 8435390
15.  Platinum-based chemotherapy for recurrent CNS tumours in young patients. 
Twenty nine patients (median age 12 years) with a CNS tumour, received platinum-based chemotherapy for assessable disease. In 23 patients there was an objective response with improvement lasting for a median duration of 11 months. There was little difference in the response to cisplatinum or carboplatin therapy. The response rates in specific disease groups were: medulloblastoma 8/10, two with a complete response (CR) and six with a partial response (PR); ependymoma 1/5 PR; pineal retinoblastoma 5/5 with three CR and two PR; primitive neurectodermal tumours (PNET) 2/2 PR and pineal germ cell tumours 6/6 with four CR and two PR. It is concluded that platinum-based chemotherapy has a beneficial effect on CNS tumours of the CNS, especially medulloblastoma, ectopic intracranial retino-blastoma and pineal germ cell tumours.
Images
PMCID: PMC1014479  PMID: 1940946
17.  Orbital recurrence of retinoblastoma successfully treated by combined therapy. 
Five children with an orbital recurrence of retinoblastoma have been successfully treated by a combination of excision biopsy of the tumour mass, radical orbital radiotherapy, and systemic chemotherapy. Nine previous children, consecutive with the five presented here, died from disseminated retinoblastoma after failure of earlier treatment programmes for orbital recurrence. An aggressive therapeutic approach is justified by this improvement in survival.
PMCID: PMC1041999  PMID: 2310733
18.  Postenucleation orbital radiotherapy for the treatment of malignant melanoma of the choroid with extrascleral extension. 
The outcome is reported in 17 patients in whom an eye was enucleated for malignant melanoma of the choroid with extrascleral extension and who subsequently underwent adjuvant external beam radiotherapy to the orbit as the primary treatment of the extraocular spread of their tumour. Extrascleral extension was encapsulated in five, non-encapsulated in two, and had been surgically transected at enucleation in 10 cases. All the patients have been followed up from enucleation to the present day. Orbital recurrence occurred in only one patient. The overall actuarial survival rate was 51% at 5 years, 44% at 10, and 33% at 15 years. A low orbital recurrence rate of 6% compares very favourably with published figures for this event after enucleation for melanoma with extrascleral extension but without radiotherapy. Adjuvant orbital radiotherapy may have a place in the treatment of selected cases of extracleral extension of intraocular malignant melanoma.
Images
PMCID: PMC1041975  PMID: 2106340
19.  Treatment of prolactinomas with megavoltage radiotherapy. 
The outcome of treatment of 36 women with prolactinomas using megavoltage radiotherapy combined with interim dopamine agonists (bromocriptine, lysuride, pergolide) was reviewed; 16 of the women showed radiological evidence of a macroadenoma. The most common presenting symptom was secondary amenorrhoea; 26 of the patients had galactorrhoea. In 29 patients who wished to conceive the ovulation rate (as indicated by circulating progesterone concentrations) was 97% and the successful fertility rate 86%. No patient had enlargement of the tumour during pregnancy and there were no complications of radiotherapy. No further tumour enlargement was detected in serial skull radiographs, and an improvement in size of the fossa was noted in 45% of those assessed. When medical treatment was withdrawn a mean of 4.2 years (range 1-11) after radiotherapy in the 27 patients who had completed their families the serum prolactin concentration had fallen appreciably in 26 of them and later became normal in eight. The incidence of growth hormone deficiency rose from 24% of the whole group before radiotherapy to 79% afterwards. Only one patient required thyroxine, and one was receiving gonadotrophin. No patient became deficient in adrenocorticotrophic hormone. A regimen of megavoltage radiotherapy and interim bromocriptine allows women with prolactinomas safely to undergo pregnancy and results in the long term prospect of tumour shrinkage and control of hyperprolactinaemia.
PMCID: PMC1441399  PMID: 6424752
20.  Monitoring salivary misonidazole in man: a possible alternative to plasma monitoring. 
British Journal of Cancer  1978;38(6):709-718.
Concentrations of misonidazole and its O-demethylated metabolite Ro 05-9963 in the plasma and saliva of 10 patients with malignant disease have been determined. A good linear correlation was established between plasma and saliva misonidazole concentration, and salivary sampling was found to be suitable for the estimation of a number of pharmacokinetic parameters. Data are also presented for serial tumour cencentrations of misonidazole and Ro 05-9963 in 3 of the 10 patients. Monitoring of salivary misonidazole concentration appears to be a useful alternative to plasma monitoring, particularly for those patients in whom plasma sampling is unsuitable or impossible.
PMCID: PMC2009825  PMID: 743488
21.  Solitary plasmacytoma of bone--a rare disorder with an unusual evolution. 
Postgraduate Medical Journal  1993;69(808):153-154.
