Magnetic resonance imaging of the carotid artery in long-term head and neck cancer survivors treated with radiotherapy.

BACKGROUND: In head and neck cancer (HNC) patients, long-term treatment-related complications include radiotherapy (RT)-induced carotid vasculopathy and stroke. The current study investigated the magnetic resonance imaging (MRI) characteristics of the carotid wall in long-term HNC survivors treated with RT. METHODS: MRI of the carotid arteries was performed within a prospective cohort of 42 HNC patients on average 7 years after RT. Two independent radiologists assessed maximal vessel wall thickness of common and internal carotid arteries. In case of wall thickening (≥ 2 mm) the MRI signals as well as length of the thickened segment were assessed. RESULTS: Mean (SD) age of the 42 patients at baseline was 53 (13) years and mean (SD) follow-up time after RT was 6.8 (1.3) years. In total 62% were men and 60% had one or more cerebrovascular risk factors. Mean (SD) dose of RT on the common carotid arteries and internal carotid arteries was 57 Gy (11) and 61 Gy (10), respectively. Wall thickening was observed in 58% of irradiated versus 27% of non-irradiated common carotid arteries and 24% of irradiated versus 6% of non-irradiated internal carotid arteries (p < 0.05). Mean (SD) thickness of the irradiated and non-irradiated common carotid arteries was 2.5 (0.9) and 2 (0.7) mm (p = 0.02). Mean thickness of the irradiated and non-irradiated internal carotid arteries was 1.8 (0.8) and 1.5 mm (0.3) (n.s.). Mean length of the thickened vessel wall was 48 mm versus 36 mm in the irradiated versus non-irradiated common carotid arteries (p = 0.03) and 20 mm versus 15 mm in the irradiated versus non-irradiated internal carotid arteries (n.s.). No significant differences were observed for signal intensities of the vessel walls. CONCLUSIONS: Our study showed significantly more vessel wall thickening in irradiated versus non-irradiated carotid arteries years after RT for HNC, while no differences in signal intensities were observed.

Long term cerebral and vascular complications after irradiation of the neck in head and neck cancer patients: a prospective cohort study: study rationale and protocol.

BACKGROUND: Successful treatment options for cancer result in more young long-term survivors prone for long-term complications. Carotid artery vasculopathy is a potential long-term complication after radiotherapy of the neck, resulting in cerebrovascular events and probably deficits in cognitive and motor functioning. Better insight into the underlying pathofysiology of radiotherapy induced carotid artery vasculopathy is needed for prognostic purposes and to develop preventive strategies. METHODS/DESIGN: The current study is a prospective cohort study on the long-term cerebral and vascular complications after radiotherapy of the neck, in 103 patients treated for head and neck cancer, included in our study database between 2002 and 2008. Baseline protocol (before radiotherapy) included screening for cerebrovascular risk factors and intima media thickness measurement of carotid arteries by ultrasonography. Follow-up assessment more than 5 years after radiotherapy included screening of cerebrovascular risk factors, cerebrovascular events, neurological examination with gait and balance tests, extensive neuropsychological examination, self-report questionnaires, ultrasonography of the carotid arteries with measurement of intima media thickness and elastography, magnetic resonance imaging of the brain and magnetic resonance angiography of the carotid arteries. DISCUSSION: The current study adds to the understanding of the causes and consequences of long-term cerebral and vascular changes after radiotherapy of the neck. These data will be helpful to develop a protocol for diagnostic and preventive strategies for long-term neurological complications in future head and neck cancer patients with anticipated radiotherapy treatment.

Prospective cohort study of carotid intima-media thickness after irradiation.

