Severe amnesia due to HHV-6 encephalitis after allogenic stem cell transplantation.
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Amnesia↗
Biomedical subjects
M J van den Bent
Publications and source records attributed to M J van den Bent.
Adjuvant treatment of high grade gliomas.
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Antineoplastic Agents↗
Neurogenic pulmonary oedema in a patient with leptomeningeal carcinomatosis.
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Adenocarcinoma↗
[Clinical reasoning and decision-making in practice. An older man with prostate carcinoma and a painless paraparesis of the legs].
A 78-year-old man with metastasised prostate carcinoma presented with a painless paraparesis. His cerebrospinal fluid showed elevated protein and a mononuclear pleiocytosis, but cytology investigations of 5 separate samples revealed no malignant cells in the cerebrospinal fluid. Extensive viral and bacterial tests (including ELISA for Borrelia burgdorferi) of serum and cerebrospinal fluid were negative. On the day radiation therapy for presumed leptomeningeal metastases was due to start the IgG and IgM Western blot for Borrelia were found to be positive, indicating neuroborreliosis. Soon after the start of antibiotic therapy the paraparesis began to improve and after four weeks the patient had made a complete recovery. In patients with a progressive paraparesis, neuroborreliosis should be considered even in the absence of pain.
Aged↗
[A patient with sinus thrombosis associated with paroxysmal nocturnal hemoglobinuria].
A 27-year-old woman with a history of aplastic anaemia complained of poor control of her right arm and hand, unsteady gait, and headache that increased while in a recumbent position. She was diagnosed with cerebral sinus thrombosis. Additional investigation revealed paroxysmal nocturnal haemoglobinuria (PNH). Treatment with heparin was initiated but stopped after the patient developed a brain haemorrhage. The patient recovered with no signs of residual symptoms and began taking oral anticoagulants as maintenance therapy. PNH is a rare acquired clonal disorder due to a defective expression of the glycosylphosphatidyl-inositol anchor membrane protein. It is characterised by haemolytic anaemia, diminished haematopoiesis, increased susceptibility for infections and a hypercoagulable state. Patients with aplastic anaemia have an increased risk of developing PNH. In patients with cerebral sinus thrombosis PNH should be considered as a possible underlying disorder. These patients should be questioned for possible clinical symptoms of PNH, such as acute abdominal pain or dark urine in the morning. For patients with these symptoms and in those with a history of aplastic anaemia or recurrent thrombosis, additional testing for PNH should be conducted.
Adult↗
[Favourable result for temozolomide in recurrent high-grade glioma].
OBJECTIVE: To describe the results of the treatment of recurrent glioma with temozolomide. DESIGN: Retrospective. METHOD: This study evaluated 77 patients with a recurrent high-grade glioma who from August 1997-December 2003 were treated with temozolomide (150-200 mg/m2/day for 5 days per 28-day cycle) following surgery and radiotherapy at the Daniel den Hoed Oncology Centre of the Erasmus MC, Rotterdam, the Netherlands. The patients were divided into 4 groups depending on histology and chemotherapy history. RESULTS: 15 patients received temozolomide for a recurrent anaplastic oligodendroglioma or mixed oligo-astrocytoma. The response in this group was 80% and after 12 months in 47% of the patients there was no disease progression. 35 patients underwent second-line chemotherapy with temozolomide after earlier chemotherapy with procarbazine, lomustine and vincristine for recurrent anaplastic oligodendroglioma or mixed oligo-astrocytoma. Response was 26% and after 12 months in 15% of patients there was still no disease progression. 14 patients were treated with temozolomide for a recurrent anaplastic astrocytoma with a response of 35% and after 12 months in 8% of these patients there was no disease progression. Of the 13 patients with a recurrent glioblastoma who were treated with temozolomide 16% responded and after 6 and 12 months 21% were still free from progression. Temozolomide was well-tolerated: 2 patients had to stop because of probable side effects. CONCLUSION. Temozolomide has an acceptable safety profile and may be regarded as the preferred treatment for recurrent anaplastic gliomas after radiotherapy. There is only a limited role for temozolomide in the treatment of recurrent glioblastoma.
