Brain metastases in patients with pelvic or abdominal malignancy do not prevail in the posterior fossa: a retrospective study.

Pelvic and gastrointestinal tumors are generally considered to have a predilection to metastasize to the posterior fossa rather than to the supratentorial brain. Review of imaging of 100 patients with brain metastases from pelvic and gastrointestinal primary tumors and of 100 patients with brain metastases from other primary tumors did not reveal a difference in distribution of brain metastases between the two groups of patients. So, there is no evidence that pelvic and gastrointestinal tumors metastasize preferentially to the posterior fossa.

Interactions of serum albumin, valproic acid and carbamazepine with the pharmacokinetics of phenytoin in cancer patients.

Phenytoin dosing is critical in cancer patients as to decreased absorption secondary to chemotherapy-induced gastrointestinal toxicity, increased phenytoin metabolism in the liver secondary to chemotherapy, extreme patient profile that falls outside the predicted pharmacokinetic population, frequent hypoalbuminaemia and polydrug treatment. A retrospective study to assess the variability of free phenytoin and the free fraction of phenytoin, as well as the influence of comedication on these parameters was performed in cancer patients by using a population approach. Two hundred fifty-eight data pairs of total phenytoin and free phenytoin were analysed from 155 cancer patients on stable phenytoin using non-linear mixed-effect modeling (NONMEM). Total and free phenytoin were determined using a fluorescence polarization immunoassay. An extensive model building procedure was subsequently used for covariate testing on the free fraction of phenytoin. Mean total phenytoin concentration was 11.7 mg/l, free phenytoin 1.25 mg/l and phenytoin free fraction 0.107. Free phenytoin was <1 mg/l on 132 occasions (51.2%) and >2 mg/l on 37 occasions (14.3%). Total and free phenytoin were significantly correlated (r(S)=0.827, P<0.01). The free fraction of phenytoin was independent of time after drug intake. Serum albumin concentrations and comedication with valproic acid or carbamazepine were identified by NONMEM as significant determinants of phenytoin free fraction. Co-medication with valproic acid and carbamazepine led to a 52.5% and 38.5% increase of the free fraction of phenytoin, respectively, and a 10 g/l decrease of serum albumin to a 15.1% increase of the free fraction of phenytoin. Phenytoin pharmacokinetics could reliably be estimated from oral doses and steady-state concentrations of protein-bound and free phenytoin. The variability in the free fraction of phenytoin could partly be explained by the influence of albumin concentrations and antiepileptic comedication. Significant alterations of the free fraction of phenytoin and free phenytoin by co-administration of valproic acid or carbamazepine suggest therapeutic drug monitoring of free phenytoin to be of potential benefit in cancer patients.

Significant variation in mortality and functional outcome after acute ischaemic stroke between Western countries: data from the tinzaparin in acute ischaemic stroke trial (TAIST).

BACKGROUND: The medical care of patients with acute stroke varies considerably between countries. This could lead to measurable differences in mortality and functional outcome. OBJECTIVE: To compare case mix, clinical management, and functional outcome in stroke between 11 countries. METHODS: All 1484 patients from 11 countries who were enrolled into the tinzaparin in acute ischaemic stroke trial (TAIST) were included in this substudy. Information collected prospectively on demographics, risk factors, clinical features, measures of service quality (for example, admission to a stroke unit), and outcome were assessed. Outcomes were adjusted for treatment assignment, case mix, and service relative to the British Isles. RESULTS: Differences in case mix (mostly minor) and clinical service (many of prognostic relevance) were present between the countries. Significant differences in outcome were present between the countries. When assessed by geographical region, death or dependency were lower in North America (odds ratio (OR) adjusted for treatment group only = 0.52 (95% confidence interval, 0.39 to 0.71) and north west Europe (OR = 0.54 (0.37 to 0.78)) relative to the British Isles; similar reductions were found when adjustments were made for 11 case mix variables and five service quality measures. Similarly, case fatality rates were lower in North America (OR = 0.44 (0.30 to 0.66)) and Scandinavia (OR = 0.50 (0.33 to 0.74)) relative to the British Isles, whether crude or adjusted for case mix and service quality. CONCLUSIONS: Both functional outcome and case fatality vary considerably between countries, even when adjusted for prognostic case mix variables and measures of good stroke care. Differing health care systems and the management of patients with acute stroke may contribute to these findings.

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.

Retinal arterial changes correlate with cerebral small-vessel disease.