BACKGROUND: Carotid artery vasculopathy is a potential long-term complication after radiotherapy (RT) of the neck, resulting in cerebrovascular events. The underlying pathophysiology is not well understood and early markers are lacking. We aimed to study whether RT of the neck is associated with increase in carotid intima-media thickness (IMT) and stroke in the first 2 years after RT in patients with head and neck cancer (HNC). METHODS: In this prospective cohort study patients treated with RT of the neck were assessed for measurement of IMT before and 2 years after RT. Endpoints were changed in IMT and incidence of first-ever stroke. RESULTS: Between 2003 and 2008 we included 69 patients (median age, 57 years [25%-75% quartile, 51-64 years], median dose of RT 66 Gy [interquartile range, 60-70]) with baseline and follow-up measurement of IMT. Median IMT at baseline and follow-up was .60 and .62 mm (ratio of geometric means 1.01; 95% confidence interval, .96-1.08; P = .63). Four of 69 patients suffered from a stroke. Mean interval from RT to stroke was 6.8 months. CONCLUSIONS: Our study showed no increase of carotid IMT in the first 2 years after RT of the neck in patients treated for HNC. This indicates that the IMT is not a reliable early marker for postirradiation vasculopathy. However, a high rate of strokes was observed. A longer follow-up period is needed to find the starting point of RT-induced vascular changes.

Increased risk of ischemic stroke after radiotherapy on the neck in patients younger than 60 years.

PURPOSE: To estimate the risk of ischemic stroke in patients irradiated for head and neck tumors. PATIENTS AND METHODS: The incidence of ischemic stroke was determined in 367 patients with head and neck tumors (162 larynx carcinomas, 114 pleomorphic adenomas, and 91 parotid carcinomas) who had been treated with local radiotherapy (RT) at an age younger than 60 years. Relative risk (RR) of ischemic stroke was determined by comparison with population rates from a stroke-incidence register, adjusted for sex and age. Other risk factors for stroke (hypertension, smoking, hypercholesterolemia, diabetes mellitus [DM]) were registered. The median follow-up time after RT was 7.7 years (3,011 person-years of follow-up). RESULTS: Fourteen cases of stroke occurred (expected, 2.5; RR, 5.6; 95% confidence interval [CI], 3.1 to 9.4): eight in patients with laryngeal carcinoma (expected,1.56; RR, 5.1; 95% CI, 2.2 to 10.1), four in pleomorphic adenoma patients (expected, 0.71; RR, 5.7; 95% CI, 1.5 to 14.5), and two in parotid carcinoma patients (expected, 0.24; RR, 8.5, 95% CI, 1.0 to 30.6). Five of six strokes in patients irradiated for a parotid tumor occurred at the ipsilateral side. Analysis of other risk factors for cerebrovascular disease showed hypertension and DM to cause an increase of the RR after RT. After more than 10 years' follow-up, the RR was 10.1 (95% CI, 4.4 to 20.0). The 15-year cumulative risk of stroke after RT on the neck was 12.0% (95% CI, 6.5% to 21.4%). CONCLUSION: This is the first study to demonstrate an increased risk of stroke after RT on the neck. During medical follow-up, preventive measures should be taken to reduce the impact of the risk factors for cerebrovascular disease, to decrease stroke in these patients.

Increased carotid wall thickening after radiotherapy on the neck.

Patients treated for head and neck tumours with local radiotherapy (RT) on the neck harbour an increased risk of stroke. This may be due to accelerated atherosclerotic changes within the RT-field; however, the real impact of local RT on the carotid artery remains debatable. The aim of the present study was to assess the difference in carotid wall thickness (intima-media thickness) in 42 unilaterally irradiated parotid tumour patients by performing B-mode ultrasonography. A mean difference in intima-media thickness (IMT) of the irradiated compared with the non-irradiated carotid artery of 0.30 mm (P=0.031) was found. A significant correlation was established with a longer post-RT interval (P=0.008). RT on the neck is associated with increased thickening of carotid IMT. Screening and treatment of additional cerebrovascular risk factors which contribute to further IMT thickening and stroke development is recommended, especially in radiotherapy patients with a favourable prognosis.

Artistic occupations are associated with a reduced risk of Parkinson's disease.