Adult↗
Salvage PCV chemotherapy for temozolomide-resistant oligodendrogliomas.
The authors investigated the results of PCV chemotherapy within a cohort of 24 patients treated within the EORTC study 26971 on temozolomide chemotherapy in recurrent oligodendroglioma. The genotype of the tumors was assessed with fluorescent in situ hybridization with locus specific probes for the region 1p36. Four of the 24 patients responded (17%). Fifty percent of patients were still free from progression at 6 months and 21% were free from progression at 12 months. Although a clear relation existed between loss of 1p and response to temozolomide chemotherapy, this relation was absent in salvage PCV chemotherapy.
Adult↗
Immediate post-radiotherapy changes in malignant glioma can mimic tumor progression.
To determine the frequency of progressive MRI lesions shortly after radiotherapy for glioma with spontaneous improvement or stabilization, the authors studied a cohort of patients treated within two prospective phase III trials with radiotherapy only. In 9 out of 32 patients, the first post-radiotherapy MRI showed progressive enhancement. In 3 of these 9 the MRI improved or stabilized for 6 months without additional treatment. The authors conclude that patients with progressive lesions within 3 months after radiotherapy should not be eligible for phase II trials on recurrent glioma.
Antineoplastic Combined Chemotherapy Protocols↗
Cognitive status and quality of life after treatment for primary CNS lymphoma.
OBJECTIVE: To evaluate the cognitive status and quality of life (QOL) in a cohort of 19 consecutive patients treated in a prospective European Organization for Research and Treatment of Cancer study (20962) for primary CNS lymphoma (PCNSL). All patients were in complete remission after combined modality treatment with IV and intrathecal high-dose methotrexate (MTX)-based chemotherapy followed by whole brain radiotherapy (WBRT). METHODS: An extensive neuropsychological assessment, including QOL measures, was conducted in 19 patients with PCNSL. The results were compared with matched control subjects with systemic hematologic malignancies treated with systemic chemotherapy or non-CNS radiotherapy. In addition, a neuroradiologic evaluation was carried out in 18 patients with PCNSL. RESULTS: Cognitive impairment was found in 12 patients with PCNSL (63%) despite a complete tumor response. Four patients (21%) showed severe cognitive deficits, and the percentage of impaired test indices correlated with age. In comparison, only two control subjects (11%) showed cognitive dysfunction (p = 0.002). Forty-two percent of the patients with PCNSL, in contrast to 81% of the control subjects, resumed work. White matter abnormalities were observed in 14 patients with PCNSL, and 14 had cortical atrophy. Cortical atrophy correlated with cognitive functioning, age, and Karnofsky performance score. Group differences in cognitive status and QOL could not be explained by anxiety, depression, or fatigue. CONCLUSIONS: Combined modality treatment for primary CNS lymphoma is associated with cognitive impairment even in patients aged <60 years.
Adult↗
The relevance of intraventricular chemotherapy for leptomeningeal metastasis in breast cancer: a randomised study.
To assess the benefit of intraventricular chemotherapy, patients with leptomeningeal metastasis (LM) from breast cancer were randomised to treatment including intraventricular (IT) chemotherapy (n=17) or to non-intrathecal (non-IT) treatment (n=18). Appropriate systemic therapy and involved field radiation therapy (RT) were given in both arms. Intention-to-treat analysis showed neurological improvement or stabilisation in 59% of the IT and in 67% of the non-IT group, with median time to progression of 23 weeks (IT) and 24 weeks (non-IT). Median survival of IT patients was 18.3 weeks and 30.3 weeks for non-IT patients (difference 12.9 weeks; 95% Confidence Interval (CI) -5.5 to +34.3 weeks; P=0.32). Neurological complications of treatment occurred in 47% (IT) vs 6% (non-IT) (P=0.0072). In conclusion, standard systemic chemotherapy with involved field RT for LM from breast cancer is feasible. Addition of intraventricular chemotherapy does not lead to survival benefit or improved neurological response, and is associated with an increased risk of neurotoxicity.
Adult↗
Diagnosis and management of oligodendroglioma.