OBJECTIVE: To examine the relation between retinal artery disease and cerebral small-vessel disease (SVD). METHODS: In a prospective cohort of patients with symptomatic atherosclerotic disease, the authors performed retinal photographs and brain MRI. Two ophthalmologists, not aware of the MR results, independently assessed retinal arterial narrowing, crossings, sclerosis, and tortuosity according to standard scoring lists. Two observers independently assessed white matter lesions (WML) and lacunar infarcts on the MR images. Lesions were considered abnormal only when both ophthalmologists or MR raters agreed. Cerebral SVD was defined as the presence of WML or lacunar infarcts. RESULTS: In 179 patients, retinal photographs and brain MRI were performed. Of the 108 patients with MR signs of SVD, 92% had at least one retinal vascular abnormality; of the 71 patients without SVD, 77% had retinal pathology (p < 0.01). All types of retinal vascular pathology occurred more frequently in patients with SVD, but only retinal arterial narrowing and sclerosis differed significantly. In the 109 normotensive patients, the presence of any retinal vascular change correlated with signs of SVD (p = 0.01). CONCLUSION: Pathologic changes in the retinal arteries parallel changes in the small cerebral arteries that cause WML and lacunes, both in hypertensive and in normotensive patients.

Response of leptomeningeal metastases from breast cancer to hormonal therapy.

Intraventricular chemotherapy with radiotherapy is the standard treatment of leptomeningeal metastasis (LM) from breast cancer; this treatment increases median survival only to about 3 months and is frequently complicated by serious side effects. The authors describe two patients with LM from breast cancer who were treated with hormonal therapy, which provided a neurologic response of at least 12 months and a survival of 14+ and 19 months. Hormonal therapy can be effective and nontoxic for patients with LM from breast cancer.

Teniposide sometimes effective in brain metastases from non-small cell lung cancer.

In a prospective study we have treated 13 patients with brain metastases from non-small cell lung cancer with intravenous teniposide, at a dose of 150 mg/m2 on days 1, 3 and 5 given every 3 weeks on an out-patient basis. Six of the 13 patients had previously been treated for brain metastases by surgery and/or radiotherapy. Seven patients experienced neurological improvement. Objective response was obtained in 3 patients (23%) (2 PR, 1 CR), and stabilization in 5 patients. Duration of response in the 3 patients with objective response was 16 weeks, 40 weeks and 80 weeks, respectively. In 2 of these patients extracranial disease responded also to teniposide therapy. Although toxicity of teniposide therapy was relatively mild, there was one patient who died as a consequence of leukopenic sepsis. The results demonstrate that teniposide has some activity in de novo as well as recurrent brain metastases from non-small cell lung cancer.

Recurrent spinal epidural metastases: a prospective study with a complete follow up.

OBJECTIVES: Prospective studies with a complete follow up in patients with spinal epidural metastases (SEM) are rare, so little is known of the incidence and relevance of recurrent spinal epidural metastases (RSEM). This prospective study was undertaken as a part of a previously started and extended prospective study to determine the occurrence and details of RSEM. METHODS: Patients with SEM of various primary malignancies were followed up until death. The diagnosis was confirmed after neurological examination by imaging studies visualising not only the clinically suspected level, but also as much of the spinal canal as possible. RESULTS: Recurrent spinal epidural metastases (RSEM) occurred in 21 of the 103 patients (20%) after a median interval of 7 months and, after treatment, a second recurrence occurred in 11 patients (11%), a third recurrence in two patients (2%), and a sixth recurrence in one patient (1%). RSEM developed about as often at the initial level (55%) as at a different level (45%), did not occur more often in patients with initially multiple SEM, but, not surprisingly, occurred much more often in patients with longer survival. About one half of the patients surviving 2 years, and nearly all patients surviving 3 years or longer developed RSEM. Ambulatory state could be preserved in most patients, even after their second recurrence. CONCLUSION: RSEM are common and even several episodes of RSEM in the same patient are not rare. Patients with SEM who survive long enough have a high risk of RSEM and prompt treatment of RSEM to maintain the ambulatory state of the patient is valuable.

[Problems in weaning from artificial ventilation: 'motor neuron disease']. / Problemen bij het ontwennen van kunstmatige ventilatie: 'motor-neuron disease'.

Three patients, two men aged 71 and one aged 73 years, were given artificial respiration because of acute respiratory failure. Subsequently they could not be weaned from artificial respiration, due to causes that were not immediately clear. It was ultimately found that the patients suffered from 'motor neuron disease', in two of them due to progressive spinal muscular atrophy, while the third, apart from loss of anterior horn motor cells, also had thoracic hydromelia. The patients died after termination of the artificial respiration.

Different types of plasminogen activator activity in human brain tumours: relation with peritumoral oedema?