Parkinson's disease (PD) is preceded by a premotor phase of unknown duration. Dopaminergic degeneration during this phase may lead to subtle cognitive and behavioural changes, such as decreased novelty seeking. Consequently, premotor subjects might be most comfortable in jobs that do not require optimal dopamine levels, leading to an overrepresentation in structured and predictable occupations, or an underrepresentation in artistic occupations. In a case-control study, 750 men with PD (onset ≥40 years) and 1300 healthy men completed a validated questionnaire about their lifetime occupational status. Occupations were classified using the RIASEC model. Odds ratios (ORs) were calculated for the conventional and artistic categories, both for the most recent occupation before symptom onset, and for the very first occupation. Because farming has been associated with a PD risk, ORs were calculated separately for farming. A reduced risk of PD was found for men with an artistic occupation late in life (OR 0.14, 95% CI 0.04-0.53), while an artistic first occupation did not prevent PD (OR 0.72, CI 0.32-1.59). Conventional occupations showed no increased risk (recent: OR 1.07, CI 0.70-1.64; first: OR 1.14, CI 0.77-1.71). In support of previous reports, farming was associated with an increased risk of PD (recent: OR 2.6, CI 1.4-4.6; first: OR 2.7, CI 1.6-4.5). PD patients were older than controls, but various statistical corrections for age all lead to similar results. Artistic occupations late in life are associated with a reduced risk of subsequent PD, perhaps because this reflects a better preserved dopaminergic state. No initial occupation predicted PD, suggesting that the premotor phase starts later in life.

Cognitive function, depression, fatigue and quality of life among long-term survivors of head and neck cancer.

BACKGROUND: Long-term cancer treatment complications become more prevalent as survival improves. Little is known about the psychological complications in long-term survivors of head and neck cancer (HNC). We investigated cognitive functioning and its relation with depression, fatigue, cognitive complaints, and brain lesions on MRI. METHODS: This study is part of a multicentre, prospective cohort study of 65 patients treated for HNC. A comprehensive neuropsychological assessment was combined with validated questionnaires on subjective memory complaints, depression, and fatigue after a median of 7 years follow-up. Results were compared with age- and education-adjusted normative data. Further, we evaluated cerebral white matter hyperintensities (WMH), brain volume, and infarctions on MRI. RESULTS: HNC patients had worse cognitive performance in two of the five assessed cognitive domains: episodic memory (z = -0.48, P = .003) and speed of information processing (z = -0.47, P < 0.001). Patients with fatigue performed worse than patients without fatigue on verbal fluency (mean difference in z-score 0.52, P = .02) and speed of information processing (0.49, P = .04). Patients with subjective memory complaints had a worse episodic memory performance (mean difference in z-score -0.96; P = .02). Patients with cerebral infarction(s) on MRI performed worse on fluency (mean difference in z-score 0.74, P = .005). A lower cognitive performance was not associated with depression, WMH or brain volume. CONCLUSION: Long-term HNC survivors showed worse cognitive functioning 7 years after treatment. Cognitive function was associated with subjective complaints and fatigue, but not with depressive symptoms. Cerebral infarctions on MRI were correlated with cognitive function, whereas WMH, and brain volume were not.

Radiotherapy for partially resected spinal ependymomas: a retrospective study of 60 cases.

Ependymomas (Es) and myxopapillary ependymomas (mpEs) are the most common primary tumours of the spinal cord. Recurrence-free survival depends on local control of the tumour. The value of additional radiotherapy (RT) is still a matter of debate. The aim of this retrospective study was to analyse radiotherapy, surgery and the preoperative state with regard to recurrence rate and long-term neurological outcome. Sixty patients with spinal Es (40) and spinal mpEs (20) were included. According to local policy, 14 patients who underwent total resection and 20 patients with incomplete resection were irradiated postoperatively. Total resection was achieved in 34 of the 60 tumours. Preoperative state and long-term outcome was assessed according to a previously published scale. When postoperative RT was applied after partial resection, only 3 of 11 Es and 1 of 9 mpEs recurred. All partially resected non-radiated Es (n=3) and 2 of the 3 partially resected non-radiated mpEs recurred. There was no recurrence after total resection. Only one of 6 patients with disseminated mpEs had clinical symptoms caused by the disseminated tumour. Long-term neurological outcome was related to preoperative conditions with no difference between partially and totally resected tumours. Our study shows that RT is only beneficial for partially resected Es and mpEs. Local recurrence-free survival of spinal Es and mpEs is obtained by total resection. Long-term neurological outcome is related to preoperative conditions. Seeding is seen in mpEs and does not cause clinical symptoms in most of the patients.