The discovery of the sensitivity to chemotherapy of oligodendroglial tumors has greatly increased the interest in this tumor type. After the first studies showing the activity of chemotherapy with procarbazine, lomustine (CCNU), and vincristine (PCV), it is now clear that temozolomide is also effective in this tumor type. Fifty percent to 70% of patients with recurrent oligodendroglial tumors may respond to chemotherapy. The histological diagnosis of oligodendroglial tumors is still subject to a significant observer bias. This variation appears to be one of the causes of the recent relative increase in incidence of oligodendroglial tumors. Genetically, 60% to 70% of oligodendroglial tumors are characterized by the loss of the short arm of chromosome 1 (1p) and the loss of the long arm of chromosome 19 (19q). Virtually all tumors with the combined loss of 1p/19q respond to chemotherapy, which has been the first demonstration of the clinical usefulness of the genotyping of brain tumors. These tumors also more often have a classical oligodendroglial histology and have a much better prognosis than oligodendrogliomas without 1p/19q loss. Although the belief is widely held that in the near future the genotype of oligodendroglial tumors may help in selecting patients for treatment, this assumption has not been proven. Prospective trials on oligodendroglial tumors with analyses of the genotype are needed before such conclusions can be drawn. In the meantime it is clear that ultimately all patients with oligodendroglial tumors die of their disease, and that novel treatments are required to improve prognosis. For an improved prognosis, a better understanding of the aberrant pathways and the driving force behind these tumors is required.
Antineoplastic Agents↗
Advances in the biology and treatment of oligodendrogliomas.
PURPOSE OF REVIEW: The sensitivity of oligodendroglioma to chemotherapy and the prognostic significance of combined loss of 1p/19q in these tumors are now well established. This review discusses recent molecular, genetic and clinical advances made in studies on oligodendroglioma and mixed oligoastrocytoma. RECENT FINDINGS: Methylation of genes is a frequent event in oligodendroglioma (OD), but no specific methylation sites have been discovered. In contrast to earlier reports, the expression of the basic helix-loop-helix transcription factors is not specific for OD, but may occur in glial tumors of all lineages. In a number of studies, the prognostic relevance of 1p/19q loss has been confirmed, and several studies have shown that loss of 1p/19q are early events in OD. No candidate genes have so far been identified on 1p36 and 19q13. Gene expression profiling using gene arrays allows the separation of glial tumors according to histology, tumor grade and prognosis. A number of genes have been identified that are significantly more highly expressed in OD. On MRI imaging, OD with combined 1p/19q loss has typical characteristics, including indistinct borders and a mixed signal intensity on T2-weighted images. Despite the large increase in knowledge on the molecular abnormalities in OD, the therapeutic options for these tumors have not improved significantly since the introduction of temozolomide. The increased survival after chemotherapy has been clearly established, but the timing of chemotherapy seems less critical. It is clear that temozolomide is a good alternative to procarbazine, CCNU and vincristine (PCV) chemotherapy, in particular, because it is better tolerated. No randomized trials, however, have compared PCV-chemotherapy to temozolomide. New agents--and probably more targeted therapies--are needed to further improve treatment. Chemo-irradiation deserves further study in anaplastic OD. SUMMARY: The progress in the understanding of genetic and molecular abnormalities of OD has improved the recognition of treatment-sensitive OD, although this has not yet been mirrored in improved therapies or new treatment options. While chemotherapy improves the outcome of OD, further improvements will likely require new drugs or new treatment concepts.
Antineoplastic Agents↗
Management of metastatic (parenchymal, leptomeningeal, and epidural) lesions.