In 20 tissue samples from human brain tumours the concentrations were measured of (1) total plasminogen activator activity, (2) tissue-type plasminogen activator (t-PA) activity, (3) urokinase-type plasminogen activator (u-PA) activity, and (4) t-PA antigen. Most tumours contained a considerable amount of t-PA, but a high interindividual and in a few cases even an intra-individual variability was observed. A weak but significant negative correlation was found between t-PA concentration and the oedema/tumour ratio, as calculated from the preoperative computerized tomography (CT) brain scanning. No correlation was found with u-PA activity. It is concluded that t-PA and u-PA are probably not important factors in the production of peritumoral cerebral oedema, but a correlation between locally different amounts of t-PA or u-PA and the locally different extent of surrounding oedema has not yet been excluded.

Malignant cutaneous melanoma associated with neurofibromatosis in two sisters from a family with familial atypical multiple mole melanoma syndrome. Case reports and review of the literature.

Two cases of malignant melanoma associated with neurofibromatosis in two first-degree female relatives from a family with familial atypical multiple mole melanoma (FAMMM) syndrome are presented. The types of neurofibromatosis and the FAMMM syndrome are discussed in relation to these cases and the family genealogic tree. Although the FAMMM syndrome could probably be seen as the underlying disease in the current cases, review of literature has failed to establish a clear relation. Research into pigmentary disturbance in neurofibromatosis is necessary to give a final explanation. To our knowledge, this is the first report in literature describing the familial occurrence of both diseases and it might present an addition to the tumor spectrum in the FAMMM syndrome.

[Acute psychosis in a patient with a combination of sickle cell disease and hemoglobin-C disease]. / Acute psychose bij een patiënt met een combinatie van sikkelcelziekte en hemoglobine C-ziekte.

A 35-year-old negroid patient, known to have sickle cell-haemoglobin C disease, after heavy exercise developed an acute thrombotic crisis localised mainly in the brain. The clinical manifestations were those of an acute psychosis with severe confusion, aggressiveness, unco-operative behaviour and incontinence for faeces and urine. With adequate therapy he recovered after a few days. This so-called cerebral sickle cell crisis, confirmed by multiple small encephalomalacia lesions on the MRI which are typical of this disease, is a rare complication and difficult to diagnose.

Early diagnosis and treatment of spinal epidural metastasis in breast cancer: a prospective study.

This prospective study evaluated the usefulness of myelography in breast cancer patients who present with radiculopathy or myelopathy. A total of 124 consecutive myelograms were performed in 100 patients. Epidural metastasis (EM) was diagnosed in 67 myelograms (54%). Multiple epidural metastases were diagnosed in 15 (22%) of those, resulting in a total of 87 epidural lesions. A complete block was found in 13 EM (15%) and an incomplete block in 14 EM (16%). Clinical data could not predict the site of EM in 29 cases (33%). Fifteen asymptomatic EM were detected in myelograms with multiple EM. Plain radiographs were of no value in determining the site of EM in 29 cases (33%), including 13 cases (15%) without vertebral metastasis at the site of EM. Treatment consisted of radiotherapy (RT) with or without systemic treatment in 52 cases (80%), systemic treatment alone in 11 cases (17%) and surgery in two patients (3%). Clinical improvement was noticed in 72%, no change in 13%, and deterioration in 15%. No difference in response was noticed between RT and systemic therapy. Before treatment 21% and after treatment 15% of the patients could not walk. The one year survival was 42%. The ambulatory status at presentation was the most important prognostic factor. Examination of the spinal fluid, obtained at myelography, disclosed meningeal carcinomatosis in 9% of the patients. Imaging of the whole spinal canal with cytological examination of the spinal fluid is recommended in breast cancer patients suspected of epidural tumour with features of radiculopathy or myelopathy, irrespective of further clinical data and plain spinal radiographs.

Response of brain metastases from breast cancer to systemic chemotherapy.

In a prospective, nonrandomized study, the response of brain metastases (BM) from breast cancer to a standard systemic chemotherapy regimen was measured by clinical follow-up and serial computed tomography (CT) scans. Treatment consisted of 4-week courses of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) in 20 patients or 3-week courses of cyclophosphamide, doxorubicin, and 5-fluorouracil (CAF) in 2 patients. Seven patients had previously received CMF or CAF as adjuvant treatment or for progressive systemic disease. Another seven patients had been previously treated for BM with the use of surgery and/or radiation therapy (RT). Based on the results of clinical follow-up and CT scan, a response that lasted at least 6 weeks was seen in 13 patients (59%; 95% confidence interval, 37% to 80%), including 4 of the 7 patients with recurrent BM. Objective tumor regression occurred after two courses of chemotherapy in 76% of the patients who could be examined and after six courses in 47%. The median duration of neurologic remission in the 13 patients was 30 weeks (range, 15 to 66 weeks). The median overall survival time was 25 weeks (range, 2 to 83 weeks). The response rate of systemic disease paralleled the neurologic response. When compared with a matched group of historical control subjects treated with RT alone, chemotherapy induced a higher rate of neurologic response and led to a longer survival time. These results warrant further studies on the use of chemotherapy in BM from breast cancer.