Chromosomal imbalances in primary oligodendroglial tumors and their recurrences: clues about malignant progression detected using comparative genomic hybridization.

OBJECT: Despite the rapid increase in knowledge concerning the genetic basis of malignant progression in astrocytic tumors, progression of oligodendroglial tumors (including both pure oligodendrogliomas and mixed oligoastrocytomas) is still poorly understood. The aim of the present study is the elucidation of chromosomal imbalances involved in the progression of oligodendroglial tumors toward malignancy. METHODS: Using comparative genomic hybridization (CGH) on snap-frozen tumor tissue, the tumor genomes of five primary oligodendroglial tumors and associated recurrent tumors were screened for chromosomal imbalances. This information was correlated with clinical data (including follow-up data) and histopathological malignancy grade. In all cases an increase in chromosomal imbalances was detected in the recurrent tumor, indicating genetic progression. In three of the five cases this correlated with malignant progression detected at the histopathological level. The results indicate that, similar to what occurs in astrocytic tumors, chromosomal imbalances harboring genes involved in the cell proliferation control mechanism at the G1-S border are involved in the progression of oligodendroglial tumors. Additionally, although gains of genetic material on chromosome 7 and losses on chromosome 10 are most frequently detected in the course of malignant progression of astrocytic tumors, either or both of these can also occur during malignant progression of typical oligodendroglial tumors that contain losses involving chromosome 1p and/or chromosome 19q. CONCLUSIONS: When performed on optimally preserved material from a small set of primary oligodendroglial tumors and associated recurrent tumors, CGH detects chromosomal aberrations that potentially play a mechanistic role in the malignant progression of these tumors.

5-FU-induced peripheral neuropathy: a rare complication of a well-known drug.

Peripheral neuropathy is a rare complication of the commonly used cytotoxic drug 5-fluorouracil (5-FU). We report a case of 5-FU-induced peripheral neuropathy in a patient with metastatic colorectal carcinoma. Discontinuation of 5-FU therapy is recommended in case of 5-FU-related neurotoxicity.

Progression of carotid intima media thickness after radiotherapy: a long-term prospective cohort study.

BACKGROUND AND PURPOSE: Carotid artery vasculopathy is a long-term complication of radiotherapy (RT) of the neck. We investigated the change in carotid intima media thickness (IMT) and the incidence of ischemic stroke in the first 7 years after radiotherapy (RT) of the neck. MATERIALS AND METHODS: A multicentre prospective cohort study among patients treated for Head and Neck Cancer (HNC) assessed carotid IMT at baseline (before RT) and after a median of 7 years follow-up. We also screened for cerebrovascular risk factors and events. RESULTS: 48 patients underwent IMT measurement at baseline and follow-up (median age 61 years, range 29-87). Mean IMT of the irradiated common carotid arteries was 0.64mm at baseline and 0.74mm at follow-up (p=0.002). Mean delta IMT in the irradiated and non-irradiated common carotid arteries were 0.11 and 0.02mm (p=0.03). Incidence rate of stroke in our cohort, compared to the Dutch population was 8.9 versus 1.5 per 1.000 person years. CONCLUSIONS: IMT in irradiated carotid arteries was significantly increased in the first 7years after RT. The incidence rate of stroke was six fold increased. Patients treated with RT for HNC have sustained risk for developing atherosclerosis of the carotid arteries and future stroke.

Outcome of carotid artery stenting for radiation-induced stenosis.

PURPOSE: Patients who have been irradiated at the neck have an increased risk of symptomatic stenosis of the carotid artery during follow-up. Carotid angioplasty and stenting (CAS) can be a preferable alternative treatment to carotid endarterectomy, which is associated with increased operative risks in these patients. METHODS AND MATERIALS: We performed a prospective cohort study of 24 previously irradiated patients who underwent CAS for symptomatic carotid stenosis. We assessed periprocedural and nonprocedural events including transient ischemic attack (TIA), nondisabling stroke, disabling stoke, and death. Patency rates were evaluated on duplex ultrasound scans. Restenosis was defined as a stenosis of >50% at the stent location. RESULTS: Periprocedural TIA rate was 8%, and periprocedural stroke (nondisabling) occurred in 4% of patients. After a mean follow-up of 3.3 years (range, 0.3-11.0 years), only one ipsilateral incident event (TIA) had occurred (4%). In 12% of patients, a contralateral incident event was present: one TIA (4%) and two strokes (12%, two disabling strokes). Restenosis was apparent in 17%, 33%, and 42% at 3, 12, and 24 months, respectively, although none of the patients with restenosed vessels became symptomatic. The length of the irradiation to CAS interval proved the only significant risk factor for restenosis. CONCLUSIONS: The results of CAS for radiation-induced carotid stenosis are favorable in terms of recurrence of cerebrovascular events at the CAS site.