PURPOSE OF REVIEW: Metastases involving the central nervous system are notorious for the functional neurologic deficits they often cause. For many patients, the overall prognosis is determined by the systemic disease status, but a subset of patients may benefit from more intensive treatment. RECENT FINDINGS: Patients in a subgroup with brain metastases qualify for more intensive treatments, like stereotactic radiosurgery, the efficacy of which seems to be similar to that of surgery for single brain metastases. Although whole brain radiotherapy after stereotactic radiosurgery decreases the outfield recurrences, there are no indications that it improves survival. So far, studies on radiosensitizers have not resulted in clear evidence of improved outcome for good prognosis in patients with brain metastases. A variety of surgical procedures offer better palliation for a subset of patients with epidural spinal metastases than radiotherapy alone. The roles of the blood-brain barrier and of the blood-cerebrospinal fluid barrier remain a source of discussion. It may be relevant for patients with micrometastases, which can potentially be cured by systemic treatment. SUMMARY: For many patients with central nervous system complications, adequate palliation can be achieved, but this requires rapid and thorough evaluation of patients with central nervous system symptoms. Early diagnosis and proper patient selection for further and more intensive treatment are the cornerstones of good palliative care in these patients.
Animals↗
Current and future trials of the EORTC brain tumor group.
The EORTC Brain Tumor Group (BTG) is dedicated to clinical research of neoplasms of the brain. In the past years the BTG has carried out phase II and phase III trials on glial tumors, brain metastases and primary CNS lymphomas. Future studies will investigate novel drugs in combination with chemo-radiotherapy in glioblastoma multiforme, radiotherapy in meningioma, and chemotherapy in medulloblastoma. The BTG will also start a new phase III trial on newly diagnosed low-grade glioma comparing radiotherapy to temozolomide. In all our trials translational research is getting more and more important, often this is one of the most important ways to get useful conclusions from clinical trials. The wide recognition of the importance of translational research for clinical trials and in particular with targeted therapies implies that this type of research will become a mandatory element in many of our future trials.
Antineoplastic Agents↗
Phase II study of first-line chemotherapy with temozolomide in recurrent oligodendroglial tumors: the European Organization for Research and Treatment of Cancer Brain Tumor Group Study 26971.
PURPOSE: Oligodendroglial tumors are chemotherapy-sensitive tumors, with two thirds of patients responding to combination chemotherapy with procarbazine, lomustine, and vincristine (PCV). Temozolomide (TMZ), a new alkylating and methylating agent, has demonstrated high response rates in patients with recurrent anaplastic astrocytoma. We investigated TMZ as first-line chemotherapy in recurrent oligodendroglial tumors (OD) and mixed oligoastrocytomas (OA) after surgery and radiation therapy. PATIENTS AND METHODS: In a prospective, nonrandomized, multicenter, phase II trial, patients were treated with 200 mg/m2 of TMZ on days 1 through 5 in 28-day cycles for 12 cycles. Patients with a recurrence after prior surgery and radiotherapy, and with measurable and enhancing disease on magnetic resonance imaging (MRI) were eligible for this study. Patients with large lesions and mass effect or with new clinical deficits were not eligible. Pathology and the MRI scans of all responding patients were centrally reviewed. RESULTS: Thirty-eight eligible patients were included. In three patients, pathology review did not confirm the presence of an OD or OA. TMZ was generally well tolerated. The most frequent side effects were hematologic; only one patient discontinued treatment for toxicity. In 20 (52.6%) of 38 patients (95% exact confidence interval, 35.8% to 69.0%), a complete (n = 10) or partial response to TMZ was observed. The median time to progression was 10.4 months for all patients and 13.2 months for responding patients. At 12 months from the start of treatment, 40% of patients were still free from progression. CONCLUSION: TMZ provides an excellent response rate with good tolerability in chemotherapy-naive patients with recurrent OD. A randomized phase III study comparing PCV with TMZ is warranted.
Adult↗
Weekly high-dose cisplatin is a feasible treatment option: analysis on prognostic factors for toxicity in 400 patients.