A 40 year old woman presented with a spinal epidural tumour, which on histology was shown to be a plasmacytoma. At that time she had no evidence of multiple myeloma. Ten months later, she developed a second isolated plasmacytoma in the spleen, for which she underwent splenectomy. Two years after her initial presentation she had another recurrence in the liver, followed by a full-blown picture of multiple myeloma. The myeloma was progressive and resistant to all forms of chemotherapy. She finally died of a massive gastrointestinal haemorrhage. The clinical features, natural evolution and management of solitary plasmacytomas are discussed.
PMCID: PMC2399632  PMID: 8506201
22.  Conservative surgery in multimodal therapy for pelvic rhabdomyosarcoma in children. 
British Journal of Cancer  1994;70(5):1004-1008.
Twenty-six previously untreated children, median age 3.4 years, with pelvic rhabdomyosarcoma (RMS) were seen between 1983 and 1988. Fourteen were girls. The planned strategy was to conserve pelvic organs, especially the bladder, by using primary chemotherapy, conservative surgery and, in most cases, radiotherapy. With a median follow-up of 71 months (range 34-103 months) overall survival was 73%, with no treatment-related death. The bladder salvage rate of 88% in survivors with bladder base/prostate primaries was much higher than that reported by the United States Intergroup Rhabdomyosarcoma Studies (IRS), though many of the preserved bladders did not function normally. We identified problems with both radiological and histological off-treatment monitoring. The overall accuracy of computerised tomographic (CT) scanning for prediction of tumour recurrence was only 81%, and endoscopic biopsies proved misleading in four of the ten bladder base/prostate patients monitored by serial cystoscopy. We conclude that a higher cure rate can be achieved by using intensive chemotherapy/radiotherapy and conservative surgery to treat children with pelvic RMS. Factors that might contribute to our favourable bladder salvage results, compared with those of the IRS, include (a) the fact that one of two specialist surgeons monitored and operated on all these patients and (b) our increasing awareness, during the study, that post-chemotherapy/radiotherapy histopathology and pelvic CT scan appearances may be misleading. Referral to paediatric centres with special experience of pelvic RMS may help raise the rate of bladder salvage in these children.
PMCID: PMC2033530  PMID: 7947076
23.  Testicular function following the treatment of Hodgkin's disease in childhood. 
British Journal of Cancer  1993;68(6):1199-1204.
Testicular function was studied in 40 males treated in childhood for Hodgkin's disease at St Bartholomew's Hospital, and the Hospital for Sick Children, London, between 1971-1985. All patients were 16 years or over at evaluation, and off treatment more than 6 years. Basal FSH, LH and testosterone levels were measured. Testicular size was measured using a Prader orchidometer, and all patients were offered a seminal analysis. Twenty-eight patients were treated with chemotherapy, usually ChlVPP. Twenty-one also had radiotherapy, five below the diaphragm. Twelve patients were treated with radiotherapy alone (five below the diaphragm). Twenty-six of 28 patients treated with chemotherapy and three of five patients treated with radiotherapy alone below the diaphragm have elevated basal FSH levels, and 18 of these also have elevated basal LH levels. Median testicular volume is 11 ml (range 5-25 ml). Eleven of 13 patients investigated are azoospermic. All patients have normal testosterone levels, and normal secondary sexual characteristics. There is no biochemical evidence of healing of the damaged germinal epithelium with elevated FSH levels persisting up to 17 years from the end of therapy. These results indicate a high incidence of damage to the germinal epithelium in patients treated with ChlVPP chemotherapy and/or radiotherapy below the diaphragm. Appropriate counselling of these patients with regard to their reproductive capabilities is essential.
PMCID: PMC1968630  PMID: 8260374
24.  Outcome of children with resistant and relapsed Hodgkin's disease. 
British Journal of Cancer  1992;66(6):1155-1158.
During the period 1974-89, 169 children with Hodgkin's disease were treated in the Paediatric Oncology Units of the Royal Marsden and St Bartholomew's Hospitals. The overall actuarial survival for the whole group was 81% at 10 years. Thirty-five of the 169 children either did not achieve a complete remission or subsequently relapsed. The estimated actuarial survival from initial relapse or failure of primary treatment was 60% at 5 years and 45% at 10 years. Over half of the patients requiring salvage therapy had declared themselves within 2 years and only 3 relapses occurred more than 3 years from diagnosis. Very few patients remain disease free long term after failure of primary and initial salvage therapy. Patients relapsing within a year of diagnosis or not achieving a complete response to primary therapy and those with disseminated relapse had a poor response to salvage therapy. A significant subgroup of patients had prolonged survival despite multiple relapses. Neither initial histology nor stage affected survival from relapse although numbers in each subgroup were small.
PMCID: PMC1978034  PMID: 1457357

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