External beam radiotherapy with endocavitary boost for nasopharyngeal cancer: treatment results and late toxicity after extended follow-up.

PURPOSE: To evaluate the long-term outcome after treatment of nasopharyngeal carcinoma and assess late toxicity in a multidisciplinary clinic. METHODS AND MATERIALS: A retrospective analysis of 117 patients treated for nasopharyngeal cancer in a single institute between 1985 and 2002 was performed. Fifty-one long-term survivors were evaluated for late toxicity by a multidisciplinary team comprising a radiation oncologist, otolaryngologist, neurologist, and oral and maxillofacial surgeon. RESULTS: The 5-year local control rate for T1 to T2 and T3 to T4 tumors was 97% and 76%, respectively. Five-year disease-free survival and overall survival were 82% and 88% for Stage I to IIb disease and 46% and 52% for Stage III to IVb, respectively. Late morbidity evaluation revealed Radiation Therapy Oncology Group (RTOG) Grade III to IV toxicity in 71% of patients. A high incidence of cranial nerve palsies (47%) and mandibular osteolysis (82%) was found, although these complications had limited clinical impact. CONCLUSIONS: The multidisciplinary late morbidity clinic revealed an unexpected high incidence of cranial nerve palsies and mandibular osteolysis and overall an RTOG Grade III to IV toxicity in 71% of patients treated for nasopharyngeal cancer. External beam radiotherapy with endocavitary brachytherapy produces excellent rates of local control for T1 to T2 tumors, but the high incidence of late toxicity suggests an overtreatment.

Malignant tumors of the nasal cavity and paranasal sinuses: long-term outcome and morbidity with emphasis on hypothalamic-pituitary deficiency.

PURPOSE: To evaluate the long-term outcome after surgery and radiotherapy for patients with sinonasal cancer and assess late toxicity, with special emphasis on hypothalamic-pituitary dysfunction. METHODS AND MATERIALS: A retrospective analysis of 168 patients treated for sinonasal cancer in a single institute between 1986 and 2006. A more detailed analysis was performed on a subgroup of 76 patients with adenocarcinoma or squamous cell carcinoma treated with curative intent. Long-term survivors were evaluated for late toxicity by a multidisciplinary team using the late effects of normal tissues (LENT SOMA) scoring system. Additional endocrinologic tests were performed for assessment of hypothalamic-pituitary function. RESULTS: Five-year actuarial local control and overall survival rates were 62% and 35% for all patients and 64% and 42% for the subgroup with squamous cell carcinoma and adenocarcinoma. In multivariate analysis, T stage was the only significant factor predicting local relapse (79% at 5 years for T1-T3 vs. 53% for T4; p = 0.006). Sinonasal mucosal melanomas had the highest rate of regional failure (33% at 5 years). Thirteen of 21 patients (62%) evaluated at the late morbidity clinic had hormonal disturbances, of whom 5 (24%) had definitive evidence of hypopituitarism with multiple hormonal deficiencies. CONCLUSION: Local failure is the dominant cause of treatment failure for patients with sinonasal cancer, with T4 stage the only independent predictor. Because of a high rate of radiation-induced hypopituitarism, we recommend endocrinologic surveillance for these patients.

Cognitive rehabilitation in patients with gliomas: a randomized, controlled trial.