In the present study we describe the toxicity of weekly high-dose (70-85 mg x m(-2)) cisplatin in 400 patients (203 men, 197 women; median age 54 years) with advanced solid tumours treated in the period 1990-2001 who took part in phase I/II trials, investigating the feasibility and efficacy of weekly cisplatin alone, or in combination with paclitaxel or etoposide. Cisplatin was administered in 250 ml NaCl 3% over 3 h, for six intended administrations. The mean number of administrations was 5.3 (range, 1-6 administrations). Reasons not to complete six cycles were disease progression (7.5%), haematological toxicity (9%), nephrotoxicity (7%), ototoxicity (2.5%), neurotoxicity (1%), gastrointestinal toxicity (1%), cardiovascular complications (0.5%) or a combination of reasons including noncompliance and patient's request (5.5%). Logistic regression analysis was used to evaluate baseline parameters for prognostic value regarding toxicity. Leukopenia correlated with etoposide cotreatment, and thrombocytopenia with cisplatin dose and prior (platinum-based) chemotherapy. Risk factors for nephrotoxicity were older age, female gender, smoking, hypoalbuminaemia and paclitaxel coadministration. Neurotoxicity >grade 1 (11% of patients) was associated with prior chemotherapy and paclitaxel coadministration. Symptomatic hearing loss occurred in 15% with anaemia as the predisposing factor. We conclude that weekly high-dose cisplatin administered in hypertonic saline is a feasible treatment regimen.
Adult↗
Adaptive intrapatient dose escalation of cisplatin in combination with low-dose vp16 in patients with nonsmall cell lung cancer.
The objective of this phase II and pharmacologic study was to explore the feasibility, toxicity and activity of adaptive intrapatient dose escalation of cisplatin in a dose-intensive weekly schedule using predefined levels of exposure, with the ultimate aim to improve the antitumour activity of the therapy in patients with nonsmall cell lung cancer (NSCLC). Platinum DNA-adduct levels in peripheral white blood cells during treatment were used as the primary parameter for adaptive dosing. If DNA-adduct levels were not available, the area under the concentration-time curve (AUC) of unbound platinum in plasma was used for dose adaptation. Target levels for DNA-adducts and AUC have been defined in a previously performed pharmacologic study. The feasibility of adaptive dosing was tested in 76 patients with stage IIIB and IV NSCLC, who were planned to receive 6 weekly courses of cisplatin at a starting dose of 70 mg m(-2), together with daily low oral dose of 50 mg VP16. In total, 37 patients (49%) who were given more than one course received a dose increase varying from 10 to 55%. The majority of patients reached the defined target levels by a dose increase during course two. Relevant grade 2 neurotoxicity was observed in eight (10%) patients and reversible ototoxicity grade 2 in 14 (18%) patients. The strategy of adaptive intrapatient dose adjustment of cisplatin is practically feasible in a research setting even when results for dose adaptation have to be reported within a short time-period of 1 week. The toxicity appeared to be manageable in this cohort of patients. In some patients, exposure after the standard dose was substantially lower than the defined target level and significant dose escalations of more than 50% had to be applied. The response rate (RR) was relatively high: overall 40% (29 out of 72 patients) partial remission (PR), in patients with stage IIIB the RR was 60% (15 out of 25 patients) and with stage IV 30% (14 out of 47 patients). Randomised studies are needed to determine whether the adaptive dosing strategy results in better efficacy than standard dosing.
Administration, Oral↗
The role of chemotherapy in brain metastases.
Despite the widely held belief of the resistance to chemotherapy of brain metastases, central nervous system metastases of a malignancy are equally sensitive to chemotherapy as its metastases elsewhere in the body. This is due to the fact that the blood-brain barrier is disrupted in contrast enhancing brain metastases, and does not limit the response to chemotherapy. Therefore, the response rate of the primary tumour. Up-front chemotherapeutic treatment instead of radiotherapy of brain metastases should therefore be based on the chemosensitivity of the primary tumor to the used regimen, and not on the question whether the used agent penetrates an intact blood-brain barrier. First-line chemotherapy for brain metastases or with only minor neurological signs and symptoms, and who have an indication for systematic chemotherapy for metastases elsewhere in the body. In contrast, central nervous system micrometastases may hide behind an intact barrier, and this may be clinically relevant in patients that can be cured with chemotherapy (like in small cell lung cancer). Cytochrome P450 3A4 inducing anti-epileptic drugs like phenytoin, carbamazepine and phenobarbital may significantly increase the metabolism of many chemotherapeutic agents like CPT11 and paclitaxel (but also of newer biological agents like many tyrosine kinase inhibitors). These anti-epileptic drugs should be avoided in patients requiring chemotherapy with agents metabolised through the cytochrome P450.
Anticonvulsants↗