Parlodel SRO in Parkinson's disease: a double-blind randomized comparison of Parlodel standard and Parlodel SRO.

In this study, we compared in an intent-to-treat analysis the tolerance and efficacy of Parlodel SRO with its standard galenic formulation in 34 patients with Parkinson's disease who received optimal levodopa therapy. The results suggest that Parlodel SRO was equally efficacious as Parlodel standard, but Parlodel SRO is better tolerated.

Meningeal carcinomatosis in breast cancer. Prognostic factors and influence of treatment.

In 58 breast cancer patients with meningeal carcinomatosis (MC) pretreatment characteristics, clinical course, and response to treatment were evaluated. Forty-four patients were uniformly treated with intraventricular chemotherapy. Fourteen patients did not receive intraventricular treatment. In the intraventricularly treated group the median survival was 12 weeks. Multivariate analysis of the pretreatment characteristics of the intraventricularly treated patients demonstrated a prognostic significance with respect to survival for age older than 55 years, lung metastases, cranial nerve involvement, cerebrospinal fluid (CSF) glucose less than 2.5 mmol/l, and CSF protein 0.51 to 1.0 g/l. Based on the significance of these predicting factors a prognostic index (PI) identified four groups of patients with a median survival of 43 weeks, 22 weeks, 11 weeks, and 3 weeks, respectively. After 6 weeks of intraventricular treatment 22 patients showed a neurologic improvement or stabilization, and nine patients showed a worsening of the neurologic signs, whereas 13 patients (30%) had already died. The responders had a median additional survival of 5 months versus 1 month for nonresponders. No relation was found between survival and intensity of the intraventricular treatment after the first 6 weeks of treatment. Almost all long survivors had also received systemic treatment for systemic disease, whereas most patients who died within 6 months did not receive systemic therapy. Radiation therapy had no influence on the survival time. Early death due to the intensive treatment occurred in three patients. In 11 of the 17 patients who survived more than 4 months an often seriously debilitating late neurotoxicity developed. The survival curve of the nonintraventricularly treated patients appeared to be essentially the same as the curve of the intraventricularly treated patients. Using the same PI the predicted survival time was also the same as in the intraventricularly treated group. It is concluded that survival in MC from breast carcinoma may be more dependent on some pretreatment characteristics than on treatment intensity. On the basis of these pretreatment characteristics the survival time seems to be predictable. Finally, late neurotoxicity due to aggressive treatment leads to impairment of the quality of life in more than 50% of the long survivors. The exact value of intraventricular and systemic therapy in patients with MC still has to be determined.

Cisplatin induced neuropathy: central, peripheral and autonomic nerve involvement.

A prospective study was performed in patients treated with cisplatin to evaluate the occurrence and degree of central, peripheral and autonomic neuropathy and to determine the most accurate method to study this neuropathy. Twelve patients were examined before, during and after treatment. Evaluation included neurologic examination, conventional nerve conduction studies of the median and peroneal nerves and short latency somatosensory evoked potentials (SSER) after median and tibial nerve stimulation. Valsalva maneuvers before and during treatment were performed in 11 patients. Symptoms of peripheral neuropathy paralleled clinical signs. Conventional nerve conduction studies did not seem to be more accurate than clinical examination in determining peripheral neuropathy. SSER appeared to be the most sensitive method for the detection of peripheral nerve impairment. A slowing of central conduction velocity occurred after cumulative doses of 200-400 mg/m2 as measured by SSER. In two patients also some involvement of the autonomic nerves was suggested.

Multiple spinal epidural metastases; an unexpectedly frequent finding.

In a prospective study, patients with known malignant disease who were suspected of having a spinal epidural metastasis, had myelography which was not confined to the clinically suspected site, but included at least the whole lumbar and thoracic spinal canal. Fifty four of the 106 myelograms revealed at least one epidural metastasis. Twelve of these 54 myelograms showed two separate lesions, and four myelograms showed three separate lesions. In all 16 cases with multiple lesions at least one of the lesions was asymptomatic at the time of the diagnosis. It is concluded that multiple spinal epidural metastases are of common occurrence and occur in about one third of the cases. This finding may have important clinical implications. Examination of the spinal canal for epidural metastases should not be confined to the clinically suspected site, but should include as extensive an area as possible of the spinal canal, whatever technique is to be used.