PURPOSE: Patients with gliomas often experience cognitive deficits, including problems with attention and memory. This randomized, controlled trial evaluated the effects of a multifaceted cognitive rehabilitation program (CRP) on cognitive functioning and selected quality-of-life domains in patients with gliomas. PATIENTS AND METHODS: One hundred forty adult patients with low-grade and anaplastic gliomas, favorable prognostic factors, and both subjective cognitive symptoms and objective cognitive deficits were recruited from 11 hospitals in the Netherlands. Patients were randomly assigned to an intervention group or to a waiting-list control group. The intervention incorporated both computer-based attention retraining and compensatory skills training of attention, memory, and executive functioning. Participants completed a battery of neuropsychological (NP) tests and self-report questionnaires on cognitive functioning, fatigue, mental health-related quality of life, and community integration at baseline, after completion of the CRP, and at 6-month follow-up. RESULTS: At the immediate post-treatment evaluation, statistically significant intervention effects were observed for measures of subjective cognitive functioning and its perceived burden but not for the objective NP outcomes or for any of the other self-report measures. At the 6-month follow-up, the CRP group performed significantly better than the control group on NP tests of attention and verbal memory and reported less mental fatigue. Group differences in other subjective outcomes were not significant at 6 months. CONCLUSION: The CRP has a salutary effect on short-term cognitive complaints and on longer-term cognitive performance and mental fatigue. Additional research is needed to identify which elements of the intervention are most effective.

Increased risk of stroke and transient ischemic attack in 5-year survivors of Hodgkin lymphoma.

BACKGROUND: Information on clinically verified stroke and transient ischemic attack (TIA) following Hodgkin lymphoma is scarce. We quantified the long-term risk of cerebrovascular disease associated with the use of radiotherapy and chemotherapy in survivors of Hodgkin lymphoma and explored potential pathogenic mechanisms. METHODS: We performed a retrospective cohort study among 2201 five-year survivors of Hodgkin lymphoma treated before age 51 between 1965 and 1995. We compared incidence rates of clinically verified stroke and TIA with those in the general population. We used multivariable Cox regression techniques to study treatment-related factors and other risk factors. All statistical tests were two-sided. RESULTS: After a median follow-up of 17.5 years, 96 patients developed cerebrovascular disease (55 strokes, 31 TIAs, and 10 with both TIA and stroke; median age = 52 years). Most ischemic events were from large-artery atherosclerosis (36%) or cardioembolisms (24%). The standardized incidence ratio for stroke was 2.2 (95% confidence interval [CI] = 1.7 to 2.8), and for TIA, it was 3.1 (95% CI = 2.2 to 4.2). The risks remained elevated, compared with those in the general population, after prolonged follow-up. The cumulative incidence of ischemic stroke or TIA 30 years after Hodgkin lymphoma treatment was 7% (95% CI = 5% to 8%). Radiation to the neck and mediastinum was an independent risk factor for ischemic cerebrovascular disease (hazard ratio = 2.5, 95% CI = 1.1 to 5.6 vs without radiotherapy). Treatment with chemotherapy was not associated with an increased risk. Hypertension, diabetes mellitus, and hypercholesterolemia were associated with the occurrence of ischemic cerebrovascular disease, whereas smoking and overweight were not. CONCLUSIONS: Patients treated for Hodgkin lymphoma experience a substantially increased risk of stroke and TIA, associated with radiation to the neck and mediastinum. Physicians should consider appropriate risk-reducing strategies.

Development of a model with which to predict the life expectancy of patients with spinal epidural metastasis.

BACKGROUND: The surgical treatment of spinal epidural metastasis is evolving. To be a surgical candidate, a patient should have a life expectancy of at least 3 months. Estimation of survival by experienced specialists has proven to be unreliable. METHODS: The Cox proportional hazards model was used to make a prediction model. To validate the model, Efron optimism correction by bootstrapping was performed. Retrospective data of patients treated for a spinal metastasis were used. Possible predictive factors were defined based on clinical experience and the literature. Statistical methods and clinical knowledge were also used to reveal an optimal set of predictors of survival. Data from patients treated at the Department of Radiation Oncology for spinal metastasis between 1998 and 2005 were evaluated. RESULTS: The case notes of 219 patients form the base of this study. In the final model, only 5 variables were required to predict the survival of a patient with spinal metastasis: sex, location of the primary lesion, intentional curative treatment of the primary tumor, cervical location of the spinal metastasis, and Karnofsky performance score. Examples with different predictors are given. The R(2) (N) index of Nagelkerke was 0.36 (95% confidence interval [95% CI], 0.28-0.48) and the c-index 0.72 (95% CI, 0.68-0.77). CONCLUSIONS: A reliable and simple model with which to predict the survival of a patient with spinal epidural metastasis is presented. Without the need for extensive investigations, survival can be predicted and only 5 easily obtainable parameters are required.

Three-dimensional (3D) reconstruction and quantitative analysis of the microvasculature in medulloblastoma and ependymoma subtypes.

In the World Health Organisation (WHO) classification of tumours of the nervous system, four main histopathological subtypes of medulloblastomas (classic medulloblastoma, desmoplastic medulloblastoma, medulloblastoma with extensive nodularity and advanced neuronal differentiation and large cell/anaplastic medulloblastoma) as well as of ependymal tumours (low-grade ependymoma, anaplastic ependymoma, myxopapillary ependymoma and subependymoma) are recognised. Under the hypothesis that the microvascular architecture of tumours is a reflection of the histopathological subtype, we performed three-dimensional reconstructions of the microvasculature in these subtypes of medulloblastomas and ependymal tumours using computerised image analysis. In addition, we quantitatively assessed three microvascular parameters (number, area, perimeter) in these neoplasms. Three-dimensional reconstructions showed a dense pattern of irregular vessels in classic and large cell medulloblastoma. In desmoplastic medulloblastoma and medulloblastoma with extensive nodularity, the vessels were more unevenly distributed and organised around the nodular areas. Classic medulloblastoma and large cell medulloblastoma had on average the largest vessel area and perimeter. The highest number of vessels was seen in classic medulloblastoma and medulloblastoma with extensive nodularity. Three-dimensional analysis of ependymal tumours showed that low-grade ependymoma had larger but fewer vessels compared to anaplastic ependymoma, while myxopapillary ependymoma had a complex, heterogeneous pattern of vessels and subependymoma few but regular vessels. In ependymal tumours, the highest values for vessel number, vessel area and vessel perimeter were found in anaplastic ependymoma and the lowest values in subependymoma. We conclude that our three-dimensional reconstructions shed unprecedented light on the tumour vasculature in medulloblastomas and ependymal tumours and expect that such reconstructions are helpful tools for further studies on tumour angiogenesis.

Decreased risk of stroke among 10-year survivors of breast cancer.

PURPOSE: To assess treatment-specific risk of cerebrovascular events in early breast cancer (BC) patients, accounting for cerebrovascular risk factors. PATIENTS AND METHODS: We studied the incidence of cerebrovascular accidents (CVA; stroke and transient ischemic attack [TIA]) in 10-year survivors of early BC (n = 4,414) treated from 1970 to 1986. Follow-up was 96% complete until January 2000. Treatment-specific incidence of CVA was evaluated by standardized incidence ratios (SIRs) based on comparison with general population rates and by Cox proportional hazards regression. RESULTS: After a median follow-up of 18 years, 164 strokes and 109 TIAs were observed, resulting in decreased SIRs of 0.8 (95% CI, 0.6 to 0.9) for stroke and 0.8 (95% CI, 0.7 to 1.0) for TIA. Significantly increased risk of stroke was found in women who had received hormonal treatment (HT; tamoxifen) and in women who had hypertension or hypercholesterolemia, with hazard ratios (HRs) of 1.9, 2.1, and 1.6, respectively. Patients irradiated on the supraclavicular area and/or internal mammary chain (IMC) did not experience a higher risk of stroke (HR = 1.0; 95% CI, 0.7 to 1.6) or TIA (HR = 1.4; 95% CI, 0.9 to 2.5) compared with patients who did not receive radiotherapy or who were irradiated on fields other than the supraclavicular area or IMC. CONCLUSION: Long-term survivors of BC experience no increased risk of cerebrovascular events compared with the general population. HT is associated with an increased risk of stroke. Radiation fields including the carotid artery do not seem to increase the risk of stroke compared with other fields.